Factor VIII

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Background

The hemostatic system, consisting of the blood vessels and their content, blood, plays a crucial role in human survival. The importance of the plasma coagulation system in protecting life by preventing further blood loss following transection of a blood vessel is well recognized. Blood is usually maintained in a fluid state, without evidence of bleeding or clotting. The presence of an X-linked pattern of inheritance of a bleeding diathesis in families, referred to as hemophilia, has been recognized for hundreds of years (see image below).[1, 2, 3]


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Obituary in the March 22, 1796, Salem Gazette (Massachusetts) for a 19-year-old man who bled to death after suffering a foot injury. Also detailed are....

That hemophilia is due to a deficiency of a factor (F) in the blood was proven in 1840 by correction of the bleeding defect with transfusion of whole blood; this was followed in 1911 by the demonstration that normal plasma could shorten the whole blood clotting time of hemophilic blood. Then, in 1937, a factor from normal plasma was shown to be effective in accelerating the coagulation of hemophilic blood, and the term antihemophilic globulin was coined; this protein is now referred to as factor VIII-C (FVIII-C).

Further progress was achieved in the 1950s with the development of cryoprecipitate and plasma concentrates to treat hemophilia A (FVIII deficiency). The clinical and therapeutic observation that clotting time was corrected after transfusion of blood from one hemophilic patient to another was followed by the description of "plasma thromboplastin component" or factor IX deficiency. This second type of deficiency was referred to as hemophilia B to differentiate it from hemophilia A.

Clarification of the structure and function of the factor VIII molecule (FVIII-C, an X-linked gene product, also known as antihemophilic globulin) noncovalently bound to von Willebrand factor (vWF, an autosomal 12p gene product) in plasma clarified the separate roles of factor VIII-C (antihemophilic globulin) and von Willebrand factor proteins. This led to an understanding of the role of the different components of the factor VIII molecule in the physiology of normal hemostasis and to a recognition that hemophilia A and von Willebrand disease were caused by a deficiency of different proteins in the factor VIII complex.

An understanding of the reasons for the development of factor VIII inhibitors in persons with hemophilia or in persons with previously normal hemostasis (referred to as acquired hemophilia) expanded understanding of the antigenic structure of the factor VIII molecule. Cloning of the factor VIII gene was followed by the preparation of recombinantly derived factor VIII (rFVIII) as replacement therapy for the missing factor. Several different vectors have now been used to correct factor VIII deficiency in humans, with many questions still to be resolved.[4, 5] The potential role of increased levels of factor VIII in thrombophilic states continues to be explored.

Primary immunodeficiency diseases (PIDs) are associated with various autoimmune complications and several manifestations of autoimmunity. Acquired hemophilia is rare in childhood even though autoantibodies may develop in various forms of primary immunodeficiency diseases. However, acquired hemophilia may rarely form factor VIII inhibitors in patients with undefined primary immunodeficiency disease features that are suggestive of autosomal recessive hyper-immunoglobulin (Ig) E syndrome.[6]

This article deals only with factor VIII-C (antihemophilic globulin), the coagulant molecule, also referred to here as factor VIII. For information about the von Willebrand portion of the molecule, see von Willebrand Disease.

For excellent patient education resources, see eMedicineHealth's patient education articles Hemophilia and Blood in the Urine.

Pathophysiology

Factor VIII (FVIII-C; antihemophilic globulin) is an essential part of the hemostatic mechanism, participating as a cofactor in the second burst of thrombin generation, which leads to clot formation (see image below). An isolated deficiency of factor VIII-C is associated with a significant bleeding diathesis, demonstrating the importance of factor VIII in hemostasis.


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The hemostatic pathway: role of factor VIII.

Production, processing, structure, and half-life

Primary sites of factor VIII-C production are thought to be the liver and the reticuloendothelial system. Liver transplantation corrects factor VIII deficiency in persons with hemophilia, and persons with mild hemophilia with progressive liver disease have a rise in factor VIII levels, thus establishing the liver as the major site of factor VIII synthesis.

Factor VIII mRNA has been detected in the liver, spleen, and other tissues.[7] Studies of factor VIII production in transfected cell lines have shown that following synthesis, factor VIII moves to the lumen of the endoplasmic reticulum, where it is bound to several proteins that regulate secretion, particularly immunoglobulin binding protein, from which it has to dissociate in an energy-dependent process. Cleavage of factor VIII's signal peptide and the addition of oligosaccharides also occur in the endoplasmic reticulum. The chaperone proteins, calnexin and calreticulin, enhance both factor VIII secretion and degradation.

A part of the factor VIII protein in the endoplasmic reticulum is degraded within the cell. The other part enters the Golgi apparatus, where several changes occur to produce the heavy and light chains and to modify the carbohydrates. The addition of sulfates to tyrosine residues of the heavy and light chains is necessary for full procoagulant activity, with the sulfated region playing a role in thrombin interaction. This posttranslational sulfation of tyrosine residues impacts the procoagulant activity of factor VIII and its interaction with von Willebrand factor. ERGIC-53 is a chaperone protein in the Golgi apparatus that facilitates secretion of both factor VIII and factor V; a single mutation in ERGIC-53 has been identified as a cause of combined deficiency of factor VIII-C and factor V.

The secreted factor VIII-C glycoprotein in plasma is a heterodimer having a carboxy terminal–derived light chain (molecular weight [MW]: 80,000) in a metal-dependent association with the amino terminal–derived heavy chain (MW: 90,000-200,000) (see image below).


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Structural domains of human factor VIII. Adapted from: Stoilova-McPhie S, Villoutreix BO, Mertens K, Kemball-Cook G, Holzenburg A. 3-Dimensional struc....

The plasma concentration of factor VIII-C is approximately 200 ng/mL, whereas that of von Willebrand factor is approximately 10 mcg/mL. von Willebrand factor appears to promote assembly of the heavy and light chains of factor VIII and more efficient secretion of factor VIII from the endoplasmic reticulum. It also directs factor VIII into the Weibel-Palade bodies, which are the intracellular storage sites for von Willebrand factor.

In plasma, factor VIII is stabilized and protected from degradation because of its association with a 50-molar excess of von Willebrand factor protein; the light chain of factor VIII-C interacts noncovalently with the N-terminal region of the von Willebrand factor protein. In the presence of normal von Willebrand factor protein, the half-life of factor VIII-C is approximately 12 hours, whereas in the absence of von Willebrand factor, the half-life of factor VIII-C is reduced to 2 hours.[8, 9, 10]

Wide interindividual variations are found in the level of factor VIII following factor VIII infusions in patients with factor VIII deficiency. In an attempt to understand this phenomenon, extensive pharmacokinetic studies were performed in 32 patients with hemophilia A (30 with severe disease and 2 with mild disease) who received replacement therapy with rFVIII or a monoclonal antibody–purified preparation. The half-life of factor VIII was found to be significantly influenced by blood type and von Willebrand factor level. The half-life of factor VIII from patients with blood type O was much shorter half-life at 15 ± 0.9 hours compared with that of type A patients, who had a longer half-life of 19.7 ± 0.9 hours (significant at P = .003). Older patients with higher von Willebrand factor levels had factor VIII with longer half-lives.[11]

Physiologically, factors such as estrogens, pregnancy, exercise, and epinephrine can raise factor VIII levels. The extent of the exercise-induced rise in factor VIII levels was shown in a study of experienced athletes after a 42-km marathon run on a relatively cool, cloudy day.[12] A 3-fold increase in levels of factor VIII-C and von Willebrand factor antigen was found, along with a change in the von Willebrand factor multimer pattern. Several drugs and progressive liver disease can induce a rise in factor VIII levels in persons with mild hemophilia A.

Activation of FVIII

Activation of coagulation is accomplished by the conversion of a series of zymogens to enzymes, with participation of cofactors leading to the conversion of fibrinogen to a stable fibrin clot. Physiologic inhibitors play a crucial role in shaping the direction of this process. Tissue factor (TF), an integral cell membrane protein (which, unlike other zymogens in hemostasis, does not require previous activation), is usually present on cells not exposed to flowing blood or is produced by cells exposed to blood, only in response to specific stimuli.

When tissue factor becomes exposed to blood under altered normal or pathologic states, it binds with a high affinity to both factor VII and factor VIIa (activated FVII); factor VII bound to tissue factor is rapidly activated to factor IIa. The TF-FVIIa complex (extrinsic pathway tenase) is regulated by tissue factor and is the most potent activator of coagulation. TF-FVIIa activates factor X to factor Xa and factor IX to factor IXa; factor XIa activates factor IX to factor IXa at a slower rate than that achieved by the TF-FVIIa complex.

Under normal conditions, a small amount of free factor VIIa (~4.34 ng/mL; ~1% of total FVII) circulates in plasma. The source of this small amount of free factor VIIa (a serine protease) in normal circulation remains unclear.[13] The free factor VIIa represents a low-grade activation of hemostasis, which is present at all times and is available to quickly accelerate thrombin generation whenever needed.

The importance of the factor IX to factor IXa activation by the TF-FVIIa complex is underscored by the fact that in patients with severely reduced levels of factor IX (hemophilia B), only approximately 10% of normally expected factor VIIa (~0.33 ng/mL) is spontaneously generated, whereas approximately half the normal amount of normal factor VIIa (~2.69 ng/mL) is found in patients with severe factor VIII-C deficiency (hemophilia A). The practical importance of this distinction is unclear because deficiency of factor VIII or factor IX is associated with a clinically indistinguishable bleeding disorder.

When factor VIII is exposed to thrombin or factor Xa, an initial and rapid 30-fold increase of its procoagulant activity takes place, with greater activation by thrombin, followed by a rapid loss of procoagulant activity of factor VIIIa. This activation accompanies proteolysis of both heavy and light chains of factor VIII at sites of tyrosine sulfate residues.

Thrombin also activates platelets, exposing the acidic inner leaflet phospholipids (phosphatidyl serine and phosphatidyl ethanolamine) to the outside, allowing factor VIIIa to bind specifically to the platelet membrane through its light chain, increasing factor VIII activity and allowing assembly of the tenase complex to proceed.[14, 15] This contributes to the development of platelet procoagulant activity, which is necessary for the second, larger burst in thrombin generation that is responsible for clot formation.

The complex of factor IXa, and its cofactor factor VIIIa, when assembled on a negatively charged phospholipid surface, represents the intrinsic pathway tenase complex. The binding of activated coagulation factors to a phospholipid surface localizes this process to sites of vascular damage. On a phospholipid surface, factor VIIIa increases the maximum velocity of factor X activation by factor IXa, by approximately 200,000-fold, leading to the large second burst of thrombin generation, following the initial small amounts of thrombin produced by the TF-FVIIa complex.

Inactivation of FVIII

Activation of factor VIII is followed by an immediate dissociation of the A2 subunit, leading to loss of activity of factor VIIIa; prolonged reaction of factor VIIIa with factor IXa leads to proteolysis of the A1 subunit and subsequent loss of factor VIIIa activity. Thus, the rapid decay of factor VIIIa results in loss of activity of the intrinsic tenase complex, self-limiting its proteolytic activity.

Another factor that critically determines the length of survival of factor VIIIa is activated protein C (APC), which, along with its cofactor, free protein S, is a potent anticoagulant. Thrombin, when bound to thrombomodulin on the surface of endothelial cells, loses its serine protease prothrombotic functions and instead supports the anticoagulant pathway by activating protein C in the presence of phospholipids and calcium. Cleavage of factor VIIIa by APC occurs at sites on both the A2 and A1 subunits. The primary substrate of APC appears to be factor Va rather than factor VIIIa, and, under physiologic conditions, the major reason for loss of factor VIIIa activity appears to be due to spontaneous dissociation of the A2 subunit of factor VIIIa, rather than APC-induced proteolysis of factor VIIIa.

In addition to APC, proteolysis of factor VIIIa may also be mediated by factor IXa, factor Xa, and thrombin; the relative importance of these pathways in vivo is unclear.

Factor V is another cofactor that has structural and functional similarities to factor VIII. A single mutation in the factor V gene leads to the production of an abnormal factor V (FV Leiden) whose activated form is less susceptible to degradation by APC, leading to a hypercoagulable state. It has been postulated that a similar mutation in the factor VIII gene might occur, leading to a thrombophilic state. However, analysis of mutant factor VIII proteins created in the laboratory showed that mutations at both the Arg 336 and Arg 562 sites (sites of APC cleavage) of factor VIII were necessary before the mutated factor VIII was resistant to APC-induced proteolysis.[16, 17]

Factor VIIIa is protected by von Willebrand factor from inactivation by APC, but von Willebrand factor is unable to prevent thrombin from activating factor VIII to factor VIIIa or prevent activation of factor VIII by factor Xa. The inhibitory and protective actions of von Willebrand factor probably result from the prevention by von Willebrand factor of the interaction of factor VIIIa with phospholipids and activated platelets. When thrombin cleaves factor VIII, von Willebrand factor is released, and factor VIIIa is freed and is capable of attaching to the platelet phospholipid, a site to which the factor VIIIa is brought by the interaction of von Willebrand factor with the platelet glycoprotein Ib receptor.

In the rare disorder of inherited combined deficiencies of factor V and factor VIII, the prothrombinase complex (extrinsic tenase) in which factor Va participates is also deficient, in addition to the deficiency in the tenase complex caused by deficiency of factor VIIIa.

Antigenic structure

The 6 structural domains in the antigenic regions of factor VIII are, in the following order, A1-A2-B-A3-C1-C2, with 3 amino acid–rich regions (AR1, AR2, AR3). Initially, factor VIIIa, resulting from limited proteolytic cleavage, is a heterodimer of a heavy chain (with A1 and A2 domains) and a light chain (with A3-C1-C2 domains) bound to von Willebrand factor. This is further cleaved to a heterotrimer by thrombin.

The carboxy terminal C2 domain binds von Willebrand factor and phospholipids; the negatively charged head of phosphatidylserine, an O-phospho-L-serine, binds factor VIIIa.[14] The C2 domain can bind either phosphatidylserine or von Willebrand factor, but not both at the same time. Interestingly, a high degree of conservation of amino acids exists between the A and C domains of factor V and factor VIII (both activated by thrombin and both substrates for APC), and both factors are suggested to have evolved from a primordial gene, with divergence of amino acids in the B domain of the molecules. Gene structure is discussed in Causes.

Epidemiology

Frequency

United States

The overall estimated frequency of hemophilia A (FVIII deficiency) is 1 case per 5,000-10,000 live male births. Approximately 50-60% of patients have severe hemophilia A (FVIII-C < 2% of normal) associated with the severest bleeding manifestations. Persons with moderately severe hemophilia (FVIII-C of 2-5%) constitute 25-30% of patients with hemophilia and manifest bleeding after minor trauma. Persons with mild hemophilia A (FVIII-C of 6-30%) comprise 15-20% of all people with hemophilia; these patients develop bleeding only after significant trauma or surgery.

Acquired hemophilia A, caused by the development of an autoantibody to factor VIII in a person with previously normal hemostasis, develops with a frequency of 1 case per 1 million population per year.

The inherited, combined deficiency of factor V and factor VIII is a rare but recognized cause of a bleeding disorder in the United States.

International

Hemophilia A is found in all ethnic groups in the world. Alloantibodies and autoantibodies to factor VIII (FVIII inhibitors) have been reported from many parts of the world.[18] The inherited combined factor V and factor VIII deficiency has been reported in patients from Europe, Tunisia, the Middle East, Iran, China, and India.

The distribution of the mutations within the factor VIII gene in 31 Taiwanese, unrelated hemophilia A patients demonstrated that 12 (38.7%) severe males and 1 (3.2%) severe female were genotyped with the recurrent IVS22 and IVS1 inversion.[19] Eleven mutations were novel: 7 caused missense substitutions, and 4 resulted in truncated proteins.

Abu-Amero et al performed detailed clinical examinations, including plasma factor VIII-C measurements) of 20 unrelated Arab patients with severe hemophilia A.[20] Intron 22 inversion was common (detected in 11 patients [55%]); 8 base substitutions (6 of which were novel) were detected in 9 patients (45%), without the presence of insertions or deletions. Some base substitutions (8) were detected, in which 6 were potentially pathologic and which correlated well with the severe clinical phenotype that was observed.[20] Abu-Amero et al recommend larger studies with more Arab patients from various Arab countries determine the prevalence of various mutations in Arabs.

Acquired hemophilia A has an incidence of approximately 1 case per million per year.[21]

Mortality/Morbidity

Intracranial bleeding was the major cause of death in individuals with hemophilia until the acquired immunodeficiency syndrome (AIDS) epidemic, which, from the late 1970s into the 1990s, became the major cause of death in this population. These individuals experience significant morbidity from frequent joint and other bleeding episodes.

Hepatitis remains a major cause of morbidity and mortality because of its progression to chronic liver disease[22] ; chronic fatigue is caused by the ongoing active viral illness and/or is related to antiviral therapy. Portal hypertension, variceal bleeding, ascites, and upper gastrointestinal (GI) hemorrhage occur as liver disease progresses. Hepatocellular carcinoma can develop as a consequence of chronic hepatitis. Emerging pathogens potentially transmitted by blood or blood products (eg, prions) will change the pattern of morbidity and mortality in the future. See Complications for a description of transfusion-transmitted illnesses.

The development of an alloantibody further complicates an already burdensome disease.

Acquired factor VIII inhibitors (autoantibodies) are associated with significant morbidity and at least a 20% mortality rate at present, but higher mortality rates prevailed earlier when currently available products to treat inhibitor patients were unavailable.[21]

The tremendous physical, psychologic, and financial burden borne by patients and their families because of the restraints imposed by recurrent bleeding must be dealt with intensively. In this setting, human immunodeficiency virus (HIV) infection adds another layer of burden.[23] Therefore, the drug addiction and abuse in this population is not surprising. All of these issues require close, coordinated care delivered by a multidisciplinary team.

Patients with combined factor V and factor VIII deficiency develop all of the complications known to develop in patients with hemophilia A due to the necessity of frequent blood or blood product replacement. The absence of a safer source of factor V, such as purified factor V concentrate, to correct the factor V deficiency requires the repeated use of fresh frozen plasma (FFP), with its potential for transmitting illnesses.

Race

Factor VIII deficiency (hemophilia A) has no ethnic or racial predilection. Middle Eastern Jews and persons from Tunisia, Iran, India, Europe, and the United States have been reported with the combined deficiency of factor V and factor VIII.

Sex

Otherwise healthy males with a single copy of the abnormal factor VIII gene in their only X chromosome have bleeding manifestations. The severity of bleeding generally depends on their basal level of factor VIII-C, but it is also influenced by the co-inheritance of other bleeding or thrombophilic mutations.

Carrier females, usually asymptomatic, have one affected and one normal X chromosome; lower levels of factor VIII-C than that expected with a carrier state have been found in such females (see image below).


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Possible genetic outcomes in individuals carrying the hemophilic gene.

One explanation is that an unbalanced inactivation of the normal X chromosome during early embryonal development results in a preponderance of the abnormal X chromosome, thus leading to a lower basal level of factor VIII-C. A combination of this unbalanced inactivation with a new factor VIII gene mutation has been shown to result in severely reduced factor VIII levels in a female (severe female hemophilia).[24]

Some data have cast doubt on a correlation between the pattern of X chromosome inactivation and the wide variation in levels of factor VIII or factor IX found in carriers of hemophilia A or B because researchers did not find a skewed pattern of inactivation of the appropriate X chromosome in carriers with either low or high levels of factor VIII or factor IX.[25] Lower basal levels of factor VIII-C in carriers is associated with a bleeding disorder, although this is less severe than that observed in the corresponding hemophilic male, due to the presence of higher basal levels of factor VIII or factor IX in the clinically symptomatic carrier.

Females with hemophilia, although rare, can arise from the union of a male with hemophilia and a carrier female; in females with X-chromosomal abnormalities, such as Turner syndrome (XO); in an X-autosome translocation involving a breakpoint in the factor VIII gene; or due to uniparental isodisomy, in which the affected female inherits 2 copies of the mutated X chromosome (and all other X chromosomal genes) from her mother. Apparently, this last example may be incompatible with life. Interestingly, isodisomy was the documented cause of male-to-male transmission of hemophilia A in one case, in which the affected male passed his abnormal X chromosome and his Y chromosome to his son, with no contribution of an X chromosome from his mother.[4]

Acquired factor VIII inhibitors develop in either sex.

Combined factor V and factor VIII deficiency is an autosomal recessive disorder with clinical manifestations in affected females and males.[5, 26, 27, 28, 29]

Age

A prenatal diagnosis of hemophilia A can be made by using markers for restriction fragment length polymorphisms, by chromosomal analysis of cells obtained by amniocentesis at approximately 16 weeks' gestation, or by chorionic villus sampling at approximately 10 weeks' gestation.

A postnatal evaluation is triggered by a history of bleeding, which can start immediately after birth (eg, intracranial bleeding) or may be delayed in those with mild hemophilia. Oral bleeding starts with teething and cuts and abrasions to the lips, tongue, and frenulum, followed by joint and muscle bleeding with the start of ambulation.

In a single-center study, the age at which bleeding starts was found to vary. Approximately 44% of affected children bled within the first year of life, whereas others did not experience their first bleeding episode until age 4 years. Recurrent episodes of joint bleeding usually started approximately 6 months after the first bleeding episode; 50% of patients had their first bleeding episode by age 1.22 years, whereas the mean age for the first joint bleed was 1.91 years. These data support the concept that primary prophylaxis need not begin at the same age in all patients.[30]

Because of the increasing safety of recombinant factor VIII concentrates, advances in therapy, home treatment, and the long-term physical and psychologic benefits of being able to lead a normal lifestyle, the Medical Advisory and Safety Committee of the National Hemophilia Foundation has endorsed the use of recombinant products wherever feasible. As early as 1994, the committee recommended prophylactic treatment as the optimal approach to hemophilic care.

A survey of written guidelines and practices of obstetricians, hematologists, and neonatologists at medical centers in the United States for the management of pregnant carriers, newborns with hemophilia, and infants with intracranial hemorrhage showed that more than 94% of these major facilities had no written guidelines.

As a result of data obtained from this survey, it has been suggested that vacuum devices and fetal scalp monitors not be used in the vaginal delivery of known carriers of hemophilia and that all infants with intracranial hemorrhage and women with postpartum hemorrhage be evaluated for a bleeding disorder. A national registry of these cases would provide the type of information necessary to develop rational national guidelines to help improve care for pregnant women with bleeding disorders.[31, 32]

Acquired factor VIII deficiency is observed in older populations, generally those older than 60 years. Inhibitors that develop in patients with hemophilia are now likely to be found in a younger age group, due to the practice of starting prophylactic replacement therapy at a younger age. An extensive European study of 467 cases of acquired hemophilia A documented that patients were aged a median of 73.9 years at diagnosis and that it was idiopathic in 51.9% of them.[33]

Bleeding in patients with a combined deficiency of factor V and factor VIII starts in childhood as the child starts ambulating, with the earliest possible evidence at the time of circumcision after birth.

History

Recurrent spontaneous or minor injury–induced episodes of joint bleeding are common in persons with severe and moderately severe hemophilia, causing severe pain and limitation of joint movement. The repeated presence of blood in the joint leads to synovial hypertrophy, with a tendency for recurrent joint bleeding, which finally results in a destructive chronic synovitis with destruction of synovium, cartilage, and bone. This leads to chronic pain, arthritis, joint stiffness, and limitation of movement due to progressive and permanent severe joint damage with progressive muscle wasting (see images below).


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Photograph of a teenage boy with bleeding into his right thigh as well as both knees and ankles.


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Photograph of the right knee in an older man with a chronically fused, extended knee following open drainage of knee bleeding that occurred many years....


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Photograph depicting severe bilateral hemophilic arthropathy and muscle wasting. The 3 punctures made into the left knee joint were performed in an at....


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Radiograph depicting advanced hemophilic arthropathy of the knee joint. These images show chronic severe arthritis, fusion, loss of cartilage, and joi....


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Radiograph depicting advanced hemophilic arthropathy of the elbow. This image shows chronic severe arthritis, fusion, loss of cartilage, and joint spa....


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Photograph of a hemophilic knee at surgery, with synovial proliferation caused by repeated bleeding; synovectomy was required.


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Large amount of vascular synovium removed at surgery.


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Microscopic appearance of synovial proliferation and high vascularity. If stained with iron, diffuse deposits would be demonstrated; iron-laden macrop....

Intramuscular hemorrhage, the second most common bleeding event, also leads to acute severe and recurring pain, swelling, and limitation of movement. The hematoma may dissect down into the fascial planes and result in neuropathies due to nerve compression, such as with psoas bleeding; large retroperitoneal bleeding can lead to hypotension.

Mucous membranes can be the site of bleeding, manifesting as epistaxis, oropharyngeal, or retropharyngeal bleeding, which can lead to acute respiratory obstruction. The GI tract may be a source of bleeding in approximately one fifth of patients, with an increasing frequency due to the consequences of cirrhosis and the use of readily available over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) for the relief of arthritic pain. Peptic ulcer disease is approximately 5 times more common in individuals with hemophilia than in the general population.

Central nervous system (CNS) hemorrhage (~3-14%) was the major cause of death in persons with hemophilia before the widespread availability and use of factor replacement to prevent bleeding and before the AIDS epidemic.[34] Approximately one third of CNS bleeding episodes lead to death, and at least half result in major, long-term sequelae. Bleeding is usually preceded by head trauma in children, whereas adults may develop CNS bleeding without obvious trauma. Symptoms are typical of any CNS event, with a variety of symptoms such as headaches, seizures, vomiting, and focal neurologic defects. Findings depend on the sites of bleeding.

Spontaneous hematuria can be seen in those with severe hemophilia. The use of NSAIDs, protease inhibitors, or over-the-counter drugs; trauma; exercise; or exertion may precipitate genitourinary (GU) bleeding. Associated clots in the GU system causing acute hydronephrosis may be a complication of the concomitant use of fibrinolytic inhibitors with factor replacement in patients with hematuria. Underlying pathology, such as nephrolithiasis, tumors, or infections, should be excluded when persistent bleeding is present. Indinavir (Crixivan; Merck & Co, Inc, Whitehouse Station, NJ) may be associated with crystalluria or calculi in HIV-infected patients.

Acute and chronic viral illnesses have been transmitted by the less pure blood products that were the only ones available to treat bleeding in the past. HIV-related illnesses and AIDS; repeated viral, fungal, and bacterial illnesses due to AIDS; malignancies, such as Kaposi sarcoma; and the aggressive AIDS-associated lymphomas are life-threatening complications.[35] Despite these problems, plasma-derived products remain a valuable resource without which many persons with hemophilia throughout the world would experience the painful consequences of recurrent bleeding. See Complications for further details.

The availability of newer recombinant products (with no risk of transmission of HIV and hepatitis) for use in home care and in-hospital treatment means that those unexposed to plasma-derived products could conceivably achieve a normal life span.

Pseudotumors are produced by a slow expansion of repeated hemorrhages in bone or soft tissues. They can be restricted by the fascial planes of a muscle, cause resorption of neighboring bone by pressure-induced ischemia, or develop under the periosteum, leading to erosion of the bony cortex. They develop slowly over months to years and often are asymptomatic, unless pressure on the nerves or vascular compromise occurs. Pseudotumors contain a brownish material and can become infected. The buttock, pelvis, and thighs are frequently involved locations for a pseudotumor (see images below).


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Large pseudocyst involving the left proximal femur.


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Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional....


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Dissection of a pseudocyst.


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Transected pseudocyst with chocolate brown-black old blood.


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Photograph of a patient who presented with a slowly expanding abdominal and flank mass, as well as increasing pain, inability to eat, weight loss, and....


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Plain radiograph of the pelvis showing a large lytic area.


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Intravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst.

Delayed bleeding develops after dental extractions; therefore, patients require appropriate presurgical and postsurgical management. If not treated appropriately, dental bleeding can persist and expand to sublingual, pharyngeal, facial, or dissecting neck hematomas or other serious bleeding.

Co-inheritance of thrombophilic mutations has been suggested as a reason for a reduction in the severity of bleeding in some individuals with severe hemophilia. A study of the correlation between concentrate utilization, incidence of bleeding episodes per year, and prevalence of hemophilic arthropathy in those with severe hemophilia with and without the factor V Leiden mutation (a known thrombophilic mutation in the white population) showed that factor V Leiden carriers indeed had fewer bleeding episodes, but the authors of this study suggested, appropriately, the need to study this issue in a larger cohort with additional testing.[36]

The development of alloantibodies in persons with hemophilia is a serious complication that leads to increased bleeding and a lack of response to the usual therapy, which can be fatal (see images below). See Complications for more information.


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Photograph depicting extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor....


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Magnetic resonance image of an extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acqui....

Acquired factor VIII inhibitors (ie, acquired hemophilia due to an autoantibody in previously hemostatically normal individuals) are a cause of significant morbidity and are associated with a mortality rate of at least 20%, because they affect elderly people who have comorbid conditions. Patients present with extensive bleeding, often life threatening, before it is recognized.

In contrast to persons with severe inherited factor VIII deficiency (hemophilia A), in whom joint bleeding is common, patients with acquired hemophilia present with large intramuscular, retroperitoneal, limb, subcutaneous, GU, GI, or excessive postoperative or postpartum bleeding. Bleeding into an extremity can result in findings that are easily confused with deep vein thrombosis. Massive upper extremity bleeding can be precipitated by a simple venipuncture. Bleeding can develop at any site.

Postpartum inhibitors usually come to attention several months after delivery (2-5 mo), when bleeding symptoms supervene; rarely, the inhibitor may develop during pregnancy.

Because of the unusual characteristics of these autoantibodies, patients may present with significant bleeding despite the presence of detectable amounts of plasma factor VIII-C activity in vitro; this residual factor VIII activity in a patient with active bleeding can mislead the clinician about the seriousness of the factor VIII deficiency.

Bleeding manifestations in homozygous patients with the combined factor V and factor VIII deficiency include variable bleeding after circumcision, ranging from severe to less than severe. Epistaxis can occur, as can gingival bleeding and easy bruising, starting with mild trauma, as occurs during normal childhood activities. Menorrhagia can start at menarche. Hemarthrosis has been reported in approximately 20% of patients; therefore, joint bleeding is less common in this group than in patients with severe hemophilia A or B.

Confusion with joint bleeding may arise when bleeding occurs in a bursa surrounding a joint. For example, bleeding in the olecranon bursa may be misinterpreted as bleeding into the elbow joint.

In the absence of appropriate factor replacement, dental extractions or other surgeries precipitate bleeding. Intracranial bleeding can develop, even after minor trauma to the head.

Due to higher basal levels of factor V and factor VIII than those found in homozygotes with combined factor V and factor VIII deficiency, only a few heterozygotes manifest excessive bleeding.[37]

Physical

Physical examination findings may include the following:

Causes

With the cloning of the factor VIII gene in 1984, a new era began in the understanding of hemophilias. A large number of mutations have been documented in the factor VIII gene and account for hemophilia A, and, in the early part of the 20th century, the prediction that approximately one third of these would have to be de novo mutations not present in the mother's X chromosome was correct. The functional defects of factor VIII-C manifested as hemophilia A are due to structural defects in the factor VIII gene (see images below).


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Structural domains of human factor VIII. Adapted from: Stoilova-McPhie S, Villoutreix BO, Mertens K, Kemball-Cook G, Holzenburg A. 3-Dimensional struc....


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Image depicting the 28q region of the X chromosome. Adapted from: Kazazian HH Jr, Tuddenham EGD, Antonarakis SE. Hemophilia A and parahemophilia: defi....

The gene for factor VIII is located on 28q (the most distal arm of the X chromosome), is approximately 186 kilobases (kb) long, and comprises approximately 0.1% of the DNA in the X chromosome; it has 26 exons and 25 introns. The site for factor VIII is linked to the locus for color-blindness and with polymorphisms at the glucose 6-phosphate dehydrogenase (G6PD) locus.

Intron 22 of the factor VIII gene, uniquely, contains 2 other genes. The first is called F8A, which is transcribed in a direction opposite to that of the factor VIII gene itself. The second gene is F8B, which is transcribed in the 3' (normal) direction similar to the factor VIII gene. Sequences called A2 and A3, homologous to the F8A sequence, are present on the X chromosome, 300 kb telomeric to the factor VIII gene.

Homologous recombination of the factor VIII gene, with inversion and crossover involving the F8A sequence in intron 22 and the homologous distal sequence on the X chromosome, results in a split in the factor VIII gene with the 2 parts aligned in opposite directions. This causes a disruption in the normal factor VIII coding sequence, with an inability to transcribe the complete, normal factor VIII protein, resulting in a loss of function. The mutation in intron 22 occurs during spermatogenesis and is a common cause of severe factor VIII-C deficiency, as it is present in approximately 40% of patients. It is easily detected using a Southern blot analysis of the patient's DNA. These patients are more likely to develop an inhibitor to factor VIII.

In one study, all detected inversions originated in a maternal grandparent during male meiosis (spermatogenesis), supporting the hypothesis that an unpaired Xq, rather than a paired X chromosome, is more likely to undergo an intrachromosomal inversion. The majority of mothers of persons with the sporadic, inversion-related severe hemophilia are carriers.[4]

The knowledge of the parental origin of the inversion mutation has important implications for genetic counseling and should help alleviate the severe emotional burden carried by mothers of persons with hemophilia, who are blamed or blame themselves for being the cause of their son's devastating illness.

Several other types of mutations have been described.

Modification of the clinical severity of the bleeding disorder resulting from a specific factor VIII mutation by co-inheritance of thrombophilic genes is increasingly recognized as a cause of the variability in bleeding manifestations within a single family with hemophilia A.[36, 39, 40] Additionally, keep in mind that phenotypic variations can be found in patients with the same genotype in a variety of hematologic disorders.[41] The case-control design has been suggested as an appropriate type of clinical study to elucidate genetic-environmental interactions.[42]

The role of genetic polymorphisms, particularly intragenic polymorphisms, should be recognized when providing genetic counseling for families with unknown mutations. Some polymorphisms are universal, whereas others appear to be restricted to particular ethnic groups; the latter situation will change as ethnic intermarriages increase with the increased globalization of populations.

Studies of a heterogeneous population in India have identified a higher heterozygosity index of polymorphic variants of 2 new variants of the multiallelic locus DXS52(St14) of the human X chromosome[43, 44] ; other intragenic polymorphisms have also been reported in this population and are of obvious use in prenatal diagnosis.[45] Data published for a Korean population showed a higher occurrence of low molecular weight (LMW) alleles in Korean persons than in white persons.[46]

Some cases of the combined deficiency of factor V and factor VIII are caused by mutations in the ERGIC53 gene, with loss of splicing or insertion of a nucleotide leading to a frameshift; both mutations identified to date result in an altered ERGIC-53 protein in the endoplasmic reticulum–Golgi apparatus. ERGIC53 has an affinity for the glycosylated B domains of both factor V and factor VIII, and the ERGIC-53 protein transports factor V and factor VIII through the secretory processes in cells.

In families with known mutations, allele-specific hybridization studies show the difference between homozygotes and heterozygotes. Because of a single error in a common processing mechanism affecting both factor V and factor VIII, a similar degree of reduction in plasma levels of factor V and factor VIII occurs in homozygotes, with levels varying 5-30%.[4, 5, 17, 26]

Other causes of this disorder remain to be identified. The Haemostasis Research Group Website (The Haemophilia A Mutation, Structure, Test and Resource Site [HAMSTeRS]) has a continually updated database of genetic defects related to hemophilia A.[47]

Laboratory Studies

Preliminary identification of the coagulation disorder: Laboratory tests include activated partial thromboplastin time (aPTT), prothrombin time (PT), platelet count, and bleeding time

Confirmatory tests and specific coagulation factor assays

Determination of the specific titer of an inhibitor to factor VIII: The Bethesda inhibitor assay has been widely used to assess the titer of an inhibitor directed against a coagulation factor. Ideally, the Nijmegen modification of the Bethesda inhibitor assay should be used to detect the presence of an inhibitor if the mixing test result is positive.[51, 52]

Identification of carriers: Carriers can be detected by linkage studies using restriction fragment length polymorphism analysis.

Other laboratory studies: These may include liver function tests, kidney function tests, HIV-1 and HIV-2 antigen and antibody tests, and tests for hepatitis A, B, C, D, and E antigen/antibody.

Alpha-fetoprotein (AFP) and other tumor markers (as needed)

Other laboratory tests or new tests: These are performed as needed or as newer tests are introduced into routine testing protocols.

Imaging Studies

Magnetic resonance imaging (MRI), computed tomography (CT) scanning, and ultrasound have all been used to localize, quantify, and serially follow a patient's bleeding response to specific therapy. The depth, location, and size of the hematoma guide the choice of diagnostic testing. A simple test, if adequate, is more appropriate for serial follow-up of the size of the hematoma during therapy. MRI and CT scanning are better for diagnosing and localizing pseudotumors. Other tests should be performed as needed to diagnose renal calculi and tumors.

Other Tests

Obtaining an electrocardiogram (ECG) may be useful as a general test.

Procedures

Arthrocentesis must not be performed, either for diagnostic or therapeutic purposes, for a routine joint bleed in a known hemophilic patient, because the procedure increases the risk of exacerbating the joint bleed (see image below). Diagnostic arthrocentesis should only be performed when an infection is suggested.


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Photograph depicting severe bilateral hemophilic arthropathy and muscle wasting. The 3 punctures made into the left knee joint were performed in an at....

Routine dental care is of the utmost importance in maintaining dental hygiene and preventing gingival bleeding.

Other procedures, such as colonoscopy, should be performed as in patients without hemophilia, when indicated. Persistent GI bleeding without an apparent cause should be evaluated with the use of endoscopy and colonoscopy to rule out underlying lesions.

Persistent GU bleeding requires evaluation for nephrolithiasis, tumors, or obstruction. If a biopsy is needed, patients require factor replacement therapy before the performance of any invasive procedure.

Surgical excision of any pseudotumor in toto is necessary, often requiring laborious, long, and extensive dissections; partial removal leads to recurrence of the pseudotumor caused by repeated bleeding. Avoid aspirating a pseudotumor because of the risk of exacerbation of already existing, slowly progressive bleeding.

Prenatal diagnosis

Histologic Findings

Synovial proliferation is caused by repeated bleeding into the joint. This results in damage to joint structures, leading to limitation of movement and deformity. The presence of excess iron in these tissues is evident microscopically. See image below for histologic features.


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Microscopic appearance of synovial proliferation and high vascularity. If stained with iron, diffuse deposits would be demonstrated; iron-laden macrop....

The gross findings of a pseudocyst with chocolate-colored inspissated material are shown in the images below.


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Large pseudocyst involving the left proximal femur.


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Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional....


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Dissection of a pseudocyst.


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Transected pseudocyst with chocolate brown-black old blood.

Medical Care

Factor VIIII (FVIII) replacement is used for acute bleeding, for perioperative prevention of bleeding during planned surgical procedures, for prophylaxis to prevent recurrent bleeding of target joints, in early institution of childhood prophylactic therapy to preserve long-term joint function, or for immune tolerance induction (ITI) regimens. Prompt and adequate therapy for bleeding is essential to avoid the long-term destructive consequences of joint bleeding. Although there are 6 wild-type factor VIII proteins, only 2 (H1 and H2) match the recombinant factor VIII products used clinically.[54]

Home care programs have made patients self-sufficient in infusing factor replacement product (see images below), with guidance and supervision from personnel at a hemophilia center or a knowledgeable physician in the local community.


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Photograph depicting the application of a Velcro tourniquet, followed by self-infusion of concentrate used for in-home therapy.


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Self-infusion of concentrate used for in-home therapy.

This has also improved quality of life by minimizing the time spent in hospital emergency departments, providing rapid and early therapy for acute bleeding, achieving a prompt reduction in pain due to early specific correction of the factor deficiency and joint immobilization, and allowing concomitant provision of appropriate narcotic and nonnarcotic analgesics.

Joint integrity can be preserved with the start of early prophylactic home care programs in childhood (maintain a minimum of 1-2% FVIII-C at all times by infusing replacement product at home 3 times per wk).

All of these allow a patient to participate in more of life's activities. The specific dose and duration of factor replacement therapy is determined by the location of the bleeding, severity of the bleeding, and known actual response to previous therapy.

Intermediate- or high-purity plasma-derived products are still available for use in patients who have previously used such products. Monoclonal antibody purified plasma–derived products are usually free of some viral contaminants. In children who are starting therapy for the first time or in persons with hemophilia who are negative for HIV, recombinant products are used whenever possible because of their presumed higher viral safety.

Importantly, be aware that approximately 25% of the lots of human albumin that contain first-generation recombinant factor VIII concentrates have been found to be positive for transfusion-transmitted (TT) virus from contaminated human serum albumin. All second-generation recombinant factor VIII preparations (free from human albumin) have been negative for the virus.[55]

See the table in the Medication section and related material for a general dosing guide for factor replacement therapy and for target factor VIII levels for acute bleeding. The duration of therapy depends on the site and cause of bleeding and response to therapy. Bolus dosing is still the most often used method of factor replacement, but a continuous infusion regimen generally reduces total administered doses by approximately 30%. Data on the lowest necessary dose for adequate therapy, a consideration because of the enormous cost of factor replacement products, are being obtained.[56]

Monitoring actual levels of factor VIII-C is necessary to confirm the presence of adequate amounts of factor VIII in vivo to correct hemostasis when (1) a patient is first treated, (2) a new factor replacement product is being used, (2) the onset of an inhibitor is suggested, (4) active ongoing bleeding is present, or (5) persistence or inadequate correction of bleeding has been encountered with previously adequate doses.

Minor bleeding, as from cuts and abrasions, may respond to conservative measures, such as pressure and ice. Mild hematuria may subside spontaneously. Note: Do not aspirate hematomas or joints or cauterize bleeding sites unless specifically indicated, because these procedures may aggravate the bleeding.

Epistaxis and moderately severe hematuria may be adequately treated by achieving and maintaining factor VIII levels in the range of 30-50%. Use a higher dose initially, followed by a gradual lowering of the dose after the bleeding is under control, and then continue factor VIII replacement until clinical and objective evidence indicates resolution of the bleeding.

Acute joint bleeding and expanding, large hematomas require adequate factor replacement for a prolonged period until the bleed begins to resolve, as evidenced by clinical and/or objective methods. Relief of the intense pain with joint bleeding frequently requires the use of narcotic analgesics; relief of pain also accompanies cessation of bleeding after adequate factor replacement.

Life-threatening bleeding episodes are generally initially treated with factor VIII levels of approximately 100%, until the clinical situation warrants a gradual reduction in dosage. Continuous intravenous infusions avoid the low troughs and excesses of intermittent bolus dosing, maintain adequate levels at all times, and save approximately 30% of expensive factor replacement product usage.[57, 58]

For serious bleeding events, continue factor replacement for at least 7-10 days because of the potential risk of recurrent bleeding. A multiple-bolus drug-dosing regimen model has been developed to better estimate the loading and maintenance dose requirements to allow maintenance of a minimum trough level of factor VIII at all times.[59] In patients who may have an intracranial hemorrhage, administer a full dose of factor concentrate before the patient is sent for any diagnostic radiologic procedures in order to avoid delays in bleeding control. Surgically drain intracranial bleeding promptly, as clinically dictated, following factor replacement therapy.

Patients with combined factor V and factor VIII deficiency require combined replacement with factor VIII concentrates and FFP for factor V, which also supplies a small amount of factor VIII. The use of 1-deamino-8-D-arginine vasopressin (DDAVP) to raise factor VIII levels (without concomitant FVIII concentrate) in combination with FFP as a source of factor V was successful in the perioperative management of an older Italian man who was undergoing surgical repair of massive bilateral inguinal hernias.[60] However, pooled solvent-detergent–treated plasma (PLAS+ SD; VI Technologies, Inc (Vitex), Watertown, Mass / American Red Cross, Washington, DC) is safer than standard FFP, because lipid-enveloped viruses are removed. See the Medication section for further details of PLAS+ SD.

Collaboration with an infectious diseases consultant is a major need in caring for patients with HIV/AIDS or hepatitis. The serious psychiatric issues present in the management of patients infected with HIV may require the assistance of a psychiatrist.[23]

Simple immediate ancillary measures of ice, pressure, elastic bandage (ACE) wrap, immobilization of the affected joint, and avoidance of NSAIDs must not be forgotten.

The benefits of prophylaxis in the management of hemophilia A should be emphasized.[61] There are clear advantages of prophylaxis for patients with hemophilia A compared with on-demand treatment, including a reduction in the number of bleeding episodes, improved joint function, and greater patient well-being. Sadly, there is a heavier economic burden with increased factor use.

Prophylactic factor replacement

Secondary prophylaxis thus far has been undertaken mainly in patients with target joint–related recurrent bleeding in a biweekly or triweekly intravenous dose of factor VIII (25-40 U/kg) to maintain trough factor VIII-C levels in the range of 3-5%. There are data which clearly show that in order to preserve joint function, primary prophylaxis must be started early in childhood, after the child experiences the first few episodes of bleeding into a joint.

This approach may appear to be an expensive proposition, but it has been shown to be good for the patient's joints and quality of life, and, over the long term, early primary prophylaxis reduces costs by reducing the number of in-hospital days and outpatient and day care visits when compared with on-demand therapy.[62, 63, 64, 65, 66] Moreover, on-demand and secondary prophylaxis do not prevent hemophilic arthropathy, whereas early primary prophylaxis better preserves normal joint structure and function and a normal quality of life, while presumably delaying or even reducing the need for early joint replacement.

As early as 1994, the Medical Advisory and Safety Committee recognized the long-term physical and psychosocial benefits of early prophylaxis in allowing the hemophiliac patient to lead a normal lifestyle, and it endorsed the principle of prophylactic therapy as the optimal approach to hemophilic care.

However, venous access problems do arise, especially in children, and indwelling lines invariably lead to recurrent infections and thrombotic complications. Subclavian, brachiocephalic, jugular, and superior venocaval thrombi have been objectively documented in hemophilic children with long-term (>1 y) central venous catheters for access. Approximately 50% of patients with central venous catheters for longer than 1 year have deep vein thrombosis.[40, 67]

An intriguing, relatively new concept is the development of an oral peptide, peptidomimetic, or other compound that may activate the coagulation mechanism, with an ability to control the extent of activation. This is the reverse side of the coin of controlled anticoagulant use in the treatment of thrombotic diseases.

Home therapy

In the last few decades of the 20th century, home therapy revolutionized the type of care provided to individuals with hemophilia. New factor replacement products resulted in improved patient outcomes, which considerably improved the quality of patients' lives.

The typical picture of earlier times of a wheelchair-bound, disabled adult with hemophilia has been replaced by that of an ambulating patient with a lesser degree of joint damage. However, the fact remains that many affected individuals require joint replacements at a younger age than persons without hemophilia but with osteoarthritis.

Patients with hemophilia and their families have become self-sufficient with the application of sterile home infusion techniques, with prompt replacement of the missing factor at the earliest evidence of pain and/or possible bleeding, rather than having to spend hours waiting for care in crowded emergency departments. Distant travel and summer camp experiences have also become feasible (see image below).


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Quality of life! A child with hemophilia at summer camp.

The availability of lyophilized replacement product, the equipment and teaching needed for intravenous self-infusion, and the security to infuse the replacement product have helped release patients from the necessity of remaining in the vicinity of a hospital for emergent care (see images below). This aspect is also extremely important from the psychologic standpoint of allowing parents and other family members to become actively involved in the care of their loved one.


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Photograph depicting the application of a Velcro tourniquet, followed by self-infusion of concentrate used for in-home therapy.


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Self-infusion of concentrate used for in-home therapy.

The subsequent increase in replacement product usage has led to an increasing risk of exposure to virally transmitted illnesses and led to the AIDS and hepatitis epidemics. Patient who are negative for HIV and the hepatitis C virus and those who have not undergone treatment as yet are now being treated exclusively with the more expensive recombinant products.

With the availability of concentrates of factor VIII and developments in the field of joint replacement, previously disabled patients can ambulate and become self-sufficient in their daily lives. There are advantages and disadvantages in using the albumin-free recombinant factor VIII concentrates in the treatment of hemophilia A.[68] The third-generation recombinant factor VIII product Advate (antihemophilic factor [Recombinant], plasma/albumin-free method; Baxter Healthcare Corporation, Westlake Village, Calif) is safe and effective in treating bleeding associated with hemophilia A.

However, controversy remains with regard to a higher risk of inhibitor development with recombinant products, and the higher cost may play a role in product choice. Each patient and family should be educated about the advantages and disadvantages of all factor VIII concentrates, and they should be allowed to make an informed decision about which replacement product to use.

Other therapeutic measures

DDAVP, or desmopressin acetate (Stimate; ZLB Behring LLC, King of Prussia, Penn), is an arginine vasopressin analogue, which, when given intravenously in a dose of 0.3 mcg/kg over 15-20 minutes, causes a transient 2- to 4-fold rise in factor VIII and von Willebrand factor levels by inducing release of factor VIII and von Willebrand factor from storage sites. The doses are usually repeated 8-12 hours later, but an approximate 30% lower response may be expected after the second dose.

Repeated administration of DDAVP results in a markedly reduced response (tachyphylaxis). Factor XI levels also rise in response to this drug. The rise in factor VIII level is accompanied by an increase in fibrinolytic activity due to the simultaneous release of tissue plasminogen activator (tPA).

DDAVP can also be given by intranasal spray (150 mcg in each nostril), but the time to maximal rise in factor VIII levels is delayed (unlike the response to an intravenous dose); therefore, extra time is required for a response. This approach may be inadequate under some clinical circumstances.

DDAVP is a good drug to use in patients with mild hemophilia (whose condition has had proven response to the drug) to prevent bleeding associated with minor procedures or surgeries that are expected to be associated with very little bleeding.

Patients must be tested and proven to have a good treatment response to DDAVP before the use of DDAVP in a patient who has been scheduled for surgery. If an appropriate rise in factor VIII level is obtained in response to the test dose of DDAVP, then at least 1 week should elapse between the date of the test dose of DDAVP and the surgery. This allows time for replenishment of endogenous stores of factor VIII-C before surgery, so that an adequate DDAVP-induced rise in factor VIII is again obtained perioperatively.

Patients with severe hemophilia are not proper candidates for DDAVP therapy, because they do not have intravascular stores of factor VIII available for release.

Hyponatremia due to water retention is a potentially serious adverse effect; a patient's oral or intravenous intake of fluids must be curtailed for approximately 12-18 hours after the administration of DDAVP, until the antidiuretic effect passes. Importantly, alert the patient to this effect, so that the patient will be aware of the distinct drop in urine volume following DDAVP administration, with an increase in urinary output when the antidiuretic effect of DDAVP wanes.

(There have been instances in which this author's patients who had been educated about the antidiuretic effect pointed out the lack of antidiuretic effect and the lack of the flushing that accompanies DDAVP administration, thus alerting the physician to the possible lack of DDAVP in the bag provided by the pharmacy.)

Antifibrinolytic agents

Preservation of the hemostatic plug formed in the presence of adequate levels of factor VIII at the time of surgical trauma (as with dental procedures or with mucosal bleeding) can be achieved by inhibiting fibrinolysis with epsilon-aminocaproic acid, also called EACA (Amicar; Xanodyne Pharmaceuticals, Inc, Newport, Ky), or tranexamic acid (trans-p-aminomethyl-cyclohexane carboxylic acid [AMCA]) (Cyklokapron, Pharmacia & Upjohn, New York, NY) given orally or, if needed, intravenously.

The first dose of EACA (5 g PO/IV slowly) is administered before the surgical procedure, along with a dose of factor VIII sufficient to raise the level, followed by a maintenance dose of EACA (1 g/h) postoperatively for several hours until it is clinically appropriate to start tapering the dose over the next several days.

An intriguing in vitro observation is the finding that EACA in a final concentration of 1.25-5 mg/mL (concentrations achievable with a large loading dose) inhibits factor VIII inhibitor activity without affecting other immunologic reactions.[43]

In vivo confirmation of this phenomenon was obtained in plasma from 2 patients with inhibitors who received EACA in a dose of 100 mg/kg over 10 minutes; the lysine-binding sites did not appear to mediate this effect.[43]

AMCA is given in a dose of 1.5 g intravenously every 6-8 hours and then tapered, as needed.

These drugs can also be used as a mouthwash for oral bleeding, and they have been used to stop local intracavitary oozing.

Antifibrinolytic agents are contraindicated in patients with hematuria because of the risk of developing a firm, occluding clot in the ureters when given simultaneously with factor replacement. These drugs are not useful in the management of joint bleeding.

In the past few years, the use of NSAIDs by individuals with hemophilia has increased in an effort to ease the pain of chronic, disabling, and frequently crippling joint disease. Although these agents allow improved joint function, because of the impact of NSAIDs on primary hemostasis, their use comes at a price of increased bleeding episodes and an increased incidence of GI and other bleeding, all requiring more use of concentrate.

Cyclooxygenase (COX)-2 inhibitors have been tried with caution, but these drugs are likely to increase the bleeding risk. Alternatives to NSAIDs, such as acetaminophen and codeine-type analgesics, are much less effective because they lack an anti-inflammatory effect; additionally, some of these drugs are addictive.

Fibrin glue

This product is very useful for controlling bleeding at surgical sites. Fibrin glue consists of a mixture of fibrinogen, thrombin, and factor XIII to cross-link freshly formed fibrin. Cryoprecipitate has also been used as a source of fibrinogen and factor XIII, with bovine thrombin used to start the clotting process. Some preparations also incorporate antifibrinolytic agents to inhibit clot lysis.

Fibrin glue has been particularly useful in orthopedic and pseudotumor-related surgical procedures and to achieve adequate hemostasis at operative sites in patients with an inhibitor to factor VIII.

Bovine thrombin present in fibrin glue can elicit an antibody, as it has in other postoperative states.[69]

Gene therapy

Several ideal characteristics have been proposed for a DNA delivery system, including the fact it (1) is produced in concentrated form, (2) is targeted to specific cell types, (3) results in long-term gene expression with stable levels for years, (4) is nontoxic, and (5) is nonimmunogenic.[70, 71]

Several studies have been undertaken in humans using different approaches to introduce the factor VIII gene into a patient so that higher factor VIII levels can be maintained in persons with severe hemophilia; maintenance of basal levels of 3-10% significantly ameliorate bleeding in patients with severe hemophilia. The most successful and least toxic method of introducing the gene remains to be determined. Some of the problems with gene therapy are as follows:

Management of inhibitors: See the Medication section.

Surgical Care

Preoperative evaluation of the aPTT, along with a mixing test that includes prolonged incubation of a patient's plasma with normal pooled plasma to exclude an inhibitor, is very important. Most individuals with hemophilia are routinely tested when examined by a physician with expertise in this area. The patient must receive the proper dose of factor VIII (FVIII) before and serially after surgery to achieve and maintain an adequate level of factor VIII-C to permit maintenance of good hemostasis. Following bone and joint surgery, prolonged replacement for several weeks is necessary not only to allow healing at the surgical site, but also to prevent bleeding during the necessary intensive postoperative physical therapy, which allows for maximum joint mobility to develop.[84]

Procedures such as endoscopies, although considered routine for unaffected people, require preprocedural factor product replacement in persons with hemophilia so that they do not bleed either during or following a needed biopsy. Postbiopsy replacement with factor VIII must continue until the biopsy site has healed.

Dental extractions or mucosal procedures can be handled with a single preprocedure dose of factor VIII, along with Amicar. A standard approach to dental extractions has been proposed based on a case-control study, which proved the validity of the tested approach.[85] In this study, patients received a single 20 mg/kg dose of AMCA, along with a single infusion of factor VIII, to achieve a peak level of approximately 30% before the dental extraction. No significant differences in bleeding rates occurred when compared with controls, with a cost reduction due to outpatient management. Routine practice is to continue therapy with antifibrinolytics in an outpatient setting for several days after the dental extraction, with a gradual tapering of the dosage over 5-7 days.

The use of ancillary measures, such as fibrin glue and antifibrinolytics (see Medical Care), is very valuable in surgical procedures in which excessive bleeding is anticipated or encountered.

Orthotopic liver transplantation for hepatic failure corrects factor VIII levels in patients with hemophilia. Interestingly, factor VIII-C levels in persons with mild hemophilia rise to normal levels as their chronic liver disease advances (author's observations).

When treating patients with combined factor V and factor VIII deficiency, a factor V level of approximately 25% is sufficient for major surgery. Maintain factor VIII levels as for patients with hemophilia A. FFP in a loading dose of approximately 20 U/kg preoperatively or emergently for a bleeding episode, followed by FFP in a dose of 5-10 U/kg every 12 hours to maintain a minimal hemostatic level of factor V, may be required.

PLAS+ SD is safer than FFP and may be substituted for FFP whenever it is available (see the Medication section). Use antifibrinolytics and other ancillary measures as discussed in the management of patients with hemophilia A (see Medical Care).

Consultations

Hematologists, orthopedists, physical therapists, dentists, social workers, psychologists, infectious disease specialists, gastroenterologists/hepatologists, geneticists, and appropriately equipped special laboratories all play important roles in providing optimal care for patients and their families.

The efforts of the National Hemophilia Foundation and its regional chapters must be recognized in helping with educating patients and their families, facilitating home care programs and summer camps, improving financial support for health care through legislation, assisting service providers, and fostering dialogue among affected individuals to exchange discussions about problems and ideas for new solutions.

Diet

A healthy, nutritional, normal diet is encouraged in patients with hemophilia. Avoidance of unproven health remedies is necessary because several of these agents have been shown to potentiate bleeding. Caution is warranted when taking any natural supplement.

Activity

Activity restrictions depend on the condition of the joints; appropriate physical activity and physical therapy must be encouraged to maintain and preserve muscle function. Studies have shown that compared with age-matched controls, children with hemophilia have poorer muscle mass and function.

Medication Summary

Prompt and early therapy for acute bleeding episodes, with appropriate replacement with factor concentrate to achieve adequate levels of factor VIII (FVIII), immobilization of acutely affected joints, and adequate pain relief with narcotic analgesics is essential. A variety of intermediate and high-purity factor VIII-containing products are commercially available.

Increasing blood product purity (high specific activity) and improved protection from viral contaminants result in increased costs because of the different methodologies that are used to purify factor VIII that is obtained from pooled human plasma and because of the screening procedures in place for blood donors. Careful screening of potential donors and viral testing of donated blood (eg, hepatitis B surface antigen [HBsAg]; antibody to hepatitis B core antigen [HBcAg]; antibody to hepatitis C virus; antibodies to HIV-1 and HIV-2; HIV p24 antigen; antibodies to human T–cell lymphotrophic virus [HTLV] types I and II; screening for elevated alanine aminotransferase [ALT]) have improved the safety of blood products.

Nucleic acid testing for hepatitis B virus, hepatitis C virus, and HIV have also been implemented, which further improves safety; however, risks remain for a variety of reasons, including the failure to detect infections during the window or incubation period before currently available test results can be interpreted (ie, if they are positive). Additionally, blood banks have a system to notify recipients of blood products if donors of those units subsequently develop certain viral illnesses.

Unknown agents are of continuing concern, as are emerging viruses and infections caused by agents for which blood products are not tested or for which tests are not available.

Some of the emerging pathogens previously referred to include HIV-2, HIV type O, hepatitis G, TT virus, human herpesvirus 8, SEN family of viruses (SEN D and H are transmitted parenterally and can cause hepatitis), and prions that cause Creutzfeldt-Jacob disease (CJD) and variant CJD (vCJD).[55, 87, 88] Higher risks of virally transmitted illnesses remain among patients who receive multiple units of factor VIII concentrates of lower purity.

Factor VIII concentrates are produced by the purification of factor VIII from pooled human plasma and are contaminated with fibrinogen, fibronectin, and other plasma proteins. Viral safety in plasma-derived products has been ensured through several techniques such as heating, pasteurization, solvent-detergent treatment, and monoclonal antibody purification; these procedures free replacement products from HIV and hepatitis C virus (lipid envelope).

Unfortunately, earlier methods that were less effective led to the wide prevalence of hepatitis and AIDS in persons with hemophilia who were previously treated with the less pure blood products. However, this does not solve the problem of transmission of nonlipid envelope viruses, such as hepatitis A and parvovirus B19.

Highly pure recombinant products should be used to treat previously untreated patients first, then patients still free of HIV and hepatitis, and, finally, patients who are hepatitis-positive but HIV-free. A negative impact on lymphocyte immune response has been found after the use of both intermediate-purity and recombinant products, but highly pure products clearly do not prevent progression or improve median survival time of HIV-positive patients with hemophilia.

First-generation recombinant products are produced in mammalian cell lines and have a small amount of human serum albumin added for stability. Contamination of first-generation recombinant products with TT virus due to the use of human serum albumin has been reported.[55] Second-generation recombinant products that do not use human albumin have been found to be free of the TT virus. A sucrose-formulated rFVIII (rFVIII-SF) was shown to be hemostatically effective in 22 surgical procedures in patients with severe hemophilia, thus substantiating its efficacy.[89] This product does not use human plasma albumin as a stabilizer, thereby minimizing the possible risks of human plasma albumin–transmitted infections.

In addition, concern exists about the transmission of transmissible spongiform encephalopathies and vCJD due to prions. With the newer blood products, previously unknown pathogens, including new murine viruses, may contaminate the product.

Newer emerging technologies, such as those using nucleic acid chemistry, are being used to inactivate viruses, bacteria, and parasites in an attempt to also remove prions, thus making blood and blood components safer than they are at present. These newer technologies attempt to preserve clinically useful components of blood while improving their safety. These methodologies could potentially be used to improve the safety of a wide variety of blood products.

Available replacement products to correct factor VIII deficiency are discussed below; the table offers general guidelines for therapy. One unit of factor VIII has 100% activity and is present in 1 mL of (adult male) plasma. One unit of factor VIII per kilogram of body weight raises the plasma factor VIII level by approximately 2%. Another way to estimate the initial dose is to calculate the plasma volume, which is, for example, 70 kg X 50 = 3500 total mL plasma volume.

In order to raise the factor VIII activity of the patient in this example from 0% to 100%, the 70-kg patient needs 3500 units of factor VIII to be given as a bolus. This assumption presupposes that all the infused factor VIII will be recovered, which is not the case. With recombinant products, up to 30% less factor VIII recovery is expected, emphasizing the variability in recovery, depending on the type of product used and the individual. Therefore, serial monitoring of factor VIII levels, particularly trough levels, is essential in order to confirm adequacy of dosing at all times.

With bolus dosing, administer the second dose of replacement product 8 hours after the first, followed by a regimen of every 12 hours. The level of factor VIII needed for hemostasis varies from 30-100%, depending on the nature of the bleeding. Examples of major bleeding include CNS, retroperitoneal, retropharyngeal, GI, and, sometimes, recurrent target joint bleeding, all of which may also require prolonged factor replacement for days to weeks.

Because of the disadvantages of bolus dosing (ie, peaks and troughs) and the potential for cost and product savings with continuous infusion regimens that would give better steady-state levels, more studies are turning to this dosing approach.

In a study of known patients with factor VIII (14 patients) or with factor IX (3 patients) deficiency undergoing major surgery, patients were treated first with a bolus dose of 50 U/kg and then with 100 U/kg.[90] At the end of surgery, a continuous infusion of factor VIII was started at 3 U/kg/h, but for patients needing therapy for longer than 10 days, the dose was reduced to 1.5 U/kg/h for the remainder of the postoperative period.[90]

Concentrates were reconstituted twice daily using a 50-mL syringe pump. All patients were also treated with AMCA at a dose of 40 mg/kg to reduce or prevent hemorrhage. Factor VIII-C levels were monitored every 4 hours the first day, then at least every 12 hours for the next 5 days. This method was found safe and effective and is being suggested as a first-line therapy in patients with hemophilia who are undergoing surgical procedures.[90]

Spontaneous disappearance is a feature of autoantibodies to factor VIII that presumably occurs when the antigenic stimulus subsides, as in most patients with postpartum inhibitors. The choice of blood product to treat severe bleeding episodes in patients with factor VIII inhibitors depends on their baseline titer.[69, 91, 92, 93]

Factor VIII concentrate may be used to overcome a low-titer inhibitor (< 5 BU), but failure of that method or the presence of a high-titer inhibitor is approached with the use of any one of the following products based on availability (cost) and experience: rFVIIa (NovoSeven; Novo Nordisk A/S, Bagsvaerd, Denmark), or anti-inhibitor coagulant complex (activated prothrombin-complex concentrates) (Feiba VH; Baxter Healthcare Corporation, Westlake Village, Calif).

The activated prothrombin-complex concentrates have a poorly defined mode of action, an unpredictable hemostatic response, and are derived from pooled plasma. Therefore, they have a greater risk of transmitting viral illnesses, require frequent administration, are associated with a greater failure rate, and induce an anamnestic rise in antibody titers.

The replacement products cannot be used in patients who have had an allergic response, they induce a predictable DIC, and they can be associated with arteriovenous thrombosis, including myocardial infarctions. With very high-titer inhibitors, ancillary modalities, such as plasma exchange, Sepharose A, or immunoglobulin column to adsorb the antibody, and intravenous IgG can all be used to emergently remove the antibody and reduce its titer. The long-term strategy uses immunosuppressive drugs to suppress antibody production.

ITI regimens use daily factor VIII doses, varying from a low of 25 U/kg/d to a high of 100 U/kg twice a day, until the inhibitor titer is 1 BU/d, then 150 U/kg/d until the inhibitor disappears. ITI is time and product intensive, is expensive, requires a high degree of compliance, and requires daily venous access with catheters, which may become infected, thrombose, or be associated with bleeding.

Acute bleeding during the ITI regimen requires the use of additional replacement products, as mentioned above. A steroid-resistant nephrotic syndrome can develop in ITI patients because of protein overload; this condition requires prompt withdrawal of the product to prevent repeated antigen exposure. An intriguing idea has been raised as to whether immune tolerance could be induced via breast milk.[94]

A study in 100 children (25 previously untreated patients) from Egypt who were treated with low-purity replacement products (cryoprecipitate or low-purity FVIII) showed a low (10%) prevalence of inhibitors, with 20% of these inhibitors being transient (all < 5 BU/mL).[95] These authors ascribed the lower frequency of inhibitors in these patients to the use of low-purity products. In this study, low-dose ITI with a dose of 25 units of FVIII/kg on alternate days was given to patients with inhibitor titers below 40 BU/mL, with a higher dosage of 50 U/kg on alternate days given to patients with inhibitor titers above 40 BU/mL. Low-dose ITI appeared to be effective only in those patients with titers below 40 BU/mL.

Although porcine factor VIII (Hyate:C) production was discontinued in 2004, Hyate:C was used successfully for many years to treat many patients with life-threatening bleeding due to inhibitors. It was the first product that came to the patient's rescue after the activated prothrombin-complex concentrates.

In a study that attempted to evaluate the presence of porcine endogenous retrovirus, both gag and pol porcine endogenous retrovirus mRNA were detected in 100% of Hyate:C lots tested, and approximately 77% of lots of Hyate:C were also positive for retroviral particles, but none of the plasma samples obtained from 88 recipients of Hyate:C had positive test results, showing that despite the presence of porcine endogenous retrovirus particles in the product, the risk of transmission of this virus to recipients was very low.[96]

Another study reported the absence of antibodies to porcine parvovirus in the plasma of Hyate:C recipients, although porcine parvovirus DNA was detected in 21 of 22 lots of Hyate:C tested.[97] Despite lack of evidence for transmission of this virus to humans, the manufacturers added the process of screening all porcine plasmas by polymerase chain reaction (PCR) before use in producing Hyate:C, a move designed to eliminate the possible risk of transmission of this virus to humans. Hyate:C was used at home for ITI therapy.

Recombinant factor VIIa (rFVIIa) is another useful product in the armamentarium available to treat patients with factor VIII inhibitors. This product represents another significant development in the therapy of inhibitor patients, allowing them to undergo previously impossible major surgical procedures, such as joint replacements and pseudocyst resections.

Because of its high cost, rFVIIa was used previously in patients with hemophilia in which other therapy had failed, but as experience with its use grows, more patients are being treated with rFVIIa. The starting dose varies from 30-90 mcg/kg intravenously, with careful monitoring for a decompensated DIC and repeat dosing every 2-3 hours. Based on data obtained in several trials, excellent or effective response of bleeding in inhibitor patients was usually observed within 12 hours of starting therapy.[98, 99, 100, 101, 102, 103]

Results of data obtained from experience with compassionate use showed that effective hemostasis was obtained in approximately 92% of bleeding episodes in inhibitor patients after 1-3 doses of rFVII 90 mcg/kg, suggesting the utility of the higher dose in inhibitor patients. In some instances, an even higher dose of up to 120 mcg/kg has been needed, at the physician's discretion, to stop abdominal bleeding in patients with factor VIII deficiency or with factor VIII antibodies; in these patients, the mean duration of drug dosing in patients with a deficiency was 7.2 days, and it was longer, 11.3 days, in patients with an inhibitor and abdominal bleeding. Generally, one additional dose of rFVIIa is given beyond the time when adequate hemostasis has been achieved.

An intriguing finding was that over a 6-month period of therapy, a decline to one third the original titer of factor VIII or factor IX inhibitors was noted in high-responder inhibitor patients who received rFVIIa at home for repeated bleeding. Continuous infusion of rFVIIa in high-titer inhibitor patients undergoing hip replacement has been hemostatically successful. Because factor VIIa in concert with tissue factor, phospholipids, and calcium activates factor X to generate thrombin, fibrinogen levels were monitored in a prospective, randomized, double-blind trial and found to be similar to baseline values, with very few patients showing a reduction in fibrinogen levels.

Additionally, follow-up samples obtained in patients who had received several doses of rFVIIa showed no antibody levels to rFVIIa above the cut-off value, and no new antibodies were found to baby hamster kidney cell proteins or murine IgG. Despite all this experience, the optimal dosage regimen for all clinical situations in inhibitor patients still requires further study. In addition, rFVIIa has been used in patients with factor VIII or factor IX deficiencies in the absence of inhibitors, but according to the authors of a randomized, double-blind trial, rFVIIa is not the optimal drug for use in these patients, particularly because rFVIII or rFIX is available for use in these patients.[17, 104]

Interferon alpha therapy has been used in patients with chronic active hepatitis C, but the long-term benefits of such therapy remain in question. AIDS was the primary cause of death in persons with hemophilia from the mid 1970s to the early 1990s. Therapy for persons positive for HIV consists of the use of multidrug "cocktails," including protease inhibitors, which increase the risk of bleeding. A telephone support group for the patient and family has been suggested.[105]

A reasonable dosage calculation guide for factor VIII is provided by the following formula:

FVIII dose (U) = body weight (kg) X desired FVIII increase (%) X 0.5 U/kg

In practice, administration of concentrates must be individualized based on (1) an evaluation of the extent, site, and cause of bleeding; (2) response to therapy; (3) current laboratory data; and (4) the patient's history.

Table. General Guidelines for Management With FVIII Concentrates for Intermittent Bolus Dosing


View Table

See Table

Continuous infusion of factor VIII can be used for treating patients after joint replacements or CNS bleeding, in which a continuous, steady level is desired. This can be achieved by an initial bolus dose, as discussed, followed by a maintenance infusion of 150 U/h, with monitoring of levels for adequacy.

DDAVP in a dose of 0.3 mcg/kg intravenously can be given for several doses every 12 hours to raise perioperative factor VIII levels in patients with mild hemophilia for minor procedures, such as dental extractions and even uncomplicated cholecystectomies. Previous proof of adequate response to DDAVP is ideal for elective procedures. Tachyphylaxis will develop. DDAVP may be combined with Amicar to inhibit fibrinolysis.

The duration of therapy varies depending on the site, size, and severity of the bleeding episode. In orthopedic procedures, replacement may be needed for weeks until physical therapy has been completed.

Products available for FVIII replacement therapy in patients with hemophilia A

Products available to treat FVIII inhibitors

Advantages and disadvantages of products used to treat patients with FVIII inhibitors

Human factor VIII concentrates may be in very limited supply. The needs of a single inhibitor patient may exhaust all factor replacement products available at several hospitals in a city because of the large doses needed, even in low-titer inhibitor patients.

Porcine factor VIII is expensive. It is effective when insignificant or no cross-reactivity occurs between porcine factor VIII and the patient's inhibitor, with a cross-reactivity titer of below 10 BU (cross-reactivity in approximately 15%; only 2% had total cross-reactivity). Good venous access is required.

rFVIIa is the most expensive of the replacement products discussed. Monitoring for DIC is optimal. Drawbacks include possible thrombotic complications, the need for good venous access, and the frequency of the intravenous doses needed. rFVIIa is effective and has markedly increased viral safety when compared with human plasma–derived products; no viral illnesses are thought to be transmitted by this product. Hemostasis is usually localized to the site of injury, with no anamnestic rise in antibody titer. It has proven safety even with home therapy.

Activated prothrombin-complex concentrates have a poorly defined mode of action, an unpredictable hemostatic response, are derived from pooled plasma (thereby posing a high risk of transmission of virally induced illnesses), and require good access and frequent administration. They have a greater failure rate, induce an anamnestic rise in antibody titer, and cannot be used at home.

ITI regimens can be associated with a nephrotic syndrome, which would require discontinuation of the product.

Use of PLAS+ SD as a source of FV

Patients with a combined deficiency of factor V and factor VIII require FFP as a source of factor V, because available factor concentrates do not supply factor V. Patients who receive multiple units of FFP have a higher risk of transfusion-transmitted viral illnesses. The use of solvent (tri{n-butyl phosphate} [TNBP]) and detergent (Triton X-100; Rohm & Haas Co, Philadelphia, Penn) to treat pooled human plasma (PLAS+ SD) results in significant inactivation of lipid-enveloped viruses (eg, HIV, hepatitis B and C). The greater degree of viral safety ensured by this treatment has led to the exclusive use of PLAS+ SD instead of FFP in some countries (Norway and Belgium).

In addition, PLAS+ SD delivers consistent and reproducible levels of coagulation factors, in contrast to the extreme variability in levels after use of FFP. Moreover, unlike in FFP, PLAS+ SD has no leukocytes, most of the physiologic inhibitors are in the normal range, coagulation zymogens are not activated, levels of other plasma proteins and immunoglobulins are normal, all lots have anti–hepatitis A virus antibody levels of ≥0.8 IU/mL (providing passive administration of antibody, which may neutralize hepatitis A virus), the largest von Willebrand multimers are absent, and efficacy in a variety of bleeding disorders has been proven.

Assays of several lots of PLAS+ SD showed that factor V activity was at 1.06 ± 0.02 IU/mL without any loss of factor V activity after solvent-detergent treatment. Importantly, factor V activity was fully preserved after 18 months of storage at –18°C. A mean factor V recovery of 169 ± 71% was obtained in 7 patients who had received PLAS+ SD in serial plasma exchanges, with an approximately 33% rise in factor V levels post exchange. Five patients with congenital factor V deficiency and active bleeding were successfully treated with this product. Following an infusion dose of 15 mL/kg, the average rise in factor V is 0.13 U/mL and the average recovery is 72% in deficient patients, with a linear increase at doses of 15-20 mL/kg.

All PLAS+ SD units should be ABO-compatible with each patient's red blood cells.[106] One of its few disadvantages is a minor allergic reaction; however, this reaction is observed with all blood products and it responds to antihistamines. Another adverse effect of PLAS+ SD may be volume overload in cardiovascularly compromised patients. Rarely, citrate toxicity, hypothermia, or other metabolic problems arise if large volumes are used, and patients may develop noncardiogenic pulmonary edema. Antibody-induced positive direct antiglobulin test (DAT) results and hemolysis may also occur rarely. This product should not be given to patients with known IgA deficiency. (For further details see the drug tables below, under the specific drugs.)

Antifibrinolytic agents

Antifibrinolytic agents are used as ancillary agents to control and reduce bleeding.

The recognition of the importance of the lysine-binding sites in various interactions in the fibrinolytic pathway led to the synthesis of lysine analogues such as EACA (6-aminohexanoic acid, Amicar) and trans-p -amiomethyl-cyclohexane carboxylic acid (AMCA, Cyklokapron). These synthetic lysine analogues induce a conformational change in plasminogen when they bind to its lysine-binding site. In the absence of EACA, plasminogen has the shape of a prolate ellipsoid; after EACA binds to plasminogen, it elongates into a long structure in which the interaction between the parts of plasminogen as they existed are lost.

In vivo, the lysine analogues probably prevent plasminogen activation and, in large doses, also bind plasmin, thereby preventing it from binding to its substrate, fibrin. When one looks at binding sites on plasminogen for EACA, the tightest binding is to kringle 1, followed by kringles 4 and 5. The interaction with kringle 2 is weak, and kringle 3 does not interact at all. A model of the structure of kringle 4 shows that the shallow trough formed by the hydrophobic amino acids is surrounded by positively and negatively charged amino acids at an ideal distance to interact with EACA.[107, 108, 109]

EACA is the most widely used antifibrinolytic drug in the United States. The minimal dose needed to inhibit either normal or excessive fibrinolysis is unknown. EACA is absorbed well orally, and 50% is excreted in the urine in 24 hours. Generally, an initial loading dose is followed by a maintenance dose to adequately inhibit fibrinolysis until excessive bleeding is controlled. The maintenance dose is then gradually tapered until it can be stopped. Rarely, myopathy and muscle necrosis may develop. Lower doses of EACA are adequate when bleeding involves the urinary tract because drug concentrations are 75- to 100-fold higher in urine than in plasma.

AMCA is also excreted rapidly in the urine, with more than 90% excreted in 24 hours. However, its antifibrinolytic effect lasts longer than that of EACA; AMCA inhibits fibrinolysis at lower plasma concentrations, although its serum half-life is similar to that of EACA. Therefore, AMCA can be given less frequently and at lower doses.

The doses of both EACA and AMCA must be reduced in patients with renal failure. See the package insert of each replacement product for the full details.

Aprotinin (Trasylol; Bayer), an antifibrinolytic drug obtained from bovine lung, is a nonhuman protein inhibitor of several serine proteases, including plasmin. It was approved by the US Food and Drug Administration (FDA) to reduce operative blood loss in patients undergoing open heart surgery. Aprotinin has also reduced blood loss and transfusion requirements in patients undergoing orthotopic liver transplantation or in patients undergoing elective resection of a solitary liver metastasis originating from a colon cancer. Aprotinin is the most expensive of the drugs discussed below, and it is now only available via a limited-access protocol.

Fergusson et al reported an increased risk for death compared with tranexamic acid or aminocaproic acid in high-risk cardiac surgery.[110] For more information, see the article from Medscape.

Blacks appear to have unique haplotypes and are twice as likely as white patients to produce inhibitors against factor VIII proteins given as replacement therapy.[54]

Factor VIII, human plasma derived (Humate-P, Alphanate, Koate-DVI, Hemofil)

Clinical Context:  Protein found in normal plasma necessary for clot formation. Can temporarily correct coagulation defect of patients with hemophilia A, in which there is deficiency of FVIII-C. Specific activity and calculated vs actual recoveries vary with each product and patient. Actual dose depends on patient's weight, severity of hemorrhage, severity of deficiency, actual recovery, presence of inhibitors, and desired level of FVIII. Control of bleeding and the FVIII level achieved in the patient are the most important determinants of dosage and duration of therapy. When inhibitors are present, dosage requirements are extremely variable and determined by clinical response and FVIII activity achieved in vivo. The need for larger amounts of antihemophilic factor than previously needed to achieve adequate hemostasis in a person known to have hemophilia may be the first clue to the presence of an inhibitor.

Pooled plasma, solvent-detergent treated (PLAS+ SD)

Clinical Context:  Pooled plasma is treated using a procedure developed by the American Red Cross and Vitex Technologies (see details under Medical Care). Solvent-detergent (SD) treatment of pooled human plasma disrupts and kills lipid-enveloped viruses (eg, HIV, hepatitis B and C). SD treatment is followed by ultrafiltration and sterile filtration; however, these treatments do not remove all viruses from plasma, nor is the method capable of totally eliminating viral infectivity from plasma-derived products. However, such treatments improve safety compared with standard FFP. Efficacy and safety have been proven in the treatment of several coagulopathies.

Per the package insert (from American Red Cross), the half-life of coagulation factors in recipients of this product is similar to reference range values at the time they were measured. SD-treated plasma, if available, can be used in patients with combined FV and FVIII deficiencies as a source of FV because no concentrate is available to treat FV deficiency.

As with any bleeding disorder, serial measurement of the specific coagulation factor in question is essential to ensure consistent hemostatic adequacy of the levels of the deficient factors. On average, 1 U of SD plasma raises factor levels by approximately 2-3%, whereas 4-6 U raises factor levels by approximately 8-18% in a 70-kg person. These numbers do not specifically apply to FV and are provided only as a general guide.

PLAS+ SD contains not less than 0.7 U/mL of FV, and serial monitoring of FV levels is necessary. PLAS+ SD should be stored at -18°C or colder and thawed at 30-37°C in a water bath with very gentle shaking; once thawed, keep at room temperature and use as soon as possible, preferably within 24 h. Thawed material should not be stored in the cold.

Antihemophilic Factor recombinant

Clinical Context:  Recombinant FVIII containing human serum albumin. Can temporarily correct the coagulation defect of patients with classic hemophilia (hemophilia A) who have a deficiency of the plasma clotting factor FVIII. Provides a means of temporarily replacing the missing clotting factor to correct or prevent bleeding episodes or to provide perioperative hemostasis.

The dose depends on patient's weight, disease severity, and duration of hemorrhage; the severity of the baseline deficiency; the presence of inhibitors; and the target FVIII level to be maintained. A positive clinical effect with cessation or prevention of bleeding in the patient is the most important determinant of the dose and duration of therapy.

When inhibitors develop or are present, the dosage requirements are extremely variable and should be determined by clinical response (larger amounts of antihemophilic FVIII may be necessary to achieve the desired results). Cannot be used to correct the deficiency in persons with von Willebrand disease.

Antihemophilic Factor recombinant (ReFacto)

Clinical Context:  Recombinant FVIII with albumin-free final formulation. Intended for promoting hemostasis by replacing FVIII activity. Used for the treatment and prevention of hemorrhagic episodes in patients with hemophilia A (congenital FVIII deficiency or classic hemophilia). ReFacto does not contain vWF.

Antihemophilic factor, porcine

Clinical Context:  Can temporarily correct the coagulation defect of patients with FVIII inhibitors. The dose depends on the patient's weight, the severity of the hemorrhage, the inhibitor's titers, and the response of the bleeding to the therapy.

The clinical effect is the most important determinant of the therapy. When inhibitors are present, the dosage requirements may vary considerably, even in the same patient. Increasing doses of porcine FVIII may sometimes be necessary.

Factor VIIa, recombinant (Novo Seven)

Clinical Context:  FVIIa activates hemostasis by combining with tissue factor and is able to achieve hemostasis by generating thrombin by directly activating FX and bypassing the need for FVIII or FIX, thus being useful even in patients with inhibitors to FVIII or FIX.

The dose depends on the inhibitor titer, patient's weight, severity of hemorrhage, and response to the therapy; see extensive discussions above. The clinical effect is most important determinant of therapy. When treating bleeding in patients with inhibitors, the dosage requirements may be extremely variable and should be guided by the clinical response.

Anti-inhibitor coagulant complex (Feiba VH Immuno)

Clinical Context:  Use in patients with FVIII inhibitors. Can temporarily correct the coagulation defect of patients with inhibitors to FVIII; generally used in patients with inhibitor titers of ≥ 5 BU/mL. The dose depends on the patient's weight, severity of hemorrhage, titer of inhibitor, and in vivo effect. The clinical effect on bleeding is the most important determinant of the dose and frequency of therapy. When inhibitors are present, the dosage requirements are extremely variable and determined by the clinical response.

Class Summary

Antihemophilic agents are used for factor VIII (FVIII) replacement therapy in patients with hemophilia A (classic hemophilia). Advantages and disadvantages of several blood products available to treat patients with factor VIII inhibitors are discussed above (see the Medication section). For all the products listed below, the physician is encouraged to read the FDA-approved package inserts for further details. Appropriate monitoring is needed to manage active bleeding and to monitor and manage any allergic reactions that may develop during infusion of foreign proteins.

Aminocaproic acid (Amicar, EACA)

Clinical Context:  Hemostatic agent that diminishes bleeding by inhibiting the fibrinolysis of the hemostatic plug. Can be used PO/IV.

Tranexamic acid (Cyklokapron)

Clinical Context:  Fibrinolytic inhibitor used with FIX replacement to reduce the need for hospitalization and more than one dose of FIX concentrate in patients with hemophilia B who require dental or sinus procedures. Can be used similarly in patients with hemophilia A. Also used to inhibit fibrinolysis in other conditions.

Aprotinin injection (Trasylol)

Clinical Context:  5/14/08: Only available via limited-access protocol.

Broad-spectrum protease inhibitor, which modulates the systemic inflammatory response associated with bypass surgery and results in the attenuation of the inflammatory response and thrombin generation and fibrinolytic response.

In platelets, reduces glycoprotein loss, whereas in granulocytes, prevents the expression of proinflammatory adhesive glycoproteins. Thus, not a pure inhibitor of fibrinolysis. Is a nonhuman protein obtained from bovine lung, with a potential for sensitization and allergic reactions, especially with repeated administration. Reactions range from rashes to anaphylaxis and death. Risk of sensitization with repeated exposure is 5%. Premedication with 50 mg diphenhydramine and 300 mg cimetidine IV with 650 mg acetaminophen PO is given 30 min before a small test dose, followed by a 30-min infusion of the regular dose to avoid hypotension.

Injectable drug that has been successfully used to reduce bleeding in patients undergoing cardiopulmonary bypass, which is its FDA-approved indication. Two different dosage regimens (A & B) have been shown to reduce bleeding in patients undergoing repeat CABG surgery who participated in a randomized clinical trial. Comparisons were made against placebo and another arm in which the drug was only given into the priming fluid. Interestingly, 1100 patients >65 y had outcomes no different than those seen in younger adults.

Class Summary

Antifibrinolytic agents are used together with single dose of factor replacement and given before minor surgical procedures (eg, dental extractions, sinus surgery) so that they can be administered in an outpatient setting with the use of a single dose of product. Concern about the possible causal relationship of these drugs with acute thrombotic events remains, although a causal relationship with thrombotic complications has been questioned, because the underlying disease state and genetic risk factors usually determine the site and extent of thrombosis. See the general discussion on these agents, preceding the discussion of specific drugs.

When antifibrinolytics are used in patients with upper urinary tract bleeding together with factor replacement therapy, the formation of a firm, unlysable clot in the urinary tract may result in acute urinary obstruction within a few hours.

Further Inpatient Care

Patients with factor VIII (FVIII) deficiency (hemophilia A) should be hospitalized for serious complications, for severe bleeding, and for major surgical procedures, all of which require complex interdisciplinary care including timely pharmacy and laboratory support. Constant close clinical evaluation and laboratory monitoring ensure adequacy of factor product replacement, pain relief, testing, and other supportive care. The hematologist must be centrally involved in this management to coordinate all care.

Further Outpatient Care

Outpatient and home care treatment are extremely important parts of patient management. Patients require adequate factor replacement product and ancillary supplies at home for product infusion, whether it is on-demand home care or prophylactic transfusions. Outpatient care in the clinic is provided for patients who require closer supervision because of events such as allergic reactions and the inability to self-infuse factor replacement product.

Inpatient & Outpatient Medications

Availability of a continuous supply of factor VIII concentrate and the supplies necessary for self-infusion is important. Patients should avoid acetylsalicylic acid (aspirin), NSAIDs, and any over-the-counter herbal medications that can precipitate bleeding.

Transfer

If a qualified hematologist and laboratory support are available, most patients with hemophilia can be cared for in a setting close to home. Laboratory support in community hospitals has improved because of the support provided by commercial referral laboratories (which are also being used by tertiary medical centers). Federal and state funding for programs may be available through the center. The costs of care are much higher at medical centers that are associated with universities.

Deterrence/Prevention

Hepatitis A and B vaccination is appropriate for all nonimmune patients.

Avoiding high-risk activities (eg, boxing, motorbike riding) and NSAIDs reduces the frequency of bleeding. Avoiding alcohol intake helps protect liver function in patients with hepatitis.

Use of barrier contraception is important to protect sexual partners of HIV-positive patients.

Complications

Factor VIII (FVIII) inhibitors in patients with hemophilia A (alloantibodies)

Approximately 20% of individuals with severe hemophilia develop inhibitors to factor VIII-C, with an overall prevalence rate of 5-10% in all persons with hemophilia; 95% of inhibitors develop in patients with factor VIII-C levels less than 5%. The development of an inhibitor is a serious complication, adding to morbidity and mortality. Inhibitor development depends on the specific genetic defect, the type of factor VIII replacement product used, and the patient's immune system.

It has been suggested that persons with severe hemophilia who were exposed to and had an induction of immune tolerance to factor VIII in utero by exposure to maternal factor VIII as a consequence of maternal-fetal hemorrhage were less likely to develop inhibitors following replacement therapy. Genetic mutations associated with inhibitor development are discussed under Causes.

Approximately 70-75% of patients with large deletions or non-sense mutations involving the A3 domain developed inhibitors, whereas non-sense mutations in the C1 or C2 domain were associated with inhibitors in approximately 25% of patients. Non-sense mutations in the heavy chain are associated with a low frequency of inhibitor formation (~8%). Patients with gross deletions (>2 kb) have 5 times the incidence of inhibitors compared with patients without deletions, based on Southern blot analysis.[112]

Use of rFVIII has been associated with a rate of inhibitor development of up to 29%, with a median of 10 days of exposure to the recombinant product before the development of an inhibitor. However, one third of these were low-titer transient inhibitors, and these patients remained responsive to factor VIII replacement therapy. Inhibitors developing in patients with mild hemophilia follow this pattern, and when replacement product is withheld, the inhibitor tends to disappear spontaneously in 1-3 months and may not reappear with subsequent reexposure to factor replacement product. A study suggested that the A2 domain and light chain of factor VIII confer greater immunogenicity toward the development of an inhibitor.[113]

Patients with low-titer inhibitors (3-5 BU) may be further classified as low responders (25%) or high responders (75%), based on the lack of or a rise in their inhibitor titer following reexposure to replacement products containing factor VIII. The former may disappear, but the latter may persist for years once they are formed, even in the absence of reexposure to factor VIII. Inhibitors appear to be more common in black and Hispanic individuals.

A rather unique factor VIII alloantibody developed in 2 unrelated individuals with mild hemophilia who had a mutation in the C1 domain of factor VIII; both patients had significant residual factor VIII activity in their plasma coexisting with anti-FVIII antibodies. One inhibitor was examined in detail and showed the ability to neutralize wild-type but not self-factor VIII and behaved like a type II inhibitor. It was able to differentiate between the mutated factor VIII that the patient had and the wild-type factor VIII because of its epitope specificity.[114]

Thus, patients whose bodies see infused, external normal factor VIII as a novel antigen or as an altered antigen because they have been acclimated only to their own, internal, immunologically altered protein (and not to the normal wild-type protein) are the ones likely to develop an inhibitor.

Acquired spontaneously developing factor VIII inhibitors (autoantibodies)

As the population ages, a rising frequency of factor VIII inhibitors is expected.

Autoimmune diseases (eg, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease), drug reactions (eg, penicillin, interferon alpha), pregnancy or the postpartum state, solid tumors, lymphoproliferative disorders, infections, skin diseases (eg, erythema multiforme, dermatitis herpetiformis), and graft versus host disease have all been associated with acquired factor VIII inhibitors. Approximately 50% of cases may not have an obvious cause.

The hypothesis that maternal sensitization to fetal factor VIII antigen during pregnancy is the cause of pregnancy-related autoantibody production has yet to be substantiated.

Characteristics of factor VIII inhibitors

Patients with severe hemophilia A have a high rate of inhibitor development (~35%), and these persons usually also have low or undetectable antigen levels. The single amino acid mutations R593C and W2229C are also associated with a high incidence of inhibitors (~40%).

Hemophilic or acquired factor VIII antibodies primarily destroy factor VIII-C activity. These antibodies usually consist of a mixture of heavy-chain subclasses of IgG4 and IgG1 with kappa or lambda light-chain specificity; the IgG4 subclass normally represents less than 5% of plasma IgG; thus, it shows a particular predilection of the inhibitor for this heavy-chain class. They tend to be species-specific in vitro and in vivo, which is why porcine factor VIII had been used successfully to control bleeding in patients with factor VIII inhibitors.

In in vitro studies, hemophilic inhibitors (alloantibodies) show a linear relationship between antibody concentration and the amount of factor VIII-C neutralized, with a time requirement of up to 2 hours for a low-concentration inhibitor. Initially, the neutralization is rapid, followed by a slow second phase. This is the classic hemophilic type I antibody.

The in vivo characteristics of acquired inhibitors (autoantibodies) are different; no linear relationship exists between inhibitor concentration and factor VIII-C neutralized, they do not totally inactivate factor VIII-C in the test tube, and clinical bleeding may be evident, showing a lack of in vivo factor VIII-C activity, even when a reasonable amount of plasma factor VIII-C activity is detected in in vitro tests. This is the type II antibody.[115]

The structural domains (previously discussed) of the antigenic regions of factor VIII are A1-A2-B-A3-C1-C2; the heavy chain has A1-AR1-A2-AR2-B, whereas the light chain has the AR3-A3-C1-C2 domains. Factor VIIIa has A1, A2, and A3-C1-C2 subunits, without domain B. Two thirds of the antibodies to factor VIII bind the A2 and C2 regions, and half of them bind the AR3 region.

Neutralizing antibodies usually detect A2, C2, and AR3-A3-C1 epitopes. Approximately two thirds of autoantibodies are directed against a single epitope, whereas only one fifth of hemophilic antibodies are against a single epitope. Anti-A2, anti-AR3-A3-C1, and anti-A2 plus anti-C2 antibodies are found more often in hemophilic patients with inhibitors. Antibodies directed against other epitopes lead to a shorter half-life of the protein without inducing a loss of factor VIII-C activity. In a given patient, the type(s) of inhibitors may change over time.

Nonneutralizing antibodies may play a role in the development of immune tolerance. An analysis of the IgG obtained by affinity chromatography on FVIII-Sepharose columns from the IgG fractions of persons with hemophilia who do not have inhibitors and from those whose inhibitor titers did not rise in response to factor VIII infusion (nonresponder inhibitor patients) had similar properties, such as recognition of light-chain epitopes similar to known factor VIII inhibitors, suggesting that factor VIII inhibitors arise from expansion of preexisting natural anti-FVIII clones. Thus, the body appears to have natural antibodies to factor VIII, as it does to other soluble proteins.[116]

It has been suggested that normal immune homeostasis can "be viewed as a network of interacting molecules, idiotypes, and anti-idiotypes: disruption of this equilibrium leads to the development of autoimmunity."[117] Other authors suggest the presence of another source of inhibitor production, one that is due to B-cell clones that have "undergone affinity maturation and hypermutation of the V regions of the antibodies they produce."[118] The possibility has been raised that this immune interaction could be modulated by passive infusion of anti-idiotypic antibodies or by active immunization with idiotypes.

Anti-C2 antibodies destroy factor VIII-C activity, primarily by blocking its interaction with phospholipids. They inhibit factor VIIIa function in the intrinsic tenase complex and, less often, interfere with thrombin-induced release of factor VIII-C from its von Willebrand factor-bound, protected state. Prevention of binding to phospholipid surfaces abolishes the procoagulant activity of factor VIII, whereas prevention of binding of factor VIII to von Willebrand factor by antibodies to factor VIII results in a markedly shortened half-life of factor VIII.

A paper demonstrating the crystal structure of the factor VIII C2 domain clarified the mechanism of action of inhibitors directed against the C2 domain and raised the possibility of producing new, recombinantly altered factor VIII specifically to reduce its immunogenicity while preserving its anticoagulant function.[119]

Circulating factor VIII immune complexes have been detected in patients with autoantibodies (type II) binding to a specific region on the light chain (not to the C2 domain) and which were protected from antigen presenting cell–mediated proteolysis, suggesting another reason for preservation of some factor VIII activity. Antibodies against the A2 domain allow factor VIII to complex with factor IXa but block activation of factor X. Alloantibodies and autoantibodies appear to be directed against similar epitopes, although they arise under different clinical circumstances.

Transient factor VIII antibodies following infection have been reported after staphylococcal sepsis[120] and a clinically significant low-titer factor VIII antibody has been reported with Lyme disease. Two patients reportedly developed anti-FVIII antibodies following injection of depot thioxanthenes, zuclopenthixol, and flupenthixol.[121] Allergic or anaphylactic reactions to other drugs such as penicillin have been followed by inhibitor development.

Patients with combined factor V and factor VIII deficiency may develop autoantibodies or alloantibodies to factor V. Multiple autoantibodies found in patients exposed to bovine thrombin can be directed against factor V due to contamination of bovine thrombin with bovine factor V. Following exposure to factor replacement product, independent alloantibodies to factor V and factor VIII could arise in a patient who has inherited 2 separate mutations to account for factor V and factor VIII deficiencies.[16, 52, 91, 122]

Therapy with rituximab may be considered for those with congenital hemophilia, high-titer neutralizing inhibitors to factor VIII, and a severe clinical course in whom standard immune tolerance induction has failed.[123] Rituximab was successfully used in a patient with juvenile systemic lupus erythematosus and acquired von Willebrand syndrome.[124]

Other complications

With chronic, severe joint deformities and arthritis, NSAID use may lead to an increase in bleeding in patients with hemophilia (see images below).


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Photograph of the right knee in an older man with a chronically fused, extended knee following open drainage of knee bleeding that occurred many years....


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Photograph depicting severe bilateral hemophilic arthropathy and muscle wasting. The 3 punctures made into the left knee joint were performed in an at....


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Radiograph depicting advanced hemophilic arthropathy of the knee joint. These images show chronic severe arthritis, fusion, loss of cartilage, and joi....


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Radiograph depicting advanced hemophilic arthropathy of the elbow. This image shows chronic severe arthritis, fusion, loss of cartilage, and joint spa....

HIV-positive persons with hemophilia who use protease inhibitors have an increased risk of bleeding.

A higher frequency of bleeding risk has been noticed by patients who use St. John's Wort (over-the-counter herbal medicine). Other natural factor replacement products may contribute to excessive bleeding.

Intermediate-purity factor replacement products may contribute to immunosuppression more than high-purity products.[125, 126]

Allergic reactions to older, less pure coagulation factor concentrates can occur as a result of sensitization to foreign proteins. These reactions include skin rash, fever, headache, and, sometimes, anaphylaxis. Allergic reactions may develop in association with any factor replacement product.

Antibody development leads to failure of usually effective therapy to control bleeding, increases morbidity and mortality, and makes even minor surgery difficult.

An anamnestic rise in antibody titers can occur following transfusion of replacement products containing factor VIII to patients who already have an inhibitor.

Gene therapy may be associated with an increased prevalence of inhibitors.

Acute decompensated DIC, myocardial infarction, or stroke can occur with the use of prothrombin complex concentrates or of rFVIIa products used to treat bleeding in patients with inhibitors.

Viruses, including hepatitis A, hepatitis C, TT, and parvovirus B19, can be transmitted parenterally, depending on the factor replacement product transfused.

Hepatitis due to viruses A-E, the new hepatitis G virus, non-A non-B hepatitis, cirrhosis, hepatic failure, and hepatocellular carcinoma develop in persons with hemophilia who receive transfusions with older, less pure replacement products.

The newly discovered SEN family of viruses is important because of their potential adverse impact in a patient co-infected with other hepatitis viruses; SEN D and H are transmitted parenterally and contribute to posttransfusion hepatitis.[88, 111]

TT virus, considered a hepatitislike pathogen, has been found in first-generation recombinant products because of the presence of TT virus in the human serum albumin used in the manufacturing process.[55] Second-generation recombinant products, free of human serum albumin, do not contain TT virus.

In addition to HIV-1, emerging viruses in this class include HIV-2 and HIV group O viruses when blood or blood-derived products are used.

Human herpesvirus 8 is another emerging pathogen.

Transmission of other, currently unknown, viruses or other pathogens is possible.

Nephrotic syndrome, especially in inhibitor patients undergoing long-term factor replacement for ITI, may lead to renal dysfunction.

Anemia, leukopenia, and thrombocytopenia could occur secondary to chronic liver disease, bone marrow suppression by viruses, or they may occur as unintended adverse effects of antiretroviral medications.

The potential transmission of prions causing CJD or new vCJD is being closely monitored. As yet, no hemophilic person or other blood product recipient is known to have developed CJD.[129]

Psychosocial impact, including addiction to narcotic analgesics, alcohol, and other substances of abuse, leads to unstable personal and work relationships.

Lack of availability of appropriate jobs; an inability to maintain a job due to recurrent illnesses; the need for repeated job absences; and the need for repeated, expensive medical care all lead to the likelihood of an inability of individuals with hemophilia to adequately support themselves economically.

Severe arthropathy develops from repeated bleeding of a target joint, with limitation of joint movement and ambulation. Muscle bleeding adds to these problems, and pseudocysts can lead to amputation.

Chronic progressive hepatitis leads to hepatic failure and may be associated with hepatocellular carcinoma if the patient survives long enough. Hepatitis can be caused by hepatitis viruses A-E and G and the SEN family of viruses A-H; SEN D and SEN H are transmitted parenterally and cause posttransfusion hepatitis.[88, 111]

HIV seroconversion and progression to AIDS are serious problems in 30-90% of patients with hemophilia who were treated with older factor replacement products; this occurred before the recognition and understanding of the role of the HIV virus and its consequences. Based on a retrospective analysis of stored hemophilic plasmas, seroconversion apparently started in 1978, with 70% of patients progressing to clinical AIDS over 11 years. The first individual with hemophilia who also had AIDS was reported from the United States in 1983.

Five percent of sexual partners are HIV positive; other household members usually remain negative. Hemophilic patients with AIDS do not develop Kaposi sarcoma, unlike AIDS patients without hemophilia who are prone to Kaposi sarcoma. Emerging pathogens include HIV 2 and HIV group O.[87]

Allergic reactions to factor replacement products, the development of inhibitors, CNS bleeding, and other infections all can lead to death. The development of inhibitors adds further complexity.

Cryoprecipitate, which can be used as a backup for emergencies, not only has factor VIII-C, but it also has von Willebrand factor, fibrinogen, and other proteins.

A study of the causes of death over a 15-year period in Scotland showed that life expectancy among patients with hemophilia increased despite the widespread prevalence of morbidity related to HIV and hepatitis C infection acquired from old plasma-derived factor replacement product that caused an increase in the use of hospital beds and a fluctuation in the need for hospitalization for bleeding.

Parvovirus B19 and TT virus are 2 nonlipid-enveloped viruses that can be transmitted by coagulation factor concentrates. TT virus has been shown to contaminate first-generation rFVIII and factor IX concentrates as a result of the use of human albumin that had been contaminated with TT virus.[55] Second-generation recombinant products that do not use human albumin have been free of TT virus.

A study of 39 children with hemophilia A and B in South Africa showed that in children exposed to locally produced factor replacement products, there was a risk of transmission of parvovirus B19, but not TTV, when compared with controls. Other emerging viruses include human herpes virus 8.[87]

A review of concerns over classic CJD or vCJD indicated that the FDA's Transmissible Spongiform Encephalopathies Advisory Committee proposal to limit the pool of blood donors and to exclude donors who, since 1980, have traveled in Europe for longer than 5 years or who have spent a total of 3 months or more in the United Kingdom reduces the risk of vCJD contamination of blood supplies. Newer blood tests for the detection of vCJD are expected in the near future.[87, 129]

Pseudocysts develop as a result of recurrent slow bleeding and lead to extensive destruction of bone (see images below).


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Large pseudocyst involving the left proximal femur.


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Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional....


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Dissection of a pseudocyst.


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Transected pseudocyst with chocolate brown-black old blood.

Prognosis

The prognosis of individuals with factor VIII deficiency (hemophilia A) depends on the type of complications a patient develops; it also depends on the type of factor product replacement the patient receives and the viral infections the patient accumulates over the years.

Newly diagnosed patients must receive recombinant products that ensure maximum safety.

Primary prophylaxis may be the best way to preserve joint function. Joint replacement is likely in the older patients with severe arthropathy. Patients with inhibitors are now able to undergo orthopedic procedures.

Early and complete genetic testing may help patients prepare for possible inhibitor development.

Blockade of T-cell activation may reduce the anamnestic rise in inhibitor titers.

Gene therapy is still in its infancy, but it is the best long-term solution. See Medical Care for details.

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

Elzbieta Klujszo, MD, Head of Department of Dermatology, Wojewodzki Szpital Zespolony, Kielce

Disclosure: Nothing to disclose.

Pere Gascon, MD, PhD, Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain

Disclosure: Nothing to disclose.

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Disclosure: Nothing to disclose.

Specialty Editors

Charles S Greenberg, MD, Director of Thrombosis and Transglutaminase Research Laboratory, Professor, Departments of Pathology and Medicine, Division of Hematology/Oncology, Duke University Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Ronald A Sacher, MB, BCh, MD, FRCPC, Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine

Disclosure: Renal Ventures Ownership interest Other

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Additional Contributors

The author gratefully acknowledges the provision of several photographs used in this article and in Factor IX by a dedicated colleague from Chicago, Margaret Telfer, MD. The author would also like to acknowledge Professor K.N. Subramanian (Department of Molecular Genetics, University of Illinois Medical Center) for general discussions relating to some aspects of the gene structure and mutation of the FVIII gene.

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  81. Coukos G, Rubin SC. Gene therapy for ovarian cancer. Oncology (Williston Park). Sep 2001;15(9):1197-204, 1207; discussion 1207-8. [View Abstract]
  82. Gura T. Hemophilia. After a setback, gene therapy progresses...gingerly. Science. Mar 2 2001;291(5509):1692-7. [View Abstract]
  83. Dunbar C. Lentiviruses get specific. Blood. Jan 15 2002;99(2):397.
  84. Aznar JA, Magallón M, Querol F, Gorina E, Tusell JM. The orthopaedic status of severe haemophiliacs in Spain. Haemophilia. May 2000;6(3):170-6. [View Abstract]
  85. Zanon E, Martinelli F, Bacci C, Zerbinati P, Girolami A. Proposal of a standard approach to dental extraction in haemophilia patients. A case-control study with good results. Haemophilia. Sep 2000;6(5):533-6. [View Abstract]
  86. Dickneite G, Metzner H, Nicolay U. Prevention of suture hole bleeding using fibrin sealant: benefits of factor XIII. J Surg Res. Oct 2000;93(2):201-5. [View Abstract]
  87. MediView Express. Recombinant therapy enhances safety and quality of life for hemophilia patients. Presented at: 53rd Annual Meeting of the National Hemophilia Foundation; November 16, 2001; Nashville, Tenn.
  88. Rigas B, Hasan I, Rehman R, et al. Effect on treatment outcome of coinfection with SEN viruses in patients with hepatitis C. Lancet. Dec 8 2001;358(9297):1961-2. [View Abstract]
  89. Scharrer I, Brackmann HH, Sultan Y, et al. Efficacy of a sucrose-formulated recombinant factor VIII used for 22 surgical procedures in patients with severe haemophilia A. Haemophilia. Nov 2000;6(6):614-8. [View Abstract]
  90. Tagariello G, Davoli PG, Gajo GB, et al. Safety and efficacy of high-purity concentrates in haemophiliac patients undergoing surgery by continuous infusion. Haemophilia. Nov 1999;5(6):426-30. [View Abstract]
  91. Hay CR, Baglin TP, Collins PW, Hill FG, Keeling DM. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the UK Haemophilia Centre Doctors' Organization (UKHCDO). Br J Haematol. Oct 2000;111(1):78-90. [View Abstract]
  92. Lusher JM. Inhibitor antibodies to factor VIII and factor IX: management. Semin Thromb Hemost. 2000;26(2):179-88. [View Abstract]
  93. Penner JA. Haemophilic patients with inhibitors to factor VIII or IX: variables affecting treatment response. Haemophilia. Jan 2001;7(1):103-8. [View Abstract]
  94. Yee TT, Lee CA. Oral immune tolerance induction to factor VIII via breast milk, a possibility?. Haemophilia. Sep 2000;6(5):591. [View Abstract]
  95. El Alfy MS, Tantawy AA, Ahmed MH, Abdin IA. Frequency of inhibitor development in severe haemophilia A children treated with cryoprecipitate and low-dose immune tolerance induction. Haemophilia. Nov 2000;6(6):635-8. [View Abstract]
  96. Heneine W, Switzer WM, Soucie JM, et al. Evidence of porcine endogenous retroviruses in porcine factor VIII and evaluation of transmission to recipients with hemophilia. J Infect Dis. Feb 15 2001;183(4):648-52. [View Abstract]
  97. Soucie JM, Erdman DD, Evatt BL, et al. Investigation of porcine parvovirus among persons with hemophilia receiving Hyate:C porcine factor VIII concentrate. Transfusion. Jun 2000;40(6):708-11. [View Abstract]
  98. Tagariello G, De Biasi E, Gajo GB, et al. Recombinant FVIIa (NovoSeven) continuous infusion and total hip replacement in patients with haemophilia and high titre of inhibitors to FVIII: experience of two cases. Haemophilia. Sep 2000;6(5):581-3. [View Abstract]
  99. Negrier C, Hay CR. The treatment of bleeding in hemophilic patients with inhibitors with recombinant factor VIIa. Semin Thromb Hemost. 2000;26(4):407-12. [View Abstract]
  100. Liebman HA, Chediak J, Fink KI, et al. Activated recombinant human coagulation factor VII (rFVIIa) therapy for abdominal bleeding in patients with inhibitory antibodies to factor VIII. Am J Hematol. Mar 2000;63(3):109-13. [View Abstract]
  101. Hough RE, Hampton KK, Preston FE, et al. Recombinant VIIa concentrate in the management of bleeding following prothrombin complex concentrate-related myocardial infarction in patients with haemophilia and inhibitors. Br J Haematol. Dec 2000;111(3):974-9. [View Abstract]
  102. Ingerslev J. Efficacy and safety of recombinant factor VIIa in the prophylaxis of bleeding in various surgical procedures in hemophilic patients with factor VIII and factor IX inhibitors. Semin Thromb Hemost. 2000;26(4):425-32. [View Abstract]
  103. Lusher JM, Roberts HR, Davignon G, et al. A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with haemophilia A and B, with and without inhibitors. rFVIIa Study Group. Haemophilia. Nov 1998;4(6):790-8. [View Abstract]
  104. Roberts HR. Thoughts on the mechanism of action of FVIIa. Presented at: Second Symposium on New Aspects of Haemophilia Treatment; 1991; Copenhagen, Denmark.
  105. Stewart MJ, Hart G, Mann K, Jackson S, Langille L, Reidy M. Telephone support group intervention for persons with hemophilia and HIV/AIDS and family caregivers. Int J Nurs Stud. Apr 2001;38(2):209-25. [View Abstract]
  106. Pooled plasma, solvent detergent treated, PLAS+SD [package insert]. Watertown, Mass: VI Technologies, Inc (Vitex) / Washington, DC, American Red Cross; September 1999.
  107. Bachmann F. The fibrinolytic system and thrombolytic agents. In: Bachmann F, ed. Fibrinolytics and Antifibrinolytics. New York, NY: Springer-Verlag; 2001:3-15.
  108. Bachmann F. The plasminogen-plasmin enzyme system. Haemostasis and Thrombosis. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2001:275-320.
  109. Bachmann F. Disorders of fibrinolysis and use of antifibrinolytic agents. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, edsTJ,. Williams Hematology. 6th ed. New York, NY: McGraw-Hill; 2001:1829-40.
  110. [Best Evidence] Fergusson DA, Hébert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. May 29 2008;358(22):2319-31. [View Abstract]
  111. Di Bisceglie AM. SEN and sensibility: interactions between newly discovered and other hepatitis viruses?. Lancet. Dec 8 2001;358(9297):1925-6. [View Abstract]
  112. Millar DS, Steinbrecher RA, Wieland K, et al. The molecular genetic analysis of haemophilia A; characterization of six partial deletions in the factor VIII gene. Hum Genet. Dec 1990;86(2):219-27. [View Abstract]
  113. Scandella DH, Nakai H, Felch M, et al. In hemophilia A and autoantibody inhibitor patients: the factor VIII A2 domain and light chain are most immunogenic. Thromb Res. Mar 1 2001;101(5):377-85. [View Abstract]
  114. Peerlinck K, Jacquemin MG, Arnout J, et al. Antifactor VIII antibody inhibiting allogeneic but not autologous factor VIII in patients with mild hemophilia A. Blood. Apr 1 1999;93(7):2267-73. [View Abstract]
  115. Nogami K, Shima M, Giddings JC, et al. Circulating factor VIII immune complexes in patients with type 2 acquired hemophilia A and protection from activated protein C-mediated proteolysis. Blood. Feb 1 2001;97(3):669-77. [View Abstract]
  116. Moreau A, Lacroix-Desmazes S, Stieltjes N, et al. Antibodies to the FVIII light chain that neutralize FVIII procoagulant activity are present in plasma of nonresponder patients with severe hemophilia A and in normal polyclonal human IgG. Blood. Jun 1 2000;95(11):3435-41. [View Abstract]
  117. Gilles JG, Vanzieleghem B, Saint-Remy JM. Factor VIII Inhibitors. Natural autoantibodies and anti-idiotypes. Semin Thromb Hemost. 2000;26(2):151-5. [View Abstract]
  118. Lacroix-Desmazes S, Moreau A, et al. Natural antibodies to factor VIII. Semin Thromb Hemost. 2000;26(2):157-65. [View Abstract]
  119. Spiegel PC Jr, Jacquemin M, Saint-Remy JM, Stoddard BL, Pratt KP. Structure of a factor VIII C2 domain-immunoglobulin G4kappa Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII. Blood. Jul 1 2001;98(1):13-9. [View Abstract]
  120. Yamamoto K, Niiya K, Shigematu T, et al. Transient factor VIII inhibitor in a hemophilia patient after staphylococcal septic shock syndrome. Int J Hematol. Dec 2000;72(4):517-9. [View Abstract]
  121. Stewart AJ, Manson LM, Dasani H, et al. Acquired haemophilia in recipients of depot thioxanthenes. Haemophilia. Nov 2000;6(6):709-12. [View Abstract]
  122. Fakharzadeh SS, Kazazian HH Jr. Correlation between factor VIII genotype and inhibitor development in hemophilia A. Semin Thromb Hemost. 2000;26(2):167-71. [View Abstract]
  123. Streif W, Escuriola Ettingshausen C, et al. Inhibitor treatment by rituximab in congenital haemophilia A - Two case reports. Hamostaseologie. May 2009;29(2):151-4. [View Abstract]
  124. Jimenez AT, Vallejo ES, Cruz MZ, Cruz AC, Miramontes JR, Jara BS. Rituximab effectiveness in a patient with juvenile systemic lupus erythematosus complicated with acquired Von Willebrand syndrome. Lupus. Aug 29 2013;[View Abstract]
  125. Hoots K, Canty D. Clotting factor concentrates and immune function in haemophilic patients. Haemophilia. Sep 1998;4(5):704-13. [View Abstract]
  126. Wadhwa M, Barrowcliffe T, Thorpe R. Immunological effects of factor VIII concentrates: characterization of transforming growth factor beta as an immunomodulatory contaminant in factor VIII concentrates. Br J Haematol. Jun 2000;109(4):901-3. [View Abstract]
  127. Yoto Y, Kudoh T, Haseyama K, Tsutsumi H. Human parvovirus B19 and meningoencephalitis. Lancet. Dec 22-29 2001;358(9299):2168. [View Abstract]
  128. Narváez Garcia FJ, Domingo-Domènech E, Castro-Bohorquez FJ, et al. Lupus-like presentation of parvovirus B19 infection. Am J Med. Nov 2001;111(7):573-5. [View Abstract]
  129. Senior K. New variant CJD fears threaten blood supplies. Lancet. Jul 28 2001;358(9278):304. [View Abstract]
  130. Schneppenheim R, Schroder J, Obser T, et al. The problem of novel FVIII missense mutations for haemophilia A genetic counseling. Hamostaseologie. May 2009;29(2):158-60. [View Abstract]
  131. Pacheco LD, Costantine MM, Saade GR, Mucowski S, Hankins GD, Sciscione AC. von Willebrand disease and pregnancy: a practical approach for the diagnosis and treatment. Am J Obstet Gynecol. Apr 22 2010;[View Abstract]
  132. Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J Biol Chem. Jun 16 1995;270(24):14477-84. [View Abstract]
  133. Bajzar L, Nesheim ME, Tracy PB. The profibrinolytic effect of activated protein C in clots formed from plasma is TAFI-dependent. Blood. Sep 15 1996;88(6):2093-100. [View Abstract]
  134. Bouma BN, von dem Borne PA, Meijers JC. Factor XI and protection of the fibrin clot against lysis--a role for the intrinsic pathway of coagulation in fibrinolysis. Thromb Haemost. Jul 1998;80(1):24-7. [View Abstract]
  135. Brinkman HJ, van Mourik JA, Mertens K. Persistent factor VIII-dependent factor X activation on endothelial cells is independent of von Willebrand factor. Blood Coagul Fibrinolysis. Apr 2008;19(3):190-6. [View Abstract]
  136. Broze GJ Jr, Higuchi DA. Coagulation-dependent inhibition of fibrinolysis: role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma. Blood. Nov 15 1996;88(10):3815-23. [View Abstract]
  137. Carlborg E, Astermark J, Lethagen S, Ljung R, Berntorp E. The Malmö model for immune tolerance induction: impact of previous treatment on outcome. Haemophilia. Nov 2000;6(6):639-42. [View Abstract]
  138. Colowick AB, Bohn RL, Avorn J, Ewenstein BM. Immune tolerance induction in hemophilia patients with inhibitors: costly can be cheaper. Blood. Sep 1 2000;96(5):1698-702. [View Abstract]
  139. Courter SG, Bedrosian CL. Clinical evaluation of B-domain deleted recombinant factor VIII in previously untreated patients. Semin Hematol. Apr 2001;38(2 suppl 4):52-9. [View Abstract]
  140. Gharagozlou S, Sharifian RA, Khoshnoodi J, et al. Epitope specificity of anti-factor VIII antibodies from inhibitor positive acquired and congenital haemophilia A patients using synthetic peptides spanning A and C domains. Thromb Haemost. May 2009;101(5):834-9. [View Abstract]
  141. Greenberg DL, Davie EW. Blood coagulation factors: their complementary DNAs, genes, and expression. In: Coleman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Hemostsis & Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2001:21-7.
  142. Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. Jun 2001;85(6):958-65. [View Abstract]
  143. Jansen M, Schmaldienst S, Banyai S, et al. Treatment of coagulation inhibitors with extracorporeal immunoadsorption (Ig-Therasorb). Br J Haematol. Jan 2001;112(1):91-7. [View Abstract]
  144. Johannessen M, Andreasen RB, Nordfang O. Decline of factor VIII and factor IX inhibitors during long-term treatment with NovoSeven. Blood Coagul Fibrinolysis. Apr 2000;11(3):239-42. [View Abstract]
  145. Kemball-Cook G, Tuddenham EGD. The molecular defect in hemophilia A. In: Forbes CD, Aledort L, Madhok R, eds. Hemophilia. London, England: Chapman & Hall; 1997:21-33.
  146. Lee DH, Walker IR, Teitel J, et al. Effect of the factor V Leiden mutation on the clinical expression of severe hemophilia A. Thromb Haemost. Mar 2000;83(3):387-91. [View Abstract]
  147. Lynch TJ. Biotechnology: alternatives to human plasma-derived therapeutic proteins. Baillieres Best Pract Res Clin Haematol. Dec 2000;13(4):669-88. [View Abstract]
  148. Mannucci PM, Tuddenham EG. The hemophilias--from royal genes to gene therapy. N Engl J Med. Jun 7 2001;344(23):1773-9. [View Abstract]
  149. Mosnier LO, von dem Borne PA, Meijers JC, Bouma BN. Plasma TAFI levels influence the clot lysis time in healthy individuals in the presence of an intact intrinsic pathway of coagulation. Thromb Haemost. Nov 1998;80(5):829-35. [View Abstract]
  150. Oliveira B, Arkfeld DG, Weitz IC, Shinada S, Ehresmann G. Successful rituximab therapy of acquired factor VIII inhibitor in a patient with rheumatoid arthritis. J Clin Rheumatol. Apr 2007;13(2):89-91. [View Abstract]
  151. Pratt KP, Shen BW, Takeshima K, et al. Structure of the C2 domain of human factor VIII at 1.5 A resolution. Nature. Nov 25 1999;402(6760):439-42. [View Abstract]
  152. Redlitz A, Tan AK, Eaton DL, Plow EF. Plasma carboxypeptidases as regulators of the plasminogen system. J Clin Invest. Nov 1995;96(5):2534-8. [View Abstract]
  153. Renault NK, Dyack S, Dobson MJ, et al. Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females. Eur J Hum Genet. Jun 2007;15(6):628-37. [View Abstract]
  154. Rubinstein R, Karabus CD, Smuts H, Kolia F, Van Rensburg EJ. Prevalence of human parvovirus B19 and TT virus in a group of young haemophiliacs in South Africa. Haemophilia. Mar 2000;6(2):93-7. [View Abstract]
  155. Sandberg H, Almstedt A, Brandt J, et al. Structural and functional characteristics of the B-domain-deleted recombinant factor VIII protein, r-VIII SQ. Thromb Haemost. Jan 2001;85(1):93-100. [View Abstract]
  156. Soucie JM, Richardson LC, Evatt BL, et al. Risk factors for infection with HBV and HCV in a largecohort of hemophiliac males. Transfusion. Mar 2001;41(3):338-43. [View Abstract]
  157. Stoilova-McPhie S, Villoutreix BO, Mertens K, Kemball-Cook G, Holzenburg A. 3-Dimensional structure of membrane-bound coagulation factor VIII: modeling of the factor VIII heterodimer within a 3-dimensional density map derived by electron crystallography. Blood. Feb 15 2002;99(4):1215-23. [View Abstract]
  158. Sutor AH, Wulff J, Ritter J, Pollmann H, Schellong G. [Hemostasis and fibrinolysis in acute lymphoblastic leukemia (ALL) in childhood--analysis of life-threatening bleeding]. Klin Padiatr. May-Jun 1984;196(3):166-73. [View Abstract]
  159. White GC 2nd. Seventeen years' experience with Autoplex/Autoplex T: evaluation of inpatients with severe haemophilia A and factor VIII inhibitors at a major haemophilia centre. Haemophilia. Sep 2000;6(5):508-12. [View Abstract]

Obituary in the March 22, 1796, Salem Gazette (Massachusetts) for a 19-year-old man who bled to death after suffering a foot injury. Also detailed are the deaths of 5 brothers by various minor injuries.

The hemostatic pathway: role of factor VIII.

Structural domains of human factor VIII. Adapted from: Stoilova-McPhie S, Villoutreix BO, Mertens K, Kemball-Cook G, Holzenburg A. 3-Dimensional structure of membrane-bound coagulation factor VIII: modeling of the factor VIII heterodimer within a 3-dimensional density map derived by electron crystallography. Blood. Feb 15 2002;99(4):1215-23; Roberts HR, Hoffman M. Hemophilia A and B. In: Beutler E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6th ed. NY: McGraw-Hill; 2001:1639-57; and Roberts HR. Thoughts on the mechanism of action of FVIIa. Presented at: Second Symposium on New Aspects of Haemophilia Treatment; 1991; Copenhagen, Denmark.

Possible genetic outcomes in individuals carrying the hemophilic gene.

Photograph of a teenage boy with bleeding into his right thigh as well as both knees and ankles.

Photograph of the right knee in an older man with a chronically fused, extended knee following open drainage of knee bleeding that occurred many years previously.

Photograph depicting severe bilateral hemophilic arthropathy and muscle wasting. The 3 punctures made into the left knee joint were performed in an attempt to aspirate recent aggravated bleeding.

Radiograph depicting advanced hemophilic arthropathy of the knee joint. These images show chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.

Radiograph depicting advanced hemophilic arthropathy of the elbow. This image shows chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.

Photograph of a hemophilic knee at surgery, with synovial proliferation caused by repeated bleeding; synovectomy was required.

Large amount of vascular synovium removed at surgery.

Microscopic appearance of synovial proliferation and high vascularity. If stained with iron, diffuse deposits would be demonstrated; iron-laden macrophages are present.

Large pseudocyst involving the left proximal femur.

Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional limb). This photo shows black-brown old blood, residual muscle, and bone.

Dissection of a pseudocyst.

Transected pseudocyst with chocolate brown-black old blood.

Photograph of a patient who presented with a slowly expanding abdominal and flank mass, as well as increasing pain, inability to eat, weight loss, and weakness of his lower extremity.

Plain radiograph of the pelvis showing a large lytic area.

Intravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst.

Photograph depicting extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.

Magnetic resonance image of an extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.

Structural domains of human factor VIII. Adapted from: Stoilova-McPhie S, Villoutreix BO, Mertens K, Kemball-Cook G, Holzenburg A. 3-Dimensional structure of membrane-bound coagulation factor VIII: modeling of the factor VIII heterodimer within a 3-dimensional density map derived by electron crystallography. Blood. Feb 15 2002;99(4):1215-23; Roberts HR, Hoffman M. Hemophilia A and B. In: Beutler E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6th ed. NY: McGraw-Hill; 2001:1639-57; and Roberts HR. Thoughts on the mechanism of action of FVIIa. Presented at: Second Symposium on New Aspects of Haemophilia Treatment; 1991; Copenhagen, Denmark.

Image depicting the 28q region of the X chromosome. Adapted from: Kazazian HH Jr, Tuddenham EGD, Antonarakis SE. Hemophilia A and parahemophilia: deficiencies of coagulation factors VIII and V. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995:3241-67; Reitsma PH. Genetic principles underlying disorders of procoagulant and anticoagulant proteins. In: Coleman RW, Hirsh J, Marder VJ, et al, eds. Hemostasis and Thrombosis: Basic Principles &amp; Clinical Practice. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:59-87; Roberts HR, Monroe DM III, Hoffman M. Molecular biology and biochemistry of the coagulation factors and pathways of hemostasis. In: Beutler E, Beutler E, Lichtman MA, et al, eds. Williams Hematology. 6th ed. New York: McGraw-Hill, 2001:1409-34; and Roberts HR, Hoffman M. Hemophilia A and B. In: Beutler E, Lichtman MA, et al, eds. Williams Hematology. 6th ed. New York: McGraw-Hill, 2001:1639-57.

Photograph depicting severe bilateral hemophilic arthropathy and muscle wasting. The 3 punctures made into the left knee joint were performed in an attempt to aspirate recent aggravated bleeding.

Microscopic appearance of synovial proliferation and high vascularity. If stained with iron, diffuse deposits would be demonstrated; iron-laden macrophages are present.

Large pseudocyst involving the left proximal femur.

Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional limb). This photo shows black-brown old blood, residual muscle, and bone.

Dissection of a pseudocyst.

Transected pseudocyst with chocolate brown-black old blood.

Photograph depicting the application of a Velcro tourniquet, followed by self-infusion of concentrate used for in-home therapy.

Self-infusion of concentrate used for in-home therapy.

Quality of life! A child with hemophilia at summer camp.

Photograph depicting the application of a Velcro tourniquet, followed by self-infusion of concentrate used for in-home therapy.

Self-infusion of concentrate used for in-home therapy.

Photograph of the right knee in an older man with a chronically fused, extended knee following open drainage of knee bleeding that occurred many years previously.

Photograph depicting severe bilateral hemophilic arthropathy and muscle wasting. The 3 punctures made into the left knee joint were performed in an attempt to aspirate recent aggravated bleeding.

Radiograph depicting advanced hemophilic arthropathy of the knee joint. These images show chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.

Radiograph depicting advanced hemophilic arthropathy of the elbow. This image shows chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.

Large pseudocyst involving the left proximal femur.

Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional limb). This photo shows black-brown old blood, residual muscle, and bone.

Dissection of a pseudocyst.

Transected pseudocyst with chocolate brown-black old blood.

Obituary in the March 22, 1796, Salem Gazette (Massachusetts) for a 19-year-old man who bled to death after suffering a foot injury. Also detailed are the deaths of 5 brothers by various minor injuries.

The hemostatic pathway: role of factor VIII.

Structural domains of human factor VIII. Adapted from: Stoilova-McPhie S, Villoutreix BO, Mertens K, Kemball-Cook G, Holzenburg A. 3-Dimensional structure of membrane-bound coagulation factor VIII: modeling of the factor VIII heterodimer within a 3-dimensional density map derived by electron crystallography. Blood. Feb 15 2002;99(4):1215-23; Roberts HR, Hoffman M. Hemophilia A and B. In: Beutler E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6th ed. NY: McGraw-Hill; 2001:1639-57; and Roberts HR. Thoughts on the mechanism of action of FVIIa. Presented at: Second Symposium on New Aspects of Haemophilia Treatment; 1991; Copenhagen, Denmark.

Cell surface–directed hemostasis (adapted from: Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. Jun 2001;85(6):958-65. Initially, a small amount of thrombin is generated on the surface of the tissue factor–bearing cell. Following amplification, the second burst generates a larger amount of thrombin, leading to fibrin (clot) formation.

Possible genetic outcomes in individuals carrying the hemophilic gene.

Photograph of a teenage boy with bleeding into his right thigh as well as both knees and ankles.

Photograph of the right knee in an older man with a chronically fused, extended knee following open drainage of knee bleeding that occurred many years previously.

Photograph depicting severe bilateral hemophilic arthropathy and muscle wasting. The 3 punctures made into the left knee joint were performed in an attempt to aspirate recent aggravated bleeding.

Radiograph depicting advanced hemophilic arthropathy of the knee joint. These images show chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.

Radiograph depicting advanced hemophilic arthropathy of the elbow. This image shows chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.

Photograph of a hemophilic knee at surgery, with synovial proliferation caused by repeated bleeding; synovectomy was required.

Large amount of vascular synovium removed at surgery.

Microscopic appearance of synovial proliferation and high vascularity. If stained with iron, diffuse deposits would be demonstrated; iron-laden macrophages are present.

Large pseudocyst involving the left proximal femur.

Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional limb). This photo shows black-brown old blood, residual muscle, and bone.

Dissection of a pseudocyst.

Transected pseudocyst with chocolate brown-black old blood.

Photograph of a patient who presented with a slowly expanding abdominal and flank mass, as well as increasing pain, inability to eat, weight loss, and weakness of his lower extremity.

Plain radiograph of the pelvis showing a large lytic area.

Intravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst.

Photograph depicting extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.

Magnetic resonance image of an extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.

Image depicting the 28q region of the X chromosome. Adapted from: Kazazian HH Jr, Tuddenham EGD, Antonarakis SE. Hemophilia A and parahemophilia: deficiencies of coagulation factors VIII and V. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995:3241-67; Reitsma PH. Genetic principles underlying disorders of procoagulant and anticoagulant proteins. In: Coleman RW, Hirsh J, Marder VJ, et al, eds. Hemostasis and Thrombosis: Basic Principles &amp; Clinical Practice. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:59-87; Roberts HR, Monroe DM III, Hoffman M. Molecular biology and biochemistry of the coagulation factors and pathways of hemostasis. In: Beutler E, Beutler E, Lichtman MA, et al, eds. Williams Hematology. 6th ed. New York: McGraw-Hill, 2001:1409-34; and Roberts HR, Hoffman M. Hemophilia A and B. In: Beutler E, Lichtman MA, et al, eds. Williams Hematology. 6th ed. New York: McGraw-Hill, 2001:1639-57.

Quality of life! A child with hemophilia at summer camp.

Photograph depicting the application of a Velcro tourniquet, followed by self-infusion of concentrate used for in-home therapy.

Self-infusion of concentrate used for in-home therapy.

Type of Hemorrhage Desired

FVIII-C Activity

Dose and Duration of Therapy
Minor

Uncomplicated

hemarthroses

Superficial large

hematomas

20-30%10-15 U/kg IV q12-24h for 1-2 d
Moderate

Hematoma with dissection

Oral/mucosal hemorrhages and epistaxis*

Hematuria

25-50%15-25 U/kg IV q12-24h for 3-7 d

(shorter time for oral hemorrhages; higher dose for hematuria)

Dental extraction(s)†50-100%25-50 U/kg IV q12h for 2-5 d
Major

Pharyngeal/retropharyngeal

Retroperitoneal

GI bleeding

CNS bleeding surgery

~50-100% until bleeding is controlled; then, gradually decrease the dosage to the minimum that is required to prevent rebleeding25-50 U/kg IV q12h for 5-10 d
*Concomitant administration of EACA or AMCA (both inhibitors of fibrinolysis) can help reduce the dose of concentrate that is required to treat such bleeding. Approximately 50% of the initial dose is given as the second dose approximately 8 hours after the first; all subsequent doses are given every 12 hours.

†For dental extractions, a single preoperative dose of factor VIII of 15 U/kg and oral or intravenous Amicar at 5 g is given, followed by an Amicar maintenance dose of 1 g/h, as discussed below, for 5-7 days, with a gradual taper.