Hemophilia A

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Practice Essentials

Hemophilia A is an X-linked, recessive disorder caused by deficiency of functional plasma clotting factor VIII (FVIII), which may be inherited or arise from spontaneous mutation. The development of inhibitory alloantibodies to FVIII can severely complicate the treatment of genetic cases. Rarely, development of autoantibodies to FVIII results in acquired hemophilia A.

Signs and symptoms

Depending on the level of FVIII activity, patients with hemophilia may present with easy bruising; inadequate clotting of traumatic or even mild injury; or, in the case of severe hemophilia, spontaneous hemorrhage.

Signs of hemorrhage include the following:

See Presentation for more detail.

Diagnosis

Laboratory studies for suspected hemophilia include the following:

Expected laboratory values are as follows:

Normal values for FVIII assays are 50-150%. Values in hemophilia A are as follows:

Imaging studies for acute bleeds are chosen on the basis of clinical suspicion and anatomic location of involvement, as follows:

Testing for inhibitors is indicated when bleeding is not controlled after infusion of adequate amounts of factor concentrate during a bleeding episode. The presence of inhibitors is indicated by failure of correction of clotting times with 1:1 mix with normal plasma. Inhibitor concentration is titrated using the Bethesda method, as follows:

See Workup for more detail.

Management

The treatment of hemophilia may involve the following:

Disposition of treatment is as follows:

For treatment of acute bleeds, target levels by hemorrhage severity are as follows:

Ideally, therapy is individualized to specific patients.  However, for general dosing, to find the number of units of factor VIII needed to correct the factor VIII activity level, use the following formula:

Dose in FVIII IU = (weight in kg) x (desired FVIII increase) x (0.5 IU/kg per IU/dL)

FVIII regimens are as follows:

The following types of FVIII concentrates are available:

Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP), has the following attributes:

The following antifibrinolytics are used in addition to FVIII replacement for oral mucosal hemorrhage and prophylaxis:

Treatments used in patients with inhibitors of FVIII are as follows:

See Treatment and Medication for more detail.

Background

Hemophilia A is an inherited, X-linked, recessive disorder caused by deficiency of functional plasma clotting factor VIII (FVIII). In a significant number of cases, the disorder results from a new mutation or an acquired immunologic process.

Morbidity and death are primarily the result of hemorrhage, although infectious diseases (eg, HIV infection, hepatitis) became prominent, particularly in patients who received blood products prior to 1985.

Laboratory studies for suspected hemophilia include a complete blood cell count, coagulation studies, and an FVIII assay. In patients with an established diagnosis of hemophilia, periodic laboratory evaluations include screening for the presence of FVIII inhibitor and screening for transfusion-related or transmissible diseases such as hepatitis and HIV infection. Measurement of FVIII levels is important for monitoring FVIII replacement therapy. (See Workup.)

The treatment of hemophilia may involve prophylaxis, management of bleeding episodes, immune tolerance induction for patients with factor inhibitors, and treatment and rehabilitation of patients with hemophilia synovitis. Treatment of patients with hemophilia ideally should be provided through a comprehensive hemophilia care center (see Treatment and Medication).[1]

Please see the following for more information:

Classification

The classification of the severity of hemophilia has been based on either clinical bleeding symptoms or on plasma procoagulant levels; the latter are the most widely used criteria. Classification according to plasma procoagulant levels is as follows:

Severe disease presents in children younger than 1 year and accounts for 43-70% of hemophilia A cases. Moderate disease presents in children aged 1-2 years and accounts for 15-26% of cases. Mild disease presents in children older than 2 years and accounts for 15-31% of cases.

Clinical bleeding symptom criteria have been used because patients with FVIII levels of less than 1% occasionally have little or no spontaneous bleeding and appear to have clinically moderate or mild hemophilia. Furthermore, the reverse is true for patients with procoagulant activities of 1-5%, who may present with clinically severe disease.

Historical background

Hemophilia is one of the oldest described genetic diseases. An inherited bleeding disorder in males was recognized in Talmudic records of the second century.

The modern history of hemophilia began in 1803 with the description of hemophilic kindred by John Otto, followed by the first review of hemophilia by Nasse in 1820. Wright demonstrated evidence of laboratory defects in blood clotting in 1893; however, FVIII was not identified until 1937, when Patek and Taylor isolated a clotting factor from the blood, which they called antihemophilic factor (AHF).

A bioassay of FVIII was introduced in 1950. Although the intimate relationship between FVIII and von Willebrand factor (vWF) is now known, it was not appreciated at the time. In 1953, decreased FVIII levels in patients with vWF deficiency was first described. Further research by Nilson and coworkers indicated the interaction between these 2 clotting factors.

In 1952, hemophilia B was described and was named Christmas disease after the surname of the first patient who was examined in detail. The differentiation of hemophilia B from hemophilia A followed the observation that mixing plasma from a patient with "true hemophilia" with plasma from a patient with Christmas disease corrected the clotting time. Hemophilia A makes up approximately 80% of hemophilia cases.

In the early 1960s, cryoprecipitate (the precipitate from fresh frozen plasma that has been thawed and centrifuged) became the first concentrate available for the treatment of patients with hemophilia. In the 1970s, lyophilized (ie, freeze-dried) intermediate-purity concentrates were obtained from large pools of blood donors. The introduction of concentrated lyophilized products that are easy to store and transport dramatically improved the quality of life of patients with hemophilia and facilitated their preparation for surgery and home care.

Unfortunately, the large size of the donor pool—as many as 20,000 donors may contribute to a single lot of plasma-derived FVIII concentrate—heightened the risk of viral contamination of commercial FVIII concentrates. By the mid-1980s, most patients with severe hemophilia had been exposed to hepatitis A, hepatitis B, and hepatitis C viruses and human immunodeficiency virus (HIV).

Viricidal treatment of plasma-derived FVIII concentrates has been effective in eliminating new HIV transmissions and virtually eliminating hepatitis B and hepatitis C exposures. The introduction of recombinant FVIII concentrate, and the gradual elimination of albumin from the production process used for these products, has virtually eliminated the risk of viral exposure.

Pathophysiology

Factor VIII production, processing, and structure

Primary sites of factor VIII (FVIII) production are thought to be the vascular endothelium in the liver and the reticuloendothelial system. Liver transplantation corrects FVIII deficiency in persons with hemophilia.

FVIII messenger RNA has been detected in the liver, spleen, and other tissues.[2] Studies of FVIII production in transfected cell lines have shown that following synthesis, FVIII 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 FVIII's signal peptide and the addition of oligosaccharides also occur in the endoplasmic reticulum. The chaperone proteins, calnexin and calreticulin, enhance both FVIII secretion and degradation.

A part of the factor FVIII 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 (vWF).

von Willebrand factor

FVIII circulates in plasma in a noncovalently bound complex with vWF, which plays significant roles in the function, production, stabilization, conformation, and immunogenicity of FVIII.[3] VWF has been termed FVIII-related antigen (FVIII-R); related terminology for FVIII is FVIII-coagulant (FVIII-C).

VWF appears to promote assembly of the heavy and light chains of FVIII and more efficient secretion of FVIII from the endoplasmic reticulum. It also directs FVIII into the Weibel-Palade bodies, which are the intracellular storage sites for vWF.

In plasma, vWF stabilizes FVIII and protects it from degradation. In the presence of normal vWF protein, the half-life of FVIII is approximately 12 hours, whereas in the absence of vWF, the half-life of FVIII-C is reduced to 2 hours.[4, 5, 6]

The clotting cascade

The role of the coagulation system is to produce a stable fibrin clot at sites of injury. The clotting mechanism has two pathways: intrinsic and extrinsic. See the image below.



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Coagulation Cascade

The intrinsic system is initiated when factor XII is activated by contact with damaged endothelium. The activation of factor XII can also initiate the extrinsic pathway, fibrinolysis, kinin generation, and complement activation.

In conjunction with high-molecular-weight kininogen (HMWK), factor XIIa converts prekallikrein (PK) to kallikrein and activates factor XI. Activated factor XI, in turn, activates factor IX in a calcium-dependent reaction. Factor IXa can bind phospholipids. Then, factor X is activated on the cell surface; activation of factor X involves a complex (tenase complex) of factor IXa, thrombin-activated FVIII, calcium ions, and phospholipid.

In the extrinsic system, the conversion of factor X to factor Xa involves tissue factor (TF), or thromboplastin; factor VII; and calcium ions. TF is released from the damaged cells and is thought to be a lipoprotein complex that acts as a cell surface receptor for factor VII, with its resultant activation. TF also adsorbs factor X to enhance the reaction between factor VIIa, factor X, and calcium ions. Factor IXa and factor XII fragments can also activate factor VII.

In the common pathway, factor Xa (generated through the intrinsic or extrinsic pathways) forms a prothrombinase complex with phospholipids, calcium ions, and thrombin-activated factor Va. The complex cleaves prothrombin into thrombin and prothrombin fragments 1 and 2.

Thrombin converts fibrinogen into fibrin and activates FVIII, factor V, and factor XIII. Fibrinopeptides A and B, the results of the cleavage of peptides A and B by thrombin, cause fibrin monomers to form and then polymerize into a meshwork of fibrin; the resultant clot is stabilized by factor XIIIa and the cross-linking of adjacent fibrin strands.

Because of the complex interactions of the intrinsic and extrinsic pathways (factor IXa activates factor VII), the existence of only one in vivo pathway with different mechanisms of activation has been suggested. See the image below.



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The hemostatic pathway. APC = activated protein C (APC); AT-III = antithrombin III; FDP = fibrin degradation products; HC-II = heparin cofactor II; HM....

FVIII and factor IX circulate in an inactive form. When activated, these 2 factors cooperate to cleave and activate factor X, a key enzyme that controls the conversion of fibrinogen to fibrin. Therefore, the lack of FVIII may significantly alter clot formation and, as a consequence, result in clinical bleeding.

Genetics

The gene for FVIII (F8C) is located on the long arm of chromosome X, within the Xq28 region. The gene is unusually large, representing 186 kb of the X chromosome. It comprises 26 exons and 25 introns. Mature FVIII contains 2332 amino acids. See the 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....

Approximately 40% of cases of severe FVIII deficiency arise from a large inversion that disrupts the FVIII gene. Deletions, insertions, and point mutations account for the remaining 50-60% of the F8C defects that cause hemophilia A.

Low FVIII levels may arise from defects outside the FVIII gene, as in type IIN von Willebrand disease, in which the molecular defect resides in the FVIII-binding domain of von Willebrand factor.

Hemophilia A

FVIII deficiency, dysfunctional FVIII, or FVIII inhibitors lead to the disruption of the normal intrinsic coagulation cascade, resulting in excessive hemorrhage in response to trauma and, in severe cases, spontaneous hemorrhage. Hemorrhage sites include joints (eg, knee, elbow); muscles; the central nervous system (CNS); and the gastrointestinal, genitourinary, pulmonary, and cardiovascular systems. Intracranial hemorrhage occurs most commonly in patients younger than 18 years and can be fatal.

Hemorrhage into joints

The hallmark of hemophilia is hemorrhage into joints. This bleeding is painful and leads to long-term inflammation and deterioration of the joint.

Human synovial cells synthesize high levels of tissue factor pathway inhibitor, resulting in a higher degree of factor Xa (FXa) inhibition, which predisposes hemophilic joints to bleed. This effect may also account for the dramatic response of activated factor VII (FVIIa) infusions in patients with acute hemarthroses and FVIII inhibitors.

Bleeding into a joint may lead to synovial inflammation, which predisposes the joint to further bleeds. A joint that has had repeated bleeds (by one definition, at least 4 bleeds within a 6-month period) is termed a target joint. Commonly, this occurs in knees.

Repeated hemarthroses lead to progressive synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage, with subchondral bone-cyst formation. This results in permanent deformities, misalignment, loss of mobility, and extremities of unequal lengths.

Inhibitors

Approximately 30% of patients with severe hemophilia A develop alloantibody inhibitors that can bind FVIII. These inhibitors are typically immunoglobulin G (IgG), predominantly of the IgG4 subclass, that neutralize the coagulant effects of replacement therapy. However, the inhibitors do not fix complement and do not result in the end-organ damage observed with circulating immune complexes

Inhibitors occur at a young age (about 50% by age 10 years), principally in patients with less than 1% FVIII. Both genetic and environmental factors determine the frequency of inhibitor development. Specific molecular abnormalities (eg, gene deletions, stop codon mutations, frameshift mutations) are associated with a higher incidence of inhibitor development. In addition, inhibitors are more likely to develop in black children. Missense mutations are associated with a low risk of inhibitor development.[7]

The association of product used with the risk of inhibitor formation remains controversial. In a study of 574 patients with severe hemophilia A, 177 of whom developed inhibitors, the risks of inhibitor development were similar with recombinant and plasma-derived FVIII products. No association was found between the development of inhibitors and the von Willebrand factor content of products, switching from a plasma-derived to a recombinant product, or switching among brands of FVIII products. Unexpectedly, however, inhibitors developed more often with second-generation full-length recombinant products than with third-generation products.[8]

A study with 303 previously untreated or minimally treated children with hemophilia demonstrated a increased risk of inhibitor formation in patients who used recombinant products.[9] However, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) concluded that "there is no clear and consistent evidence of a difference in the incidence of inhibitor development between the two classes of factor VIII medicines: those derived from plasma and those made by recombinant DNA technology."[10]

In the United States, levels of FVIII inhibitors are most often measured by the Bethesda method. In this method, 1 Bethesda unit (BU) equals the amount of antibody that destroys one half of the FVIII in an equal mixture of normal plasma and patient plasma in 2 hours at 37°C. Inhibitor levels are described as low titer or high titer, depending on whether they are less than or more than 5 BU, respectively; high-titer inhibitor levels are typically far higher than 5 BU.

The Nijmegen modification uses immunodepleted FVIII–deficient plasma instead of an imidazole saline buffer to ensure pH control to prevent non–antibody-mediated loss of FVIII-C activity during the prolonged 2-hour incubation period.[11] The Bethesda assay tends to underestimate the titer of VIII autoantibody because of its characteristics, in contrast to a hemophilic antibody.[12] The Oxford assay is another modification of the Bethesda inhibitor test.

Acquired hemophilia

Acquired hemophilia is the development of FVIII inhibitors (autoantibodies) in persons without a history of FVIII deficiency. This condition can be idiopathic (occurring in people >50 y), it can be associated with collagen vascular disease or the peripartum period, or it may represent a drug reaction (eg, to penicillin). High titers of FVIII autoantibodies may be associated with lymphoproliferative malignancies.[13]

Etiology

Hemophilia A is caused by an inherited or acquired genetic mutation that results in dysfunction or deficiency of factor VIII, or by an acquired inhibitor that binds factor VIII. Of genetic cases, up to approximately one third are the result of de novo mutations not present in the mother's X chromosome.

Inadequate factor VIII results in the insufficient generation of thrombin by the FIXa and FVIIIa complex by means of the intrinsic pathway of the coagulation cascade. This mechanism, in combination with the effect of the tissue-factor pathway inhibitor, creates an extraordinary tendency for impaired clotting in response to trauma and, especially in persons with severe hemophilia, with spontaneous bleeding.

Hemophilia A is inherited in an X-linked recessive pattern. The gene for FVIII is located on the long arm of the X chromosome in band q28. The factor VIII gene is one of the largest genes, comprising approximately 0.1% of the DNA in the X chromosome; it is 186 kilobases (kb) long and has a 9-kb coding region that contains 26 exons. The mature protein contains 2332 amino acids and has a molecular weight of 300 kd. It includes 3 A domains, 1 B domain, and 2 C domains.

Intron 22 of the factor VIII gene, uniquely, contains two other genes. The first gene, F8A, is transcribed in a direction opposite to that of the factor VIII gene itself. The second gene, F8B, 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 two 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 deficiency; 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.[14]

The knowledge of the parental origin of the inversion mutation has important implications for genetic counseling.

Several other types of mutations have been described. Point mutations can lead to mild, moderate, or severe deficiency of factor VIII, depending on the effect of that mutation on factor VIII gene function.

Missense mutations, such as the G-to-A single-base substitution, alter the amino acid composition of the molecule, producing a dysfunctional molecule (FVIII antigen present with reduction in FVIII activity); these mutations are associated with mild, moderate, or severe factor VIII reductions and are associated with the development of factor VIII inhibitors. Intracellular accumulation of factor VIII induced by Arg 593→Cys and Asn 618→Ser missense mutations also result in reduction of cross-reacting material in severe hemophilia A.

Gene deletions lead to factor VIII deficiency, and large gene deletions result in severe hemophilia, with no detectable factor VIII antigen; such patients are more susceptible to inhibitor development. Insertions are apparently uncommon in the factor VIII gene, but they usually lead to severe hemophilia A.[15] Nonsense mutations and abnormal splicing may also occur.

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

Combined factor V and factor VIII deficiency

Combined FV and FVIII deficiency is an autosomal recessive disorder, with clinical manifestations in affected females and males. The disorder is caused by mutations in one of two genes, lectin mannose binding protein 1 (LMAN1) or multiple coagulation factor deficiency 2 (MCFD2), which encode proteins involved in the intracellular transport of FV and FVIII; the coagulation factors themselves are normal.[16]

Epidemiology

Hemophilia A is the most common X-linked genetic disease and the second most common factor deficiency after von Willebrand disease (vWD). The worldwide incidence of hemophilia A is approximately 1 case per 5000 males, with approximately one third of affected individuals not having a family history of the disorder. The prevalence of hemophilia A varies with the reporting country, with a range of 5.4-14.5 cases per 100,000 males.

In the United States, the prevalence of hemophilia A is 20.6 cases per 100,000 males. In 2016, the number of people in the United States with hemophilia was estimated to be about 20,000.[17]

Approximately 50-60% of patients have severe hemophilia A (FVIII < 2% of normal), associated with the severest bleeding manifestations. Approximately 25-30% have moderate hemophilia (FVIII 2-5%) and manifest bleeding after minor trauma. Those with mild hemophilia A (FVIII 6-30%) comprise 15-20% of all people with hemophilia; these patients develop bleeding only after trauma or surgery.

Acquired hemophilia A, caused by the development of an autoantibody to FVIII in a person with previously normal hemostasis, develops with a frequency of 1 case per 1 million population per year.[18] Acquired FVIII deficiency is observed in older populations, generally those older than 60 years.

The inherited, combined deficiency of factors V and VIII is a rare but recognized cause of a bleeding disorder. The prevalence is estimated to be 1 case per million population.[16]

Racial, sexual, and age-related differences in incidence

Hemophilia A occurs in all races and ethnic groups. In general, the demographics of hemophilia follow the racial distribution in a given population; for example, rates of hemophilia among whites, African Americans, and Hispanics in the US are similar.

Because hemophilia is an X-linked, recessive condition, it occurs predominantly in males. Females usually are asymptomatic carriers. However, mild hemophilia may be more common in carriers than previously recognized. In 1 study, 5 of 55 patients with mild hemophilia (factor levels 5-50%) were girls.[19]

Females may have clinical bleeding due to hemophilia if any of the following 3 conditions is present:

In genetic cases, significant deficiency in FVIII may be evident in the neonatal period. It continues through the life of the affected individual. The absence of hemorrhagic manifestations at birth does not exclude hemophilia.

Prognosis

With appropriate education and treatment, patients with hemophilia can live full and productive lives. Prophylaxis and early treatment with FVIII concentrate that is safe from viral contamination have dramatically improved the prognosis of patients with severe hemophilia. Nevertheless, approximately one quarter of patients with severe hemophilia aged 6-18 years have below-normal motor skills and academic performance and have more emotional and behavioral problems than others.[21]

Factor concentrates have made home-replacement therapy possible, improving patients' quality of life. In addition, the era of replacement therapy brought dramatic gains in life expectancy. For patients with severe hemophilia, life expectancy rose from 11 years or less before the 1960s to almost 60 years prior to HIV epidemic in the 1980s.[2, 4]

Increasing evidence associates hemophilia with low bone mineral density and increased fracture risk in both children and adults. Physical inactivity (which may be worsened by arthropathy) and vitamin D deficiency seem to play a fundamental role.[22]

Viral infection from contaminated FVIII concentrate became a problem during the replacement era. Most patients with hemophilia who received plasma-derived products that were not treated to eliminate potential contaminating viruses became infected with HIV or hepatitis A, hepatitis B, or hepatitis C viruses.

The most serious of these was HIV infection. The first deaths of people with hemophilia due to AIDS were observed in the early 1980s. Rates of seroconversion were more than 75% for those with severe disease, 46% for moderate disease, and 25% for mild disease.

In the United States, death rates of patients with hemophilia increased from 0.4 deaths per million population in 1979-1981 to 1.2 deaths per million population in 1987-1989; AIDS accounted for 55% of all hemophilia deaths. Causes of death shifted from intracranial and other bleeding to AIDS and cirrhosis from hepatitis. AIDS remains the most common cause of death in patients with severe hemophilia.[4] Indeed, HIV-infected individuals are more likely to die of that disease than from hemophilia.

With improved screening of donors, new methods of factor concentrate purification, and recombinant concentrates, infectious complications now are only historically important. However, even with these methods, some viruses (eg, parvovirus B-19) cannot be removed and may be transmitted through plasma-derived products. Other potential infectious agents include the prions that cause Creutzfeldt-Jakob disease. With the development of animal protein–free products, the risk of contamination with these agents may be decreased.

Intracranial hemorrhage and hemorrhages into the soft tissue around vital areas, such as the airway or internal organs, remain the most important life-threatening complications. The lifetime risk of intracranial bleeding is 2-8% and accounts for one third of deaths due to hemorrhage, even in the era of factor replacement. Intracranial hemorrhage is the second most common cause of death and the most common cause of death related to hemorrhage. Of patients with severe hemophilia, 10% have intracranial bleeding, with a mortality rate of 30%.

Chronic debilitating joint disease results from repeated hemarthrosis; synovial membrane inflammation; hypertrophy; and, eventually, destructive arthritis. Early replacement of coagulation factors by means of infusion is essential to prevent functional disability. Thus, prophylactic therapy administered 2-3 times weekly, starting when patients are young, is considered the standard of care in most developed countries.

Before the widespread use of replacement therapy, patients with severe hemophilia had a shortened lifespan and diminished quality of life that was greatly affected by hemophilic arthropathy. Home therapy for hemarthroses became possible with factor concentrates. Prophylactic use of lyophilized concentrates that eliminate bleeding episodes help prevent joint deterioration, especially when instituted early in life (ie, at age 1-2 y).

Overall, the mortality rate for patients with hemophilia is twice that of the healthy male population. For severe hemophilia, the rate is 4-6 times higher. If hepatitis and cirrhosis are excluded, the overall mortality rate of patients with severe hemophilia A is 1.2 times that of the healthy male population.[4]

Patient Education

Starting in infancy, regular dental evaluation is recommended, along with instruction regarding proper oral hygiene, dental care, and adequate fluoridation. Encourage the patient to engage in appropriate exercise. Advise the patient against participating in contact and collision sports.

Patient and family education about early recognition of hemorrhage signs and symptoms is important for instituting or increasing the intensity of replacement therapy. This treatment helps prevent the acute and chronic complications of the disease, which range from those that can impair quality of life to those that are life-threatening.

Educating patients and family members about factor replacement administration at home has greatly enhanced the quality of life of patients with severe hemophilia by allowing prompt infusion for bleeds and markedly reducing the need for emergency department visits. Parents often can learn to infuse children as young as 2 years, and, by 8-10 years, most children with hemophilia can learn to self-infuse.

For patient education information, see the Blood and Lymphatic System Center, as well as Hemophilia.

History

For patients in whom hemophilia is suspected, inquire about the following:

For individuals with documented hemophilia, ascertain the type of deficiency (eg, factor VIII [FVIII], FIX, von Willebrand), degree of factor deficiency, known presence of inhibitors, and HIV/hepatitis status. For patients with mild-to-moderate disease, determine responsiveness to desmopressin acetate (DDAVP).[5]

Signs and symptoms of hemorrhage include the following:

Evidence of infectious disease includes the following:

Newborn boys with severe hemophilia may present with prolonged bleeding at circumcision. Easy bruising may occur at the start of ambulation or primary dentition. Older patients may have a history of hemarthroses and prolonged bleeding with surgical procedures, trauma, and dental extraction, and may have spontaneous bleeding in soft tissues.

A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is diagnosed. Factors that elevate FVIII levels (eg, age, ABO blood type, stress, exercise) may mask mild hemophilia.

Weight-bearing joints and other joints are principal sites of bleeding in patients with hemophilia. The muscles most commonly affected are the flexor groups of the arms and gastrocnemius of the legs. Iliopsoas bleeding is dangerous because of the large volume of blood loss and because compression of the femoral nerve may occur.

In the genitourinary tract, gross hematuria may occur in as many as 90% of patients. In the GI tract, bleeding may complicate common GI disorders. Bleeding in the CNS is the leading cause of hemorrhagic death in patients with hemophilia.

Acquired hemophilia

Acquired hemophilia due to an autoantibody in previously hemostatically normal individuals tends to affect elderly persons who have comorbid conditions, but may also develop post partum. Persons with acquired hemophilia may experience extensive, often life threatening, bleeding before the condition is recognized.

In contrast to persons with severe inherited hemophilia A, in whom joint bleeding is common, patients with acquired hemophilia present with large intramuscular, retroperitoneal, limb, subcutaneous, genitourinary, 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 acquired hemophilia usually comes to attention 2 to 5 months after delivery, when bleeding symptoms supervene. Rarely, the inhibitor may develop during pregnancy.

Physical Examination

Systemic signs of hemorrhage include the following:

Organ system–specific signs and symptoms of hemorrhage include the following:

Signs of infectious disease include the following:

Approximately 30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding (eg, after circumcision). Approximately 1-2% of neonates have intracranial hemorrhage. Other neonates may present with severe hematoma and prolonged bleeding from the cord or umbilical area.

After the immediate neonatal period, bleeding is uncommon in infants until they become toddlers, when trauma-related soft-tissue hemorrhage occurs. Young children may also have oral bleeding when their teeth are erupting. Bleeding from gum and tongue lacerations is often troublesome because the oozing of blood may continue for a long time despite local measures.

As children grow and become more physically active, hemarthroses and hematomas occur. Chronic arthropathy is a late complication of recurrent hemarthrosis in a target joint. Traumatic intracranial hemorrhage is a serious life-threatening complication that requires urgent diagnosis and intervention.

Petechiae usually do not occur in patients with hemophilia. The reason is that petechiae are manifestations of capillary blood leakage, which is typically the result of vasculitis or abnormalities in the number or function of platelets.

Hemophilia is classified according to clinical severity as mild, moderate, or severe (see Table 1, below). Patients with severe disease usually have less than 1% factor VIII (FVIII) activity and experience spontaneous hemarthrosis and soft-tissue bleeding in the absence of apparent precipitating trauma. Patients with moderate disease have 1-5% FVIII activity and bleed with minimal trauma. Patients with mild hemophilia have more than 5% factor activity and bleed only after significant trauma or surgery.

Table 1. Hemophilia Severity, Factor Activity, and Hemorrhage Type



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See Table

Direct the examination to identify signs related to spontaneous bleeding, or bleeding with minimal challenge, in the joints, muscles, and other soft tissues. Observe the patient's posture. Examine the weight-bearing joints, especially the knees and ankles, and, in general, the large joints for deformities or ankylosis. Look for jaundice and other signs of liver failure (eg, cirrhosis), and for signs of opportunistic infections in patients who are HIV positive.

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 common locations for a pseudotumor (see the images below).



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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.



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

Approach Considerations

Laboratory studies for suspected hemophilia include a complete blood cell count, coagulation studies, and a factor VIII (FVIII) assay. Never delay indicated coagulation correction pending diagnostic testing.

On the hemoglobin/hematocrit assay, expect normal or low values. Expect a normal platelet count. On coagulation studies, the bleeding time and prothrombin time (which assesses the extrinsic coagulation pathway) are normal.

Usually, the activated partial thromboplastin time (aPTT) is prolonged; however, a normal aPTT does not exclude mild or even moderate hemophilia because of the relative insensitivity of the test. The aPTT is significantly prolonged in severe hemophilia.

For FVIII assays, levels are compared with a normal pooled-plasma standard, which is designated as having 100% activity or the equivalent of FVIII U/mL. Normal values are 50-150%. Values in hemophilia are as follows:

Aging, pregnancy, oral contraceptive use, and estrogen replacement therapy are associated with increased FVIII levels. Because FVIII is a large molecule that does not cross the placenta, the diagnosis can be made at birth with quantitative assay of cord blood.

Differentiation of hemophilia A from von Willebrand disease is possible by observing normal or elevated levels of von Willebrand factor antigen and ristocetin cofactor activity. Bleeding time is prolonged in patients with von Willebrand disease but normal in patients with hemophilia.

In patients with an established diagnosis of hemophilia, periodic laboratory evaluations include screening for the presence of FVIII inhibitor and screening for transfusion-related or transmissible diseases such as hepatitis and HIV infection. Screening for infection may be less important in patients who receive only recombinant FVIII concentrate.

Imaging studies for acute bleeds

Early and aggressive imaging is indicated, even with low suspicion for hemorrhage, after coagulation therapy is initiated. Imaging choices are guided by clinical suspicion and the anatomic location of involvement.

Head CT scans without contrast are used to assess for spontaneous or traumatic intracranial hemorrhage. Perform magnetic resonance imaging (MRI) on the head and spinal column for further assessment of spontaneous or traumatic hemorrhage. MRI is also useful in the evaluation of the cartilage, synovium, and joint space.

Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions. This technique is not helpful for evaluating the bone or cartilage. Special studies such as angiography and nucleotide bleeding scan may be clinically indicated.

Testing for Inhibitors

Laboratory confirmation of a FVIII inhibitor is clinically important when a bleeding episode is not controlled despite infusion of adequate amounts of factor concentrate. For the assay, the aPTT measurement is repeated after incubating the patient's plasma with normal plasma at 37°C for 1-2 hours. If the prolonged aPTT is not corrected, the inhibitor concentration is titrated using the Bethesda method. Ideally, the Nijmegen modification of the Bethesda inhibitor assay should be used to detect an inhibitor if the mixing test result is positive.[11]

By convention, more than 0.6 Bethesda units (BU) is considered a positive result for an inhibitor. Less than 5 BU is considered a low titer of inhibitor, and more than that is a high titer. The distinction is clinically significant, as patients with low-titer inhibitors may respond to higher doses of FVIII concentrate while those with high-titer inhibitors require treatment with agents that bypass FVIII and consideration for induction of immune tolerance.

Caution is warranted when obtaining blood samples for coagulation assays from heparinized central lines because of the effect of heparin contamination on all coagulation test results. The excess heparin causes false-positive results and/or higher inhibitor titer values than are actually present in the patient, because heparin is also an inhibitor of coagulation.

One study found significant heparin contamination in 45% of all specimens obtained through implanted venous access devices. These researchers suggested that all blood samples obtained from such devices, which are usually flushed with heparin, should be treated with heparinase before performing an inhibitor assay.[23]

Carrier Testing and Fetal Testing

Screening for carrier status can be performed by measuring the ratio of FVIII coagulant activity to the concentration of von Willebrand factor (vWF) antigen. A ratio that is less than 0.7 suggests carrier status.

Direct genetic testing for known gene mutation is more accurate. Linkage analysis by restriction fragment length polymorphism (RFLP) in multiple family members can be used. Direct mutation analysis is available in several laboratories for unknown FVIII mutations. Inversion of the FVIII gene can be detected by Southern blot.

For prenatal testing, carriers whose mutation has been identified can have chorionic villus sampling at approximately 10-12 weeks' gestation or amniocentesis at 16-20 weeks' gestation to obtain fetal cells for DNA analysis or for linkage studies. If DNA analysis cannot be performed, then fetal blood obtained by fetoscopy at approximately 20 weeks' gestation can be assayed for factor VIII level.

All of those procedures carry a risk ranging from a low of 0.5% for maternal-fetal complications to a high of 1-6% for fetal death from fetoscopy. These procedures should be undertaken only after patients receive intense genetic and obstetric counseling. Genetic counseling before the woman becomes pregnant is ideal and may help couples make informed decisions before conception.

Noninvasive prenatal diagnosis using quantitative digital polymerase chain reaction testing of free fetal DNA in the maternal circulation has been reported. However, this technique remains a research tool.[24]

If the fetus is a female, the couple may elect to carry the pregnancy to term because carriers rarely have bleeding problems. If the fetus is a severely affected male, the couple must make a decision about continuing the pregnancy to term. With pregnancies that will be carried to term, prenatal diagnosis allows for planning of delivery so as to minimize the risk of intracranial hemorrhage (eg, avoidance of vacuum devices).[24]

Radiography

Radiography for joint assessment is of limited value in acute hemarthrosis. Evidence of chronic degenerative joint disease may be visible on radiographs in patients who have been untreated or inadequately treated or in those with recurrent joint hemorrhages. In these patients, radiographs may show synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage that progresses with subchondral bone cyst formation.

Hemophilic arthropathy evolves through 5 stages, starting as an intra-articular and periarticular edema due to acute hemorrhage and progressing to advanced erosion of the cartilage with loss of the joint space, joint fusion, and fibrosis of the joint capsules.[6] See the image below. For discussion of the 5-stage Arnold-Hilgartner classification of hemophilic arthropathy, see Imaging in Musculoskeletal Complications of Hemophilia.



View Image

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

Approach Considerations

The treatment of hemophilia may involve prophylaxis, management of bleeding episodes, treatment of factor VIII (FVIII) inhibitors, and treatment and rehabilitation of hemophilia synovitis. Use of factor replacement products and other medications, including pain medications, is typically required.

Treatment of patients with hemophilia ideally should be provided through a comprehensive hemophilia care center. These centers, which are found in many US cities, follow a multidisciplinary approach, with specialists in hematology, orthopedics, dentistry, and surgery; nurses; physiotherapists; social workers; and related allied health professionals. Patients treated at comprehensive care clinics have been shown to have better access to care, less morbidity, and better overall outcome.

Ambulatory replacement therapy for bleeding episodes is essential for preventing chronic arthropathy and deformities. Home treatment and infusion by the family or patient is possible in most cases. Prompt and appropriate treatment of hemorrhage is important to prevent long-term complications and disability.

Dose calculations are directed toward achieving an FVIII activity level of 30-40% for most mild hemorrhages, of at least 50% for severe bleeds (eg, from trauma) or prophylaxis of major dental surgery or major surgery, and 80-100% in life-threatening hemorrhage. Hospitalization is reserved for severe or life-threatening bleeds, such as large-soft tissue bleeds; retroperitoneal hemorrhage or other internal bleeding; and hemorrhage related to head injury, surgery, or dental work.

Patients can be treated with prophylaxis or with intermittent, on-demand therapy for bleeding events. Prophylaxis has been shown in many studies to prevent or at least reduce the progression of damage to target sites, such as joints.[25, 26] According to a review of 6 randomized controlled trials, preventive therapy started early in childhood, as compared with on-demand treatment, can reduce total bleeds and bleeding into joints, resulting in decreased overall joint deterioration and improved quality of life.[27]

In most developed countries with access to recombinant product, prophylaxis is primary (ie, therapy is started in patients as young as 1 y and continues into adolescence). A cost-benefit analysis indicates that this approach reduces overall factor use and significantly reduces morbidity.[28] In situations in which this is not feasible, secondary prophylaxis (ie, therapy after a target joint has developed, to prevent worsening of the joint) is instituted for a defined period.

For prophylaxis, dosing is designed to maintain trough levels of 2% or higher. This usually requires the administration of FVIII 3 times per week. Individualized therapy (ie, tailored prophylaxis) has been also used with success; the best approach has yet to be determined.

The treatment of patients with inhibitors of FVIII is difficult. Bleeding episodes in patients with low-titer inhibitors (ie, concentrations below 5 Bethesda units [BU]) occasionally can be overcome with high doses of factor VIII.[29] Options in other cases include a variety of agents that bypass FVIII, such as activated FVII and emicizumab; desensitization; and immune tolerance induction.

In patients who develop synovitis from joint bleeds, injection of radioisotopes into the joint to ablate the synovium (radiosynovectomy) can be used to decrease bleeding, slow progression of cartilage and bone damage, and prevent arthropathy. Unresponsive cases may require arthroscopic synovectomy or arthroplasty.[30]

Increasing evidence associates hemophilia with low bone mineral density; consequently, careful assessment and management of fracture risk are recommended. Regular exercise, fall prevention strategies, and optimization of calcium and vitamin D intake are recommended, along with prophylactic factor replacement therapy in severe hemophilia.[22]

Please see the following for more information:

Prehospital Care

Rapid transport to definitive care is the mainstay of prehospital care. Prehospital care providers should do the following:

Emergency Department Care

Before a patient with hemophilia is treated, the following information should be obtained:

Use aggressive hemostatic techniques. Correct coagulopathy immediately. Include a diagnostic workup for hemorrhage, but never delay indicated coagulation correction pending diagnostic testing. If possible, draw blood for the coagulation studies (see Workup), including 2 blue-top tubes to be spun and frozen for factor and inhibitor assays.

Minor bleeding, as from cuts and abrasions, may respond to conservative measures, such as pressure and ice. Mild hematuria may subside spontaneously. 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 FVIII 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 FVIII 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 bleeds 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 FVIII 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 reduce usage of expensive factor replacement product by approximately 30%.

If admission is indicated, disposition (intensive care unit vs floor) should be based on severity of hemorrhage and potential for morbidity and death. Choose the attending service based on the etiology and site of hemorrhage. Hematology/ blood bank/pathology consultation is mandatory.

Patients whose condition and bleeding are stabilized should be transferred to a comprehensive hemophilia care center for further treatment and monitoring. These centers offer a multidisciplinary approach by specialists experienced in hemophilia.

Further outpatient care for patients with minor hemorrhage (not life threatening) consists of continued hemostatic measures (eg, brief joint immobilization, bandaging). Hematologist or primary care physician follow-up care is indicated. The patient should continue factor replacement and monitoring.

If a patient has HIV seroconversion, arrange appropriate outpatient care at a specialty infectious disease clinic. These patients require monitoring of their CD4 count, observation for adverse effects of anti-HIV treatment, and monitoring for and treatment of possible opportunistic infections.

Factor VIII Concentrates

Various FVIII concentrates are available to treat hemophilia A. Fresh frozen plasma and cryoprecipitate are no longer used in hemophilia because of the lack of safe viral elimination and concerns regarding volume overload.

Various purification techniques are used in plasma-based FVIII concentrates to reduce or eliminate the risk of viral transmission, including heat treatment, cryoprecipitation, and chemical precipitation. These techniques inactivate viruses such as hepatitis B virus, hepatitis C virus, and HIV. However, the transmission of nonenveloped viruses (eg, parvovirus and hepatitis A virus) and poorly characterized agents (eg, prions) is still a potential problem.

Many recombinant FVIII concentrates are currently available. The advantage of such products is the elimination of viral contamination. Third-generation products with no exposure to animal proteins further decrease this risk. The effectiveness of these products appears comparable to that of plasma-derived concentrates. Concerns regarding higher incidences of inhibitor development appear to be unwarranted.

With wider availability of improved products (ie, better stability, purity), use of continuous infusion for administration has incrementally increased. Continuous infusion of antihemophilic factors prevents the peaks and valleys in factor concentrations that occur with intermittent infusion; this benefit is particularly important when treatment is required for prolonged periods.

Besides improved hemostasis, continuous infusion decreases the amount of factor used, which can result in significant savings. The indications for this approach include the following:

In most minor-to-moderate bleeding episodes, intermittent boluses are adequate. Intermittent boluses can also be used prophylactically, especially in the treatment of recurrent bleeding in target joints.

Doses of FVIII concentrate are calculated according to the severity and location of bleeding. Guidelines for dosing are provided in Table 2 below. As a rule, FVIII 1 U/kg increases FVIII plasma levels by 2%. The reaction half-time is 8-12 hours. Target levels by hemorrhage severity are as follows:

Table 2. General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia



View Table

See Table

Variations in responses related to patient or product parameters make determinations of factor levels important. These determinations are performed immediately after infusions and thereafter to ensure an adequate response and maintenance levels. Obtain factor level assays daily before each infusion to establish a stable pattern of replacement regarding the dose and frequency of administration.

Desmopressin

Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP), is considered the treatment of choice for mild and moderate hemophilia A. It is not effective in the treatment of severe hemophilia. DDAVP stimulates a transient increase in plasma FVIII levels. Other possible mechanisms of action are noted.

DDAVP may result in sufficient hemostasis to stop a bleeding episode or to prepare patients for dental and minor surgical procedures. A test dose should be performed before prophylactic use. It can be intravenously administered at a dose of 0.3 mcg/kg of body weight in the inpatient setting. Its peak effect is observed in 30-60 minutes.

If the test dose produces an appropriate rise in the FVIII level, at least 1 week should elapse before performance of any procedures. This allows time for replenishment of endogenous stores of FVIII, so that an adequate DDAVP-induced rise in FVIII is obtained for the procedure.

A concentrated DDAVP intranasal spray is available for outpatient use. Its effectiveness is similar to that of the intravenous preparation, although its peak effect is observed later, at 60-90 minutes after administration.

Hyponatremia due to water retention is a potentially serious adverse effect. Patients should be advised to limit water intake for approximately 12-18 hours after the administration of DDAVP, until the antidiuretic effect passes, and should avoid three consecutive daily doses. In addition, patients should be alerted to the distinct drop in urine output they will experience after DDAVP administration, and the subsequent increase when the antidiuretic effect of DDAVP wanes.

Tachyphylaxis may occur even after first dose, but the drug can be effective again after several days. A minor adverse effect of DDAVP is facial flushing.

Management of Bleeding Episodes by Site

Musculoskeletal bleeding

The most common sites of clinically significant bleeding are joint spaces. Weight-bearing joints in the lower extremities are often target areas for recurrent bleeding. Joint hemorrhage is associated with pain and limitation in the range of motion, which is followed by progressive swelling in the involved joint.

Immobilization of the affected limb and the application of ice packs are helpful in diminishing swelling and pain. Early infusion upon the recognition of initial symptoms of a joint bleed may often eliminate the need for a second infusion by preventing the inflammatory reaction in the joint. Prompt and adequate replacement therapy is the key to preventing long-term complications. Cases in which treatment begins late or causes no response may require repeated infusions for 2-3 days.

Do not aspirate hemarthroses unless they are severe and involve significant pain and synovial tension. Some hemarthroses may pose particular problems because they interfere with the blood supply. Arthrocentesis is indicated if septic arthritis is suspected.

Hip joint hemorrhages can be complicated by aseptic necrosis of the femoral head. Administer adequate replacement therapy for at least 3 days.

Deep intramuscular hematomas are difficult to detect and may result in serious muscular contractions. Appropriate and timely replacement therapy is important to prevent such disabilities.

Iliopsoas muscle bleeding may be difficult to differentiate from hemarthrosis of the hip joint. Physical examination usually reveals normal hip rotation but significant limitation of extension. Ultrasonography in the involved region may reveal a hematoma in the iliopsoas muscle. This condition requires adequate replacement therapy for 10-14 days and a physical therapy regimen that strengthens the supporting musculature.

Closed-compartment hemorrhages pose a significant risk of damaging the neurovascular bundle. These occur in the upper arm, forearm, wrist, and palm of the hand. They cause swelling, pain, tingling, numbness, and loss of distal arterial pulses. Infusion must be aimed at maintaining a normal level of FVIII. Other interventions include elevation of the affected part to enhance venous return and, rarely, surgical decompression.

Oral bleeding

Oral bleeding from the frenulum and bleeding after tooth extractions are not uncommon. Bleeding is aggravated by the increased fibrinolytic activity of saliva. If not treated appropriately, dental bleeding can persist and expand to sublingual, pharyngeal, facial, or dissecting neck hematomas or other serious bleeding.

Combine adequate replacement therapy with an antifibrinolytic agent (epsilon-aminocaproic acid [EACA]) to neutralize the fibrinolytic activity in the oral cavity. Topical agents such as fibrin sealant, bovine thrombin, and human recombinant thrombin can also be used.[31]

Hematoma in the pharynx or epiglottic regions frequently results in partial or complete airway obstruction; therefore, it should be treated with aggressive infusion therapy. Such bleeding may be precipitated by local infection or surgery.

Dental extractions or mucosal procedures can be handled with a single preprocedure dose of FVIII, to achieve a peak level of approximately 30%, along with a single 20 mg/kg dose of EACA.[32] Routine practice is to continue antifibrinolytic therapy in an outpatient setting for several days after the dental extraction, with a gradual tapering of the dosage over 5-7 days.

Gastrointestinal bleeding

GI bleeds are much less common in persons with hemophilia than in those with von Willebrand disease and, therefore, require an evaluation for an underlying cause. Manage GI hemorrhage with repeated or continuous infusions to maintain nearly normal circulating levels of FVIII.

Intracranial bleeding

Intracranial hemorrhage is often trauma induced; spontaneous intracranial hemorrhages are rare. If CNS hemorrhage is suspected, immediately begin an infusion prior to radiologic confirmation. Maintain the factor level in the normal range for 7-10 days until a permanent clot is established.

All head injuries must be managed with close observation and investigated by imaging such as CT scanning or MRI. If the patient is not hospitalized, instruct the patient and his or her family regarding the neurologic signs and symptoms of CNS bleeding so that the patient can know when to return for reinfusion.

Treatment of Patients with Inhibitors

Inhibitors are antibodies that neutralize factor VIII (FVIII) and can render replacement therapy ineffective. They are found more commonly in patients with moderate to severe hemophilia (up to 30% of those with severe disease) who have received significant amounts of replacement therapy. Inhibitors develop in relatively young children, usually within their first 50 exposures to FVIII.

Rarely, inhibitors can develop in individuals without genetic hemophilia (eg, elderly persons, pregnant women). These occasionally are responsive to immunosuppressive therapy (eg, prednisone).

The treatment of patients with inhibitors of FVIII is difficult. Assuming no anamnestic response, low-titer inhibitors (ie, concentrations below 5 Bethesda units [BU]) occasionally can be overcome with high doses of factor VIII.[29] There is no established treatment for bleeding episodes in patients with high-titer inhibitors.

Other approaches to treating patients with FVIII inhibitors include the following:

Emicizumab

Emicizumab is a first-in-class bispecific monoclonal antibody that performs the function of activated FVIII, bridging activated FIX and FX to restore the coagulation cascade, but is unaffected by FVIII inhibitors. In November 2017, following a priority review, the FDA approved emicizumab for routine prophylaxis of bleeding episodes in adult and pediatric patients (including newborns) with hemophilia A who have FVIII inhibitors. Approval was based on the HAVEN 1 and 2 clinical trials. In 2018, the FDA approved the use of emicizumab for patients without FVIII inhibitors, based on the HAVEN 3 trial results.[50]

The HAVEN 1 trial included 109 adult and adolescent males aged 12 years or older who had hemophilia A with inhibitors. Patients taking emicizumab experienced about 2.9 treated bleeding episodes per year, compared with about 23.3 treated bleeding episodes per year for patients who did not receive prophylactic treatment, representing an 87% reduction in the rate of treated bleeding episodes (P < 0.001). Emicizumab-treated patients also reported an improvement in hemophilia-related symptoms (painful swellings and joint pain) and physical functioning (pain with movement and difficulty walking).[33]

Interim results from the single-arm HAVEN 2 study in children aged younger than 12 years with hemophilia A with inhibitors who received emicizumab prophylaxis are consistent with the positive results from the HAVEN 1 study. After a median observation time of 12 weeks, only 1 of the 19 study patients receiving emicizumab reported a treated bleed.[34]

Three patients in the HAVEN 1 trial who experienced breakthrough bleeding despite emicizumab prophylaxis and were treated with PCC developed thrombotic microangiopathy (TMA). Episodes of TMA occurred only in patients who received, on average, cumulative doses of PCC of more than 100 U/kg daily for 24 hours or more. This complication appears to represent a unique interaction between emicizumab and PCC, as no cases of TMA had previously been reported in patients receiving PCC alone. Strategies for treating breakthrough bleeding in patients receiving emicizumab may include the use of recombinant FVIIa, FVIII in patients with a low inhibitor titer, and lower doses of PCC.[35]

Recombinant activated factor VII

Recombinant activated FVII (FVIIa; Eptacog Alfa or NovoSeven) has become the first choice of bypassing agents.[36] Recombinant FVIIa is a vitamin K–dependent glycoprotein that is structurally similar to human plasma–derived FVIIa.[37] It is manufactured by using DNA biotechnology.

Intravenous recombinant FVIIa has been studied for the treatment of bleeding episodes and for providing hemostasis during surgery in patients with a particular bleeding diathesis.[36] Recombinant FVIIa is also effective and well tolerated in patients with acquired hemophilia and in those with Glanzmann thrombasthenia.

To date, recombinant activated FVIIa has proved to be relatively free of the risk of antigenicity, thrombogenicity, and viral transmission. However, the cost of this product and its short half-life have precluded its use as prophylaxis in patients with inhibitors for FVIII; furthermore, when it has been used for this indication, select patients have had severe complications related to bleeding.

In pediatric patients, off-label treatment with recombinant FVIIa significantly reduced blood product administration, with 82% of patients subjectively classified as responders. Clinical context and pH values before administration were independently associated with response and 28-day mortality. Thromboembolic adverse events were reported in 5.4% of patients.[38]

Desensitization

Desensitization in nonemergency situations also may be feasible. This approach comprises large doses of FVIII along with steroids or intravenous immunoglobulin (IVIG) and cyclophosphamide. Success rates of 50-80% have been reported. In life-threatening bleeding, methods to quickly remove the inhibiting antibody have been tried. Examples include vigorous plasmapheresis in conjunction with immunosuppression and infusion of FVIII with or without antifibrinolytic therapy.

Immune tolerance induction

In ITI, tolerance to FVIII is induced by means of regular exposure to FVIII over several months to years.[29, 39] The overall likelihood of success with ITI is 70% ± 10%.

Factors associated with successful outcome of ITI include the following[40] :

First described by Backmann in 1977, ITI has been used with variations in the dosing schedule for FVIII and with or without immunosuppressive therapy (eg, cyclophosphamide, prednisone). Most of the recent protocols that use FVIII alone have avoided use of immunosuppression because of the toxicity risk. This technique is well established in acquired hemophilia but not in congenital hemophilia.

Rituximab, a chimeric human-mouse monoclonal antibody against CD20 that rapidly and specifically depletes B cells, has been used with success in ITI.[41, 42] A 4-week course of weekly rituximab, with or without prednisone and/or cyclophosphamide, has shown durable and complete responses in several small trials in patients with autoimmune hemophilia and inhibitor titers of 5 to more than 200 BU.[43] Rituximab appears to be more effective in treating inhibitors in acquired hemophilia than in hereditary hemophilia.[44, 45]

The choice of FVIII dosing regimen for ITI has ranged from 50 IU/kg 3 times weekly to 300 IU/kg/d. An international study in patients with severe hemophilia and high-titer inhibitors found no significant difference between low-dose and high-dose ITI in terms of the percentage of subjects achieving tolerance (70%) or in the time taken to achieve tolerance. However, the study was stopped early because of safety considerations involving bleeding (significantly more common early on in the low-dose arm) and lack of statistical power.[40]

Prophylactic Treatment

Most of the care for children with severe hemophilia now takes place at home, in the community, and at school, allowing these children to participate in normal activities that are otherwise impossible. This approach resulted from the development of prophylactic regimens of factor concentrate infusions that are administered at home, usually by a parent.

The main goal of prophylactic treatment is to prevent bleeding symptoms and organ damage, in particular to joints. Hemophilia arthropathy that results from recurrent or target joint bleeding can be prevented by this method.

Prophylaxis is not universally accepted, with only about half the children with hemophilia A receiving this treatment modality in the United States. Reasons cited for the lack of acceptance include need for venous access, factor availability, repeated venipunctures, and cost, among others. Research questions that remain unanswered include when to initiate and stop infusions, dosing, and dose schedule.

In December 2013, the US Food and Drug Administration (FDA) expanded the indication for anti-inhibitor coagulant complex (Feiba NF) to include routine prophylaxis in patients with hemophilia A or B who have developed inhibitors. Approval was based on data from a pivotal phase III study in which a prophylactic regimen resulted in a 72% reduction in median annual bleed rate compared with on-demand treatment.[46] An earlier study showed a 62% reduction in all bleeding episodes with prophylaxis versus an on-demand regimen.[47]

In June 2014 the FDA approved a long-acting recombinant FVIII–Fc fusion protein (rFVIIIFc) product (Eloctate) for control of bleeding episodes, management of perioperative bleeding, and routine prophylaxis in patients with hemophilia A. For routine prophylaxis, rVFIIIFC is infused every 4 days, whereas other available recombinant FVIII products are administered every 2-3 days.[48, 49]

The rFVIIIFc product was developed by fusing rFVIII to the Fc portion of IgG1, which allows a naturally occurring pathway to prolong the product's duration of action. FDA approval was based on a study in 164 patients with hemophilia A in which the median rate of bleeding episodes with prophylactic use of rFVIIIFc was 1.6 per year, compared with 33.6 per year in patients receiving on-demand treatment.[48, 49]

Other rFVIII products are also approved by the FDA for routine prophylaxis (eg, NovoEight, Kogenate, Nuwiq, Adynovate, Kovaltry, Afstyla, Jivi). Adynovate and Jivi are pegylated rFVIII products that allow less frequent administration. The frequency of administration for Jivi is every 5 days for prophylaxis, whereas, Adynovate is administered 2 times per week.

Emicizumab

The bispecific monoclonal antibody emicizumab is approved for prophylaxis in adults and children (including newborns) who have hemophilia A with or without FVIII inhibitors (see Treatment of Patients with Inhibitors). The HAVEN 3 trial demonstrated that emicizumab prophylaxis is also effective in patients without inhibitors.[50]

In this phase III trial, 152 patients 12 years of age or older who had been receiving episodic treatment with FVIII were randomized to emicizumab prophylaxis once weekly or every 2 weeks, or no prophylaxis. The annualized bleeding rate was 1.5 in patients receiving weekly dosing and 1.3 with biweekly dosing, versus 38.2 events in patients receiving no prophylaxis. More than half of the study patients who received prophylaxis had no treated bleeding events. Those patients who had previously received FVIII prophylaxis had significantly lower bleeding rates with emicizumab prophylaxis.[50]

Assessing adherence to prophylaxis

The Validated Hemophilia Regimen Treatment Adherence Scale–Prophylaxis (VERITAS-Pro) prophylaxis is a patient/parent questionnaire that uses 6 subscales (time, dose, plan, remember, skip, communicate), each containing 4 items, to assess patient adherence to prophylactic hemophilia treatment. In a study of 67 patients with hemophilia, including 53 with severe FVIII deficiency, Duncan et al found a strong correlation between VERITAS-Pro scores and adherence assessments (eg, infusion log entries).[51]

Pain Management

Pain management can be challenging in patients with severe hemophilia. Acute bleeding in joints and soft tissues can be extremely painful. This requires immediate analgesic relief.

Hemophilic chronic arthropathy is painful. Narcotic agents have been used, but their benefit for long-term therapy is limited by side effects, the development of tolerance, and the risk of addiction.

Nonsteroidal anti-inflammatory drugs can be effective in managing acute and chronic arthritic pain. Although they pose a risk of gastrointestinal bleeding, their effects on platelet function are reversible. Avoid aspirin because of its irreversible effect on platelet function. Other analgesics may include acetaminophen in combination with small amounts of codeine or synthetic codeine analogs.

Complications

HIV-associated immune thrombocytic purpura is an exceedingly serious complication in patients with hemophilia because it may result in lethal intracranial bleeding. Correct platelet counts to less than 50,000/mL. Steroids are of limited effectiveness, and intravenous immunoglobulin or anti-Rh(D) generally induces only transient remissions. Anti-HIV medications and splenectomies may result in long-term improvement of thrombocytopenia.

Allergic reactions are occasionally reported with the use of factor concentrates. Premedication or adjustment of the rate of infusion may resolve the problem.

Deterrence/Prevention

Do not circumcise boys born to mothers who are known or thought to be carriers of hemophilia unless disease in the infant has been excluded with appropriate laboratory testing. Perform blood assays of FVIII with cord blood. When a cord blood sample is not available, obtain a sample from a superficial limb vein; avoid femoral and jugular sites.

Routine immunizations that require injection (eg, diphtheria, tetanus toxoids, and pertussis [DPT] or measles-mumps-rubella [MMR] vaccines) may be given by means of a deep subcutaneous (rather than deep intramuscular) injection with a fine-gauge needle. Administer the hepatitis B vaccine (now routinely administered to all children) soon after birth to all infants with hemophilia. Administer the hepatitis A vaccine to those individuals with hemophilia and no hepatitis A virus antibody in their serum.

In severe hemophilia, consider prophylactic or scheduled factor VIII. Prophylactic replacement of FVIII is used to maintain a measurable level at all times, with the goal of avoiding hemarthrosis and the vicious cycle of repetitive bleeding and inflammation that results in destructive arthritis.[52] This goal is achieved by administering factor 2-3 times a week. The National Hemophilia Foundation has recommended the administration of primary prophylaxis, beginning at the age of 1-2 years.

Carrier testing is valuable for women who are related to obligate carrier females or males with hemophilia. Carrier testing may prevent births of individuals with major hemophilia. This testing can be offered to women interested in childbearing who have a family history of hemophilia. Prenatal diagnosis is important even if termination of the pregnancy is not desired because plans for delivery and neonatal management can be made.

Preimplantation genetic diagnosis has been used as a possible alternative to prenatal diagnosis in combination with in vitro fertilization to help patients avoid having children with hemophilia or other serious inherited diseases.[53, 54, 55] The genetic diagnosis is made by using single cells obtained during biopsy from embryos before implantation. For this, fluorescence in situ hybridization is used. This technique circumvents pregnancy termination. However, it is expensive and has limited success rates, with a 22% chance for a live birth.[24]

Activity

Generally, individuals with severe hemophilia should avoid high-impact contact sports and other activities with a significant risk of trauma. However, mounting evidence suggests that appropriate physical activity improves overall conditioning, reduces injury rate and severity, and improves psychosocial functioning. Kumar et al reported that aerobic exercise on a stationary cycle resulted in significant improvement in hemostatic indices in post-adolescent patients with mild to moderate hemophilia A.[56]

Patients with severe hemophilia can bleed from any anatomic site after negligible or minor trauma, or they may even bleed spontaneously. Any physical activity may trigger bleeding in soft tissues. Prophylactic factor replacement early in life may help prevent bleeding during activity, as well as helping to prevent chronic arthritic and muscular damage and deformity.

Gene Therapy

With the cloning of FVIII and advances in molecular technologies, the possibility of a cure for hemophilia with gene therapy was conceived.[57] Possible approaches to gene therapy for hemophilia A include the following[58] :

Preclinical studies in mice and dogs with hemophilia have resulted in long-term correction of the bleeding disorders and, in some cases, a permanent cure. Preliminary results in human trials of gene therapy for hemophilia B have yielded encouraging results, but hemophilia A has proved more problematic, given the much larger size of FVIII DNA and the frequent development of neutralizing antibodies.[59] Implantation of liver-derived stem cells that have been expanded in vitro is under consideration, as these could theoretically induce a steady-state production of quantities of factor sufficient to prevent spontaneous bleeding.[60]

In December 2017, Rangarajan et al reported sustained rises in FVIII levels and declines in bleeding rates in patients with severe hemophilia A who received gene therapy with a single intravenous dose of valoctocogene roxaparvovec, a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain–deleted human FVIII. In the seven participants who received a high dose of of valoctocogene roxaparvovec, FVIII activity levels remained in the normal range 1.5 years after gene transfer, and their annualized bleeding rate dropped from 16.5 to 0. All participants were able to completely discontinue prophylactic FVIII infusions, and none developed FVIII inhibitors.[61, 62]

Consultations

Management should be provided in coordination with a comprehensive hemophilia care center. Specific consultations may be indicated with a hematologist, blood bank, pathologist, or others as indicated by hemorrhagic complications. Early hematology consultation for management of inhibitors is essential. Annual dental evaluation is recommended.

A genetic counselor may be consulted. Genetic testing for hemophilia A is available and must be offered to potential carriers. Prenatal testing is performed by using amniocentesis or chorionic villus biopsy.

Before elective surgery is planned, a hematologist should be consulted to arrange adequate coverage with antihemophilic factors and to arrange close follow-up to ensure that factor levels are sufficient during the operation and in the recovery and healing period.

Consult an orthopedic surgeon in cases of permanent joint deformities resulting from recurrent hemarthrosis, as may occur in relatively neglected cases or, occasionally, in cases of repetitive bleeding in a single joint despite intensive prophylactic replacement of factor and physiotherapy. Open surgical or arthroscopic synovectomy may decrease bleeding and pain in the affected joint.

Radiosynovectomy

In patients who develop synovitis from joint bleeds, intra-articular injection of radioisotopes to ablate the synovium (radiosynovectomy) can be used to decrease bleeding, slow progression of cartilage and bone damage, and prevent arthropathy. Yttrium-90 and rhenium-186 have proved equally effective for radiosynovectomy.[63] A review by Rodriguez-Merchan et al concluded that radiosynovectomy is effective, safe, and well tolerated.[63]

The review by Rodriguez-Merchan included 500 synovectomies in 443 joints of 345 patients with chronic hemophilic synovitis. One to three injections were administered, with a 6-month interval between injections. On average, the number of hemarthroses decreased by 64.1%, articular pain decreased by 69.4%, the degree of synovitis decreased by 31.3%, and the World Federation of Haemophilia score improved by 19%. Only four complications (0.9%) occurred. In 28 joints (6.3%), arthroscopic synovectomy or total knee replacement was eventually required.[30]

 

 

Guidelines Summary

Guidelines on the management of acute joint bleeds and chronic synovitis in hemophilia were issued by the United Kingdom Haemophilia Centre Doctors' Organisation in 2017.[64] Recommendations on hemostatic management of patients with hemophilia A without inhibitors were as follows:

Recommendations for hemostatic management of patients with inhibitors to FVIII were as follows:

 

Medication Summary

Factor VIII (FVIII) is the treatment of choice for acute or potential hemorrhage. Recombinant FVIII concentrate is generally the preferred source of factor VIII. Prophylactic administration of FVIII is often recommended for pediatric patients with severe disease. The FVIII activity level should be corrected to 100% of normal for potentially serious hemorrhage (eg, central nervous system, trauma related, gastrointestinal [GI], genitourinary, epistaxis) and to 30-50% of normal for minor hemorrhage (eg, hemarthrosis, oral mucosal, muscular).

One unit of FVIII is the amount of FVIII in 1 mL of plasma (1 U/mL or 1%). The volume of distribution of FVIII is that of plasma, approximately 50 mL/kg. The difference between the desired FVIII activity level and the patient's native FVIII activity level can be calculated by simple subtraction and expressed as a fraction (eg, 100% - 5% = 95% or 0.95).

To determine the number of units of FVIII needed to correct the FVIII activity level, use the following formula:

Units FVIII = (weight in kg)(50 mL plasma/kg)(1 U FVIII/mL plasma)(desired FVIII level minus the native FVIII level)

As an example, an 80-kg individual diagnosed with hemophilia with known 1% FVIII activity level presents to the emergency department with a severe upper GI bleed. The correct dose of FVIII to administer in this case would be calculated as follows:

Units FVIII = (80 kg)(50 mL/kg)(1 U FVIII/mL)(0.99) = 3960

The next dose should be administered 12 hours after the initial dose and is one half the initial calculated dose. Minor hemorrhage requires 1-3 doses of FVIII. Major hemorrhage requires many doses and continued monitoring of FVIII activity with the goal of keeping the trough activity level at no lower than 50%. Continuous infusions of FVIII may be considered for major hemorrhage.

The specific factor product that patients use is often part of their individualized treatment plan. Patients, or parents of young children, will usually be well educated on their dosing/products. This information also can be found on institutional treatment center/blood bank databases.

Other medicinal adjuncts to factor VIII (eg, desmopressin acetate [DDAVP], antifibrinolytics) often are useful in achieving hemostasis and can lessen the need for FVIII infusion. Antifibrinolytic agents, such as aminocaproic acid and tranexamic acid, are especially useful for oral mucosal bleeds but are contraindicated as initial therapies for hemophilia-related hematuria originating from the upper urinary tract because they can cause obstructive uropathy or anuria.

Antihemophilic factor recombinant (Advate, Adynovate, Afstyla, Eloctate, Helixate FS, Jivi, Kogenate FS, Kovaltry, NovoEight, Nuwiq, Obizur, Recombinate, Xyntha)

Clinical Context:  These are synthetic products and are the most commonly used form of treatment when the administration of clotting protein factor VIII is indicated. In hemophilia A patients, it temporarily restores hemostasis

Factor VIII, human plasma derived (Monoclate-P, Hemofil M, Koate DVI)

Clinical Context:  These are pooled plasma products (high purity) with factor VIII, which is necessary for stable clot formation and for maintenance of hemostasis.

Anti-inhibitor coagulant complex (Feiba NF, Feiba VH Immuno)

Clinical Context:  This agent is a freeze-dried sterile human plasma fraction with FVIII inhibitor bypassing activity. It contains factors II, IX, and X, mainly nonactivated; and FVII, mainly in the activated form. It may shorten the activated partial thromboplastin time of plasma containing factor VIII inhibitors.

Anti-inhibitor coagulant complex is indicated for prevention and control of spontaneous hemorrhage or bleeding during surgical interventions in hemophilia patients who have autoantibodies or alloantibodies to coagulation factors. It is also indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B who have developed inhibitors.

Factor VIIa, recombinant (NovoSeven RT)

Clinical Context:  Recombinant activated factor (FVIIa) is indicated for the treatment of bleeding episodes in patients with hemophilia A and inhibitors. When complexed with tissue factor, this agent can activate the conversion of coagulation factor X to factor Xa as well as coagulation factor IX to IXa. Factor Xa, in complex with other factors, then converts prothrombin to thrombin, which leads to the formation of a hemostatic plug by converting fibrinogen to fibrin and thereby inducing local hemostasis. This process may also occur on the surface of activated platelets.

Antihemophilic factor/von Willebrand factor complex (Alphanate, Humate P, Wilate)

Clinical Context:  Antihemophilic Factor (FVIII) and von Willebrand Factor (VWF) are constituents of normal plasma, which are required for clotting. Temporarily increases the plasma level of FVIII, thus minimizing the hazard of hemorrhage in patients with hemophilia A; FVIII is an essential cofactor in activation of Factor X leading to formation of thrombin and fibrin. Indicated for control and prevention of bleeding episodes for hemophilia A in adults and children (brand dependent).

Class Summary

FVIII concentrates replace deficient FVIII in patients with hemophilia A, with the goal of achieving a normal hematologic response to hemorrhage or preventing hemorrhage. Recombinant products should be used initially and subsequently in all newly diagnosed cases of hemophilia that require factor replacement. Agents that bypass FVIII activity in the clotting cascade (eg, activated FVII) are used in patients with FVIII inhibitors.

Emicizumab (Hemlibra, emicizumab-kxwh)

Clinical Context:  Emicizumab is a first-in-class bispecific monoclonal antibody that bridges activated FIX and FX to restore the function of activated FVIII. It is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients (including newborns) with hemophilia A with or without factor VIII inhibitors.

Rituximab (Rituxan)

Clinical Context:  Rituximab is a monoclonal antibody directed against the CD20 antigen on B-lymphocytes. It is recommended as second-line therapy in immune tolerance induction regimens for patients with FVIII inhibitors, especially those with high inhibitor titers. This agent binds to, and mediates destruction of, B-cells, thereby decreasing production of FVIII inhibitors and autoimmunization.

Class Summary

Monoclonal antibodies are used to bind to one specific substance in the body (eg, molecules, antigens). This binding is very versatile and can mimic, block, or cause changes to enact precise mechanisms (eg, bridging molecules, replacing or activating enzymes or cofactors, immune system stimulation).

Desmopressin (DDAVP, Stimate)

Clinical Context:  Desmopressin causes a transient increase (up to 4-fold) in FVIII plasma levels of patients with mild hemophilia A. It also produces a dose-dependent increase in plasminogen activator. It is useful for minor hemorrhage episodes only. It may be useful in patients with FVIII inhibitors.

Desmopressin Increases the cellular permeability of the collecting ducts, resulting in renal reabsorption of water. Tachyphylaxis may occur even after first dose, but drug can be effective again after several days.

Class Summary

Desmopressin transiently increases the FVIII plasma level in patients with mild hemophilia A.

Epsilon aminocaproic acid (Amicar)

Clinical Context:  This lysine inhibits fibrinolysis by blocking the binding of plasminogen to fibrin and inhibiting plasminogen and conversion to plasmin, resulting in the inhibition of fibrinolysis. The principal drawbacks of this agent are that thrombi formed during treatment are not lysed, and its effectiveness is uncertain. It has been used to prevent recurrence of subarachnoid hemorrhage.

This agent is widely distributed. Its half-life is 1-2 hours. Peak effect occurs within 2 hours. Hepatic metabolism is minimal.

Tranexamic acid (Cyklokapron, Lysteda)

Clinical Context:  This agent is an alternative to aminocaproic acid. It inhibits fibrinolysis by displacing plasminogen from fibrin. It also inhibits the proteolytic activity of plasmin.

Class Summary

These agents are used in addition to factor VIII replacement for oral mucosal hemorrhage and prophylaxis, as the oral mucosa is rich in native fibrinolytic activity. Their use is contraindicated as initial therapies for hemophilia-related hematuria originating from the upper urinary tract because they can cause obstructive uropathy or anuria. They should not be used in combination with prothrombin complex concentrate (PCC).

What is hemophilia A?What are the signs and symptoms of hemophilia A?Which lab studies are performed in the evaluation of suspected hemophilia A?Which lab values suggest hemophilia A?What values for factor VIII (FVIII) assays indicate hemophilia A?What is the role of imaging studies in the diagnosis of hemophilia A?What is the role of inhibitors testing in the diagnosis of hemophilia A?What is included in the treatment of hemophilia A?Where is treatment for hemophilia A administered?What are the treatment options for acute bleeds in hemophilia A?How is the number of units of factor VIII needed to correct the factor VIII activity level in hemophilia A determined?What are the possible regimens for factor VIII (FVIII) dosing in hemophilia A?What types of factor VIII (FVIII) are available for the treatment of hemophilia A?What are the attributes of desmopressin vasopressin analog for the treatment of hemophilia A?What is the role of antifibrinolytics in the treatment of hemophilia A?Which treatments are used for hemophilia A in patients with inhibitors of factor VIII (FVIII)?What is hemophilia A?What causes morbidity and death in patients with hemophilia A?Which lab studies are performed in the evaluation of suspected hemophilia A?What are the treatment options for hemophilia A?How is the severity of hemophilia A classified?What is the historical background of hemophilia A?What is the pathophysiology of acquired hemophilia A?What is the pathophysiology of factor VIII (FVIII) in hemophilia A?What is the role of the von Willebrand factor (vWF) in the pathophysiology of hemophilia A?What is the role of the coagulation system in the pathogenesis of hemophilia A?What is the role of genetics in the pathophysiology of hemophilia A?What is the role of factor VIII (FVIII) in the pathophysiology of hemophilia A?What causes hemorrhage into joints in the pathophysiology of hemophilia A?What is the role of alloantibody inhibitors in the pathogenesis of hemophilia A?What causes inhibitor formation in patients with hemophilia A?What are the methods used to measure levels of factor VIII (FVIII) inhibitors in hemophilia A?What causes hemophilia A?What is the role of factor VIII (FVIII) in the etiology of hemophilia A?What is the role of genetics in the etiology of hemophilia A?Which genetic mutations have a role in the etiology of hemophilia A?What is the role of gene deletions in the etiology of hemophilia A?What is the role of combined factor V (FV) and factor VIII (FVIII) in the etiology of hemophilia A?What is the prevalence of hemophilia A?What are the racial predilections of hemophilia A?How does the presentation of hemophilia A differ in females?In which age group is hemophilia A typically identified?What is the prognosis of hemophilia A?How have factor concentrates improved the prognosis of hemophilia A?Which factors increase the risk of fractures in patients with hemophilia A?How do viral infections affect the prognosis of hemophilia A?What are the death rates of hemophilia A in the US?Which infectious agents may be transmitted in factor concentrates to patients with hemophilia A?What are possible life-threatening complications of hemophilia A?What causes chronic debilitating joint disease in patients with hemophilia A?What is the mortality rate for hemophilia A?What is included in patient education for hemophilia A?What should be the focus of the history for suspected hemophilia A?What are the signs and symptoms of hemorrhage in hemophilia A?What is the evidence of infectious disease in hemophilia A?Which clinical history is characteristic of severe hemophilia A?Which clinical history is characteristic of mild or moderate hemophilia A?What are the principal bleeding sites in patients with hemophilia A?Which clinical history is characteristic of hemophilia A in the genitourinary tract?Which clinical history is characteristic of acquired hemophilia A?What are the systemic signs of hemorrhage in hemophilia A?What are the physical findings characteristic of hemophilia A?What are the signs of infectious disease in hemophilia A?What is the manifestation of severe hemophilia A?What are physical findings characteristic of hemophilia A after the immediate neonatal period of?What are the physical findings characteristic of hemophilia A in growing children?What is the manifestation of petechiae in hemophilia A?How is hemophilia A classified?What are pseudotumors in hemophilia A?Which conditions should be included in the differential diagnosis of hemophilia A?How is hemophilia A differentiated from hemophilia B?What are the differential diagnoses for Hemophilia A?What is the role of lab studies in the workup of hemophilia A?What is the role of imaging studies in the workup of hemophilia A?How is the presence of factor VIII (FVIII) inhibitor confirmed in hemophilia A?What tests are performed for hemophilia A carrier and fetal screening?What is included in the prenatal testing of hemophilia A carriers?What is the role of radiography in the workup of hemophilia A?What are the treatment options for hemophilia A?How are dose calculations determined in the treatment of hemophilia A?What is the role of prophylaxis in the management of hemophilia A?What are the treatment options for hemophilia A and inhibitors of factor VIII (FVIII)?How is synovitis due to hemophilia A joint bleeding treated?How can fractures be prevented in hemophilia A?What is included in prehospital care for hemophilia A?What should be obtained before emergency department (ED) treatment is initiated for hemophilia A?What is included in initial emergency department (ED) care for hemophilia A?How is minor bleeding managed in hemophilia A?How is epistaxis or moderately severe hematuria treated in hemophilia A?How is acute joint bleeding and expanding hematuria treated in hemophilia A?How are life-threatening bleeding episodes initially treated in patients with hemophilia A?What are indications for admission to an intensive care unit for treatment of hemophilia A?When should patients with hemophilia A be transferred for treatment to a hemophilia care center?What is included in outpatient care for hemophilia A patients with minor hemorrhage?What is included in outpatient care of hemophilia A patients with HIV seroconversion?Which factor VIII (FVIII) concentrates are used for the treatment of hemophilia A?What is the indication for continuous infusion of factor VIII (FVIII) concentrates in the treatment of hemophilia A?What is the proper dosing of factor VIII (FVIII) concentrate for the treatment of hemophilia A?What is the role of desmopressin vasopressin analog in the treatment of hemophilia A?How is desmopressin vasopressin analog administered for the treatment of hemophilia A?When can desmopressin vasopressin analog be administered by intranasal spray for the treatment of hemophilia A?What are adverse effects of desmopressin vasopressin analog for hemophilia A?What are the most common sites of clinically significant bleeding in hemophilia A?How are musculoskeletal bleeding episodes managed in patients with hemophilia A?How are oral bleeding episodes managed in patients with hemophilia A?How are GI bleeding episodes managed in patients with hemophilia A?How are intracranial bleeding episodes managed in patients with hemophilia A?What is the primary treatment for hemophilia A with factor VIII (FVIII) inhibitors?What are alternative treatment options for hemophilia A with factor VIII (FVIII) inhibitors?What is the role of emicizumab in the treatment of hemophilia A?What is the role of recombinant activated factor VIII (FVIII) the treatment of hemophilia A?What is the role of desensitization in the treatment of hemophilia A?Which factors are associated with successful outcome of immune tolerance induction (ITI) in the treatment of hemophilia A?How is immune tolerance induction (ITI) administered in the treatment of hemophilia A?What is the role of rituximab in the treatment of hemophilia A?What are the dosing regimen used for immune tolerance induction (ITI) in the treatment of hemophilia A?What are the benefits of prophylactic treatment for hemophilia A?What is the main goal of prophylactic treatment of hemophilia A?What is the prevalence of prophylactic treatment of hemophilia A?What is the role of recombinant FVIII products in the treatment of hemophilia A?How is adherence to prophylaxis for hemophilia A assessed?How is pain managed in patients with hemophilia A?What are potential complications of hemophilia A?How should routine vaccinations be administered to children with hemophilia A?How is repetitive bleeding and inflammation prevented in severe hemophilia A?What is the role of carrier testing in the prevention of hemophilia A?What is the role of preimplantation genetic diagnosis in the prevention of hemophilia A?Which activity restrictions are indicated for patients with hemophilia A?What is the role of gene therapy in the treatment of hemophilia A?What is the efficacy of gene therapy for hemophilia A?Which specialist consultations may be beneficial in the treatment of hemophilia A?What is the role of radiosynovectomy in the treatment of hemophilia A?Which medications are used in the treatment of hemophilia A?What is the calculation for number of units of factor VIII (FVIII) needed to correct factor VIII (FVIII) activity level for hemophilia A?Where should the factor products used in the treatment of a specific patient with hemophilia A be recorded?Which medical adjuncts to factor VIII (FVIII) are used in the treatment of hemophilia A?Which medications in the drug class Antifibrinolytic Agents are used in the treatment of Hemophilia A?Which medications in the drug class Vasopressin-Related are used in the treatment of Hemophilia A?Which medications in the drug class Monoclonal Antibodies are used in the treatment of Hemophilia A?Which medications in the drug class Coagulation Factors are used in the treatment of Hemophilia A?

Author

Douglass A Drelich, MD, Director, Cardeza Foundation, Hemostasis and Thrombosis Center, Associate Director, Cardeza Special Coagulation Laboratory, Thomas Jefferson University Hospital; Assistant Professor of Medicine, Sidney Kimmel Medical College of Thomas Jefferson University

Disclosure: Received income in an amount equal to or greater than $250 from: Bayer, Octapharma, BPL, CSL Behring (Advisor Board Member).

Chief Editor

Srikanth Nagalla, MBBS, MS, FACP, Associate Professor of Medicine, Division of Hematology and Oncology, UT Southwestern Medical Center

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam.

Additional Contributors

Emmanuel C Besa, MD, Professor Emeritus, 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.

Gary D Crouch, MD, Associate Professor, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Uniformed Services University of the Health Sciences

Disclosure: Nothing to disclose.

Mary A Furlong, MD, Associate Professor and Program/Residency Director, Department of Pathology, Georgetown University School of Medicine

Disclosure: Nothing to disclose.

Robert A Zaiden, MD, Assistant Professor, Division of Hematology/Oncology, Department of Medicine, University of Florida at Jacksonville College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Dimitrios P Agaliotis, MD, PhD, FACP Consulting Staff, Department of Medicine, Baptist Health System

Dimitrios P Agaliotis, MD, PhD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Hematology, and Florida Medical Association

Disclosure: Nothing to disclose.

Jeffrey L Arnold, MD, FACEP Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center

Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians

Disclosure: Nothing to disclose.

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

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Max J Coppes, MD, PhD, MBA President, BC Cancer Agency, Vancouver

Max J Coppes, MD, PhD, MBA, is a member of the following medical societies: Alberta Medical Association, American College of Healthcare Executives, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research

Disclosure: Astellas Pharma US Inc Honoraria Chair Endpoint Review Committee

Brendan R Furlong, MD Clinical Chief, Department of Emergency Medicine, Georgetown University Hospital

Brendan R Furlong, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine

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

Pere Gascon, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, New York Academy of Medicine, New York Academy of Sciences, and Sigma Xi

Disclosure: Nothing to disclose.

William G Gossman, MD Associate Clinical Professor of Emergency Medicine, Creighton University School of Medicine; Consulting Staff, Department of Emergency Medicine, Creighton University Medical Center

William G Gossman, MD is a member of the following medical societies: American Academy of Emergency Medicine

Disclosure: Nothing to disclose.

Lawrence F Jardine, MD, FRCPC Associate Professor, Department of Pediatrics, Schulich School of Medicine and Dentistry, University of Western Ontario; Head, Section of Pediatric Hematology and Oncology, Children's Hospital of Western Ontario; Associate Scientist, Child Health Research Institute

Lawrence F Jardine, MD, FRCPC is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, Canadian Medical Protective Association, Children's Oncology Group, College of Physicians and Surgeons of Ontario, Hemophilia and Thrombosis Research Society, Ontario Medical Association, and Royal College of Physicians and Surgeons of Canada

Disclosure: Baxter Honoraria Consulting; Bayer Honoraria Consulting; Novartis Honoraria Speaking and teaching

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

Disclosure: Nothing to disclose.

Adonis Lorenzana, MD Consulting Staff, Department of Pediatric Oncology, St John Hospital and Medical Center

Adonis Lorenzana, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

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

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Saduman Ozturk, PA-C Physician Assistant, Bone Marrow Transplant Center, Florida Hospital Cancer Institute

Disclosure: Nothing to disclose.

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

Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching

Hadi Sawaf, MD Director, Pediatric Hematology Oncology, Van Elslander Cancer Center; Clinical Assistant Professor, Wayne State University School of Medicine

Hadi Sawaf, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Clinical Oncology, and American Society of Hematology

Disclosure: Nothing to disclose.

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

Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association

Disclosure: Renal Ventures Ownership interest Other

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

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, New York Academy of Medicine, and Sigma Xi

Disclosure: Nothing to disclose.

Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology

Disclosure: Novartis Honoraria Speaking and teaching; Novartis Consulting fee Speaking and teaching; Ariad Honoraria Speaking and teaching; Celgene Honoraria Speaking and teaching

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

Acknowledgments

The authors gratefully acknowledge the provision of several photographs used in this article by a dedicated colleague from Chicago, Margaret Telfer, MD. The authors 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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Coagulation Cascade

The hemostatic pathway. APC = activated protein C (APC); AT-III = antithrombin III; FDP = fibrin degradation products; HC-II = heparin cofactor II; HMWK = high-molecular-weight kininogen; PAI = plasminogen activator inhibitor; sc-uPA = single-chain urokinase plasminogen activator; tc-uPA = two-chain urokinase plasminogen activator; TFPI = tissue factor pathway inhibitor; tPA = tissue plasminogen activator

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.

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.

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

Coagulation pathway.

The hemostatic pathway. APC = activated protein C (APC); AT-III = antithrombin III; FDP = fibrin degradation products; HC-II = heparin cofactor II; HMWK = high-molecular-weight kininogen; PAI = plasminogen activator inhibitor; sc-uPA = single-chain urokinase plasminogen activator; tc-uPA = two-chain urokinase plasminogen activator; TFPI = tissue factor pathway inhibitor; tPA = tissue plasminogen activator

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.

Coagulation Cascade

Classification Factor Activity, % Cause of Hemorrhage
Mild>5-40Major trauma or surgery
Moderate1-5Mild-to-moderate trauma
Severe< 1Spontaneous
Indication or Site of Bleeding Factor level Desired, % FVIII Dose, IU/kg Comment
Severe epistaxis; mouth, lip, tongue, or dental work20-5010-25Consider aminocaproic acid (Amicar), 1-2 d
Joint (hip or groin)4020Repeat transfusion in 24-48 h
Soft tissue or muscle20-4010-20No therapy if site small and not enlarging (transfuse if enlarging)
Muscle (calf and forearm)30-4015-20None
Muscle deep (thigh, hip, iliopsoas)40-6020-30Transfuse, repeat at 24 h, then as needed
Neck or throat50-8025-40None
Hematuria4020Transfuse to 40% then rest and hydration
Laceration4020Transfuse until wound healed
GI or retroperitoneal bleeding60-8030-40None
Head trauma (no evidence of CNS bleeding)5025None
Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs)10050Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented†
Trauma with bleeding, surgery80-1005010-14 d