Factor VII Deficiency

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Practice Essentials

The inherited deficiency of factor VII (FVII), the crucial enzyme triggering blood coagulation, is the most common of the rare coagulation disorders transmitted in autosomal recessive manner. The clinical features are highly variable, ranging from severe (eg, intracranial or gastrointestinal hemorrhage) to milder (eg, epistaxis) to asymptomatic.[1]

On hemostatic testing, patients with factor VII deficiency have a normal aPTT and a prolonged PT; bleeding time is usually within the reference range. A specific assay for factor VII, using known factor VII–deficient plasma, is required to confirm the diagnosis. See Workup.

The choice of treatment for patients with factor VII deficiency depends on the site and severity of bleeding and the baseline factor VII activity. Therapeutic options for major bleeds include recombinant activated factor VIIa (rFVIIa), plasma-derived factor VII, fresh frozen plasma, and prothrombin complex concentrates.[2]  Prophylaxis with rFVIIa may be used in patients who have experienced major bleeds. See Treatment and Medication.

 

 

 

Background

The discovery of vitamin K–dependent factors evolved slowly, after the initial identification of the role of prothrombin in blood clotting 100 years ago. In 1951, Alexander and colleagues identified factor VII as the key initiator of coagulation when they reported the first case of factor VII deficiency in a child and called it serum prothrombin conversion accelerator deficiency.[3]

Pathophysiology

Blood coagulation is a series of reactions in which plasma zymogens are converted into active enzymes. The final event of these reactions is the formation of an insoluble fibrin clot. These coagulant reactions are regulated by a number of stimulatory and inhibitory mechanisms. Thus, coagulation is a finely regulated system that maintains blood in a fluid phase but can rapidly respond to injury for the formation of clots. Factor VII is a vitamin K–dependent serine protease glycoprotein (also known as stable factor or proconvertin) with a pivotal role in hemostasis and coagulation. Other vitamin K–dependent factors include prothrombin, factors IX and X, and proteins C and S.

Tissue factor is an intrinsic membrane glycoprotein that is normally not exposed on the surface of intact blood vessels. When the vascular lumen is damaged, tissue factor is exposed and then binds to the small amounts of circulating factors VIIa and VII. This facilitates conversion of factor VII to factor VIIa. Factor VIIa bound to tissue factor in the presence of calcium and phospholipids facilitates the conversion of factor IX to factor IXa and factor X to factor Xa. Coagulation has traditionally been considered to occur via extrinsic and intrinsic pathways. Although this division is useful for understanding in vitro laboratory coagulation tests, no such division occurs in vivo because the tissue factor VIIa complex is a potent activator of factor IX and factor X.

Protein structure

Factor VII is synthesized in the liver and secreted as a single-chain glycoprotein of 48 kd. The epidermal growth factor domain has a calcium ion – binding site that to some degree mediates interaction with the tissue factor exposed at the site of vessel injury. Factor VII is now converted to factor VIIa. Gamma-glutamyl carboxylase catalyzes carboxylation of  glutamine to Gla residues in the amino-terminal portion of the molecule. The carboxylase is dependent on a reduced form of vitamin K for its action. Whenever each glutamyl residue is carboxylated, the reduced vitamin K is converted to the epoxide form. Vitamin K epoxide reductase is required to convert the epoxide form of vitamin K back to the reduced form.

Warfarin inhibits the activity of vitamin K epoxide reductase and prevents recycling of vitamin K back to the reduced form, thus interfering with the synthesis of factor VII and other vitamin K–dependent factors. Warfarin poisoning can be reversed by administering vitamin K. Mutations of carboxylase can lead to low levels of all the gamma-carboxyglutamic acid domain-containing factors (ie, prothrombin; factors VII, IX, and X; protein C).[4]

Properties of factor VII

Factor VII is coded by the gene on band 13q34, closely located to the gene for factor X (F10). The plasma concentration of factor VII is 0.5 mg/L, and the plasma levels are determined by genetic and environmental factors.[5, 6] Factor VII has the shortest half-life of all procoagulant factors (3-6 h). Hence, when a problem with synthesis occurs, as in liver failure, vitamin K deficiency, or warfarin therapy, the factor VII level first decreases in the plasma, followed by a decrease in other vitamin K–dependent factors.

Factor VII levels are elevated during pregnancy in healthy females. Plasma factor VII levels also increase with age and are higher in females and in persons with hypertriglyceridemia. A strong contribution of the factor VII genotype to factor VII levels has been demonstrated, and different factor VII genotypes can result in up to several-fold differences in mean factor VII levels.

Activation

The major proportion of factor VII circulates in plasma in zymogen form, and activation of this form results in cleavage of the peptide bond between arginine 152 and isoleucine 153.

Rapid activation also occurs when factor VII is combined with its cofactor, which is the tissue factor in the presence of calcium (autocatalysis). This reaction may be initiated by a small amount of preexisting factor VIIa. Conversion of factor VII to factor VIIa is catalyzed by a number of proteases, including thrombin, factor IXa, factor Xa, factor XIa, and factor XIIa. Comparison of these proteins has shown that factor Xa, in association with phospholipids, has the highest potential to activate factor VII.[4, 7, 8]

Factor IXa is responsible for basal levels of plasma factor VIIa in healthy individuals. Patients with hemophilia B (factor IX deficiency), unlike patients with hemophilia A (factor VIII deficiency), have very low concentrations of circulating factor VIIa and achieve normal levels of VIIa within a few hours of infusion of purified factor IX.

Factor VIIa can be detected in plasma by a sensitive assay using a recombinant soluble form of tissue factor. The mean plasma concentration is 3.6 ng/mL in healthy individuals. The half-life of factor VIIa is relatively long (2.5 h) compared with other activated coagulation factors.

A summary of the structure and properties of coagulation factor VII is as follows:

Role of factor VII in coagulation and coagulation pathways

The association of factor VIIa with tissue factor enhances the proteolytic activity by (1) bringing the binding sites for both the substrate (factors X and IX) and the enzyme (VIIa) into closer proximity and by (2) inducing a conformational change, enhancing the enzymatic activity of factor VIIa.

The factor VIIa/tissue factor complex formed as a result of binding of small amounts of preexistent plasma factor VIIa activates factor X and factor IX. The rate of factor X activation by this pathway (extrinsic) is approximately 50 times slower than the rate achieved by factor IXa, factor VIIIa, phospholipid, and calcium ions (intrinsic pathway). Factor Xa formed by both enzyme complexes binds to membrane-bound factor Va to produce the prothrombinase complex. This complex converts prothrombin to thrombin, which results in the formation of fibrin clots. Note the image below.



View Image

Factor VII. Intrinsic and extrinsic pathways of coagulation. Factor VII/tissue factor complex activates factor IX and factor X. Factor IXa along with ....

Inhibition of the extrinsic pathway of coagulation

Activation of factor X by the factor VIIa–tissue factor complex results in the interaction of factor Xa with factor Va to form a prothrombinase complex. Very small amounts of thrombin formed during this initiation phase of thrombin generation subsequently activate platelets, factor VIII, factor V, and factor XI. This leads to the propagation phase, wherein the bulk of the thrombin is generated. The initiation and propagation phases of the coagulation system are differentially regulated by the inhibitors. Tissue factor pathway inhibitor targets factor VIIa/tissue factor/factor Xa product complex and principally serves to regulate the initiation phase of the reaction.

The antithrombin III/heparin complex plays a major role in the inhibition of all vitamin K–dependent proteases except factor VIIa.

Factor VII deficiency

Because factor VII deficiency is a rare disease, data concerning the pathophysiology are limited. Both qualitative and quantitative forms of factor VII deficiency have been noted. Factor VII Padua I has been described in one kindred with an abnormal rabbit brain prothrombin time (PT) but a normal ox brain PT; factor VII (Verona) is associated with an abnormal form of factor VII, and kindreds with heterozygosity for this type have been reported. Factor VII Padua 2 is a double-heterozygote condition associated with abnormal coagulation test results with only ox brain thromboplastin.

Over 220 different mutations have been identified since the isolation of the factor VII gene (F7). Most described mutations are missense mutations. Nonsense mutations, small deletions, and splice-site abnormalities have also been identified. A few large genomic rearrangements and six common variants have been identified. Nevertheless, in spite of an exhaustive direct sequencing of F7 exons and exon-intron junctions and of the proximal promoter region, a significant proportion of defective alleles has not been identified yet. The rate of uncharacterized F7 disease alleles ranges from 2% to 8% in Europe, and a similar estimate (7%) was made in India.[1]

Factor VII coagulant activities measured in the laboratory are not well correlated with bleeding manifestations.[9] This is partly because different F7 mutations express different levels of coagulant activity. Additionally, factor VII activity levels are variable when assayed in the presence of tissue factor obtained from different species.

Approximately two thirds of the mutations seem to affect the protease domain, indicating that loss of protease function is the most common cause of the clinical phenotype.[9]

The donor splice mutation in intron 7 (IVS7+7) was first described in Italy. Ala294Val and Ala294Val;404delC was first described by Arbini et al in Polish patients and by Bernardi et al in Italian patients.[10] According to Herrmann et al, this was found to be the most common type of mutation in Europe.[9] In the same study, homozygous conditions to mutations Val (-17) Ile, Phe4Leu, Cys135Arg, Ala244Val, Ala294Val;404delC, and IVS4+1G>A were associated with factor VII activities of 8%, less than 1%, 1-4%, 3%, less than 1%, and 7%, respectively. Factor VII activities ranging from 75-80% were found in heterozygous patients with donor splice mutation IVS7+7, which is thus considered a mild mutation.[9]

Factor VII activity is influenced by mutations of F7 and by allelic polymorphic variations of the gene. Eight polymorphisms within F7 are known, 3 of which (ie, an insertion polymorphism of the promoter, a repeat polymorphism within intron 7, the Arg353Gln polymorphism of exon 8) influence the level of factor VII activities. Analysis of 7 of the polymorphisms in 14 patients showed only a mild decrease (> 50%) of factor VII levels in those without an identified mutation compared with those with an identified mutation. These data appear to indicate that patients with activated factor VII levels greater than 50% are less likely to have a definitive F7 mutation, although polymorphisms of the F7 gene can be detected in these patients.[11]

A detailed database of mutations is available at the MRC Haemostasis & Thrombosis Database Resource Site.

Increased factor VII plasma levels and associations with thrombotic disease

The Northwick Park Heart Study was a prospective study in which factor VII levels were found to be strongly associated with coronary risk. This study showed that elevated factor VII levels were related to fatal myocardial infarctions but not to nonfatal myocardial infarctions.[12]

The Atherosclerosis Risk in Communities Study, a prospective study of hemostatic factors and the prevalence of coronary heart disease, showed no association of coronary disease with factor VII. In this study, only elevated levels of fibrinogen, WBCs, factor VIII, and von Willebrand factor were identified as risk factors associated with coronary heart disease, but their measurement in healthy subjects did not seem to be beneficial beyond more established risk factors.

In the Prospective Cardiovascular Munster study, factor VII:c levels were elevated in patients who had coronary events, but, after multiple logistic regression analysis, factor VII:c was not identified as an independent risk factor for coronary events.

The results of the Survival of Myocardial Infarction Long-Term Evaluation study (the largest published case-controlled study showing the relationship between genetic polymorphisms and disease) demonstrated that a genetic propensity to high factor VII levels is not associated with a risk for myocardial infarction.

Another prospective study, the Edinburgh Artery Study, also failed to confirm factor VII as an independent predictor of coronary disease.

Because the association between increased factor VII levels and cardiovascular disease is controversial, whether elevated factor VII levels should be taken into account in the presence of additional risk factors when assessing cardiovascular risk remains unclear.[5, 13, 14]

Neither factor VII:c levels nor F7 polymorphisms have been associated with cerebrovascular disease.[15]

Venous thromboembolism has been reported in patients with factor VII deficiency; hence, this deficiency does not offer protection against deep venous thrombosis.

Epidemiology

Frequency

International

Hereditary factor VII deficiency is a rare autosomal recessive bleeding disorder first described by Alexander et al in 1951.[3] Prevalence is estimated to be 1 case per 500,000 persons in the general population. Dubin-Johnson syndrome and Rotor syndrome are associated with a high prevalence of factor VII deficiency.[16]

Acquired factor VII deficiency from inhibitors is very rare. Cases have been reported with the deficiency occurring in association with drugs such as cephalosporins, penicillins, and oral anticoagulants. Acquired factor VII deficiency has also been reported to occur spontaneously or with other conditions, such as myeloma, sepsis, and aplastic anemia, and with interleukin-2 therapy and antithymocyte globulin therapy.

Race

Specific mutations and polymorphisms are known to occur in some populations. Among Iranian and Moroccan Jews, a missense Ala244Val mutation is responsible for frequent occurrences of disease. A study of residents of southern Israel consisting primarily of Jews of North African descent, Ashkenazi Jews and Bedouins, found an incidence of 1:13,000 for factor VII deficiency (activity under 60%) and 1:40,000 for severe factor VII deficiency (activity under 10%).  The majority of severe disease was found among Bedouin residents with a high prevalence of consanguineous marriage.[17]

The highest frequencies of the polymorphism, an Arg353Gln substitution, are observed in Gujaratis (25%) and Dravidian Indians (29%) compared with northern Europeans (9%) and Japanese (3%), resulting in decreases in factor VII levels.[18]

Prognosis

Morbidity and mortality rates vary with the severity of the factor deficiency. Severe factor VII deficiencies (< 1%) result in bleeding disorders indistinguishable from severe hemophilia A or hemophilia B. Recombinant agent therapy and early intervention of joint disease may result in improved outcomes, as in persons with hemophilia A.  

Patient Education

Patients and family members should be educated about the disease and its transmission. Genetic counseling is recommended. Advise patients to seek medical attention early during the development of symptoms, to consult with specialists, and to comply with follow-up requirements.

For patient education resources, see Hemophilia.

History

Bleeding history is a crucial element in the evaluation of any patient with a hemorrhagic disorder. Of all factors evaluated, clinical history appears to be the best predictor of bleeding risk after hemostatic challenges in inherited FVII deficiencies.[19] In patients with susceptibility to severe bleeds, the first severe bleeds usually occur soon after birth or in infancy; in particular, umbilical cord stump bleeds are associated with a high risk of developing further severe bleeds at a very young age.[2]  

A bleeding disorder is considered likely when a bleeding tendency is discovered in one or more family members or when an abnormal coagulation assay result is obtained as a part of a routine examination or before surgery.[20] Knowing the mode of inheritance of hereditary disorders is important when eliciting the family history. Factor VII deficiency is an autosomal recessive disease, unlike hemophilia, which is an X-linked recessive disease.

Only homozygote or compound heterozygote patients with factor VII deficiency are symptomatic. Heterozygotes who have partial factor VII deficiency may not exhibit hemorrhagic manifestations, even following trauma. In symptomatic patients, clinical phenotypes do not necessarily correlate with factor VII levels. A multicenter European study of patients who are congenitally factor VII deficient showed that clinical symptoms did not vary with the frequency of functional polymorphisms and that homozygotes with the same mutation presented with striking differences in severity of bleeding.[21]

Patients with factor VII levels of less than 1% frequently present with bleeding symptoms indistinguishable from those of persons with severe hemophilia A or hemophilia B. They may present with life-threatening intracerebral hemorrhage manifesting as headaches, seizures, or focal deficits or with recurrent hemarthrosis leading to severe arthropathy. Intracranial hemorrhage has been reported, especially in neonates after vaginal delivery.

Unlike in hemophilia, hemarthrosis rarely occurs but may be precipitated by trauma. Patients should be asked about recurrent joint pain, swelling, and motion limitation. Hemarthrosis is sometimes heralded by an aura of mild discomfort that becomes progressively painful over a period of minutes to hours. In children, hemarthrosis usually occurs when the affected child begins to walk.

Patients with factor VII levels of 5% or more have much milder disease characterized by epistaxis, gingival bleeding, menorrhagia, and easy bruising. In patients with mild disease, dental extractions, tonsillectomy, and procedures involving the urogenital tract are frequently associated with bleeding (due to local fibrinolysis), while surgical procedures such as laparotomy, herniorrhaphy, appendectomy, and hysterectomy are not. Postpartum hemorrhage is noted in patients with levels less than 10-20% of the reference range.

In one study, menorrhagia was the most prevalent type of bleeding (46.4% of women), and was the presentation symptom in 12% of cases.[22]

Bleeding isolated to a single organ or system (eg, hematuria, hematemesis, hemoptysis) is less likely to be due to a hemostatic abnormality than to a local cause such as neoplasm or ulcer.

A family history is particularly important when a hereditary factor deficiency is considered likely. A specific inquiry should be made about consanguinity. Population genetics information may be helpful; for example, a higher frequency of factor VII deficiency is observed in Iranian and Moroccan Jews.

Drug history is important; drugs of concern may include hepatotoxic drugs, oral anticoagulants (eg, warfarin), and agents such as aspirin. Nutritional history is important to assess the likelihood of vitamin K deficiency. Rarely, drugs such as penicillins and cephalosporins have been associated with selective factor VII deficiency, but other antibiotics can cause vitamin K deficiency and consequently inhibit the synthesis of functional vitamin K-dependent factors, including factor VII.

Physical Examination

Physical findings depend on the site and severity of bleeding.

Hemarthrosis may lead to findings of joint swelling, motion limitation, and mild fever. If significant fever develops, infection should be considered. Repeated hemarthrosis leads to joint deformity complicated by muscle atrophy and contractures.

Focal neurological deficits depend on the location of bleeding into the nervous system. Symptoms and signs of subdural hematoma may be delayed for weeks.

Bruising and soft tissue bleeding may be observed with or without trauma. Large hematomas may expand locally and cause compression of adjacent organs, blood vessels, and nerves. Pharyngeal and retropharyngeal hematomas may enlarge and obstruct the airway.

Laboratory Studies

Routine initial hemostatic tests for suspected factor VII deficiency include the following:

A normal aPTT and a prolonged PT in a patient with a lifelong history of a tendency for mild or severe bleeding is consistent with the diagnosis of factor VII deficiency or the presence of an inhibitor to factor VII.

Bleeding time is usually within the reference range.

With no significant clinical bleeding but a prolonged PT and a normal aPTT, the patient has either mild factor VII deficiency or is taking oral anticoagulants.

To distinguish between factor VII deficiency and the presence of an inhibitor to factor VII, mixing studies are useful. PT testing is repeated using a 1:1 mixture of the patient's plasma and normal plasma. Normal plasma is a source of factor VII; therefore, when such a mixture normalizes the prolonged PT, the patient likely has a deficiency of factor VII. When the mixture still results in a prolonged PT, sometimes after initial correction, an inhibitor to factor VII is probably present.

A specific assay for factor VII, using known factor VII–deficient plasma, is required to confirm the diagnosis. Factor VII antigen can be measured using a radioimmunoassay.

Functional factor VII assays are as follows:

Immunological factor VII assays can be used to measure factor VII:Ag (antigen levels). This can be an enzyme-linked immunosorbent assay or an immunoradiometric assay.

A factor VIIa:c assay is used to evaluate therapeutic factor VIIa levels. This is an enzyme-linked immunosorbent assay using specific antibodies or soluble mutant tissue factor that is insensitive to native factor VII but that serves as a cofactor for factor VIIa catalyzed activation of factor X.

A more definitive approach involves genetic analysis of mutant genes in involved families.

Imaging Studies

CT scan and ultrasound have been used to localize, quantify, and serially monitor the location and response of bleeding to specific therapy.

Plain radiography is not useful for evaluating soft tissue damage.

MRI can be used to assess soft tissue damage; is a better modality to evaluate joint effusion, synovial hyperplasia, and cartilage loss; and can help localize the bleeding site. MRI is beneficial for evaluating reversible joint changes for earlier intervention in persons with hemophilia A and B.

Medical Care

Replacement therapy for persons with factor VII deficiency depends on the site and severity of bleeding and the baseline factor VII activity. Mild bleeding associated with bruising and skin lacerations may not require any replacement and can be controlled by applying local pressure at the bleeding site. Minimal mucosal bleeding episodes, such as epistaxis and during dental procedures, can be managed with antifibrinolytic agents or fibrin glue.

For spontaneous hemorrhage or mild trauma, therapeutic factor VII levels of 5-10% are sufficient to stop bleeding. This level may be achieved by administering fresh frozen plasma (FFP) at a dose of 5-10 mL/kg of body weight and repeating the dose every 8-12 hours for 1-2 days.

For major hemorrhage or surgery, FFP may be administered in a loading dose of 15-20 mL/kg and followed by 3-6 mL/kg every 8-12 hours until the surgical wound heals. This may require 5-7 days of treatment. Potential drawbacks of plasma infusion include volume overload, infectious complications, or an inability to achieve high levels of factor VII.

Highly purified factor VII concentrates are useful in patients with severe bleeding or as prophylaxis for surgery. Unlike factor VIII and factor IX deficiencies, for which levels of 100% are required before surgery, factor VII deficiency requires levels in the range of 10-15% to produce efficient hemostasis. For major surgery, trough levels of factor VII must not fall to less than 20 U/dL.

Prothrombin complex concentrates are also a source of factor VII but carry the risk of infectious complications and thrombosis. When prothrombin concentrates are used, doses of 50 U/kg every 8 hours for 24 hours, followed by plasma infusions, have been shown to be effective for major orthopedic surgery.

Recombinant factor VIIa (rFVIIa) is approved by the US Food and Drug Administration (FDA) for the prevention and treatment of bleeding episodes in patients with congenital factor VII deficiency.  Because rFVIIa is produced by recombinant technology, it does not carry the risk of infectious complications. The recommended dose of rFVIIa for treatment of hemorrhage is 15–30 mcg/kg every 4–6 h until hemostasis is achieved. For perioperative replacement therapy, a dose of approximately 20 mcg/kg has proved effective in over 95% of cases; the  infusion should be repeated approximately 8 times in patients at high risk (ie, those with a history of major bleeding).[23]

Although rFVIIa is approved for bolus infusion only, continuous infusion of clotting factor concentrates is recommended for patients with hemophilia, as it avoids peaks and troughs in factor levels; may reduce the amount of clotting factor concentrates administered and, consequently, cost; and reduces the administative burden. A review by Rajpurkar and Cooper identified studies and case reports of continuous rFVIIa infusion for 46 surgeries (major and minor) in 26 patients with congenital factor VII deficiency, and concluded that the practice is effective and safe. Perioperative dosing ranged from 0.2–30.0 mcg/kg/h, with a duration of treatment ranging from 8 hours to 10 days.[24]

Patients with severe congenital factor VII deficiency who have experienced central nervous system or gastrointestinal bleeding or hemarthrosis are at risk for further major or life-threatening hemorrhage and may be considered for long-term prophylaxis. In the literature, dosages for prophylaxis have varied, with 20-30 mcg/kg of rFVIIa twice or three times weekly reported as effective. Dose and frequency can be tailored on the basis of clinical response, as neither FVII activity nor thrombin generation parameters predict the efficacy of prophylaxis.[25, 26]

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Surgical Care

Prophylactic administration of factor VII concentrates or plasma may help minimize bleeding during surgery. For surgery, factor VII concentrates have been used in doses ranging from 8-40 U/kg every 4-6 hours.

Fibrin glue or fibrin tissue adhesives have been used as adjunctive therapy to achieve hemostasis. Fibrin glue contains fibrinogen, thrombin, and factor XIII.

Antifibrinolytic agents such as epsilon-aminocaproic acid and tranexamic acid have been used to enhance hemostasis during dental procedures as an adjunct to replacement therapy.

Consultations

Obtain consultations with orthopedists, physical therapists, general surgeons, dental surgeons, and genetic counselors as needed.

Diet and Activity

Instruct patients to maintain a regular, healthy diet without restrictions.

Recommend that patients limit activity of the involved joints or muscles during acute bleeding episodes. Early physical therapy is recommended once bleeding is resolved to prevent contractures or deformity.

Complications

Infectious complications from transfusion of plasma or factor concentrates include HIV infection and hepatitis. Transmission of other infectious disease is always a theoretical possibility (eg, variant Creutzfeldt-Jakob disease). Recurrent hemarthrosis leads to joint deformities and disability. Occupational and social rehabilitation is necessary.

Long-Term Monitoring

Perform annual history and physical examinations and test for hepatitis virus and HIV. Order MRI or CT scans for follow-up of joint deformities. Regular screening tests include cholesterol, prostate-specific antigen levels, colonoscopy, and mammography. In addition, vaccination for hepatitis A and B viruses, dental care, orthopedic follow-up, and patient education are recommended.

Medication Summary

Recombinant factor VIIa

rFVIIa is licensed by the US Food and Drug Administration for the treatment of bleeding in individuals with hemophilia A and B with acquired inhibitors and for persons with congenital factor VII deficiency. rFVIIa is produced in vitro in baby hamster kidney cells that are transfected with F7.[27]

Although originally developed for the treatment of inhibitor-complicated hemophilia A and B, novel indications for rFVIIa (based on case reports and smaller clinical trials) include use in patients with liver disease, thrombocytopenia, or qualitative platelet dysfunction and in patients with no coagulation disorders who are bleeding as a result of extensive surgery or major trauma.[7, 28, 16, 29, 30] Use of rFVIIa to control bleeding has increased among patients with intracranial bleeding, cardiac surgery, prostatectomy, trauma, and liver transplantation over the past few years.[31] The benefits of rFVIIa are uncertain, and no mortality reduction is seen. The various dosages used in the above-mentioned conditions vary and are outlined in the review by Logan et al.[32]

Coagulation factor VIIa, recombinant (NovoSeven)

Clinical Context:  Supplied in 1.2- and 4.8-mg vials. Half-life of rFVIIa is 2-3 h. Cleared from plasma more rapidly in children than in adults.

Class Summary

The mechanism by which factor VIIa maintains normal hemostasis is unknown. Clot-promoting activity of rFVIIa is primarily mediated through the tissue factor pathway, although direct activation of primary hemostasis may also occur.

Tissue factor-dependent and tissue factor-independent enhancement of thrombin generation have been suggested to play a role.[33, 29] Factor VIIa alone, in the absence of tissue factor, can generate factor IXa and factor Xa on the surface of activated platelets, which, in turn, induces the coagulation cascade to form thrombin.[34]

Mechanism of action of rFVIIa in patients with Glanzmann thrombasthenia and Bernard-Soulier syndrome is thought to be from thrombin generation on the surface of platelets, resulting in faster platelet activation and aggregation.[7]

In a study that evaluated rFVIIa in patients with acute intracerebral hemorrhage, the mortality was relatively reduced by 38% at 3 months when rFVIIa was administered within 4 hours of the hemorrhage. Accelerated thrombin generation from activated platelets at the sites of ruptured arterioles after administration of rFVIIa provides hemostatic effect and improved the outcome of these patients.[35]

By similar mechanisms, rFVIIa is also effective at controlling refractory bleeding in trauma patients.[36] Gastrointestinal bleeding in patients with cirrhosis has responded positively to rFVIIa.

Fresh frozen plasma (FFP, Octaplas)

Clinical Context:  FFP is used to correct coagulation factor deficiency when hemostasis is urgently required. FFP is separated within 8 h of whole blood collection and frozen at -18°C. Each unit of FFP contains 200 U of each coagulation factor. Volume transfused should correct factor VII level to at least 30% of normal levels. Octaplas is a solvent detergent treated, pooled FFP.

Factor IX complex (Proplex, BeneFix, Hemodyne)

Clinical Context:  Contains factor VII 68-91 U/mL. Viral inactivation with dry heat (60°C [140°F] for 144 h). Prothrombin complex concentrates contain variable amounts of factors II, VII, IX, and X.

Class Summary

These agents are indicated for the correction of abnormal hemostatic parameters.

Aminocaproic acid (Amicar)

Clinical Context:  Inhibits fibrinolysis via inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. Main problem is that the thrombi that form during treatment are not lysed and effectiveness is uncertain.

Class Summary

These agents increase circulating plasmin levels and decrease plasminogen levels.

What is factor VII deficiency?What is the role of protein structure to the pathophysiology of factor VII deficiency?What are the physiologic properties of factor VII?What is the role of activation in the pathophysiology of factor VII deficiency?What is the role of coagulation pathways in the pathophysiology of factor VII deficiency?What is the pathophysiology of factor VII deficiency?What is the association with thrombotic disease and factor VII deficiency?What is the mortality and morbidity associated with factor VII deficiency?What is the global prevalence of factor VII deficiency?What are the racial predilections of factor VII deficiency?What are the sexual predilections of factor VII deficiency?Which age groups have the highest prevalence of factor VII deficiency?What is the prognosis of factor VII deficiency?What is included in patient education about factor VII deficiency?Which clinical history findings are characteristic of factor VII deficiency?Which physical findings are characteristic of factor VII deficiency?Which conditions are included in the differential diagnoses of factor VII deficiency?What are the differential diagnoses for Factor VII Deficiency?What is the role of lab tests in the workup of factor VII deficiency?How is the diagnosis of factor VII deficiency confirmed?What is the role of imaging studies in the workup of factor VII deficiency?How is factor VII deficiency treated?What is the role of recombinant factor VIIa (rFVIIa) in the treatment of factor VII deficiency?What is the role of surgery in the treatment of factor VII deficiency?Which specialist consultations are beneficial to patients with factor VII deficiency?Which dietary modifications are used in the treatment of factor VII deficiency?Which activity modifications are used in the treatment of factor VII deficiency?What are the possible complications of factor VII deficiency?What is included in the long-term monitoring of factor VII deficiency?Which medications are used in the treatment of factor VII deficiency?Which medications in the drug class Antifibrinolytic agents are used in the treatment of Factor VII Deficiency?Which medications in the drug class Blood products are used in the treatment of Factor VII Deficiency?Which medications in the drug class Antihemophilic agents, drug-product derivatives are used in the treatment of Factor VII Deficiency?

Author

Muhammad A Mir, MD, FACP, Assistant Professor of Medicine (Hematology, Blood/Marrow Transplant) Milton S Hershey Medical Center, Pennsylvania State University College of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

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

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MBBCh, FRCPC, DTM&H, Professor of Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Disclosure: Nothing to disclose.

Chief Editor

Perumal Thiagarajan, MD, Professor, Department of Pathology and Medicine, Baylor College of Medicine; Director, Transfusion Medicine and Hematology Laboratory, Michael E DeBakey Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

Additional Contributors

Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Disclosure: Nothing to disclose.

Acknowledgements

Francisco J Hernandez-Ilizaliturri, MD Associate Professor of Medicine, Department of Medicine, Assistant Professor of Immunology, Department of Immunology, Roswell Park Cancer Institute, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Francisco J Hernandez-Ilizaliturri, MD is a member of the following medical societies: American Association for Cancer Research and American Society of Hematology

Disclosure: Nothing to disclose.

Ganapathy S Krishnan, MBBS Fellow, Department of Hematology and Oncology, Michigan State University

Ganapathy S Krishnan, MBBS is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

Jeyanthi Ramanarayanan, MD Assistant Professor, Medical Oncology, Veterans Affairs Medical Center of Buffalo

Jeyanthi Ramanarayanan, MD is a member of the following medical societies: American Association of Physicians of Indian Origin and American Society of Hematology

Disclosure: Nothing to disclose.

References

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  2. Napolitano M, Siragusa S, Mariani G. Factor VII Deficiency: Clinical Phenotype, Genotype and Therapy. J Clin Med. 2017 Mar 28. 6 (4):[View Abstract]
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Factor VII. Intrinsic and extrinsic pathways of coagulation. Factor VII/tissue factor complex activates factor IX and factor X. Factor IXa along with factor VIIIa results in formation of more factor Xa. Factor Xa along with factor Va converts prothrombin to thrombin.

Factor VII. Intrinsic and extrinsic pathways of coagulation. Factor VII/tissue factor complex activates factor IX and factor X. Factor IXa along with factor VIIIa results in formation of more factor Xa. Factor Xa along with factor Va converts prothrombin to thrombin.