Factor VII Deficiency 

Updated: Jul 18, 2017
Author: Muhammad A Mir, MD, FACP; Chief Editor: Perumal Thiagarajan, MD 

Overview

Background

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.

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.[1]

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.

Pathophysiology

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 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).[2]

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.[3, 4] 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.[2, 5, 6]

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:

  • Synthesis and localization - Synthesized in the liver and circulates in the plasma as a zymogen

  • Half-life - 3-6 hours

  • Molecular weight - 50,000

  • Structure - Amino-terminal (light chain) Gla domain, carboxy-terminal (heavy chain) catalytic domain, 2 epidermal growth factor domains

  • Cofactor - Tissue factor

  • Substrate - Factor VIIa/tissue factor complex activates factors X and IX

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.

Factor VII. Intrinsic and extrinsic pathways of co 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.

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

To date, fewer than 200 cases of true factor VII deficiency have been reported. 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.

Approximately 30 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.

Factor VII coagulant activities measured in the laboratory are not well correlated with bleeding manifestations.[7] 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.[7]

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.[8] According to Herrmann et al, this was found to be the most common type of mutation in Europe.[7] 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.[7]

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. A recent 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 to 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.[9]

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.[10]

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 (ie, 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.[3, 11, 12]

Neither factor VII:c levels nor F7 polymorphisms have been associated with cerebrovascular disease.[13]

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.[1] 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.[14]

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.

Mortality/Morbidity

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.

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. 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.[15]

Sex

Factor VII deficiency has no reported predilection for either sex.

Age

Factor VII deficiency has no reported predilection for any particular age group.

 

Presentation

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.[16] 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.[17]

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 vary from mild to severe and 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.[18]

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.

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

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.

 

DDx

Diagnostic Considerations

Other problems to be considered in the differential diagnosis include the following:

  • Liver disease

  • Oral anticoagulation (eg, with warfarin)

  • Factor X deficiency and some variants of factor IX deficiency: Patients with these conditions may also occasionally exhibit prolonged PTs. In contrast to factor VII deficiency, the activated partial thromboplastin time (aPTT) is also prolonged.

  • Familial multiple factor deficiency type III: Inherited combined deficiency of prothrombin and factors VII, IX, and X has been reported. Levels of factor VII in this syndrome are lower than those in disorders with other vitamin K-dependent factors.

  • Factor V deficiency and lupus anticoagulants: These should be also considered in the differential for a prolonged PT.

  • Combined deficiency of factors VII and X: This has also been reported to occur, albeit rarely.

  • Liver disease, vitamin K deficiency, and oral coagulant-induced conditions: These conditions can be differentiated from factor VII deficiency by measuring other vitamin K-dependent factor levels, which are also decreased. These 3 conditions are associated with isolated prolongation of the PT, which is later followed by a prolonged aPTT.

Differential Diagnoses

 

Workup

Laboratory Studies

Routine initial hemostatic tests include an aPTT, a PT, and a platelet count. 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:

  • To determine the severity, factor VII activity levels (factor VII:c) are measured using a single-stage, PT-based assay.

  • The factor VII:c assay uses the ability of tissue factor to promote the conversion of factor VII to factor VIIa and measures the total clotting activity of factor VII and factor VIIa. Results can vary dramatically depending on the source of tissue factor used in the in vitro assay.

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.

 

Treatment

Medical Care

Replacement therapy for persons with factor VII deficiency depends on the site and severity of bleeding and the baseline factor VII activity.

Long-term prophylaxis with 10-50 U/kg 1-3 times per week has been successful in children with severe factor VII deficiency. 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 occurs with 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 plasma 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, plasma 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. Plasma infusion may be associated with disadvantages such as 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) has proven effective in clinical trials as a treatment for bleeding in hemophilia A patients with inhibitors and in limited numbers of factor VII–deficient patients. rFVIIa is produced by recombinant technology and thus does not carry the risk of infectious complications. Note the following:

  • rFVIIa may be the treatment of choice for previously untreated patients with factor VII deficiency but is currently an expensive treatment. An online registry, the Seven Treatment Evaluation Registry (STER) has been set up, which helps in prospective study to evaluate the efficacy and safety of various therapies with which FVII-deficient patients may be treated.[19]

  • rFVIIa has been effective in the treatment of blood loss associated with various conditions, but reports from larger studies are not yet available to confirm these findings.[20] Off-labeled use of rFVII for 5 in-hospital indications including intracranial hemorrhage, cardiac surgery, trauma, liver transplantation, and prostatectomy were reviewed in a systematic literature review (16 RCTs and 6 observational studies) by Yank et al.[21] This analysis suggested no mortality reduction for any of the above indicated off-label conditions. In addition, there was an increased risk for thromboembolism. With the rapid increase over the past few years of the drug for off-label indications,[22] it is necessary to reconsider rFVII treatment given the limited efficacy without proven mortality benefit, costs involved, and the risks associated with thromboembolism.

  • rFVIIa is reportedly effective in controlling intracranial bleeding when administered within 3-4 hours of onset (from phase II studies, class IIb, level of evidence B), this is being confirmed in larger studies.[23] There is no proven efficacy for mortality reduction from systematic analysis of various studies.

  • In a comprehensive study of 35 randomized clinical trials of rFVIIa, patients, particularly elderly persons, who were treated with high doses of rFVIIa on an off-label basis experienced a substantially higher risk of arterial, but not venous, thromboembolic events.[24] Pooled data analysis reported by Levi et al showed an increased risk of arterial thrombosis when rFVIIa was administered in large doses for off-label indications to patients older than 65 years compared to younger patients.[24]

  • A single-center case series involving 15 patients who received rFVIIa for acute liver failure did not show any benefit in terms of length of hospital stay or mortality.[25]

  • A retrospective study of rVIIa use compared with standard therapy in warfarin-induced intracranial hemorrhage did not find any increased incidence of thrombotic complications when adjusted for preexisting thromboembolic risk factors in both groups.[26]

  • A retrospective review of 63 patients with warfarin-associated intracranial hemorrhage comparing fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), and rVIIa (all in conjunction with vitamin K) found both PCC and rVIIa to be superior to FFP in speed of reversal and less INR rebound, but rVIIa was more expensive than the other two.[27]

  • A Cochrane systematic review of 2 clinical trials involving nearly 500 patients with upper gastrointestinal bleeding secondary to liver disease was inconclusive, and a benefit of rVIIa in this scenario could not be established.[28]

  • Off-label attempts to correct newer anticoagulants such as dabigatran (in conjunction with hemodialysis) with rVIIa have been reported but remain experimental.[29]

  • A large systematic review evaluated the studies involving off-label use of rVIIa for in-hospital indications, including intracranial hemorrhage, cardiac surgery, trauma, prostatectomy, and liver transplantation, failed to show any mortality benefit, although the risk of arterial thromboembolism increased with several indications.[30]

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

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

Activity

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.

 

Medication

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.[31]

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.[5, 32, 14, 33, 34] 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.[22] The benefits of rFVII is 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.[35]

Antihemophilic agents, drug-product derivatives

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.[36, 33] 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.[37]

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.[5]

In a recent 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.[38]

By similar mechanisms, rFVIIa is also effective at controlling refractory bleeding in trauma patients.[39] Gastrointestinal bleeding in patients with cirrhosis has responded positively to rFVIIa.

Coagulation factor VIIa, recombinant (NovoSeven)

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.

Blood products

Class Summary

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

Fresh frozen plasma (FFP, Octaplas)

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)

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.

Antifibrinolytic agents

Class Summary

These agents increase circulating plasmin levels and decrease plasminogen levels.

Aminocaproic acid (Amicar)

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.

 

Follow-up

Further Outpatient Care

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.

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.

Prognosis

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 excellent patient education resources, see eMedicineHealth's patient education article Hemophilia.

 

Questions & Answers

Overview

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?

Presentation

Which clinical history findings are characteristic of factor VII deficiency?

Which physical findings are characteristic of factor VII deficiency?

DDX

Which conditions are included in the differential diagnoses of factor VII deficiency?

What are the differential diagnoses for Factor VII Deficiency?

Workup

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?

Treatment

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?

Medications

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?

Follow-up

What is included in the long-term monitoring of factor VII deficiency?

What are the possible complications of factor VII deficiency?

What is the prognosis of factor VII deficiency?

What is included in patient education about factor VII deficiency?