Less Common Congenital Disorders of Hemostasis

Pathogenesis and Genetics

Three individual genes on the long arm of chromosome 4 encode for the α, β, and γ chains that constitute the fibrinogen molecule. Fibrinogen is a homodimer that consists of two identical pairs of three chains, intertwined to form a trinodular fibrinogen structure. Fibrinogen is converted to a visible fibrin clot by thrombin, which cleaves fibrinopeptides A and B from the α and β chains, respectively. Gene defects in any of the three chains can result in afibrinogenemia. A list of reported mutations in the FGA, FGB, and FGG genes resulting in this disorder can be found on the Internet at http://www.hgmd.org , http://site.geht.org/base-fibrinogene/ (Groupe Francais d'Etudes sur l'Hemostase et la Thrombose), and http://www.ncbi.nlm.nih.gov/gene . The most common mutations resulting in complete absence of fibrinogen occur in the gene that encodes for the α chain.

Afibrinogenemia is inherited in an autosomal recessive pattern, and symptomatic individuals are homozygotes. Heterozygous individuals usually have mild hypofibrinogenemia and are asymptomatic unless the fibrinogen level is less than 50 mg/dL. The estimated incidence of congenital afibrinogenemia is approximately 1 per million population, and usually a history of consanguinity is reported within the family. This disorder occurs in either sex, with no known racial predilection. The characteristics of three patients with afibrinogenemia are shown in Table 4.4 .

Clinical Manifestations

Individuals with congenital afibrinogenemia have a lifelong bleeding tendency of variable severity. Hemorrhagic manifestations are usually observed in the neonatal period with bleeding from the umbilical cord (approximately 75% of cases) and after circumcision. In infancy or childhood, intracerebral hemorrhage is a leading cause of death. Easy bruising and mucosal, gastrointestinal (GI), and genitourinary hemorrhages are common. Patients with afibrinogenemia have an increased tendency to spontaneous splenic rupture, poor wound healing, and painful bone cysts. The latter occur in the diaphysis of long bones during childhood from recurrent hemorrhages during bone remodeling. Hemarthroses occur in up to 20% of patients, but musculoskeletal bleeding that leads to chronic hemophilic arthropathy, as seen in patients with classic hemophilia, is surprisingly uncommon. Spontaneous abortions, which usually occur early in pregnancy, are common in affected women, who are also prone to menometrorrhagia, abruptio placentae, and postpartum hemorrhage. It is surprising that thrombosis has been reported in some patients with afibrinogenemia, even in the absence of replacement therapy, but whether such patients have true afibrinogenemia as opposed to dysfibrinogenemia is not completely clear. Thrombin generation is normal in these patients, and platelet aggregation occurs, even though fibrinogen is absent, which may explain why patients with undetectable fibrinogen levels have fewer long-term effects from repeated hemorrhaging than do patients with classic hemophilia and similar disorders.

Diagnosis

The diagnosis of afibrinogenemia is based on the findings of a careful history taking and the results of coagulation screening tests. Patients have a long history of intermittent hemorrhagic episodes, usually in the soft tissues, and all screening tests of coagulation, including prothrombin time (PT), PTT, and thrombin clotting time (TCT) (also known as thrombin time [TT]), exhibit infinite clotting times. Results of these tests normalize in vitro after 1 : 1 mixing of patient plasma with normal plasma, which excludes the presence of an inhibitor.

To confirm the diagnosis of afibrinogenemia, specific fibrinogen assays should be performed using clotting and immunologic methods, both of which will show no detectable fibrinogen. Bleeding time in afibrinogenemic patients is prolonged because of the absence of platelet fibrinogen. Mild thrombocytopenia has also been reported in approximately 25% of patients with congenital afibrinogenemia, but platelet counts are usually not lower than 100,000/µL.

Delayed-type hypersensitivity skin tests in individuals with afibrinogenemia typically show only erythema and no induration because of the lack of fibrin deposition in the subcutaneous tissue. The erythrocyte sedimentation rate is also very low in these individuals because fibrinogen is one of the main determinants of this rate.

Differential Diagnosis

Hereditary dysfibrinogenemia, especially in homozygotes or combined heterozygotes, may result in very low to virtually undetectable fibrinogen levels and must be distinguished from true afibrinogenemia. Sensitive tests for fibrinogen always detect some amount of protein in dysfibrinogenemia but not in true afibrinogenemia.

Acquired fibrinogen abnormalities must also be excluded. Severe disseminated intravascular coagulation can result in virtual absence of fibrinogen, but usually levels of other clotting factors and platelets are also markedly decreased. Acquired hypofibrinogenemia has been reported in liver disease and with the use of certain medications, such as sodium valproate and L-asparaginase, both of which impair the hepatic synthesis of fibrinogen. These acquired defects can be excluded easily through a careful history.

Treatment

The treatment of choice for individuals with afibrinogenemia and hypofibrinogenemia is purified and virally inactivated fibrinogen concentrates. Cryoprecipitate, a source rich in fibrinogen, can also be used when concentrates are not available. Solvent detergent–treated products are preferred to inactivate the human immunodeficiency virus (HIV) and hepatitis viruses. Replacement treatment is obviously indicated for episodes of active bleeding, before surgery, and during pregnancy. To achieve hemostasis, maintaining the fibrinogen level at 100 to 150 mg/dL is usually adequate. Prophylactic therapy is always indicated before operations are performed and throughout pregnancy. To avoid miscarriage, a fibrinogen level greater than 50 mg/dL must be maintained during the first two trimesters, greater than 100 mg/dL during the end of pregnancy, and greater than 150 mg/dL in the peripartum period.

Each bag of cryoprecipitate, which contains approximately 250 to 300 mg of fibrinogen, will raise the fibrinogen level by approximately 10 mg/dL, and the fibrinogen has an in vivo half-life of approximately 2 to 4 days. Thus 10 to 20 bags of cryoprecipitate are usually adequate for an individual who weighs 70 kg. However, daily monitoring of fibrinogen levels is necessary if the fibrinogen dose is to be determined because fibrinogen levels can vary over time. For major surgical procedures (e.g., knee replacement) or severe trauma, the duration of daily treatment with fibrinogen may be as long as 2 to 3 weeks. For minor trauma, a single dose of fibrinogen sufficient to raise the level to 50 to 100 mg/dL is usually adequate for hemostasis. Administration of 1-desamino-8- d -arginine vasopressin (DDAVP) may reduce bleeding time in some patients, but given alone, it is not adequate for hemostasis.

Complications of replacement therapy include risk of allergic reaction, transmission of viral disease, and very rarely the development of antifibrinogen antibodies. Thrombotic phenomena have been reported in patients after the fibrinogen level has been normalized. Some episodes have occurred in women who are taking oral contraceptives, which suggests that they may have had an underlying hypercoagulable state. Should thrombotic phenomena occur during the perioperative period, appropriate anticoagulation therapy should be used in combination with fibrinogen replacement.

Pathogenesis and Genetics

Congenital dysfibrinogenemia is characterized by the synthesis of an abnormal fibrinogen molecule that does not function properly and results in at least one of the following: (1) abnormal fibrinopeptide release, (2) defects in fibrin polymerization, (3) abnormal fibrin stabilization, or (4) resistance to fibrinolysis. The most common dysfibrinogenemias are those that cause polymerization defects.

In most cases, congenital dysfibrinogenemia is inherited as an autosomal dominant trait with high levels of penetrance, but some patients exhibit an autosomal recessive inheritance pattern. Patients may be homozygous or heterozygous for the defect. Most affected individuals are heterozygous, with approximately 50% normal fibrinogen, which is adequate for normal hemostasis unless the dysfunctional molecule disrupts the function of the normal fibrinogen component. Some individuals with dysfibrinogenemia have fibrinogen levels that are well below normal.

Clinical Manifestations

Clinically, patients with dysfibrinogenemia have one of the following phenotypes: no hemorrhagic manifestations; mild to moderate bleeding, usually after trauma; thromboses; or a combination of thrombotic and hemorrhagic manifestations. Approximately 43% of all individuals with congenital dysfibrinogenemia are asymptomatic, approximately 20% have bleeding symptoms, and 17% report thrombotic manifestations. Approximately 20% of patients experience a combination of bleeding and thrombosis. The bleeding tendency is variable, and most individuals have mild to moderate hemorrhage. Easy bruising, soft tissue bleeding, menorrhagia, and intraoperative and postoperative bleeding are the most common events. Both venous and arterial thromboses, including deep vein thrombosis (DVT) of the lower extremities, pulmonary embolism (PE), recurrent spontaneous abortion, and thrombosis of the carotid arteries and abdominal aorta, have been associated with congenital dysfibrinogenemia. Dysfibrinogenemias most likely associated with bleeding occur with abnormalities in the amino terminus of the α chain, although exceptions to this generalization have been found. Thrombotic manifestations, on the other hand, are most often associated with fibrinogen variants that have a free cysteine residue that results in a disulfide linkage to albumin. These variants are resistant to lysis by plasmin, which probably accounts for their thrombotic tendency. However, in many cases, thrombotic manifestations may be related to concurrent disorders (e.g., factor V Leiden mutation, protein C deficiency) rather than to the abnormal fibrinogen molecule itself, and clinicians should be aware of these possibilities. Because a normal fibrin clot provides the necessary framework for normal wound healing, it is not surprising that poor healing and dehiscence of wounds are seen in some patients with dysfibrinogenemia. Examples of dysfibrinogenemia in the α, β, and γ chains are shown in Table 4.5 .

Diagnosis

In most cases of dysfibrinogenemia, results of screening tests of coagulation such as PT, PTT, and TT are prolonged and may or may not correct with 1 : 1 mixing of patient plasma with normal plasma. This occurs because some dysfibrinogenemias interfere with normal fibrin formation. In some dysfibrinogenemias associated with thrombotic episodes, the TT may be shorter than normal. Fibrinogen levels are variable and can be relatively normal or low. Immunologic methods may show normal levels of fibrinogen; at the same time, reduced levels of fibrinogen can be detected on functional analysis. Other important diagnostic tests include reptilase time and fibrinogen immunoelectrophoresis. Reptilase, derived from snake venom, cleaves fibrinopeptide A from the α chain, which results in the formation of visible clot, even in the presence of heparin. Reptilase time is often prolonged and may be more sensitive than TT. Fibrinogen immunoelectrophoresis sometimes shows an abnormal migration in agarose gel. However, definitive diagnosis depends on biochemical characterization of the fibrinogen defect, which may require amino acid sequencing. More sophisticated diagnosis requires genetic analyses that are not available in most clinical coagulation laboratories.

Differential Diagnosis

Dysfibrinogenemias can also be acquired, particularly in patients with liver disease of varying causes. Frequently, the abnormality is due to an increase in sialic acid residues. In dysfibrinogenemia associated with liver disease, levels of other clotting proteins synthesized by the liver are low. Autoantibodies against fibrinogen in nondeficient individuals should be distinguished from dysfibrinogenemia because they interfere with fibrinogen function and mimic the abnormalities seen with dysfibrinogenemia. The development of antifibrinogen antibodies has been associated with systemic lupus erythematosus, ulcerative colitis, liver cirrhosis, and other disorders. Fibrinogen degradation products seen in many diseases may also interfere with normal fibrinogen function and may produce a condition that resembles dysfibrinogenemia.

Treatment

Therapy is obviously not indicated in patients with congenital dysfibrinogenemia who are asymptomatic. To treat dysfibrinogenemic patients who are known to bleed, fresh frozen plasma (FFP), cryoprecipitate, or fibrinogen concentrates should be administered for control of bleeding episodes or for prophylaxis before operative procedures. Guidelines provided earlier in the afibrinogenemia section can also be applied to the dysfibrinogenemias. Dysfibrinogenemic patients who have thrombotic episodes require anticoagulation. Recurrent thrombotic episodes require prophylactic anticoagulation with parenteral or oral anticoagulants. Women with recurrent spontaneous abortion and dysfibrinogenemia should be treated with fibrinogen replacement therapy throughout the course of pregnancy, as indicated in the section on afibrinogenemia.

Pathogenesis and Genetics

Various mutations in the prothrombin gene (F2) have been discovered and are listed on the Internet at http://www.hgmd.org , http://www.ncbi.nlm.nih.gov/gene , and http://www.isth.org?MutationsRareBleedin . These usually are caused by a missense mutation (i.e., the substitution of a single amino acid in regions that affect the function and/or structure of the prothrombin molecule). These mutations result in dysprothrombinemia, in which prothrombin activity level is reduced and prothrombin antigen levels may be normal or decreased, as is shown in Table 4.6 .

Prothrombin is normally converted to thrombin, which is necessary for the formation of a normal fibrin clot. Molecular defects in dysprothrombinemia may affect the N-terminal (amino terminal) pro-piece of prothrombin or the C-terminal (carboxy terminal) thrombin portion of the molecule. Defects in the pro-piece usually result in delayed thrombin generation, but the thrombin that is generated functions normally. An example of a defect in the pro-piece of the molecule is prothrombin San Juan. Defects in the thrombin end of the molecule, such as prothrombin Quick II, result in the generation of an abnormal thrombin. In some patients, dysprothrombinemia may be homozygous; in others, it may be heterozygous or compound heterozygous.

Dysprothrombinemia is inherited in an autosomal recessive pattern. No predilection for race is known, although many patients are of southern European ancestry. Complete deficiency of prothrombin has not been reported and is probably incompatible with life. Mice in whom the gene has been knocked out do not survive in utero—a fact that supports the important role of prothrombin in embryogenesis.

Clinical Manifestations

According to the recent International Society of Thrombosis and Haemostasis (ISTH) classification, prothrombin deficiency can be classified based on the association between clinical severity and coagulant activity level. Severe patients with prothrombin levels below 5% can have hemarthroses and intracranial bleeding. These individuals are usually homozygous or compound heterozygous. Moderate patients with blood levels between 5% and 10% can have easy bruising, epistaxis, hematoma, and postoperative bleeding. In women, menorrhagia, postpartum hemorrhage, and miscarriage have been reported. Patients with levels greater than 10% are considered mild and usually are asymptomatic but may develop bleeding after undergoing tooth extractions and surgical procedures.

Diagnosis

The diagnosis of dysprothrombinemia is suggested by a lifelong history of bleeding in patients with prolonged PT and PTT values that are corrected when patient plasma is mixed 1 : 1 with normal plasma. Bleeding time and TT are normal. Definitive diagnosis requires a specific assay for prothrombin functional activity. Immunologic assays of prothrombin may be helpful, but results are sometimes normal. Patients with type I deficiency have similar levels of prothrombin on functional and immunologic assays; in patients with type II deficiency, prothrombin antigen levels are normal but functional prothrombin levels are low.

Differential Diagnosis

Hereditary prothrombin deficiency must be distinguished from other congenital deficiencies that are characterized by prolonged PT and PTT and normal TT. The most common deficiencies showing this pattern are factor V and factor X deficiencies; these can be diagnosed with the use of specific assays for each of these factors V and X. Acquired prothrombin deficiency is commonly seen in patients with liver disease, vitamin K deficiency, or ingestion of vitamin K antagonists, such as warfarin or superwarfarins, both of which are found in rodenticides. In all these conditions, levels of all vitamin K–dependent factors, including protein C and protein S, are low. The surreptitious use of warfarin or superwarfarins, such as brodifacoum, should be suspected in individuals with a severe bleeding tendency who are otherwise apparently healthy and have no liver dysfunction. Such patients often ingest rodenticides and induce bleeding symptoms for secondary gain. Superwarfarins cannot be detected by simple warfarin assays, but specific testing is available at reference laboratories.

Dysprothrombinemias must also be distinguished from other causes of vitamin K deficiency, such as treatment with antibiotics that contain the N -methyl-thio-tetrazole side chain present in third-generation cephalosporins. This side chain inhibits the vitamin K–dependent γ-carboxylation of glutamic acid residues required for production of normal prothrombin and other vitamin K–dependent factors.

Antibodies against prothrombin can be seen in patients with the lupus anticoagulant, antiphospholipid syndrome (APLS), and systemic lupus erythematosus and, on rare occasions, in isolated cases. These antibodies usually cause a true prothrombin deficiency through accelerated clearance of the antibody-prothrombin complex. Patients with this type of acquired prothrombin deficiency report symptoms similar to those of patients with dysprothrombinemia, except that symptoms are not lifelong.

Treatment

Pure prothrombin concentrates are not available for clinical use. Patients with minor bleeding episodes may not need replacement therapy but may respond to infusion of FFP. Those with major hemorrhage can be treated with FFP at a loading dose of 15 to 20 mL/kg of body weight, followed by 3 mL/kg every 12 to 24 hours, because the half-life of prothrombin is approximately 3 days. Prothrombin levels of 20% to 40% are usually sufficient to maintain adequate hemostasis. In patients with recurrent bleeding episodes, prophylactic plasma infusions can be administered every 3 to 5 weeks.

An alternative treatment for dysprothrombinemia is the use of prothrombin complex concentrate (PCC). Some of these concentrates contain significant quantities of prothrombin and other vitamin K–dependent factors. Care should be taken when PCCs are used because they have been associated with thromboembolic complications, presumably due to contamination with variable quantities of activated factors VIIa, Xa, and IXa. Three PCCs are commercially available on the US market—Bebulin VH (Shire, Lexington, Massachusetts), Profilnine SD (Grifols Biologicals, Los Angeles, California), and Kcentra (CSL Behring, Kankakee, Illinois); these consist of varying levels of vitamin K–dependent factors. Therefore before using PCCs for replacement therapy in patients with prothrombin deficiency, the clinician should know the prothrombin content of a particular product, as is shown in Table 4.7 . One regimen consists of an initial loading dose of 20 U/kg of prothrombin, followed by 5 U/kg every 24 hours. Care should be taken to avoid exceeding the 20-U/kg dose because of the risk of dangerous thrombotic phenomena. Patients should be monitored for the development of disseminated intravascular coagulation during and after PCC use. To avoid the use of PCCs in patients who need extensive surgery, plasma exchange using FFP for replacement can be performed before the time of the operation so that near-normal levels of prothrombin can be achieved.

Pathogenesis and Genetics

Factor V is a glycoprotein that is found in plasma and in the alpha granules of platelets. The origin of the factor V found in platelets is not known for certain. Most secretable platelet-derived factor V is believed to be derived from plasma, although this concept has been challenged. Even though hepatocytes synthesize most of the plasma factor V, megakaryocytes have been shown to contain factor V messenger RNA. Platelet factor V accounts for approximately 20% of the total body pool of factor V and is released on activation and degranulation of platelets. The relative roles of plasma and platelet factor V in hemostasis are not precisely defined, although platelet factor V is known to be fully functional.

Congenital factor V deficiency, which is inherited as an autosomal recessive trait, is characterized by decreased or absent factor V activity in plasma and platelets. Consanguinity is common in affected patients. Molecular variants ( F5 gene mutations) that account for factor V deficiency have been increasingly reported and can be found on the Internet at http://www.hgmd.org and http://www.ncbi.nlm.nih.gov/gene . Examples of factor V variants are given in Table 4.8 . Although reports have described factor V deficiency in which neither plasma nor platelet factor V can be detected, there is reason to suspect that minute levels of factor V sufficient to sustain life may be present in vivo. In addition, patients with congenital deficiency of factor V have low plasma levels of tissue factor pathway inhibitor (TFPI), a condition that enhances thrombin generation, which possibly rescues them from fatal hemorrhage. In some patients who have no detectable factor V, bleeding symptoms may be minor; in other patients, bleeding symptoms are more severe.

In any discussion of blood clotting factor V, one must remember that not only does factor V play a role in preventing hemorrhage, but it also helps regulate coagulation reactions, so that mutations which prevent its cleavage by activated protein C (e.g., factor V Leiden) predispose the patient to thrombotic rather than hemorrhagic complications.

Clinical Manifestations

Factor V deficiency occurs in mild (>10%), moderate (1% to 10%), and severe (<1%) forms. Patients with severe deficiency (<1%) usually develop symptoms within the first 6 years of life and have umbilical stump bleeding, easy bruising, and epistaxis. Menorrhagia and postpartum and postoperative hemorrhage have also been described. Hemarthroses may occur, but these are usually traumatic in origin. In contrast to patients with less than 1% factor VIII or IX activity, who experience frequent spontaneous hemarthroses, those with less than 1% factor V activity have few joint hemorrhages. This suggests that even severely affected patients with factor V deficiency do not completely lack the factor. For example, mice that are completely deficient in factor V—a condition produced using gene knockout techniques—experience neonatal death but may be rescued by the insertion of a minigene that expresses less than 1% normal factor V activity. Clinical evidence suggests that the bleeding tendency correlates to a greater extent with platelet factor V levels than with plasma levels. Mildly affected patients are asymptomatic when factor V plasma levels are greater than 10%, which makes diagnosis difficult; some cases may not be diagnosed until the patient reaches adulthood. Paradoxically, several reports have described patients with congenital factor V deficiency who had thrombosis. Inhibitors to factor V are very rare in patients with congenital factor V deficiency.

Diagnosis

Laboratory evaluation reveals prolonged PT and PTT and normal TT. In severely affected patients who lack platelet factor V, bleeding time is also prolonged and may sometimes be longer than 20 minutes. Definitive diagnosis of factor V deficiency requires the use of a specific factor V assay.

Differential Diagnosis

Acquired factor V deficiency may be seen in patients with significant liver disease and in those with disseminated intravascular coagulation. A syndrome of combined congenital deficiencies of factors V and VIII may be diagnosed and must be distinguished from simple factor V deficiency (see later discussion).

Spontaneous development of inhibitors of factor V in patients without factor V deficiency have been frequently reported after surgery and in association with the use of antibiotics such as aminoglycosides and penicillin. Some inhibitors have been reported in patients with infection (tuberculosis) and certain malignancies. In more than half of patients with acquired inhibitors, antibodies disappear spontaneously within a period of several weeks to months. Some patients develop factor V antibodies after they have been exposed to topical bovine thrombin that contains bovine factor V. Human antibodies to these bovine products may cross-react with human thrombin and human factor V; in some cases, bleeding is severe. The treatment of choice for hemorrhaging patients is corticosteroids and exchange transfusion. Frequently, no therapy is required and the event is transient. Platelet factor V deficiency, initially reported as factor V Quebec, has now been shown to be a platelet disorder caused by an increased expression and storage of urokinase plasminogen activator (uPA) in megakaryocytes from a tandem duplication of PLAU, the uPA gene.

Treatment

No commercial factor V concentrates are available for replacement therapy in factor V deficiency. Patients with minor bleeds, such as those caused by epistaxis or dental extraction, can be treated with local measures and antifibrinolytic therapy, including tranexamic acid and ε-aminocaproic acid. FFP is the treatment of choice when more serious bleeding occurs. Patients with mild to moderate hemorrhagic episodes can be treated with plasma at a loading dose of 15 to 20 mL/kg of body weight, followed by 3 to 6 mL/kg every 24 hours, to achieve a level of approximately 20% of normal. More frequent infusions are not necessary, given the long half-life of factor V (approximately 36 hours). Higher levels may be achieved through plasma exchange using FFP as replacement in patients who have severe hemorrhage or are undergoing surgery, or when fluid overload is a concern. Platelet transfusions have been reported to correct bleeding in some patients because they are a source of factor V; however, they are not always effective and have the potential for causing the development of antiplatelet alloantibodies. Factor VIIa has been used to staunch bleeding in some patients; it is less likely to be effective in patients with undetectable levels of factor V.

Pathogenesis and Genetics

Because the factor VIIa–tissue factor complex is essential for the initiation of coagulation in vivo, a deficiency of or structural defect in the factor VII molecule can lead to significant bleeding symptoms. The gene is located on the long arm of chromosome 13, close to the gene for factor X. Approximately 1% of factor VII circulates in its active form (i.e., factor VIIa); it has a biologic half-life of approximately 3.5 hours—very similar to the half-life of the zymogen. More than 50% of patients seem to have low functional activity and antigen levels; others have a dysfunctional molecule (normal antigen levels and reduced activity). Factor VII deficiency is inherited in an autosomal recessive fashion, with bleeding symptoms occurring mostly in homozygotes and double heterozygotes. Numerous and various genetic mutations have been described, many with a phenotypic expression that leads to mild, moderate, or severe bleeding manifestations. A detailed database of these mutations ( F7 gene) can be found on the Internet at http://www.hgmd.org , http://www.isth.org/?page=RegistriesDatabases and https://www.ncbi.nlm.nih.gov/gene .

A remarkable difference has been observed between genotype and phenotype in factor VII variants. Some mutations are associated with virtually undetectable factor VII levels as measured by clotting or immunologic assays, and yet the patient experiences little or no bleeding. PT, which is prolonged in factor VII deficiency, is variable depending on the source of the tissue factor. Ox brain and other tissue factor preparations of nonhuman origin may yield very different results from those obtained with the use of human tissue factor. A clear example of this discrepancy is seen in factor VII Padua (Arg304Gln). Presumably, different human FVII polymorphisms are associated with varying responses to different tissue factor sources. It is generally agreed that human tissue factor should be preferentially used in all clotting assays for factor VII, especially for confirmation of original diagnosis. Variability in the clinical expression of factor VII deficiency has led to confusion regarding treatment of patients with this disorder. Examples of factor VII variants are provided in Table 4.9 .

Clinical Manifestations

The clinical manifestations of factor VII deficiency vary widely from patient to patient, and a poor correlation has been found between plasma level of factor VII and bleeding symptoms. As was stated earlier, this may be explained by the fact that in vitro factor VII activity is dependent on the type of tissue factor used in the assay. Results of assays that use human tissue factor seem to correlate best with the bleeding diathesis. In some patients, less than 1% factor VII activity is seen when rabbit tissue factor is used in the assay, although measurable factor VII activity is observed when human tissue factor is used.

In general, individuals with factor VII levels lower than 10% of normal are more likely to exhibit hemorrhagic episodes than are those with higher levels of this factor. Often, bleeding in factor VII–deficient patients is characterized by easy bruising (36%), epistaxis (60%), and gum bleeding (34%). Women may experience menorrhagia (69% of females), menometrorrhagia, and postpartum bleeding. Postoperative bleeding is not rare but almost always occurs in severely affected patients. Patients with factor VII levels lower than 1% may have severe bleeding equivalent to that seen in patients with hemophilia A or B, with hemarthroses (19%), retroperitoneal bleeding, GI bleeding (15%), and fatal intracranial hemorrhage (2.5%). However, rarely, patients with activity levels lower than 1% have no history of bleeding but are identified by a workup to investigate a prolonged PT. Central nervous system (CNS) bleeding has been reported most often in infants after vaginal delivery, with an incidence of up to 16%. Thrombotic episodes have been described in 3% to 4% of factor VII–deficient patients, but in most of them, other risk factors, including surgery and replacement therapy, have been identified. Inhibitory antibodies against exogenously administered factor VII have been reported in very few patients with severe congenital deficiency of factor VII.