Chapter 81: Inherited Deficiencies of Coagulation Factors II, V, V + VIII, VII, X, XI, and XIII

• Inherited deficiencies of coagulation factors other than factor VIII (hemophilia A) and factor IX (hemophilia B) are rare bleeding disorders that occur in most populations.

• Patients are usually homozygotes or compound heterozygotes.

• Factor XI and factor VII deficiency occur relatively frequently, and other deficiencies are relatively rare (Table 81–1).

• The severity of the bleeding disorder usually relates to the severity of the factor deficiency.

• All may be caused by decreased synthesis of a specific coagulation factor, by synthesis of a dysfunctional form of the coagulation factor, or both.

• Inherited deficiency of a coagulation factor does not protect patients from thrombosis.

Pathogenesis

• Hypoprothrombinemia or dysprothrombinemia may be involved.

• Both are inherited as autosomal recessive disorders.

• Both interfere with hemostasis by impairing thrombin generation.

Clinical Features

• The disorders are characterized by mucocutaneous and soft-tissue bleeding, usually in proportion to the severity of the functional prothrombin deficiency.

• Bleeding may be spontaneous if prothrombin levels are less than 1%. Hemarthroses may occur.

• Individuals with higher prothrombin levels have a variable bleeding tendency, and some may be asymptomatic.

Laboratory Features

• The activated partial thromboplastin time (aPTT) and prothrombin time (PT) are prolonged. The thrombin time (TT) is normal.

• Diagnosis is established by demonstrating reduced levels of functional prothrombin.

• Both functional and antigen assays are required to identify dysprothrombinemia. Immunoelectrophoretic studies may demonstrate some forms of dysprothrombinemia.

Differential Diagnosis

• Differential diagnosis includes inherited factor V or factor X deficiency, acquired deficiency of the vitamin K–dependent factors, or lupus anticoagulant.

Treatment

• Prothrombin deficiency may be corrected with intravenous prothrombin complex concentrates, but with risk of transmission of viruses not inactivated by solvent detergent treatment and/or nanofiltration and induction of intravascular coagulation.

• Fresh-frozen plasma is also effective but carries a risk of transmitting infectious agents. Solvent detergent treatment of pooled plasma reduces this risk, but viruses that are not inactivated in the pooled plasma source may still be transmitted (eg, parvovirus, hepatitis A virus).

• Bruises and mild superficial bleeding do not require treatment.

• The biologic half-life of prothrombin is 3 days, and a single treatment for a bleeding episode may suffice.

• Prothrombin levels of 10% to 25% are usually sufficient for hemostasis.

Pathogenesis

• Inherited factor V deficiency is transmitted as an autosomal recessive disorder.

• Homozygotes have a moderate bleeding tendency that is usually due to a true deficiency, but the disorder may also be caused by dysfunctional factor V.

• Heterozygotes are usually asymptomatic.

Clinical Features

• Patients with 1% to 10% factor V activity have lifelong bleeding, usually expressed as ecchymoses, epistaxis, gingival bleeding, excessive bleeding from minor lacerations, and menorrhagia.

• Hemarthroses or intracranial hemorrhage has been reported.

• Severe bleeding may occur after trauma, dental extraction, or surgery.

Laboratory Features

• Factor V deficiency is characterized by prolongation of both the aPTT and the PT.

• Diagnosis requires specific demonstration of a factor V deficiency.

Differential Diagnosis

• The clinical and laboratory features of hereditary combined factor V and factor VIII deficiency are the same as those of factor V deficiency. Specific assay for factor VIII deficiency is needed to differentiate these diseases.

• The clinical features of severe liver disease or disseminated intravascular coagulation (DIC) are usually sufficient to permit diagnosis of this cause of acquired factor V deficiency.

• Acquired inhibitors of factor V may appear rarely after surgery or during therapy with antibiotics or other drugs, and they can cause severe bleeding. These inhibitors often disappear spontaneously.

Treatment

• Severe or continuing mild bleeding is treated with replacement therapy using fresh-frozen plasma. A factor V level of 25% is usually sufficient for hemostasis. The plasma factor V half-life is 12 to 14 hours.

• Infusion of a loading dose of 20 mL/kg of fresh-frozen plasma followed by 5 to 10 mL/kg every 12 hours for 7 to 10 days is usually adequate to ensure hemostasis.

• Minor lacerations may be treated with local measures.

• Antifibrinolytic therapy may be effective in epistaxis or gingival bleeding.

• A rare, autosomal recessive trait with reduced levels of both factor V and factor VIII expressed as a moderately severe lifelong bleeding disorder.

• The molecular basis of this condition relies on null mutations in the endoplasmic reticulum–Golgi intermediate compartment (ERGIC)-53 gene, now called the LMAN1 gene.

• Diagnosis requires specific assays of both factor V and factor VIII.

• Minor bleeding may respond to antifibrinolytic therapy.

• For severe bleeding or prophylaxis before surgery or dental extraction, replacement of both factor V, using fresh-frozen plasma, and factor VIII, using a factor VIII concentrate, is required.

Pathogenesis

• Factor VII deficiency is inherited as an autosomal recessive trait.

• The disorder is symptomatic only in homozygotes or compound heterozygotes.

• The disease may be caused by decreased production of factor VII, production of a factor VII with decreased functional activity, or both. Levels of factor VII antigen may be normal, reduced, or zero.

• Three polymorphisms of the factor VII gene that lead to reduced levels of factor VII but do not lead to abnormal bleeding have been described. These reduced levels of factor VII may be of benefit by lowering the risk of myocardial infarction.

Clinical Features

• Patients with factor VII levels below 1% may have a severe bleeding disorder indistinguishable from severe hemophilia A or B.

• Most patients with levels of factor VII of 5% or more have disease characterized by easy bruising, gingival bleeding, epistaxis, and menorrhagia.

• Dental extractions, tonsillectomy, and genitourinary tract surgery may induce excessive bleeding if no preoperative replacement therapy is given, but operations such as laparotomy and herniorrhaphy may not lead to excessive bleeding.

• Postpartum hemorrhage is unusual in women with factor VII deficiency.

Laboratory Features

• The diagnosis is suggested by a prolonged PT with a normal aPTT.

• Diagnosis requires demonstration of isolated factor VII deficiency by specific assay.

• Factor VII antigen can be detected by radioimmunoassay.

• The mutant gene can be detected by molecular biology techniques.

Differential Diagnosis

• Acquired factor VII deficiency occurs in patients with liver disease, vitamin K deficiency, and those receiving vitamin K antagonists.

• Rarely, patients may have an inherited deficiency of factor VII and X, factor VII and IX, or of all vitamin K–dependent factors.

Treatment

• Skin lacerations require only local hemostasis. Antifibrinolytic therapy is usually effective in patients with menorrhagia, epistaxis, and/or gingival bleeding.

• Replacement therapy is necessary in patients with severe bleeding, such as hemarthroses or intracerebral hemorrhage, and may be required with surgery, depending on the severity of the deficiency, bleeding history, and the operative site.

• Replacement may be achieved with plasma, prothrombin complex concentrates, specific factor VII concentrates, or recombinant human factor VIIa.

• The possibilities for transmission of viral infection and induction of thrombosis must be considered when selecting a therapeutic agent.

• The half-life of factor VII is approximately 5 hours. Hemostasis is achieved with levels between 10% and 25%.

• If plasma is used for major surgery, the recommended initial dose is 15 mL/kg, followed by 4 mL/kg every 6 hours for 7 to 10 days.

• Replacement therapy with plasma may lead to fluid overload requiring diuretic therapy or plasmapheresis.

Pathogenesis

• Factory X deficiency is inherited as an autosomal recessive trait.

• Heterozygotes have factor X levels about 50% of normal and are usually asymptomatic.

• The disease may be caused by decreased production of factor X, production of factor X with decreased functional activity, or both.

Clinical Features

• Patients with factor X levels of less than 1% have severe bleeding, primarily in the joints, soft tissues, and from mucous membranes. Menorrhagia may be a major problem.

• In patients with mild to moderate factor X deficiency, bleeding usually occurs after trauma or surgery.

Laboratory Features

• The PT and aPTT are both prolonged, as is the Russell viper venom time. The TT is normal.

• Diagnosis requires demonstration of isolated factor X deficiency by specific assay.

• Factor X antigen can be detected by immunologic techniques.

Differential Diagnosis

• Laboratory testing will differentiate inherited factor X deficiency from deficiency of prothrombin, factor V, factor VII, multiple factor deficiencies, vitamin K deficiency, liver disease, or the lupus anticoagulants.

• Acquired factor X deficiency may occur in patients with primary amyloidosis due to selective binding of factor X to amyloid fibrils or to the presence of an abnormal form of factor X.

• Acquired isolated factor X deficiency has been reported to be associated with a number of other disorders. Acquired inhibitors of factor X also occur.

Treatment

• Factor X deficiency may be treated with prothrombin complex concentrates that contain factor X. Because of the (theoretical) risk of thrombosis with these concentrates, it is recommended that divided doses be used if more than 2000 units are required.

• For soft tissue, mucosal, or joint hemorrhages, replacement of factor X to 30% of normal is recommended. More serious bleeding requires replacement to 50% to 100%.

• The biologic half-life of factor X is 24 to 40 hours. Continuing therapy should be given every 24 hours.

• Fresh-frozen plasma may also be used to replace factor X deficiency but carries the risks of viral infection and fluid overload.

Pathogenesis

• Factor XI deficiency is an autosomal recessive disorder caused by deficient production of factor XI in almost all instances.

• Homozygotes or compound heterozygotes have factor XI levels of less than 15% of normal.

• Factor XI is essential for the activation by thrombin of thrombin-activatable fibrinolysis inhibitor (TAFI) or carboxypeptidase B, an enzyme that inhibits fibrinolysis. This may result in increased fibrinolytic activity, with consequent increase in bleeding.

Clinical Features

• Most patients with factor XI deficiency are Jewish.

• Bleeding is usually related to trauma or surgery.

• Excessive bleeding may begin at the time of injury or be delayed for several hours.

• There appears to be a greater bleeding tendency in genotypes with lower levels of factor XI, and with surgery or injury at sites of high fibrinolytic activity, such as the urinary tract, tonsils, nose, or tooth sockets.

• Some patients who are heterozygous for factor XI deficiency may have excessive bleeding.

• Inhibitors of factor XI may develop in deficient patients who have received replacement therapy, but these do not appear to increase the risk of bleeding in most such patients.

Laboratory Features

• The aPTT is prolonged; the PT is normal.

• Diagnosis requires specific demonstration of a factor XI deficiency.

• The patient’s genotype can be determined by molecular biology techniques.

Treatment

• Patients with severe factor XI deficiency may be given replacement therapy with fresh-frozen plasma, recognizing the attendant risk of transmission of infectious agents or allergic reactions. Alternatively, in some countries (plasma-derived) purified and virus-inactivated factor XI concentrates are available.

• The mean half-life of factor XI is about 48 hours.

• Trough levels of factor XI of 45% maintained for 10 to 14 days provide adequate hemostasis after major surgery or surgery at sites with high fibrinolytic activity.

• Surgery in areas of lower fibrinolytic activity requires factor XI trough levels of 30% maintained for 5 to 7 days.

• Antifibrinolytic therapy may be effective in achieving hemostasis after dental extraction, and is a similarly useful adjunct for treating patients after operation on sites with high local fibrinolytic activity.

• Heterozygous patients with a negative bleeding history, no associated hemostatic abnormality, and a factor XI level above 45% probably do not need treatment when undergoing surgery.

• Such individuals with a positive bleeding history and requiring surgery should have appropriate treatment of any associated disorder and replacement of factor XI to trough levels of 45% for 5 days.

Pathogenesis

• Factor XIII deficiency is a lifelong bleeding disorder transmitted as an autosomal recessive trait.

• Factor XIII deficiency leads to clots that are less stable mechanically and more susceptible to fibrinolysis, resulting in the bleeding disorder.

Clinical Features

• Ecchymoses, hematomas, and prolonged post-traumatic bleeding are common.

• Bleeding from the umbilical cord of newborns occurs frequently.

• Intracranial hemorrhage occurs more often with factor XIII deficiency than with the other coagulation factor deficiencies when matched for the level of coagulation factor.

• Habitual abortion and poor wound healing also occur.

Laboratory Features

• Screening tests for coagulation abnormalities are all usually normal in factor XIII deficiency, although in some cases, the thrombin time may be minimally prolonged. The diagnosis is established by demonstrating increased clot solubility in 5-M urea or by chemical assays for factor XIIIa activity.

• Deficiency of α₂-antiplasmin gives a similar pattern as factor XIII deficiency but can be diagnosed by specific assay.

• Acquired factor XIII deficiency may occur in DIC, primary fibrinolysis, or if an inhibitor develops to factor XIII. Factor XIII levels may also be decreased after major surgery, during chronic inflammatory conditions (eg, inflammatory bowel disease), and major trauma.

Treatment

• Replacement therapy may be achieved with plasma or cryoprecipitate, with attendant risks of transmission of infectious agents, or with virus-inactivated concentrates of factor XIII from plasma, if available.

• Factor XIII levels of less than 5% will achieve hemostasis.

• The half-life of factor XIII is 19 days.

• Prophylactic therapy using plasma infusions every 4 weeks can achieve normal hemostasis and prevent habitual abortions.