Rare Hereditary Coagulation Factor Abnormalities

Rare bleeding disorders consist of inherited quantitative or functional deficiencies of factors I (fibrinogen), II, V, VII, X, XI, and XIII; combined factor deficiencies, particularly of factors V and VIII; inherited quantitative or functional deficiencies of vitamin K–dependent factors; and disorders of excessive fibrinolysis. Rare bleeding disorders constitute about 3% to 5% of all inherited bleeding disorders. Many of these disorders, which are variable in their bleeding phenotype, may be encountered in the neonatal period and early childhood, whereas others present later in life. Each of these disorders is reviewed in this chapter; however, the reader is referred to reviews or hemostasis texts in the references for a more complete description of these abnormalities.

Fibrinogen Disorders

Fibrinogen is the most abundant clotting factor in human plasma, with normal concentrations ranging between 200 to 450 mg/dL. The hereditary fibrinogen deficiency states (afibrinogenemia and hypofibrinogenemia) and functional abnormalities (dysfibrinogenemias), which account for only 7% of the rare bleeding disorders in the most recent World Federation of Hemophilia annual survey, are among the rarest of the rare bleeding disorders. These disorders should be considered when a prolonged thrombin time (TT) is found in a patient with a history of bleeding who is otherwise essentially healthy. Prolongations of the prothrombin time (PT) and activated partial thromboplastin time (APTT) are found in patients with afibrinogenemia and variably in patients with severe hypofibrinogenemia and some types of dysfibrinogenemia, with PT being more sensitive to a moderate decrement in plasma fibrinogen levels.

Hypofibrinogenemia and Afibrinogenemia

Genetic abnormalities that cause decreased fibrinogen synthesis may occur either as a heterozygous deficiency (hypofibrinogenemia) or as a homozygous deficiency (afibrinogenemia). Clinical findings include ecchymoses, subcutaneous hematomas, hemarthroses, mucosal bleeding, menorrhagia, and postoperative bleeding. Because bleeding severity is strongly associated with fibrinogen activity, patients with fibrinogen activity levels of greater than 100 mg/dL seem to be completely protected from bleeding symptoms, whereas patients with activity levels greater than 70 mg/dL are protected from spontaneous bleeding. Afibrinogenemia presents early in life, frequently in the neonatal period, with gastrointestinal bleeding, hemorrhage from delivery-associated trauma, and bleeding with circumcision. In contrast, patients with hypofibrinogenemia may remain undiagnosed until later in life; their condition may be detected as a result of preoperative screening or after posttraumatic bleeding, except in females, for whom menorrhagia may be the only symptom. Pregnancy complications, particularly spontaneous abortions and placental abruption, have also been reported and are known to occur in laboratory animals that have severe hypofibrinogenemia. Surprisingly, symptoms in patients with afibrinogenemia are not as severe as those seen in persons with the classic hemophilic disorders.

Laboratory evaluation of a patient with afibrinogenemia reveals prolongations of the TT, PT, and APTT (see Chapter 29 ). The best screening tests to detect fibrinogen deficiency are the TT and reptilase time, which measure the time required for conversion of fibrinogen in plasma to a fibrin clot. Reptilase is a thrombinlike enzyme obtained from snake venom. Unlike the TT, the reptilase time is unaffected by heparin treatment. Thus if one encounters a very prolonged TT, the possibility of heparinization must be considered, but marked prolongation of the reptilase time is suggestive of fibrinogen deficiency. Fibrinogen may be detected by functional, precipitation, or immunologic assays. The amount of fibrin clot needed for clot detection is greater with automated clotting instruments than with manual methods. Consequently, these tests are frequently prolonged to the limits of the instrument even though some fibrinogen may be present and a clot may be detected with use of manual methods. However, patients with afibrinogenemia generally have undetectable levels of fibrinogen. Although more than 80 distinct mutations in genes encoding fibrinogen have been identified, genetic testing of patients with afibrinogenemia and hypofibrinogenemia is of no direct value in guiding clinical management.

Because fibrinogen is the ligand for the glycoprotein IIb/IIIa receptor that enables platelet aggregation, both the bleeding time and the results of platelet aggregation tests are usually abnormal. Interestingly, in the absence of fibrinogen, von Willebrand factor is able to bind to the glycoprotein IIb/IIIa complex on platelets and provides a backup mechanism for platelet aggregation, which may result in a reduction in symptoms associated with this disorder. In many patients a small amount of platelet fibrinogen might facilitate some of these interactions, although this fibrinogen is not believed to be derived from synthesis by megakaryocytes; rather, it is believed to be acquired from plasma.

Clinical bleeding episodes in patients with afibrinogenemia, similar to those observed in patients with hemophilia, require episodic replacement therapy. Because of the long plasma half-life of fibrinogen (about 4 days), prophylactic infusions of fibrinogen should be considered in patients with severe symptoms. With the availability of fibrinogen concentrates, fibrinogen replacement therapy has become simpler compared with cryoprecipitate and fresh-frozen plasma (FFP). RiaSTAP is the only fibrinogen concentrate available in the United States. Because it is derived from pooled human plasma, the risk of transmission of bloodborne pathogens is always a possibility, although such transmission is exceedingly rare. Compared with cryoprecipitate, which has a fibrinogen content of about 10 mg/mL, the fibrinogen content of RiaSTAP is more than 20 mg/mL. Hemorrhagic symptoms are usually controlled by initially achieving plasma levels of 80 to 100 mg/dL and achieving maintenance at a level greater than 50 to 60 mg/dL until the bleeding subsides. To raise the fibrinogen level to 100 mg/dL in an afibrinogenemic patient, approximately 0.17 unit/kg of cryoprecipitate and 60 mg/kg of RiaSTAP must be infused. Because of the prolonged half-life of fibrinogen, replacement therapy can be provided at intervals of 3 to 4 days.

Dysfibrinogenemia

Numerous dysfibrinogenemias, which are named after the city in which they were originally identified, have been reported. Most dysfibrinogenemias are associated either with no clinical symptoms or with hemorrhage, whereas others, interestingly, are associated with a predisposition to venous or arterial thrombosis (see Chapter 33 ). In one series more than half of patients experienced no clinical complications, whereas bleeding occurred in 25% and thrombosis occurred in 20%. Functional abnormalities of fibrinogen are generally inherited in an autosomal-dominant manner. Occasionally, however, index cases are associated with consanguinity and major hemorrhagic or thrombotic symptoms. Hereditary dysfibrinogenemia that is associated with hemorrhage usually results in a prolonged TT. Laboratory evaluation for dysfibrinogenemia includes functional and immunologic assays for fibrinogen, which should show a normal level of fibrinogen antigen in the presence of reduced functional fibrinogen. The ratio of functional to antigenic fibrinogen is usually less than 0.5. The reptilase time may also be prolonged. An occasional person with dysfibrinogenemia may have a prolonged PT or APTT. The inability of some abnormal fibrinogen to clot completely in vitro can result in false-positive results in fibrin(ogen) degradation product tests. TT and reptilase time are often prolonged in persons who have dysfibrinogenemia associated with thrombosis, though the TT is substantially shortened in some variants. Molecular testing may be of clinical significance in persons with dysfibrinogenemia because some mutations may be predictive of a bleeding phenotype and other mutations may be predictive of thrombosis, but currently molecular testing is only available through research laboratories. Infusion of fibrinogen in the form of cryoprecipitate may be indicated in patients who have clinical bleeding, with a normal rate of survival of this fibrinogen to be expected. Fibrinogen concentrates are not approved for use in persons with dysfibrinogenemia but may be used off-label in patients with a severe bleeding diathesis.

Severe liver disease is occasionally associated with acquired dysfunction of fibrinogen. Studies usually demonstrate that this disease is not hereditary in nature, and the liver disease is generally overt.

Prothrombin Disorders

Prothrombin, or factor II, is a vitamin K–dependent glycoprotein with a plasma concentration of approximately 100 µg/mL. The hemostatic level of prothrombin is around 20% to 40%. Prothrombin deficiency is exceedingly rare, with a prevalence of about 1 in 1 to 2 million people, but in a few North American series it has been noted to disproportionately affect Latinos. Similar to congenital abnormalities of fibrinogen, defects in prothrombin present either as quantitative (hypoprothrombinemia, or type 1 disorders) or functional deficiency (dysprothrombinemia, or type 2 disorders). Aprothrombinemia is incompatible with life. Hypoprothrombinemia is inherited as autosomal-recessive defects in the prothrombin gene, leading to decreased production of protein. The mutations resulting in dysprothrombinemia either cause defective activation of the prothrombin molecule by factor Xa or result in its altered interaction with fibrinogen. Occasionally prothrombin deficiency can occur in association with combined deficiency of other vitamin K–dependent factors because of mutations in either the γ-glutamyl carboxylase gene or the vitamin K epoxide reductase gene.

Clinical presentation is strongly associated with the level of functional protein. Heterozygotes are usually asymptomatic, although postoperative bleeding has been reported. Clinical bleeding in homozygotes ranges from easy bruising and mucosal bleeding to severe posttraumatic or postoperative bleeding. Hematomas, umbilical cord bleeding, intracranial bleeding, and major hematomas after vaccination have been reported in the neonatal period. Although the APTT may be slightly prolonged, the hallmark of disorders of prothrombin is usually a prolonged PT and a normal TT. In some cases of dysprothrombinemia, such as prothrombin Cardeza, the PT may be nearly normal even though prothrombin activity is markedly reduced, and thus specific prothrombin assays comparing immunologic levels with functional levels are required to diagnose dysprothrombinemias. The lack of deficiencies of other vitamin K–dependent factors (i.e., factors VII, IX, and X) and liver-dependent factors (i.e., factor V and fibrinogen) usually directs attention to the diagnosis of a hereditary deficiency of prothrombin. Immunoassays and assays of electrophoretic mobility help identify dysprothrombinemia. Molecular testing is only available in the research setting and does not provide much clinical utility.

Treatments currently available for prothrombin deficiency include FFP and prothrombin complex concentrates (PCCs). Acute bleeding episodes can be easily treated with FFP. A dose of 15 to 20 mL/kg will usually raise the factor level by about 25%. Given the long half-life of prothrombin (approximately 60 hours), transfusion volume is usually not an issue. Three-factor PCCs contain factors IX, X, and prothrombin and a small amount of factor VII; the amounts vary from product to product and from lot to lot. Four-factor prothrombin factor concentrates contain all four vitamin K–dependent procoagulant factors and the antithrombotic proteins C and S; a description of the actual units of each factor in each vial accompany the product. Four-factor PCCs are indicated for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (e.g., warfarin) therapy. These products are labeled and dosed on the basis of factor IX units. These products are not approved for prothrombin deficiency, but a dose of 20 to 30 units/kg will usually be hemostatic. Thrombotic complications resulting from supratherapeutic levels of other factors remain a potential problem. Antifibrinolytic agents are a useful adjunct to factor replacement but are best avoided in combination with PCCs.

Factor V Deficiency

Factor V deficiency, which was first reported by Owren in 1947, has also been termed parahemophilia . Its prevalence has been estimated to be 1 in 1 million people with no ethnic predisposition. It is transmitted autosomally and is generally symptomatic only in the homozygous or compound heterozygous state. Factor V activity has limited correlation with bleeding severity. Mucocutaneous bleeding and hematomas are the most common symptoms, but hemarthroses, gastrointestinal tract bleeding, and central nervous system bleeding are rarely encountered. Menarche is frequently associated with severe menorrhagia. Both the PT and the APTT are prolonged, which usually prompts specific factor assays. Immunoassays for factor V are not readily available, and thus most cases are defined by identification of functional deficiencies of factor V with the use of clotting assays. Liver disease, disseminated intravascular coagulopathy, a factor V inhibitor, and combined factor V and VIII deficiency states must be ruled out before diagnosing factor V deficiency.

Clinical bleeding can be controlled with FFP, which is the only currently available source of factor V. Normal hemostasis is achieved with levels greater than 20%. In a patient with severe factor V deficiency, hemostasis can be achieved with a loading dose of 15 to 20 mL of plasma per kilogram of body weight. The half-life of factor V is 12 to 36 hours, and hence daily infusions of plasma are sufficient. Factor V is more labile in FFP compared with other hemostatic factors, and thus it is important to use FFP that is less than 1 to 2 months old. Mild mucocutaneous bleeding can be treated with antifibrinolytic agents. In rare instances, alloantibodies to factor V can develop in patients with congenital factor V deficiency who are, of course, quite symptomatic, but their condition can generally be managed by infusing fresh platelets that contain normal platelet factor V and account for about 20% of circulating factor V.

Occasionally one may encounter a patient who has an acquired inhibitor to factor V. These patients have usually undergone surgical procedures in which topical bovine thrombin has been used. A mixing study can be performed to confirm the presence of an inhibitor. Even though the PT is markedly prolonged, some of these patients do not have major hemorrhagic symptoms.

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