Rare Coagulation Factor Deficiencies

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Chapter 62 Rare Coagulation Factor Deficiencies

David Gailani, Anne T. Neff

Table 62-1 Properties of Plasma Coagulation Factors and Characteristics of Deficiency States

Table 62-2 Treatment Considerations for Rare Coagulation Factor Deficiencies

FFP, Fresh frozen plasma; CRYO, cryoprecipitate; PCC, prothrombin complex concentrate.

* Preferred treatment for congenital deficiency.

† Assuming baseline fibrinogen is not known.

Adjuncts to Factor Replacement Therapy in Congenital Factor Deficiencies

The antifibrinolytic agents ε-amino caproic acid and tranexamic acid can be effective adjuncts to factor replacement when treating congenital or acquired bleeding disorders and may be useful alternatives to replacement therapy for mild bleeding or minor procedures. These drugs inhibit clot dissolution by blocking plasminogen activation and plasmin activity and are particularly valuable when bleeding involves tissues with high fibrinolytic activity such as the oral cavity. They are also useful for treating menorrhagia, limiting blood loss with surgery, controlling epistaxis, and reducing some types of gastrointestinal bleeding. A typical loading dose of ε-amino caproic acid is 50 to 100 mg/kg followed by 2 to 4 grams every 6 hours. If bleeding subsequently occurs, the dose can be increased to a maximum of 24 grams in 24 hours. ε-Amino caproic acid is available in oral and intravenous formulations. Identical dosing may be used for either preparation because of excellent bioavailability. For dental extraction in factor VIII or IX deficiency, many centers use a single 50% to 100% loading dose of clotting factor concentrate followed by seven days of ε-amino caproic acid as the sole prophylaxis, and it is reasonable to extrapolate this approach to patients with some of the rare bleeding disorders. Patients with factor XI deficiency do well with antifibrinolytic agents alone for tooth extractions. Dental procedures such as scaling or root canal can be performed safely using ε-amino caproic acid or tranexamic acid mouthwash prepared from the intravenous formulation three to four times daily with or without systemic antifibrinolytic therapy.

Prolonged therapy with antifibrinolytic agents must be undertaken with caution in patients who are not mobile, who have a history of thromboembolic events, or who have significant urogenital bleeding. These drugs interfere with urokinase-mediated fibrinolytic activity in the genitourinary tract and can cause renal outflow obstruction by thrombotic occlusion of the ureters. Concomitant use of antifibrinolytic agents with activated prothrombin complex concentrates or recombinant factor VIIa may result in a particularly high risk for thrombus formation. Patients may develop nausea or vertigo with high doses of ε-amino caproic doses, and rarely, rhabdomyolysis.

Hemorrhage may be controlled or prevented in rare bleeding disorders with recombinant factor VIIa. The mechanism by which this agent works is not completely understood in all situations, particularly for deficiencies of factors in the common pathway (prothrombin and factors V and X). For patients with rare bleeding disorders and an immunoglobulin inhibitor directed against the missing factor, factor VIIa may be the treatment of choice. Doses range from 15 to 120 mcg/kg every 2 to 6 hours depending upon the severity of bleeding. In factor XI–deficient patients without inhibitors, doses of 15 to 30 mcg/kg every 2 to 4 hours are often sufficient. A dose of 90 mcg/kg every 2 to 3 hours has been used in patients with congenital factor V deficiency or combined deficiencies of factors V and VIII, patients with acquired factor X deficiency associated with amyloidosis, and patients with antibody-mediated acquired prothrombin deficiency associated with lupus anticoagulants. An attractive aspect of using factor VIIa in place of FFP is the smaller volume of material infused. Factor VIIa is also associated with a lower risk for reactions associated with plasma infusions such as fever, urticaria, transfusion-related acute lung injury (TRALI), and anaphylaxis. Caution must be exercised when using factor VIIa in older patients with cardiovascular disease, because arterial thrombosis can result, particularly when therapy is combined with fibrinolytic inhibitors or prothrombin complex concentrate.

Treating Factor XI–Deficient Patients

When preparing patients with severe factor XI deficiency (plasma factor XI level <20% of normal) for an invasive procedure, it is important to keep in mind that (1) a negative bleeding history does not indicate a low risk with subsequent procedures, (2) certain procedures are associated with lower bleeding risks than others, and (3) patients with very low factor XI levels (<1%) often develop neutralizing inhibitors with replacement therapy. These observations have led to refinements in treatment recommendations that limit exposure to factor XI by targeting replacement therapy to certain clinical situations. Replacement therapy to reach appropriate target levels may be required for patients with mild factor XI deficiency (levels of 20% to 40% of normal) undergoing certain types of procedures.

Antiplatelet drugs should be stopped 1 week before surgery. The prothrombin time and platelet count should be normal, and the possibility of coexisting hemostatic abnormalities thoroughly investigated. Patients with factor XI levels greater than 40% to 45% generally do not experience bleeding, and a history of excessive bleeding in such an individual suggests other hemostatic abnormalities are present. If the patient has been exposed to factor XI in the recent past, the possibility that a neutralizing inhibitor is present should also be considered.

Factor replacement is required for most major surgery in factor XI–deficient patients and should be initiated before the procedure. Surgery on the oropharynx, nasopharynx, or urinary tract should be treated with FFP or factor XI concentrate to keep the plasma level at ≈40% of normal for at least 7 days. A similar strategy is appropriate for neurosurgery, head and neck surgery, cardiothoracic procedures, and major abdominal or pelvic surgery. For nasal surgery and oral procedures such as tonsillectomy, supplementing replacement therapy with antifibrinolytic therapy should be strongly considered. For prostatectomy and other surgery on the lower urinary tract, flushing the bladder with saline containing an antifibrinolytic agent may be beneficial. Minor surgery can be treated with replacement to maintain levels of 30% for 5 days.

A “wait and see” strategy, in which replacement is withheld unless bleeding occurs, appears to be appropriate for procedures such as circumcision, appendectomy, and some orthopedic surgery, as well as with normal vaginal deliveries. There are insufficient data to determine whether epidural anesthesia is safe in the absence of factor coverage, and replacement therapy should be used.

Factor XI concentrates are likely to become more popular in the near future for treating factor XI–deficient patients, and it is important to recognize that use of earlier versions of these preparations were associated with a high (10%) incidence of thromboembolism. The majority of thrombotic events occurred in older adult patients with preexisting cardiovascular disease, and these patients should probably not be treated with factor XI concentrate unless absolutely necessary. For other patients, the concentrates offer an effective form of treatment that requires a much smaller volume of infusion than does therapy with FFP.

Alternatives to factor replacement are recommended in several situations. Tooth extraction or skin biopsies can be managed with antifibrinolytic drugs alone (ε-amino caproic acid 5 to 6 g every 6 hours or tranexamic acid 1 g every 6 hours), starting 12 hours before the procedure and continuing for 7 days. Fibrin glues can be used in place of fibrinolytic therapy for skin biopsy or resection of skin lesions. Recombinant factor VIIa has been used successfully in factor XI–deficient patients with and without factor XI inhibitors and may be appropriate in situations in which exposure to plasma products needs to be limited.

Patients with factor XI deficiency can experience thromboembolic episodes. Aspirin or clopidogrel can be used in factor XI–deficient patients with myocardial infarction or other manifestations of atherosclerosis, whereas atrial fibrillation or venous thromboembolism should be treated with warfarin, with the goal of not allowing the INR to exceed 2.5.

Laboratory Testing in Rare Coagulation Factor Deficiencies

When deficiency of a coagulation factor is being considered, it is important to remember that (1) acquired conditions causing multiple factor deficiencies are more common than congenital deficiency of a single factor and (2) common nonspecific inhibitors of coagulation, such as lupus anticoagulants and heparin, will interfere with coagulation factor assays. Unexplained prolongation of the PT or PTT should be evaluated in a qualified laboratory. If at all possible, the plasma should be from blood collected by venipuncture. In our experience, the common practice of collecting blood from central venous catheters/ports or peripheral intravenous catheters frequently introduces fluids or drugs that adversely affect clotting assays and may contribute to misdiagnosis. Some laboratories use the thrombin time assay to screen samples for possible contamination with heparin or direct thrombin inhibitors to avoid this pitfall.

The initial evaluation of a plasma sample with a prolonged PT or PTT should start by repeating the abnormal test on a mixture of patient and normal plasma to determine whether the prolonged clotting time is related to a clotting factor deficiency (clotting time becomes normal with mixing) or an inhibitor that neutralizes clotting factor activity (clotting time remains prolonged with mixing). The mixing study should be performed with and without prolonged incubation (2 hours), because some antibody inhibitors show a time-dependent pattern of inhibition. Slight (a few seconds) prolongation of the PT or PTT can be difficult to evaluate with a mixing study. We evaluate such samples with assays for lupus anticoagulants before measuring specific levels of coagulation factors.

The antibodies to clotting factors that most physicians are familiar with neutralize factor activity and generate abnormal results on a mixing study (i.e., mixing with normal plasma fails to correct the abnormal clotting time). However, it is important to recognize that nonneutralizing antibodies can also be associated with severe factor deficiency. These antibodies typically enhance clearance of the clotting factor from the plasma in vivo and will not be detected by a mixing study. A failure to respond to replacement therapy in the absence of a clearly measurable inhibitor suggests this diagnosis. In our practice, we have observed severe acquired deficiencies of prothrombin, factor X, factor XI, and factor XIII caused by nonneutralizing antibodies.

If the level of a vitamin K–dependent protein (prothrombin or factors VII, IX, or X) is low, levels of factor V and at least one other vitamin K–dependent factor should be determined. If multiple vitamin K–dependent factors are low and factor V is normal, a process affecting vitamin K is likely. If factor V is also low, liver disease or DIC should be considered. Tests for hepatic function (albumin) or injury (transaminases) can facilitate interpretation of the coagulation factor studies. Distinguishing DIC from liver disease can be difficult, because results of standard tests such as the PT, PTT, platelet count, and fibrinogen and D-dimer levels may be abnormal in both conditions. Measuring factor V and factor VIII may be useful in this situation, because both factors are often low in DIC, whereas factor VIII is normal or elevated in liver disease.

Patients with factor XI, factor XII, prekallikrein, or high-molecular-weight kininogen deficiency may require anticoagulation for thromboembolism or other indications. Assays based on contact activation such as the PTT or the activated clotting time cannot be used for monitoring therapy with heparin or direct thrombin inhibitors such as argatroban or lepirudin in these patients, because the baseline test result will be abnormal. Many hospital laboratories now measure heparin with chromogenic assays based on factor Xa inhibition. Specific assays for argatroban and lepirudin are less readily available. Alternatively, low-molecular-weight heparin, fondaparinux or one of the new oral thrombin or factor Xa inhibitors that do not require monitoring may be used in these situations.

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Chapter 62 Rare Coagulation Factor Deficiencies

David Gailani, Anne T. Neff

Table 62-1 Properties of Plasma Coagulation Factors and Characteristics of Deficiency States

Table 62-2 Treatment Considerations for Rare Coagulation Factor Deficiencies

FFP, Fresh frozen plasma; CRYO, cryoprecipitate; PCC, prothrombin complex concentrate.

* Preferred treatment for congenital deficiency.

† Assuming baseline fibrinogen is not known.

Adjuncts to Factor Replacement Therapy in Congenital Factor Deficiencies

The antifibrinolytic agents ε-amino caproic acid and tranexamic acid can be effective adjuncts to factor replacement when treating congenital or acquired bleeding disorders and may be useful alternatives to replacement therapy for mild bleeding or minor procedures. These drugs inhibit clot dissolution by blocking plasminogen activation and plasmin activity and are particularly valuable when bleeding involves tissues with high fibrinolytic activity such as the oral cavity. They are also useful for treating menorrhagia, limiting blood loss with surgery, controlling epistaxis, and reducing some types of gastrointestinal bleeding. A typical loading dose of ε-amino caproic acid is 50 to 100 mg/kg followed by 2 to 4 grams every 6 hours. If bleeding subsequently occurs, the dose can be increased to a maximum of 24 grams in 24 hours. ε-Amino caproic acid is available in oral and intravenous formulations. Identical dosing may be used for either preparation because of excellent bioavailability. For dental extraction in factor VIII or IX deficiency, many centers use a single 50% to 100% loading dose of clotting factor concentrate followed by seven days of ε-amino caproic acid as the sole prophylaxis, and it is reasonable to extrapolate this approach to patients with some of the rare bleeding disorders. Patients with factor XI deficiency do well with antifibrinolytic agents alone for tooth extractions. Dental procedures such as scaling or root canal can be performed safely using ε-amino caproic acid or tranexamic acid mouthwash prepared from the intravenous formulation three to four times daily with or without systemic antifibrinolytic therapy.

Prolonged therapy with antifibrinolytic agents must be undertaken with caution in patients who are not mobile, who have a history of thromboembolic events, or who have significant urogenital bleeding. These drugs interfere with urokinase-mediated fibrinolytic activity in the genitourinary tract and can cause renal outflow obstruction by thrombotic occlusion of the ureters. Concomitant use of antifibrinolytic agents with activated prothrombin complex concentrates or recombinant factor VIIa may result in a particularly high risk for thrombus formation. Patients may develop nausea or vertigo with high doses of ε-amino caproic doses, and rarely, rhabdomyolysis.

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