Hereditary coagulation disorders
Inherited coagulation abnormalities involve all of the coagulation factors except factors III and IV. The most common and most severe of these abnormalities is factor VIII deficiency, called hemophilia A, or classical hemophilia. Factor IX deficiency is called hemophilia B. Both types are X-linked. Typical manifestations of hemophilia A include severe and protracted bleeding, after even minor trauma, and spontaneous bleeding into joints (hemarthroses), the central nervous system, and the abdominal cavity.
Treatment of hemophilia A involves infusion of factor VIII. With the availability of recombinant factor VIII, the risk of transmission of hepatitis B and C and HIV has now been mostly eliminated. However, about 5%–10% of patients with hemophilia A develop inhibiting antibodies, presumably due to sensitization following administration of factor VIII. These inhibitors bind to the infused factor VIII and render it ineffective; subsequently, the patient will need bypassing agents such as recombinant factor VIIa or an anti-inhibitor coagulant complex. Antibodies inhibiting coagulation can also develop in healthy older patients, in nonhemophilic patients after drug reactions, and in those with inherited vascular disorders. Clinical manifestations range from mild bleeding to full-blown hemophilia that correlates with level of factor deficiency. The aPTT is prolonged, while the PT is normal. Treatment involves various regimens of coagulation factor replacement and immunosuppression in an attempt to eliminate the inhibitor. However, during episodes of bleeding or as prophylaxis before surgery, patients with high titers of inhibitor should receive recombinant factor VIIa or an anti-inhibitor coagulant complex as first-line therapy. Emicizumab, a monoclonal antibody that binds factor IXa and supplants the need for factor VIIIa as a cofactor for factor X activation, was recently approved by the FDA. An investigational monoclonal antibody, concizumab, which inhibits the tissue factor pathway, is now in clinical trials. Gene therapy is currently in the developmental phase but could further transform the outlook for these patients.
Von Willebrand disease (vWD) is the most common inherited bleeding disorder: low levels of von Willebrand factor (vWF) are found in 1% of the population. The 2 main functions of vWF are stabilizing factor VIII to prevent degradation and promoting platelet adhesion. There are 3 major types of vWD. Type 1 is autosomal dominant and accounts for 75% of cases. Type 2 (15%–20% of cases) has 4 subtypes and is predominantly autosomal dominant, and type 3 (5%) is autosomal recessive. Type 1 manifests with mild mucocutaneous bleeding, and most forms of type 2 are associated with mild to moderate bleeding. In contrast, the recessively inherited forms are associated with very low levels of factor VIII and severe bleeding. A form of vWD also occurs in patients with aortic valve stenosis and in some patients with thrombocythemia. Desmopressin, a synthetic form of vasopressin (antidiuretic hormone), may be used for episodes of bleeding and administered preoperatively to reduce risk of surgical bleeding. Plasma-derived concentrates to replace vWF are available for patients who cannot tolerate desmopressin or need prolonged treatment.
Bhat R, Cabey W. Evaluation and management of congenital bleeding disorders. Hematol Oncol Clin North Am. 2017;31(6):1105–1122.
Oldenberg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377(9):809–818.
Acquired coagulation disorders
Vitamin K deficiency Vitamin K is required for the production of factors II (prothrombin), VII, IX, and X in the liver. Normal diets contain large amounts of vitamin K, which is also synthesized by intestinal flora. Causes of vitamin K deficiency include biliary obstruction and various malabsorption syndromes (including sprue, cystic fibrosis, and celiac disease), in which intestinal absorption of vitamin K is reduced. Suppression of endogenous gastrointestinal flora, seen commonly in hospitalized patients on prolonged broad-spectrum antibiotic therapy, decreases intestinal production of vitamin K. However, clinical deficiency occurs only if dietary intake is also diminished. Nutritional deficiency is unusual but may occur with prolonged parenteral nutrition. Laboratory evaluation reveals prolongation of both PT and, later in the course of the disease, aPTT. Most forms of vitamin K deficiency respond to subcutaneous or intramuscular administration of 20 mg of vitamin K1; coagulation defects normalize within 24 hours. Vitamin K1 should not be given intravenously because of the risk of sudden death from an anaphylactoid reaction.
One special form of vitamin K deficiency is hemorrhagic disease of the newborn, which is the result of a normal mild deficiency of vitamin K–dependent factors during the first 5 days of life and the absence of the vitamin in maternal milk. This condition is now rare in developed countries because of the routine administration of vitamin K to newborns. (See also the section Antiphospholipid Syndrome in Chapter 9.)
Liver disease Hemostatic abnormalities of all types may be associated with disease of the liver, the site of production of all the coagulation factors except factor VIII and factor XIII A-subunit. As liver dysfunction develops, levels of the vitamin K–dependent factors decrease first, followed by those of factors V, XI, and XII; both PT and aPTT are prolonged. Thrombocytopenia, primarily the result of hypersplenism, and a prolonged bleeding time due to platelet dysfunction are common. In addition, intravascular coagulation and fibrinolysis are often present, further complicating the clinical picture.
Mild hemorrhagic symptoms are common in patients with significant liver disease. Severe bleeding is usually gastrointestinal in origin, arising from peptic ulcers, gastritis, or esophageal varices. Treatment is difficult at best and consists of blood and coagulation factor replacement. Local measures, such as vasopressin infusion or balloon tamponade of bleeding varices, can sometimes control potentially catastrophic bleeding.
Disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC) is a complex syndrome involving widespread activation of the coagulation and fibrinolytic systems within the general circulation. The syndrome is a secondary process, triggered by exposure of procoagulants to the bloodstream, which activates the coagulation cascade, resulting in formation of fibrin and fibrin degradation products (fibrin split products), resulting in occlusion of the microcirculation as well as various forms of organ failure and, occasionally, thrombosis of larger vessels. Subsequently, utilization and consumption of the coagulation factors and platelets produce bleeding. Laboratory findings may vary but usually include thrombocytopenia, hypofibrinogenemia, and elevated levels of fibrin split products. PT and aPTT are usually, but not invariably, prolonged.
Clinically, 2 forms of DIC are recognized. Acute DIC is characterized by the abrupt onset of severe, generalized bleeding. The most common causes are obstetric complications (most notably abruptio placentae and amniotic fluid embolism), septicemia, shock, massive trauma, malignancy (especially acute promyelocytic leukemia), ABO incompatibility, and major surgical procedures. Bleeding, thrombocytopenia, prolonged PT/aPTT, reduced procoagulant factors, low plasma fibrinogen, and reduced levels of coagulation inhibitors are characteristics of acute DIC. Treatment, other than specific measures aimed at the underlying disease, is controversial. Among the modalities used are heparinization and replacement of blood, platelets, and fibrinogen.
Chronic DIC is associated with disseminated solid-tumor neoplasms (pancreatic, ovarian, gastric, or brain) and autoimmune diseases. Laboratory values range from normal to moderately abnormal; levels of coagulation factors may even be elevated (high plasma fibrinogen). Bleeding and thrombosis (especially lower extremity deep venous thrombosis and pulmonary embolism) may occur, but the syndrome remains undiagnosed in most patients unless renal failure results from intravascular coagulation in the kidney. Many patients with chronic DIC do not require specific therapy for the coagulopathy because it is not severe enough to present a major risk of bleeding or thrombosis. On occasion, chronic DIC may convert to the acute form.