New Trends in Diagnosis and Management of Acquired Coagulation Factor Disorders

Abstract

Acquired disorders of hemostasis are significantly more common than inherited disorders of hemostasis. Acquired disorders of coagulation may be physiological (pregnancy, the newborn and with advancing age) or pathological as a complication of multi-system disease. The potential acquired causes to consider are diverse, ranging from autoimmune thrombocytopenia, acquired bone marrow disorders, hemorrhagic side effects of antiplatelet or anticoagulant drugs, acquired deficiencies (commonly of factor VIII or VWF), thyroid disease, Cushing’s syndrome (including iatrogenic), liver and renal disease. The most common causes of acquired clotting factor deficiencies associated with bleeding are decreased or abnormal synthesis of clotting factors caused by liver disease or disseminated intravascular coagulation (DIC). The latter is seen in many severe illnesses, including metastatic cancer and infectious diseases. Vitamin K deficiency is another common cause of bleeding especially in hospitalized patients. Uncommon causes of acquired coagulation bleeding disorders include antibodies to coagulation factors and abnormal fibrinolysis. Acquired coagulation inhibitors, also known as circulating anticoagulants, are antibodies that bind to coagulation factors and neutralize their activity or accelerate their clearance. Inhibitors occurring in patients with inherited deficiencies of coagulation factors are termed allo-antibodies, while those developing spontaneously in subjects with no previous coagulation abnormality are designated as auto-antibodies. Auto-antibodies against all of the coagulation factors have been described, however those directed against factor VIII are the most commonly found. Inhibitors of factor VIII that occur in non-hemophiliacs produce a condition called acquired hemophilia A, with an incidence of about 1/ million people/year. Approximately 50% of acquired hemophilia A patients display underlying conditions, including autoimmune disorders, hematologic malignancies, solid tumors and pregnancy. . Idiopathic cases can also occur in elderly patients of either sex although in some cases an underlying disorder may be diagnosed long after the onset of the coagulation abnormality. Acquired von Willebrand disease is a relatively rare acquired bleeding disorder that usually occurs in elderly patients. Various underlying diseases have been associated with AVWD, most commonly hematoproliferative disorders, including monoclonal gammopathies, lymphoproliferative disorders, and myeloproliferative disorders. The medical history in the patient is the most sensitive ‘‘test’’ for such disorders. The site and the nature of the bleeding, the severity and duration of the bleed, the age of onset of the bleeding and physical examination may give a clue to the diagnosis. The coagulation test(s) showing prolongation will depend on the location of the target factor within the coagulation cascade. It may prolonging APTT only or prolongs both PT and APTT. The routine coagulation assays and mixing studies is usually required. Once a factor inhibitor is identified from an initial work-up, its strength or titre is determined by a Bethesda assay. Therapeutic strategy includes treatment of acute bleeds and, in parallel, the eradication of the antibodies. Treatment of bleeding depends on severity and site. Bypassing agents as APCC and rFVIIa are the most commonly used and recommended first-line treatments. Alternatively the extracorporeal removal of the autoantibody by therapeutic plasmapheresis, or immunoadsorption of Ig to staphylococcal protein A, or to polyclonal sheep antibodies, can be used for achieving drop of the inhibitor titer.