Detecting and Quantifying Functional Inhibitors in Hemostasis

Functional inhibitors of hemostasis are immunoglobulins that interfere with blood coagulation. Two different classes of inhibitors can be recognized. Most frequent are lupus anticoagulants, a subgroup of antiphospholipid antibodies, which bind to a complex of phosphoplipids and phospholipid-binding proteins (β2-glycoprotein 1, prothrombin and others) resulting in prolongation of clotting times. Antiphospholipid antibodies, especially the lupus positive ones, are well-recognized risk factors for venous and arterial thrombosis. However, occasionally patients with lupus anticoagulants present with hemorrhagic diathesis when one or more coagulation factors are decreased. The latter may be caused by elevated clearance of coagulation proteins–phospholipids complexes that are bound to non-neutralizing lupus antibodies. Lupus inhibitors are outside the scope of this chapter and are discussed elsewhere (Chapter 16). The other class of inhibitors recognizes functional epitopes of one of the individual coagulation proteins thereby inhibiting the functionality of that specifi c protein. Two different subclasses have been described: autologous and allogenic inhibitors. Autologous inhibitors may develop in patients with previously normal hemostasis by a deregulation of the immune system. The most frequent spontaneous autologous inhibitor is directed against factor VIII (FVIII). The reported incidence is 1 in 1.48 million/year. Autologous FVIII inhibitors, mostly affecting elderly people, are in a minority of cases associated with an autoimmune disease or with malignancy but frequently have no underlying associated disease. It is a serious complication because of bleeding problems with a mortality of about 10%. Autologous inhibitors against each of the clotting factors V, XI, XII, XIII and the vitamin K dependent proteins are described but are very rare. Allogenic inhibitors against individual coagulation factors may develop in patients with congenital factor defi ciency because of treatment with the missing coagulation factor or in patients otherwise treated with clotting products. Among these inhibitors, FVIII inhibitors in hemophilia A patients who are treated with FVIII products are most frequent. The overall inhibitor incidence is 25–30% with the highest reported incidence in severely affected patients with genotypes that completely lack FVIII. The lowest incidence is reported in mild hemophiliacs. The development of FVIII inhibitors usually occurs early after the beginning of therapy (less than 30 exposure days) and for this reason generally occurs during childhood. Factor IX (FIX) inhibitors in patients with hemophilia B are much less common (1.5–3%) than FVIII inhibitors. Because of the low incidence little is known about its risk factors and immunologic processes associated with development. Factor XI (FXI) inhibitors may occur in severe FXI defi ciency (FXI:C <0.01 IU/mL) which is almost exclusively described in Azkenazi and Iraqi Jews. The Quality in Laboratory Hemostasis and Thrombosis, 1st edition. By F. Eric Preston, Steve Kitchen and John D. Olson. Published 2009 by Blackwell Publishing. ISBN: 978-1-4051-6803-8