Acquired Factor VIII Inhibitors: Pathophysiology and Treatment

Abstract

Hemophilia A is classically caused by a congenital deficiency of factor VIII, but an acquired form due to inhibitors to factor VIII (FVIII) typically presents later in life. Patients who develop such acquired factor VIII inhibitors may present with catastrophic bleeding episodes, despite having no prior history of a bleeding disorder. Though the disorder is rare, it is known to cause significant morbidity and mortality. This review will focus on what is currently known about acquired hemophilia A, its pathogenesis, its associated etiologies, and its treatment. Factor VIII and Acquired InhibitorsFactor VIII functions as a cofactor to factor IXa in the tenase complex, and a deficiency of factor VIII thus reduces the generation of thrombin on the surface of activated platelets. Factor VIII is synthesized as a 330-kDa precursor protein with an A 1 -a 1 -A 2 -a 2 -B-a 3 -A 3 -C 1 -C 2 domain structure. 1After proteolytic processing, FVIII associates with von Willebrand Factor (vWF) in heterodimers of a heavy (A 1 -a 1 -A 2 -a 2 ) and a light (a 3 -A 3 -C 1 -C 2 ) chain associated by a metal ion interaction. Most acquired FVIII inhibitors bind to the A2, A3 or C2 domains.2,3 Anti-C2 antibodies disrupt the binding of FVIII to phospholipid and vWF, while antibodies to A2 and A3 interfere with FVIII binding to factor X and factor IXa.In congenital hemophilia A patients treated with factor VIII, alloantibodies to FVIII develop in 20-40% of patients. By contrast, acquired inhibitors/autoantibodies against FVIII in nonhemophiliacs occur in only about one case per million per year. 4 In acquired hemophilia, autoantibodies are characteristically non-complement fixing, nonprecipitating immunoglobulins from the IgG family that bind FVIII in a time-and temperature-dependent manner. 5While most alloantibodies inactivate FVIII in direct proportion to their concentration (first-order kinetics), acquired inhibitors/autoantibodies show a non-linear inactivation pattern (type II or second-order kinetics). The kinetics plots in Figure 1 show a linear inactivation of FVIII by a type 1 alloantibody, with eventual complete inhibition of the FVIII activity. By contrast, the type 2 antibody shows a rapid initial inactivation phase followed by a slower phase of equilibrium where some factor VIII can usually be measured.

Rituximab in the treatment of autoimmune haematological disorders

“…The disease occurs when patients develop autoantibodies, or 'inhibitors', directed against the factor VIII (FVIII) clotting factor. Patients who develop such acquired FVIII inhibitors may present with catastrophic bleeding episodes, despite having no prior history of a bleeding disorder (Ma & Carrizosa, 2006). It is associated with considerable morbidity, as demonstrated by a survey of 215 non-haemophiliac patients who had developed inhibitors to FVIII; in this study major bleeding occurred in >80% of patients, with a mortality rate of approximately 20% (Green & Lechner, 1981).…”

Hemorrhagic pleural effusion related to acquired coagulation factor VIII deficiency: A case report

“…Pericardial bloody effusion associated with factor VIII deficiency is a rare complication and may often be overlooked. Patients with factor VIII deficiency may develop serious and fatal complications, such as intracerebral hemorrhage, muscle bleeding, hematuria, epistaxis and gastrointestinal bleeding (4). The present study reported a life-threatening case of pericardial bloody effusion following cardiac tamponade and arrhythmia in a 39-year-old male whose factor VIII activity measured 14%.…”

“…1 3 Urology, 4 Radiotherapy and 5 Cardiology, Xiamen Chang Gung Hospital, Xiamen, Fujian 361000, P.R. China right ventricular anterior wall near to the apex, with evidence of right atrial and ventricular collapse and pericardial thickening.…”

Acquired haemophilia in a patient with discoid lupus

“…It is unclear whether the known and untreated chronic discoid lupus erythematodes is a predisposing factor for the development of acquired haemophilia A. Since rare cases of underlying non-systemic cutaneous diseases have been described in the literature [1,2], we assume that the discoid lupus in our patient might well be a predisposing disease.…”

“…Effective treatment involves not only the initial treatment of acute haemorrhage with factor VIII concentrates, a factor-VIII-bypassing-agent such as recombinant FVIIa or activated prothrombin complex concentrate but also the eradication of the inhibitor by 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 immunosuppression, plasmapheresis or immunoadsorption or a combination of these modalities [1,5,6].…”