Hemophilia with factor VIII inhibitors

Patients with bleeding disorders are at risk of developing antibodies against the protein that is absent, present in reduced amounts, or present in an inactive form in their blood. Such coagulation inhibitors make treatment very difficult. Inhibitors of factor VIII are the most common and develop in 5-20% of patients with hemophiha A. Inhibitors of factor IX develop in 1-4% of patients with hemophilia B (3,4). Patients with factor VIII inhibitors present clinically either as high responders who show a strong anamnestic response and a sharp rise in inhibitor concentrations after exposure to factor VIII, or low responders, who show little or no anamnestic response (5). 

This may explain the effectiveness of treating patients with hemophilia who have inhibitors with high doses of factor VIII. Another approach involves the use of prothrombin complex concentrate to treat bleeding episodes in patients with factor VIII inhibitors (38) however, thromboembolic complications related to higher doses of prothrombin complex concentrate have been described, although these are relatively rare (39,40). Thrombotic events are extremely rare when highly purified factor IX is used. Activated prothrombin complex concentrate is also effective in patients with factor VIII inhibitors (41). Serious complications are rare, but disseminated intravascular coagulation has been reported (42). 

Schwarzinger I, Pabinger I, Korninger C, et al. Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates. Am J Hematol 1987 24(3) 241-5. 

Treatment options for patients with inhibitors are high dosages of clotting factor or recombinant factor Vila for both hemophilia A and B or, in the case of hemophiha A, porcine factor VlllrC or activated prothrombin complex (37). Regular administration of intermediate or low-dose factor Vin concentrates leads to the rapid disappearance of factor VIII inhibitors in some high responders (27) this is thought to be due to the development of immune tolerance. 

Prescott R, Nakai H, Saenko E L, et al. (1997). The inhibitor antibody response is more complex in hemophilia A patients than in most nonhemophiliacs with factor VIII autoantibodies. Recombinate and Kogenate Study Groups. Blood. 89 3663-3671. 

Prothrombin complex concentrates are available in three main types the most effective are four-factor concentrates containing factors II, VII, IX, and X. Three-factor concentrates (mainly in use in the USA) lack factor VII and are less effective in reversing oral anticoagulation therapy. The third type consists of activated products, such as factor VIII inhibitor bypassing activity (FEIBA) these products are not indicated for reversal of oral anticoagulation, but they are indicated for treatment of inhibitors (anti-factor VIII antibodies) in patients with hemophilia A [31 ]. FEIBA is associated with thrombotic events [67 ]. 

The individual responsiveness to desmopressin is consistent, and a test dose administered at the time of diagnosis or prior to therapy is the best predictor of response. Generally, DDAVP is more effective in vWD than in hemophilia patients, with an average 30% to 50% increase in vWF and factor VIII levels. In patients with an adequate response, desmopressin is first-line therapy because it allows for once-daily administration (elevates plasma levels for 8-10 hours), does not pose a threat in terms of viral transmission, and the cost is substantially less than that of the plasma-derived products. Fibrinolysis inhibitors (50-60 mg/kg of aminocapriotic acid every 4—6 hours or trenex-amic acid 10-15 mg/kg every 8-12 hours) and OCs are used successfully in the management of epistaxis and menorrhagia or as adjuvant treatments. 

Hemophilia There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In some patients, additional Factor VIII was required. 

Indications Treatment of bleeding episodes in hemophilia A or B patients with inhibitors to factor VIII or factor IX... 

B. Indications and use NovoSeven is indicated for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to factor VIII or factor IX. It should be administered to patients only under the direct supervision of a physician experienced in the treatment of hemophilia. 

Lusher JM, Arkin S, Abildgaard CF, et al. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A safety, efficacy, and development of inhibitors. N Engl J Med 1993 328(7) 453—9. 

Recombinant and high-purity coagulation factor products appear to have a greater tendency to induce inhibitors than human-derived concentrates of intermediate or low purity (7). These intermediate-purity or low-purity human-derived concentrates are probably more suitable for inducing immune tolerance in patients with hemophilia with inhibitors. It has been suggested that for immune tolerance a high content of Von Willebrand factor in factor VIII concentrates is required, although direct comparisons of different products have not been made (8). 

In two patients with hemophilia with antibodies to both human and porcine factor VIII, continuous recombinant factor Vila resulted in hematuria (21). In neither case was a cause of the hematuria found. The author suggested that mucosal bleeds, such as hematuria, are characterized by high fibrinoljdic activity locally and may require higher peak concentrations of factor VII to generate sufficient thrombin to achieve and sustain hemostasis. The need for a full thrombin burst could relate to the role of thrombin in the activation of thrombin-activatable fibrinolysis inhibitor. 

Lyophilized factor VIII has been used as substitution therapy in patients with hemophilia A. Most, but not all, recombinant factor VIII (recFVIII) is structurally and immunologically similar to plasma-derived factor VIII, and it has been well tolerated by patients in clinical trials. A major concern about recombinant factor VIII has been the occurrence inhibitors (1). However, there is evidence that there is no difference in the occurrence of inhibitors between recombinant factor VIII and plasma-derived factor VIII (2). 

In two studies of previously untreated patients with severe hemophilia, who were given two different recombinant factor VIII products, the incidence of development of an inhibitor was comparable (about 30%) (29). 

In 31 previously untreated and minimally treated children with severe hemophilia A, who received full-length recombinant factor VIII (formulated with sucrose) for home therapy and surgery, there was no difference in the incidence of inhibitor formation compared with other recombinant products or plasma-derived products (2). 

Two patients (aged 60 and 73 years) with mild and moderate hemophilia respectively, without a family history of inhibitor formation, were exposed to factor VIII for more than 50 days. An inhibitor developed in both patients after an intermediate factor VIII product was replaced by a high-purity factor VIII product, which was given by continuous infusion during a surgical procedure. 

If the inhibitor activity is under 10 Bethesda units/ml, patients can be treated with increased doses of factor VIII or IX concentrates (43). In addition, patients with hemophilia A with low or intermediate antibody titers can also be treated with porcine factor VIII (43). However, hemorrhagic episodes in patients with antibody activity over 10 Bethesda units/ml may result in life-threatening hemorrhage that cannot be treated by conventional therapy (26,43). Prevention or treatment of clinically significant bleeding episodes in these patients can be achieved by using so-called bypassing therapies, such as recombinant factor Vila and activated prothrombin complex (23/26,43). Recombinant factor Vila is both effective and safe in the treatment of inhibitors directed to either factor VIII or IX (44,45). 

Febrile reactions occurred in two patients after the initial bolus administration of porcine factor VIII C in a retrospective study of 29 treatments with porcine factor VIII C in 18 patients with hemophilia A with inhibitors (13). 

Reeonibinant factor Vlll is indicated fur the treatment of sTassieuI hemophilia (hemophilia A) and for the prevention jnil treatment of hemorrhagic episodes and perioperative mtinajtement of patients with hemophilia A. The drug is also indicated for the treatment of hemophilia A in persons who pi>se.s.s inhibitors to factor VIII. 

Figure 100-3 summarizes the therapeutic options in the management of hemophilia A patients with inhibitors. The same algorithm can be apphed to the management of hemophilia B patients, except that factor IX should be substituted for factor VIII. The use of porcine factor Vin is not indicated for the inhibitors in hemophilia B. 

Bray GL, Gomperts ED, Courier S, et al. A multicenter smdy of recombinant factor VIII (Recombinate) Safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate study group. Blood 1994 83 2428-2435. 

Factor IX is an antihemophilic agent that restores hemostasis in patients with factor IX deficiency. It is indicated in the control and prevention of hemorrhagic episodes in patients with hemophilia B (factor IX deficiency) (Proplex T only) bleeding episodes in patients with inhibitors to factor VIII, and prevention or control of bleeding episodes in patients with factor VII deficiency. 

McFarland was the first to report the development of hemophilia in a 45-year-old patient who had received repeated transfusions. Several case reports have appeared. At first it was believed that the hemorrhagic diathesis resulted from the accumulation of coagulation inhibitors heparin was often incriminated. Only in the 1950 s was the immunological pathogenesis of the disease accepted. Inhibitors of factors VIII (hemophilia A) and IX (hemophilia B) have been reported. The acquired inhibitors to factor VIII have been studied most extensively. In fact, the inhibitors have been purified. They are believed to be y-globulins with a sedimentation constant of 7 S. 

Yoshioka A, Nishio K, Shima M. Thrombelastgram as a hemostatic monitor during recombinant factor Vila treatment in hemophilia A patients with inhibitor to factor VIII. Haemostasis 1996 26(Suppl. 1) 139 2. 

Gouw SC, van den Berg HM, Fischer K, Auerswald G, Carcao M, Chalmers E, et al. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A the RODIN study. Blood 2013 121(20) 4046-55. 

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