How we choose factor VIII to treat hemophilia

In high-income countries, the large availability of coagulation factors for replacement therapy of patients with hemophilia A has raised the life expectancy of these lifelong bleeders to that of males from the general population. The practicing clinician is offered a multitude of choices among several commercial brands of factor VIII extracted from human plasma or engineered from mammalian cell cultures by means of recombinant DNA technology. This article has the goal to offer our opinions on how to choose among the different products, that we consider interchangeable relevant to their clinical efficacy in the control of bleeding and safety from pathogen transmission. Hence, the main determinants of our choices are price and the risk of occurrence of factor VIII inhibitory alloantibodies. With this as background, we present the rationale underlying the choices for different categories of patients with severe hemophilia A: previously untreated patients, multiply treated patients, and patients undergoing immune tolerance induction with large doses of factor VIII to eradicate inhibitors. Mention is also made to the possible strategies that should be implemented to make available coagulation factors for replacement therapy in developing countries.     

Transient factor VIII inhibitor in a hemophilia patient after staphylococcal septic shock syndrome

We report a transient type I factor VIII inhibitor that arose in a 30-year-old hemophilia patient just after staphylococcal septicemia. This situation usually occurs early in the course of substitution therapy with factor VIII concentrate in hemophilia patients. Although disseminated intravascular coagulation and acute respiratory distress syndrome developed after septic shock, the patient recovered following intravenous administration of antibiotics (meropenem and gentamycin), an antithrombin preparation, high-dose methylprednisolone, and recombinant factor VIII concentrate (rFVIII). During this therapy, however, activated partial thromboplastin time gradually lengthened. On the seventh day of hospitalization, intracranial hemorrhage occurred with right hemiplegia, even though the substitution therapy had continued at the same dosage (30 U/kg per day) of rFVIII. At that point, 4 Bethesda units of the type I inhibitor against factor VIII were detected in the plasma. Increased amounts (46 U/kg per day) of rFVIII and prednisolone were administered, and hypothermic therapy was initiated. Following these treatments, the patient's general condition gradually improved, and within 25 days the inhibitor titer dropped to undetectable levels and did not recur during treatment. These clinical findings suggest that the staphylococcal septic shock may have acted as a trigger in the development of transient factor VIII inhibitor in this patient.     

Cardiac tamponade in a patient with moderate hemophilia A and factor VIII Inhibitors

Cardiac tamponade is a rare, life-threatening complication of hemophilia. The management of pericardial bleeding in hemophilia A patients with inhibitors is particularly challenging because antibodies to factor (F) VIII render the use of high-dose FVIII ineffective. Fortunately, the management of uncontrollable bleeding in patients with hemophilia and inhibitors has improved since the introduction of treatments that bypass the need for FVIII and FIX. A case of hemopericardium complicated by cardiac tamponade occurring one month following an upper respiratory tract infection in a patient with hemophilia and FVIII inhibitors is presented. Management of the present case was based on current guidelines on the use of recombinant FVIIa for acute bleeding in patients with hemophilia and inhibitors. The subsequent development of hemothorax in the present case indicates that a more protracted course of recombinant FVIIa is justified following pericardiocentesis for pericardial bleeding in hemophilia with inhibitors. Alternative approaches to the management of this complication are also reviewed.     

Experience with highly purified porcine factor VIII in a patient with haemophilia A and a factor VIII inhibitor

Highly purified porcine factor VIII has been advocated for the treatment of bleeding episodes in patients with haemophilia who have inhibitors to factor VIII. This approach has been successful in a patient with an intermediate potency inhibitor showing little cross-reactivity to porcine material. As in some other reported cases, a severe allergic reaction occurred on one occasion but did not preclude the subsequent use of the porcine concentrate in carefully controlled conditions.     

Successful use of recombinant factor VIIa for emergency fasciotomy in a patient with hemophilia A and high-titer inhibitor unresponsive to factor VIII inhibitor bypassing activity

We report a patient with hemophilia A and high-titer factor VIII inhibitor who developed compartment syndrome of his forearm following trauma. Emergency fasciotomy was performed. Initial hemostatic treatment with factor VIII inhibitor bypassing activity (FEIBA) was unsuccessful. Bleeding was controlled with recombinant factor VIIa.     

Correlation between factor VIII genotype and inhibitor development in hemophilia A

The development of neutralizing antibodies, or inhibitors, against infused factor VIII represents a significant complication of treatment for hemophilia A. Although it is likely that both genetic and environmental factors influence whether patients form inhibitors, correlations between types of factor VIII mutations and inhibitor development are becoming apparent. Approximately 20% of all patients with severe hemophilia A generate inhibitors. Of these inhibitor patients, 90% have inversions, large deletions or nonsense mutations of the factor VIII gene that would be predicted to eliminate production of factor VIII antigen. In contrast to patients with severe disease, inhibitor formation in patients with mild/moderate hemophilia A is rare. Inhibitor patients with mild/moderate disease typically have missense mutations that may cause local conformational changes within immunogenic domains of factor VIII and lead to production of dysfunctional antigen. Taken together, hemophilia A patients are predisposed to inhibitor development with mutations causing infused factor VIII to be perceived as either 1) a completely novel antigen or 2) an immunologically altered antigen.     

Normal pregnancy in a patient with a postpartum factor VIII inhibitor

A patient who had developed a VIII:C IgG-Kappa antibody after her first delivery became pregnant for a second time. At that time the titer of the inhibitor had increased fourfold, remaining at high levels throughout the rest of the pregnancy. The neonate exhibited an inhibitor with characteristics identical to that of the mother which could not be detected 3 months after birth. No hemorrhagic complications in either of the subjects were observed.     

Remission of a non-haemophilic patient with acquired factor VIII inhibitor treated with infusion of factor VIII and corticosteroid

A 61-years old woman who had been healthy without history of abnormal bleeding, developed widely spread ecchymosis and intramuscular bleeding in March, 1987. She was hospitalized for this hemorrhagic diathesis in May, 1987 and the following laboratory data were revealed: activated partial thromboplastin time (APTT), 76.7 seconds; factor VIII procoagulant activity, 2%; factor VIII inhibitor, 27 Bethesda units/ml. The inhibitor was an immunoglobulin of IgG type. Her clinical data of the blood were normal, and tests for antibodies, such as RA test, LE test and thyroid test were negative. Physical examination revealed ecchymosis over her right arm and swelling and pain in the right arm. She was first treated with a large dose of factor VIII concentrates, but the effect was insufficient. Then prednisolone was given, which resulted in decreasing of the inhibitor and improvement of the coagulation profiles. This treatment appeared to offer effective control on severe hemorrhage in patients with factor VIII inhibitors.     

Acquired factor VIII inhibitor associated with chronic interferon-alpha therapy in a patient with haemophilia A

SUMMARY. Both the development of factor VIII inhibitors and infection by hepatitis C virus are serious complications of haemophilia A. We describe the first reported case of the subsequent development of a factor VIII inhibitor in a patient with haemophilia A after treatment with interferon-alpha for chronic active hepatitis C.     

High-dose factor VIII inhibits factor VIII-specific memory B cells in hemophilia A with factor VIII inhibitors

Hemophilia A in its severe form is a life-threatening hemorrhagic disease that is caused by mutations in the factor VIII (FVIII) gene (symbol F8). About 25% of patients who receive replacement therapy develop neutralizing antibodies that inhibit the function of substituted FVIII. Long-term application of high doses of FVIII has evolved as an effective therapy to eradicate the antibodies and to induce long-lasting immune tolerance. Little is known, however, about the immunologic mechanisms that cause the down-modulation of anti-FVIII antibodies by high doses of FVIII. We report that high doses of FVIII inhibit the restimulation of FVIII-specific memory B cells and their differentiation into antibody-secreting plasma cells in vitro and in vivo in a murine model of hemophilia A. The inhibition of memory B-cell responses is irreversible and not mediated by FVIII-specific T cells. Furthermore, it seems to involve the activation of caspases. We conclude that the inhibition of FVIII-specific memory B cells might be an early event in the down-modulation of anti-FVIII antibodies in patients with hemophilia A who receive high doses of FVIII.