Successful self-infusion of activated prothrombin complex concentrate for prophylaxis in a child with a factor VIII inhibitor

Regular self-infusion of an activated prothrombin complex concentrate (APCC) has been successfully introduced to a 14-year-old boy with hemophilia A. The child was diagnosed as a neonate, and at age 7 years, developed a high titer (127 BU/mL) factor VIII inhibitor coincident with a protracted ankle joint bleeding. From age 7-10 years, he received on-demand therapy using a prothrombin complex concentrate (PCC), PROPLEX-ST. From age 10-14 years, he received prophylaxis with PROPLEX-ST, initiated after an intracranial hemorrhage and coincident anamnestic inhibitor response. Throughout 7-year period of PCC treatment, he experienced recurrent bleeding episodes. Self-prophylaxis with APCC, FEIBA VH [Anti-inhibitor Coagulant Complex] (50 U/kg/dose three times per week) using infusion pump was initiated at 14 years of age and has continued for 2 years. There were no bleeding, thrombotic events or other adverse events after initiation of this prophylaxis, and inhibitor levels decreased to 1 BU/mL. His quality of life was improved, particularly with respect to school. Our long observation proposes a well-disciplined home-based FEIBA prophylaxis in inhibitor-positive hemophiliacs.     

Purified factor IX using monoclonal immunoaffinity technique: clinical trials in hemophilia B and comparison to prothrombin complex concentrates.

Replacement therapy for hemophilia B (factor IX deficiency) using prothrombin complex concentrate (PCC) has been associated with serious complications of thromboembolic events and transmission of viral infections. Monoclonal antibody-purified factor IX (Mononine) provides a highly purified factor IX concentrate, while eliminating other vitamin K-dependent factors (II, VII, and X). Mononine was evaluated for in vivo recovery, half-life, and for its safety and efficacy in 10 patients with hemophilia B. The in vivo recovery of factor IX with Mononine was a 0.67 +/- 0.14 U/dL (mean +/- SD) increase per 1U/kg of infused factor IX, and the biologic half-life (t1/2), determined using the terminal phase of elimination, was 22.6 +/- 8.1 hours. Comparison of in vivo recovery of other vitamin K-dependent factors following a single infusion of either Mononine or PCC showed that, whereas Mononine infusion caused no changes in other vitamin K-dependent factors or in prothrombin activation fragment (F1+2), PCC infusion was associated with significant increases of factors II (2.7 U/dL per 1 U/dL of IX increase) and X (2.2 U/dL for 1 U/dL for 1 U/dL of IX). Patients who used Mononine as their sole therapeutic material during the 12-month period showed an excellent response in hemostasis for their bleeding episodes. Their experience with long-term use of Mononine was at least equivalent to their previous experience with PCC in the frequency and amount of factor usage. No patients developed antibody against mouse IgG or an increase in IX inhibitor during the 12-month period. These results indicate that monoclonal antibody-purified factor IX concentrate provides hemostatically effective factor IX replacement while avoiding extraneous thrombogenic substances.     

Rituximab as an adjuvant therapy to immune tolerance in a haemophilia A boy with high inhibitor titre

We report a haemophilia A boy with high inhibitor titre (170 BU) who experienced five life-threatening bleeding episodes during a one-year period from 9 to 21 months. At the age of 22 months, he received rituximab (375 mg m(-2) per dose) at one- and three-week intervals, three courses each and alternative daily treatment with factor VIII concentrate at doses of 100 units kg(-1) for 24 weeks and 50 units kg(-1) for the following 28 weeks. Although the pretreatment inhibitor level of 4.5 BU showed an anamnestic response reaching the maximum level of 200 BU at the 9th week of treatment, it gradually declined to 30 BU at the 22nd week and was constantly maintained at 25-30 BU for the following 30 weeks. Only three bleeding episodes of two haematomas and one haemarthrosis were found during the one-year treatment period. No opportunistic infection occured during this period.     

Decline of factor VIII and factor IX inhibitors during long-term treatment with NovoSeven.

Recombinant factor VIIa (rFVIIa) (NovoSeveng) is used to treat bleeding episodes in hemophilia A and B patients with inhibitor antibodies against factor VIII (FVIII) and factor IX. rFVIIIa has been studied in home treatment of mild-to-moderate joint, muscle, and mucocutaneous bleeds to assess safety and efficacy. Treatment with other factor concentrates was allowed according to treating physician's judgment. Blood samples were drawn before study start and after 6 and 12 months. It has thus been possible to follow the inhibitor titres during this period. Analyses of 53 patients (49 hemophilia A, four hemophilia B) showed inhibitor levels up to 1,208 BU/ml before study start. Based on the first analysis, hemophilia A patients were divided into high responders (> 5 BU/ml; 28 patients), low responders (> 1 and < 5 BU/ml; 15 patients) and very low responders (< or = 1 BU/ml; six patients). In high responders receiving rFVIIa as only treatment, FVIII inhibitor titre decreased to one-third of the initial level. For high responders receiving other factor treatments such as FVIII or prothrombin complex concentrates, inhibitor titre remained unchanged. Titres for low responders and very low responders remained unchanged independent of treatment. Thus, when rFVIIa is used as the only coagulation factor to treat hemophilia A/B high-responder inhibitor patients, inhibitor level declines significantly.     

Acquired hemophilia: a case report

Acquired hemophilia is a severe bleeding diathesis that affects both males and females. It is caused by suddenly appearing autoantibodies that interfere with coagulation factor VIII activity. This disorder is characterized by spontaneous and post-traumatic subcutaneous bleeds and massive mucosal hemorrhages. We report in the current article a case of acute renal failure and bleeding from the urinary tract caused by idiopathic acquired hemophilia in a 54-year-old woman. Hemostatic tests indicated prolonged activated partial thromboplastin time (APTT) to 107.8 sec (norm 26-36 sec), normal value of the prothrombin index which was 82% (norm 70-130%), increased fibrinogen concentration to 583 mg/dl (normal value 200-400 mg/dl), the bleeding time was 5 min and 20 s (norm < 10 min) and the platelet count was 366 x 10(9)/l (norm 130-400 x10(9)/l). The autoantibody against factor VIII in a titer of 121 Bethesda Units/ml (BU/ml) and decreased factor VIII activity to 2% (norm 50-150%) with normal plasma concentration of factor IX. Activated (FEIBA, Baxter) and nonactivated prothrombin complex concentrates (factor IX concentrate) have been used in the treatment of bleeding episode. Immunosuppressive treatment with the combination of oral prednisone 60 mg/24h and cyclophosphamide 150 mg/24h was administered in order to remove the factor VIII inhibitor. Reduction of the factor VIII inhibitor titer to 38 BU/ml and increase of factor VIII activity to 4% was initially achieved. This treatment has been continued for two years and led to normalization of hemostatic parameters (APTT 26 sec, factor VIII activity 108%) which means a total removal of factor VIII inhibitor.     

Results of secondary prophylaxis in children with severe hemophilia

In this study, 13 children with severe hemophilia were given routine replacement infusions of factor VIII or IX to treat arthropathy. The children who had a mean age of 6.9 years (range 2.0–12.5) at initiation of prophylaxis had experienced an average of 43 acute hemorrhages (range 8–127) in the year prior to prophylaxis, of which a mean of 24 (range 5–46) were into joints. Therapy was begun in five children, using factor VIII concentrate at 20 U/kg three times a week, and one boy received factor IX concentrate 40 U/kg twice a week. This dose schedule was inadequate for three factor VIII-deficient boys and for the one factor IX-deficient boy. Two of three factor VIII-deficient boys responded to an increase to 30 U/kg prior to the 3-day interval. The dose frequency was increased to three times a week for the factor IX-deficient boy, but he continued to bleed and was taken to synovectomy. One of the original five factor VIII-deficient boys plus seven other factor VIII-deficient boys were begun on factor VIII 20 U/kg every other day; 3 boys ceased bleeding. Trough factor VIII levels were measured 24 hr after an infusion in the five boys who continued to bleed. Factor VIII dosage was adjusted to achieve a trough level of >1%; 4 responded to an increase in the dose of factor VIII; 1 had an adequate trough but, due to compliance issues, was taken to synovectomy. Serial clinical and radiographic assessments determined stabilization of joint disease in more than one-half of the boys. No child showed reversal of abnormal radiographic findings. Institution of aggressive factor VIII and IX concentrate in children with established hemophilic arthropathy does not reverse joint disease but may alter the clinical course of hemophilia. Future studies to compare this intervention with primary prophylaxis instituted prior to the onset of recurrent joint hemorrhage are warranted. © 1994 Wiley-Liss, Inc.     

Myocardial infarction after FEIBA therapy in a hemophilia-B patient with a factor IX inhibitor

Summary A case of myocardial infarction (MI) in a hemophilia B patient with a factor IX (FIX) inhibitor (6BU) is described. MI occurred after two infusions of FEIBA concentrate. Unexpectedly, these infusions resulted in a neutralization of the inhibitor and a consistent plasma FIX activity which may have increased the thrombotic risks. Four days later, a psoas hematoma was suspected. At that time the inhibitor remained undetectable, allowing a therapy with purified FIX concentrates. No recurrence of thrombotic complication was observed. This is an additional illustration of the thrombotic risks associated with the use of activated prothrombin complex concentrates, especially in patients having pre-existing risk factors for thrombosis. The management of bleeding episodes in hemophilia B patients with inhibitor represents an especially difficult challenge.     

Heart transplant in a factor VIII-deficient patient with a high-titre inhibitor: perioperative management using high-dose continuous infusion factor VIII and recombinant factor VIIa.

Four years prior to transplantation, a 14-year-old boy with severe haemophilia A and a high-responding factor VIII (FVIII) inhibitor developed an anteroseptal myocardial infarct while receiving high doses of an activated prothrombin complex concentrate (PCC). Cardiac transplantation was required for survival because of the ensuing cardiomyopathy. At surgery, the patient's inhibitor titre was 1.8 Bethesda units (BU). High-dose bolus therapy, followed by a continuous infusion of FVIII provided excellent operative and initial postoperative haemostasis without additional blood-product support. Once anamnaesis developed on day 6 postoperatively, recombinant factor VIIa (rFVIIa) therapy was initiated. Haemostasis remained excellent, except for the transient increase in chest-tube bleeding that was noted on day 7. epsilon-Aminocaproic acid was added and haemostasis was re-established. On day 15, rFVIIa was replaced with alternate day infusions of prothrombin complex concentrates (PCCs). On day 21 following the transplant, the patient was discharged, remaining on daily FVIII immune tolerance and thrice-weekly PCC prophylaxis. He remains well 24 months after transplant with an inhibitor titre of 39 BU. This paper describes the second case of cardiac transplantation complicated by haemophilia and an inhibitor, and discusses preoperative planning and operative and postsurgical haemostasis management.     

Sensitive solid phase enzyme immunoassay for factor IX antigen and classification of hemophilia B

A sensitive solid phase enzyme immunoassay (EIA) was developed for the measurement of factor IX antigen (IX:AG), using rabbit antihuman factor IX antiserum and beta-D-galactosidase, which enabled us to detect IX:AG as low as 10(-4)U/ml. 37 patients with severe hemophilia B have been investigated by EIA, inhibitor neutralization assay and bovine brain prothrombin time. They could be divided into four genetic variants. 25% had normal levels of IX:AG but decreased levels of factor IX clotting activity. On crossed immunoelectrophoresis of the hemophilia B+ and hemophilia BM, we could not find abnormalities in electrophoretic mobilities compared to normal subjects in the presence of 1 mM Ca++ lactate.     

Successful induction of immune tolerance with FIX recombinant in a patient with haemophilia B with inhibitor

We describe successful induction of immune tolerance in a 12-month-old patient with severe haemophilia B and low-titre and low response antifactor IX inhibitor at 5 Bethesda Unit (BU). Immune tolerance induction (ITI) was started with recombinant factor (rFIX) at 40-50 U kg(-1) day(-1) (1000 U three times per week) and 2 years after the beginning of therapy the inhibitor had been reduced to undetectable values. As complications, which appeared during the ITI, the patient presented minor haemorrhagic complications, which remitted following the administration of rFVIIa, and recurring infections of the catheter, requiring the withdrawal and subsequent placement of a new catheter.     

Comparative efficacy of nonheated and heat-treated factor IX complex concentrate in treatment of hemophiliacs with inhibitors

To determine if heat-treated factor IX complex concentrate is as effective as nonheated factor IX complex concentrate for treatment of subjects with hemophilia A and antifactor VIII antibodies (inhibitor patients), we have retrospectively reviewed consecutive home treatment records of ten inhibitor patients who had been receiving nonheat-treated factor IX complex concentrate (NHT-Konyne) and subsequently converted to heat-treated factor complex concentrate (Konyne-HT) when it was licensed in late 1984. Overall, 162 of 284 (57%) separate bleeding episodes treated with NHT-Konyne and 53 of 80 (66.3%) separate bleeding episodes treated with Konyne-HT required only one treatment course of approximately 60-75 U/kg. The distribution of bleeding sites and the absolute factor IX unitage required per treatment episode were similar for both preparations. These data suggest that the percentage of hemophilic inhibitor patients responding to factor IX complex concentrate remains at least 50%, as was reported several years ago in a controlled study, and that inhibitor bypass activity has not altered by heat treatment.     

Spontaneous disappearance of an IgA anti-factor IX inhibitor in a child with Christmas disease

The few inhibitors to blood coagulation factor IX in patients with Christmas disease (hemophilia B) that have been studied have been shown to belong to the IgG class of immunoglobulins. We report the first case in which a factor IX inhibitor was of the IgA class. Additionally, he appears to be the youngest patient with hemophilia B to have developed an inhibitor. His inhibitor complicated treatment of the patient for several years because of its anamnestic rise following factor IX concentrate administration. It then spontaneously vanished and has not returned in spite of repeated factor IX complex administration.     

Disappearance of inhibitor to factor IX in a patient with severe haemophilia B and immunological characterization of the inhibitor

Disappearance of an inhibitor to factor IX in an 11-year-old boy with haemophilia B is described. He had been given a total of 14,200 units of a prothrombin complex concentrate (PCC) before an inhibitor to factor IX developed. He subsequently received four separate infusions of PCC and his inhibitor titre rose in response to the treatment for the following 4 years. No inhibitor is presently detected despite repeated administration of PCC. Immunological characterization of the inhibitor by inhibitor neutralization assays, modified crossed-immunoelectrophoresis and enzyme-linked immunosorbent assay demonstrated that it contained IgG2 and IgG4 heavy chains and kappa and lambda light chains. No large deletion of the factor IX gene in the patient was observed using cDNA (cVII).     

Successful completion of left total hip arthroplasty by inhibitor neutralization therapy in a hemophilia B patient with high responding inhibitor

Major surgery in hemophilia patients has been facilitated by the development of coagulation concentrates. However, it is still difficult to manage bleeding during major surgery in patients with inhibitors to FVIII/IX. In addition, there have been few reports of major surgery in hemophilia B with high responding inhibitors. We report a 26-year-old hemophilia B patient with high responding factor IX inhibitor who demonstrated severe hemophiliac arthropathy in his left hip joint. Total hip arthroplasty was performed with a high dose of FIX followed by recombinant FVIIa. His inhibitor titer was decreased from 111 BU/ml to 1.0 BU/ml at surgery by avoiding the use of FIX concentrates. Thus, we could use high dose FIX for the management of surgical bleeding. Anamnestic response occurred on the 7th day after surgery and FIX concentrates were switched to recombinant FVIIa. The whole process was safely managed without any excess bleeding or adverse effects. The successful use of high dose FIX followed by recombinant FVIIa suggests that even major surgery could be safely performed in hemophilia B patients with a low titer of high responding inhibitors.     

Selective B-cell depletion with rituximab for the treatment of patients with acquired hemophilia

The activity and safety profile of selective B-cell depletion with rituximab, an anti-CD20 monoclonal antibody, were evaluated in 10 patients with acquired hemophilia. Rituximab was given intravenously at the dose of 375 mg/m(2) once weekly for 4 consecutive weeks. Infusion-related side effects were observed in 3 patients but were of mild intensity and did not require discontinuation of treatment. Eight patients with Factor VIII (FVIII) inhibitor titers between 4 and 96 Bethesda units per milliliter (BU/mL) achieved a complete remission, which was defined as a return to normal FVIII activity and undetectable FVIII inhibitor titers. Two more patients with inhibitor levels greater than 100 BU/mL experienced only a partial transient decrease of the inhibitor after rituximab alone, but they achieved a complete response after being challenged with a combination of rituximab plus pulse intravenous cyclophosphamide. With a median follow-up of 28.5 months (range, 12-41 months), 3 patients have thus far relapsed. Retreatment with the monoclonal antibody at the same dose and schedule resulted in a new sustained response in all these patients. In conclusion, rituximab appears an effective and well-tolerated treatment for patients with acquired hemophilia and low inhibitor titers. A reinforcement of therapy with other agents seems to be required to achieve a full and durable response in those patients with high inhibitor levels.     

Thrombin generation is not increased in the blood of hemophilia B patients after the infusion of a purified factor IX concentrate

Prothrombin complex concentrates (PCC), licensed for the treatment of hemophilia B, are known to carry a significant risk of thromboembolic complications. Although the reasons for thrombogenicity are not completely understood, several manufacturers have developed purified factor IX concentrates that contain negligible amounts of the other vitamin K-dependent factors. To evaluate whether or not the infusion of such a factor IX concentrate is followed by lesser activation of the hemostatic system than by the infusion of a PCC, we performed a series of coagulation assays on 11 hemophilia B patients before and after the administration of these two types of concentrate using a randomized cross-over design. The levels of prothrombin fragment F1 + 2, a sensitive measure of the in vivo cleavage of prothrombin by factor Xa, was significantly increased in plasma after PCC, but not after factor IX concentrate. Plasma fibrinopeptide A, a sensitive index of the enzymatic activity of thrombin on fibrinogen, also increased significantly after PCC but not after factor IX concentrate. The fragment B beta 15-42, a sensitive index of the enzymatic action of plasmin on fibrin II, did not change after either concentrate. There were also no differences in less sensitive coagulation measurements, such as plasma fibrinogen, antithrombin III, and fibrin monomers, nor in indices of platelet activation, such as beta-thromboglobulin and platelet factor 4. These findings show that the infusion of a purified factor IX concentrate can result in substantially less activation of the coagulation cascade than may be seen with PCC.     

Cost effectiveness of prophylactic treatment with activated prothrombin complex concentrate in a patient with inhibitor-positive hemophilia A

Patients with hemophilia and high titers of inhibitors are hard to treat during bleeding events and consequently are more likely to incur high treatment costs and to experience deterioration in quality of life. We report here the case of a boy with hemophilia A and high titers of inhibitors who responded well to prophylactic activated prothrombin complex concentrate (APCC) treatment. Previously, he had to be hospitalized frequently because of painful bleeding of target joints of the knee and ankle. At the age of 4 years and 3 months, APCC prophylaxis at a dose of 60 U/kg, three times a week, was initiated together with on-demand therapy with recombinant factor VIIa. This reduced the frequency and severity of bleeding and ended the need for hospitalization. This, together with a decreased requirement for bypass agents, APCC treatment significantly reduced the cost of treatment for this patient.     

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.     

Combined factor IX and protein C deficiency in a child: Thrombogenic effects of two factor IX concentrates

We have recently described an unusual situation which involved a combination of a factor IX and a protein C deficiency in a young child who presented, according to the bleeding tendency, as a hemophilia B patient in this particular hemophiliac, baseline prothrombin fragment F₁₊₂ levels were unexpectedly elevated and increased after an injection of a very high purity factor IX concentrate. This observation raised a question regarding the substitution schedule in the case of repeated injections of factor IX, since the thrombotic tendency has been a major concern with some factor IX concentrates. We monitored factor IX, prothrombin fragment F₁₊₂ and D-dimer plasma levels before and during the 6 hr following the injection of an immunopurified factor IX concentrate. The results showed an increase in the F₁₊₂ levels after the factor IX injection, but an increase lower than previously observed with an ion-exchange chromatography-purified concentrate. Furthermore the F₁₊₂ level returned to baseline value 6 hr after administration. This factor IX concentrate seems to be best for use in the patient where repeated injections are involved (as employed during surgery). Moreover, the data point out the advantage of a monoclonal antibody-purified factor IX concentrate over less purified concentrates in a specific situation, with regard to the thrombogenic risk.     

Rituximab in the treatment of acquired factor VIII inhibitors

Autoantibodies against factor VIII (FVIII) are rare but can cause life-threatening bleeding requiring costly factor replacement and prolonged immunosuppression. We report 4 consecutively treated patients whose acquired FVIII inhibitors responded rapidly to immunosuppressive regimens that included rituximab, a monoclonal antibody against CD20(+) B cells. Three patients had spontaneously occurring inhibitors. The fourth, a patient with mild hemophilia A, developed both an autoantibody and an alloantibody following recombinant FVIII treatment. Pretreatment FVIII activities ranged from less than 1% to 4% and inhibitor titers from 5 to 60 Bethesda units (BU). One patient with polymyalgia rheumatica who developed the inhibitor while receiving prednisone responded to single agent rituximab. The hemophilia patient had rapid resolution of the autoantibody, whereas the alloantibody persisted for months. Responses continue off treatment from more than 7 to more than 12 months. This report adds to the growing evidence that rituximab has efficacy in immune disorders resulting from autoantibody formation.