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.     

Transplacental transfer of postpartum inhibitors to factor VIII

Summary.  Acquired haemophilia due to antibodies directed against coagulation factor VIII is a well-recognized cause of severe haemorrhage in adults but an uncommon cause of bleeding in children. We present the cases of a mother with a life-threatening postpartum haemorrhage due to an autoantibody to factor VIII and her newborn who developed symptomatic bleeding after a minor surgical intervention as a result of transplacental transfer of the autoantibody. Both patients were treated with infusions of recombinant factor VIIa to control bleeding. The mother required immunosuppressive therapy to decrease inhibitor levels and the infant's levels decreased over time without specific treatment. We also provide a concise review of postpartum haemophilia and transplacental transmission of factor VIII autoantibodies to the neonate – a rare but potentially life-threatening complication of acquired haemophilia in women of childbearing age.     

Immunogenetics of factor VIII inhibitor development

Objective: Progressive destruction of joints resulting from recurrent intra-articular haemorrhage represents the major morbidity resulting from haemophilia A or B. In addition to systemic clotting factor replacement, therapies localized to haemophilic joints may provide adjunctive protection. In a factor VIII^-/- mice model, we investigated if extra-vascular delivery of recombinant human clotting factor VIII (rhFVIII) via intra-articular (IA) injection can prevent bleeding-induced joint damage, and also examined the possibility that IA delivery of FVIII carries greater risk of developing anti-rhFVIII inhibitor antibody. Methods: FVIII^-/- mice received rhFVIII by inserting a 30.5 G needle into the left knee joint, along with a range doses of FVIII(100, 25 and 5 IU kg⁻¹) in 5 μL, normal saline as the control. Comparison group received the same needle injury and intravenous (IV) rhFVIII (100, 25 and 5 IU kg⁻¹). 14 days after injury, both knee joints were collected for histological examination. To exclude the possibility that IA clotting factor was entering into circulation, mice received 100 IU kg⁻¹ rhFVIII IA, and FVIII activity was measured by aPTT. To see if IA rhFVIII delivery can carry greater risk of developing anti-FVIII antibody, mice were treated with a total dose of 300 IU kg⁻¹ rhFVIII over 10 days, either by IA or IV. 14 days after exposure, anti-FVIII was detected. After induction of anti-FVIII antibody by IV rhFVIII, mice were subjected either to needle puncture under coverage of bypassing agent (FEIBA) 100 IU kg⁻¹ or 100 IU kg⁻¹ IV rhFVIII, or needle puncture with 25 IU kg⁻¹ rhFVIII. Control mice received needle puncture with normal saline. Two weeks later, knee joints were collected for histological examination. Summary: Mice receiving only saline at the time of needle puncture developed synovitis (mean score 5.0 ± 0.5). Mice treated with 25 IU kg⁻¹ IA rhFVIII developed better protection than mice treated with 100 IU kg⁻¹ IV rhFVIII (lower pathology score for IA, 0.733 ± 0.278 vs. IV 2.57 ± 1.70) and even better protection was achieved by the dose of 100IU IU kg⁻¹ IA (Pathology score of 0.25 ± 0.31). IA injection of 100 IU kg⁻¹ rhFVIII did not lead to increased circulating FVIII activity at any time point up to 48 h. In IV-treated mice, 100% of mice developed anti-FVIII antibody (8.06BU), while only 50% of mice developed anti-FVIII inhibitor at the lowest detection limit (0.61BU). In the presence of inhibitory antibody, only 46% of mice receiving IV FVIII survived the needle injury, 58% with FEIBA and 100% of mice survived with 25 IU kg⁻¹ FVIII IA injection. In the saline-injected control mice, needle injury led to a mean pathology score of 6.8. Neither IV FVIII nor FEIBA provided effective protection, with pathology scores of 6.3 and 5.4, respectively. Surprisingly, 25 IU kg⁻¹ IA rhFVIII produced a pathology score of only 1.7. Conclusion: Extravascular rhFVIII in the joint space can contribute protection against bleeding-induced joint damage. Intra-articular rhFVIII delivery did not induce greater risk of inhibitory antibody formation in FVIII knockout mice than circulating factor VIIII challenge; in fact, a lower incidence was observed. In the presence of anti-FVIII inhibitory antibodies, IA delivery of FVIII still can offer protection from bleeding-induced joint damage.     

Variation in factor VIII inhibitor reactivity with different commercial factor VIII preparations

Summary. During treatment of a haemophilia A patient with a high-responding inhibitor against factor VIII coagulant activity (VIII:C), we observed a difference in recovery of VIII:C depending upon which factor concentrate was infused. Inhibitor plasma samples or IgG fraction from seven patients were tested against a panel of seven different commercially available factor VIII concentrates of which five were plasma-derived and two recombinant. In two of the plasma samples, inhibitor titres manifested a wide range of values depending upon which concentrate was used in the test system. Thus, inhibitor neutralization was less and VIII:C recovery greater when factor VIII concentrates containing large amounts of von Willebrand factor were used than when highly purified concentrates containing no von Willebrand factor or only trace amounts were used. In both of these two patients the inhibitor was directed against the light chain of factor VIII, and it is possible that the epitope of the light chain with which the inhibitor reacts is partly blocked by the von Willebrand factor.
We conclude that inhibitors may differ in their reactivity with factor VIII molecules contained in clotting factor concentrates, and that there is factor VIII epitope variation between different concentrates. These findings have implications for the selection of concentrates for the treatment of inhibitor patients and the haemostatic effect may be improved if a concentrate giving the lowest inhibitor titre is chosen. Thus, in vitro testing of inhibitor reactivity with a panel of concentrates is recommended when treatment of inhibitor patients with factor VIII concentrates is considered.     

Combination immunosuppressive therapy after factor VIII infusion for acquired factor VIII inhibitor

STUDY OBJECTIVE: To evaluate the effectiveness of combined cyclophosphamide, vincristine, and prednisone (CVP) therapy after antigenic stimulation with factor VIII in the eradication of factor VIII inhibitor. DESIGN: Factor VIII activity and inhibitor titer were measured before and after FVIII-CVP therapy and patients with factor VIII inhibitor were followed for at least 2 years. SETTING: The first course of therapy was carried out in the hospital when nonhemophiliac patients were admitted for bleeding. Otherwise, treatment was administered at the outpatient clinic. PATIENTS: From 1975 to 1986 we studied 12 nonhemophiliac and 5 hemophiliac patients with factor VIII inhibitor treated with FVIII-CVP and followed at our clinic. INTERVENTION: Patients were infused with one dose of factor VIII concentrate, 50 to 100 U/kg body weight, followed by cyclophosphamide, 500 mg on day 1 and 200 mg/d on days 2 to 5; vincristine, 2 mg on day 1; and prednisone, 100 mg/d on days 1 to 5. This regimen was repeated every 3 to 4 weeks. RESULTS: Of 12 nonhemophiliac patients, 11 responded after 1 to 3 courses of FVIII-CVP with complete disappearance of the inhibitor without recurrence. Among 5 patients with hemophilia who were given 3 to 8 courses, only 1 patient responded with a transient disappearance of inhibitor. Mild neutropenia and infection occurred in 3 patients and required antibiotic treatment. CONCLUSION: Factor VIII-CVP therapy is highly effective in the eradication of factor VIII inhibitor in nonhemophiliac patients but not in patients with hemophilia.     

Long-term high dose factor VIII treatment of 3 haemophiliacs with factor VIII inhibitor

3 patients with haemophilia A and inhibitor against Factor VIII were developing progressive haemophiliac arthropathy due to the non-feasibility of prophylactic treatment. In order to suppress inhibitor formation, long-term treatment with high-dose Factor VIII (100 units per kg body weight twice daily) was initiated. Prothrombin complex concentrate was given only for bleeding episodes. Though all 3 patients were high responders, they presented different treatment courses. 2 became low responders after 4 and 11 months' treatment, respectively. 1 patient had no demonstrable inhibitor after start of treatment. In all 3 patients, prophylactic treatment was established, in 1 case still with increased doses compared to non-inhibitor patients. The high-dose Factor VIII treatment makes in possible to provide prophylactic treatment for the high-responder inhibitor patients. However, the extremely high costs represent a serious obstacle to this treatment.     

Immunoblot analysis shows changes in factor VIII inhibitor chain specificity in factor VIII inhibitor patients over time

We have used immunoblotting of purified factor VIII (FVIII) to determine whether or not changes in FVIII chain specificity occur during the course of an inhibitor. Serial plasma samples from 15 inhibitor patients (13 hemophilic and two spontaneous) were analyzed. Nine of the 15 antibodies, all with epitopes on the 44-kilodalton (Kd) thrombin fragment of the 92-Kd FVIII heavy chain and/or the 72-Kd thrombin fragment of the 80-Kd FVIII light chain, showed no change in FVIII chain specificity. However, six of the inhibitors analyzed showed changes in FVIII fragment specificity. Four inhibitors (three hemophilic and one spontaneous) reactive with 72-Kd thrombin fragment also became reactive with the 44-Kd thrombin fragment after an anamnestic response to FVIII infusion. Another inhibitor with epitopes on both the 54-Kd and 44-Kd thrombin fragments lost most of its reactivity with the 44-Kd fragment but retained its reactivity with the 54-Kd fragment following a FVIII infusion. The inhibitor later regained its 44-Kd-fragment reactivity but lost its 54-Kd-fragment reactivity following treatment with FEIBA, FVIII inhibitor bypassing activity. The last inhibitor studied had an antibody to either the 44-Kd fragment or to both the 44-Kd and 72-Kd fragments during anamnestic responses to FVIII. These data indicate that a FVIII inhibitor patient can potentially produce antibody to multiple areas on the FVIII molecule and that this must be taken into account in the design of specific therapeutic products.     

Successful treatment of a patient with postpartum factor VIII inhibitor with recombinant human interferon alpha 2a

A patient who had developed a postpartum inhibitor to factor VIII and who did not respond to repeated therapy with steroid and high-dose intravenous gammaglobulin G was treated with one short course of low-dose recombinant interferon alpha 2a (rhIFN) s.c. Within 7 weeks from the start of rhIFN treatment, the inhibitor disappeared. It remains undetectable 8 months after therapy.     

IgA inhibitor to factor VIII/von Willebrand factor

A 60-year-old Black female presented with a haemorrhagic diathesis and an acquired factor VIII/von Willebrand factor (VIII/vWf) inhibitor. This inhibitor was classified as an IgA immunoglobulin and was active not only against factor VIII coagulant (VIII:C) activity but also against plasma von Willebrand factor (vWf). The purified IgA also interacted with normal platelets to inhibit ristocetin-induced platelet aggregation (RIPA). In contrast, studies with haemophilia A plasma and platelets revealed that the inhibitor did not react significantly with these plasmas or platelets. The significant differences in the inhibition of vWf assay both of the plasma and the platelets of the haemophilia A patients suggests that part of the haemorrhagic diathesis may be related not only to the inhibition of VIII:C but also to interference with platelet function. In addition, these studies suggest that there may be significant differences in the factor VIII-related antigen (VIII R:Ag) on platelets in haemophilia A patients compared to normal.     

Porcine factor VIII: pharmacoeconomics of inhibitor therapy

The treatment of acquired haemophilia is characteristically exceedingly expensive and thus a cost-benefit analysis of the several available treatment strategies is urgently needed. To address this issue, decision-analysis techniques were used to construct a cost-minimization model to compare the cost of treatment with porcine factor VIII (pFVIII), human FVIII (hFVIII) or an activated prothrombin complex concentrate (APCC). This model was based upon the results of a comprehensive literature search of all relevant clinical studies and case series. To supplement these data, a panel of haemophilia specialists was presented with a clinical scenario describing an acquired haemophilia patient with an acute haemorrhage in whom the human and porcine inhibitor titres were initially unknown. Based on this scenario and on their own clinical experience, the expert panel assessed the applicability of the model as initially constructed, assigned probabilities of success to each treatment and recommended appropriate initial dosing and follow-up regimens. This information was incorporated into the model and a simulation was conducted from which the costs of care were calculated. Sensitivity analyses were then conducted on all parameters. The results of the model show that treatment initiated with pFVIII would be more cost effective compared with treatment sequences initiated with an APCC or hFVIII, respectively. The model indicates that initial treatment with pFVIII in this scenario may be the preferred strategy clinically, as well as on economic grounds.     

Acquired haemophilia A in women postpartum: management of bleeding episodes and natural history of the factor VIII inhibitor

Abstract: The present study reports on the treatment of bleeding episodes and the natural history of factor VIII inhibitors in 4 patients with acquired haemophilia A postpartum. Low titre type II factor VIII inhibitors in 3 patients and high titre type I inhibitor in 1 patient became apparent immediately to 7 months after delivery. High dose human factor VIII concentrate substitution was effective in controlling bleeding episodes in two cases of factor VIII inhibitor type II, but ineffective in 1 patient with high titre type I factor VIII inhibitor. High dose gammaglobulin intravenously in 1 patient with type II factor VIII inhibitor induced a partial correction of factor VIIIc levels for 2 wk. Immunosuppressive treatment in all 4 patients with acquired haemophilia A postpartum did not reduce the potency of the factor VIII inhibitors. The low titre type II inhibitors spontaneously disappeared in all 3 patients within a few months to 1 yr after discontinuation of the immunosuppressive treatment. The high titre type I factor VIII inhibitor persisted for more than 24 yr. We conclude that immunosuppression in 4 women with acquired haemophilia A postpartum did not significantly affect the factor VIII inhibitor titre.     

Acquired factor VIII inhibitor presenting as macular haemorrhage

We report a rare case of idiopathic acquired factor VIII inhibitor in an 80-year old Chinese man presented as sudden onset of monocular blindness because of macular haemorrhage. This was complicated by painful glaucoma that did not respond to medical treatment. The patient died of cerebral haemorrhage shortly afterwards. Most cases of reported intraocular bleeding in acquired haemophiliacs are iatrogenic because of intraocular operations in undiagnosed cases, and spontaneous intraocular haemorrhage has never been reported. The literature reports of intraocular bleeding in hereditary and acquired haemophilia cases are summarized.     

Acquired factor VIII inhibitor preceding chronic lymphocytic leukemia

Summary An acquired factor VIII inhibitor was found in an 82-year-old woman who presented with numerous spontaneously appearing ecchymoses. Coagulation studies revealed the presence of a prolonged activated partial thromboplastin time that was not corrected by 11 mixture with normal fresh plasma after a 2–h incubation. Factor VIII: C was 4%, and the titer for factor VIII inhibitor was 9 Bethesda units. Three months later, after a retroperitoneal hemorrhage, a lymphocytosis was found in her peripheral blood with morphological and surface immunophenotype characteristics of B-cell chronic lymphocytic leukemia, later confirmed by bone marrow morphological and immunocytochemical examinations. To our knowledge, this is the first report of an autoimmune factor VIII inhibitor associated with chronic lymphocytic leukemia.     

Acquired factor VIII inhibitor in a non-haemophilic boy

We describe the case of a previously healthy 8-year-old non-haemophilic boy who developed a factor VIII inhibitor of unknown origin. The symptoms of this disease were haemorrhages in the muscles of the right thigh, numerous bruises and a large haematoma of the right crus with subsequent tissue necrosis. Activated and non-activated prothrombin complex concentrates were administered in the therapy of the haemorrhages. To eliminate factor VIII inhibitor, the patient was treated first with prednisone, then immunoglobulin G and finally with a combination of prednisone and cycylophosphamide, without any effect. A total spontaneous remission was observed after 15 months from the beginning of the disease.