The management of acquired haemophilia

Summary.  Acquired haemophilia is a rare but life-threatening bleeding diathesis that usually is caused by autoantibodies to factor VIII (FVIII). The disorder generally affects older persons, often is linked to other autoimmune diseases or cancer, may develop in the postpartum period, and is associated with a distinct bleeding pattern. In contrast to the haemarthroses that typify congenital haemophilia, acquired haemophilia bleeds are characterized by haemorrhage into soft tissue and muscle and the gastrointestinal and genitourinary tracts. A prolonged activated partial thromboplastin time, coupled with a normal prothrombin time, is highly indicative of a circulating anticoagulant; the inhibitor is then quantified with the modified Bethesda assay. Effective control of bleeding is the first step in management and often requires the use of the bypassing agents, either activated prothrombin complex concentrate or recombinant activated factor VII. Elimination of the FVIII antibody is the second goal of therapy. Corticosteroids, cyclophosphamide, and rituximab may eradicate autoantibodies and restore normal haemostasis.     

Successful major and minor surgery using factor VIII inhibitor bypassing activity in patients with haemophilia A and inhibitors

Summary.  Surgeries are being increasingly performed in patients with haemophilia A and high-titre inhibitors. Optimal bypassing agent regimens need further delineation. Data pertaining to surgeries from 1989 to 2004 at a single centre were retrospectively analysed. Patients received a standardized factor eight inhibitor bypassing activity (FEIBA) dose for both major and minor elective or emergency surgeries. The standard FEIBA dose was 70 U kg⁻¹ per infusion. FEIBA was infused at 9 and 1 h before and 8 h after operation. Infusions were routinely repeated every 8 h afterward. Haemostatic efficacy was assessed on the basis of blood loss, occurrence of haematoma and transfusion requirements. Seven adult patients underwent a total of 12 operations: 10 major and two minor. Ten procedures were elective. The median cumulative numbers of infusions and days of therapy were 46 and 17, respectively. Cumulative total FEIBA consumption was a median of 3185 U kg⁻¹. Observed blood losses, haematoma incidence and transfusion requirements were comparable to those expected for noncoagulopathic patients undergoing similar procedures. The only large haematoma occurred after a hip prosthesis operation and resolved under continuing FEIBA treatment. There were no cases of disseminated intravascular coagulation or other thromboembolic complications. FEIBA provides an effective and safe first-line peri- and postoperative haemostatic therapy for patients with haemophilia A and inhibitors, allowing both major and minor operations to be successfully performed.     

How I manage patients with acquired haemophilia A

Acquired haemophilia A (AHA) is a potentially life‐threatening bleeding disorder occurring in patients without a previous personal or family history of bleeding. Development of immune‐mediated autoantibodies against coagulation factor VIII is associated with a wide range of clinical disorders including pregnancy, autoimmune disorders, malignancy, or with no apparent disease. There exists great potential for morbidity and mortality related to acute and recurrent bleeding episodes, making prompt diagnosis and treatment necessary. The two primary goals of treatment focus on cessation of bleeding and eradication of the acquired factor VIII inhibitor. No randomized clinical trials have been conducted regarding treatment, so expert clinical opinion guides therapeutic intervention. This current report provides a profile of patient characteristics, an algorithm for diagnosis, and outlines treatment recommendations based upon current guidelines and clinical experience. As first‐line interventions for acute bleeding and inhibitor eradication are generally accepted, we will emphasize discussion of second‐line therapeutic options.     

Postpartum acquired haemophilia: clinical recognition and management

Postpartum acquired haemophilia is a rare but serious complication of an otherwise normal pregnancy. Patients usually present with postpartum haemorrhage (PPH) or uncontrolled bleeding following surgical interventions, which fail to respond to conservative treatment. A high index of clinical suspicion along with early laboratory diagnosis and prompt institution of appropriate therapy is essential for the management of acute bleeding episodes. Our patient, a 32-year-old female, presented with severe PPH and shock. She had undergone dilation and curettage three times, with subsequent total abdominal hysterectomy and internal iliac artery ligation, before she was diagnosed with acquired haemophilia (factor VIII autoantibodies) and an inhibitor level of 8 Bethesda units (BU). The patient underwent an abdominal laparotomy for removal of the abdominal packing used in the previous operation, and blood and blood clots, and was given FEIBA(R) therapy. The patient responded to these measure and the factor VIII inhibitor level decreased to 2 BU at the time of discharge 10 weeks later.     

An acquired factor VIII inhibitor in association with a myeloproliferative/myelodysplastic disorder presenting with severe subcutaneous haemorrhage

We report a 71-year-old man who presented with severe subcutaneous and later psoas muscle haemorrhage in the presence of a raised white cell count and hepatosplenomegaly. A circulating factor VIII (FVIII) inhibitor was detected and bone marrow morphology confirmed the presence of a myeloproliferative/myelodysplastic disorder. Initial treatment with high dose FVIII followed by recombinant factor VIIa was unsuccessful. Haemorrhage was controlled by the administration of activated prothrombin complex concentrate (FEIBA; Baxter healthcare, CA, USA) in combination with prednisolone, cyclophosphamide and i.v. immunoglobulin. The inhibitor became undetectable 14 weeks after presentation. The white cell count responded initially to hydroxyurea and later to cyclophosphamide. There have been only two previous reports of acquired haemophilia A in association with myelodysplastic disorders and no previous report of an association with a myeloproliferative disorder.     

Cross-reactivity to porcine factor VIII of factor VIII inhibitors in patients with haemophilia in Australia and New Zealand

Abstract Background: Inhibitory antibodies which neutralise factor VIII develop in 10–20% of individuals with inherited haemophilia A and rarely as autoantibodies in normal individuals to cause acquired haemophilia. The antibodies are directed against human factor VIII but cross-react to varying degrees with porcine factor VIII. Porcine factor VIII can be used for treatment in individuals with low cross-reactivity.
Aims: To determine the cross-reactivity of factor VIII inhibitors between human factor VIII and porcine factor VIII, in a population of patients with inherited and acquired haemophilia A. Also, to determine whether patients with inherited haemophilia and inhibitors have a higher incidence of factor VIII gene inversion in intron 22.
Methods: Samples and data sheets from 43 patients with inherited and ten with acquired haemophilia were submitted from hospitals in Australia and New Zealand. Inhibitor levels to human and porcine factor VIII were measured by the Bethesda method in 39 with inherited and nine with acquired haemophilia A.
Results: Of 39 patients with inherited haemophilia A, cross-reactivity was 0% in 17 patients,1–19% in six, 20–39% in 11 and 40–80% in five. In six of nine patients with acquired haemophilia cross-reactivity was 7%. In inherited severe haemophilia A, the frequency of the intron 22 inversion was not greater in 37 study patients than in 28 patients without an inhibitor.
Conclusions: Many patients in Australia and New Zealand with inhibitors to human factor VIII presently show a low or absent level of cross-reactivity to porcine factor VIII. These may respond to treatment with this concentrate at least in the short term. There remains a group of patients with high cross-reactivity who will respond only to recombinant factor Vila or prothrombin complex concentrates.     

Low response to high-dose intravenous immunoglobulin in the treatment of acquired factor VIII inhibitor

Prednisone is the classic first-line therapy to suppress an acquired factor VIII inhibitor and may achieve complete remission in about 30% of patients. More recently, promising results have been reported with high-dose intravenous immunoglobulin (IVIg). However, after an extensive review of the literature, we found only three complete remissions (12%) among the 26 assessable patients treated by IVIg. These data are in agreement with the low response to IVIg that we experienced in our series of patients. This study suggests that steroids should still be preferred to IVIg, an expansive therapy, to suppress an acquired factor VIII inhibitor.     

Effects of factor VIII inhibitor bypassing activity (FEIBA), recombinant factor VIIa or both on thrombin generation in normal and haemophilia A plasma

Summary.  Factor VIII inhibitor bypass activity (FEIBA) and recombinant factor VIIa (rFVIIa) are the common bypassing agents for treating haemophilia A or haemophilia B patients who developed an inhibitor to factor VIII or IX, respectively. As these preparations differ in their composition and mode of action, combined therapy, either sequential or simultaneous has recently been used for achieving haemostasis during bleeding episodes in patients who became refractory to FEIBA or rFVIIa when each was given alone. In this in vitro study, we show by a sensitive assay of thrombin generation that phospholipids present in FEIBA and other procoagulants contribute to FEIBA's activity and that exogenous phospholipids are essential for the activity of rFVIIa. We also demonstrate that the combination of FEIBA and rFVIIa has a marked synergistic effect on thrombin generation in plasma of a haemophilia A patient with a high titre of an inhibitor. It is conceivable that simultaneous administration of small doses of FEIBA and rFVIIa may be beneficial in treating haemophilia A patients, with an inhibitor to FVIII, who are resistant to conventional therapy.     

A survey of patients with acquired haemophilia in a haemophilia centre over a 28‐year period

Data of patients with acquired inhibitors to clotting factors seen in a haemophilia centre from 1970–98 was collected. Twenty‐four patients with anti‐factor VIII antibodies and four with acquired von Willebrand disease case records were evaluable. Two‐thirds of the patients were females and their age ranged from 2 to 92 years (median 69). There was no correlation between the inhibitor titres and the severity or the pattern of bleeding. Porcine factor VIII and activated prothrombin complex were both effective for acute bleeds. Prednisolone and cyclophosphamide proved valuable for suppression of the antibodies without adverse effects even in the elderly group of patients. Three deaths were directly related to bleeding. This review has shown the life‐threatening nature of this acquired bleeding disorder, its variable clinical presentation and the importance of early referral to a specialist centre for appropiate therapy.     

Acquired inhibitor to factor VIII: report of two unusual cases

Summary . The present report describes two unusual cases of bleeding due to development of inhibitor against factor VIII. One of the patients was known to have severe haemophilia B (factor IX < 1%) and the other, a healthy male of 46 years, spontaneously started to bleed and was found to have developed inhibitors to factor VIII:C along with other autoantibodies. Development of inhibitors to coagulation factors is a serious clinical problem in de-veloped countries and is more so in developing countries where treatment options are often limited.     

FEIBA in the treatment of acquired haemophilia A: Results from the prospective multicentre French ‘FEIBA dans l'hémophilie A acquise’ (FEIBHAC) registry

Factor VIII inhibitor bypass activity (FEIBA) is a recommended first‐line bypassing agent for bleeding episodes in patients with acquired haemophilia A (AHA). Due to the low incidence of AHA, available clinical data on FEIBA treatment are limited. The study aim was to delineate practice patterns in FEIBA treatment of AHA patients, the haemostatic efficacy of FEIBA, including criteria for its assessment, and safety. A prospective registry was established of AHA patients receiving FEIBA for bleeding episodes or prophylaxis at the time of invasive procedures. Data were collected at 16 participating centres in France. Patients were followed up for 3 months. Haemostatic efficacy, FEIBA regimen and FEIBA‐related adverse events were documented. Thirty‐four patients averaging 81.8 years old with standard deviation (SD) 8.1 years were included in the study: 33 for acute bleeding and one for haematoma evacuation. The mean initial dose of FEIBA for acute bleeding was 75.4 U kg^?1 (SD, 7.7 U kg^?1), most often administered twice daily, and the median duration of FEIBA treatment was 4.0 days (interquartile range, 2.2–8.0 days). FEIBA was effective in managing 88.0% of bleeding episodes (95% confidence interval, 75.8–94.5%). No baseline variables influencing treatment response could be identified. The sensitivity and specificity of an objective haemostatic efficacy scale in predicting sequential investigator assessments of haemostatic efficacy were 45.3% and 84.1% respectively. Four patients experienced a total of six serious adverse events possibly related to FEIBA. In the first prospective study specifically focused on FEIBA treatment of patients with AHA, 88.0% of bleeding episodes were effectively managed.     

Acquired haemophilia in recipients of depot thioxanthenes.

We present two cases in which the occurrence of acquired haemophilia is associated with the use of depot preparations of the thioxanthenes zuclopenthixol and flupenthixol. These drugs have not previously been implicated in the aetiology of acquired haemophilia.     

Successful treatment of acquired haemophilia with prednisolone therapy

Acquired hemophilia is a rare, life threatening coagulopathy in adults caused by the development of autoantibodies against to factor VIII. No general consensus exists on the best therapeutic approach. We report here a case that presented with extensive cutaneous and mucosal bleedings due to factor VIII inhibitors and treated successfully with steroid therapy alone but complicated with a life threatening thromboembolic attack during her follow up. In conclusion, corticosteroids are "cost effective therapy" associated with high inhibitor elimination rates and although recurrence of inhibitor in a patient with factor VIII inhibitor is an expected clinical situation thrombosis risk should also be considered.     

Thrombelastographic monitoring of recombinant factor VIIa in acquired haemophilia

Summary.  Monitoring of the global haemostatic capacity is desired to optimize the treatment with bypassing agents in inhibitor patients. Thrombelastographic methods have been used in ex vivo studies and were suggested useful to evaluate the individual response to bypassing agents. This study aimed at assessing changes in thrombelastographic profiles and their association to clinical outcome in patients treated with recombinant factor VIIa (rFVIIa). Ten patients with acquired haemophilia were treated with rFVIIa for acute bleeding. Thrombelastography was performed after activation with a small amount of tissue factor in samples obtained before and after in vivo administration of rFVIIa. In patients studied before and after a first dose, correction of the thrombelastographic profile was observed but did not predict cessation of bleeding. During steady-state dosing, the median Alpha angle tended to be higher in patients with a good clinical treatment response as compared with patients with a partial or poor response. Similar trends were observed for clotting time and clot formation time. A good clinical treatment response was more frequent in patients with a fully corrected trough-level thrombelastographic profile as compared with patients with an abnormal profile. However, a poor treatment response was observed also in a surgical patient with a normal thrombelastographic profile during steady-state dosing. In conclusion, thrombelastographic monitoring was sensitive to haemostatic changes in response to treatment with rFVIIa. In the limited number of patients studied here, a better clotting profile during steady-state dosing was associated with a better clinical treatment response.     

High-titre factor VIII inhibitor in two children with mild haemophilia A

A frequently encountered complication of therapy given to patients with severe haemophilia A is the development of antibodies to infused factor VIII. While much less common, inhibitors also occur in patients with mild or moderate severity haemophilia A. Often thought to be of low titre and transient, several cases of high-titre inhibitors have been described in patients with mild or moderate haemophilia A. Generally these occur in adults or adolescents following significant infused factor VIII exposure. A review of reported cases revealed only two cases of high-titre inhibitor formation in mild haemophilia A patients younger than 10 years of age. We wish to report our experience with an additional two children with mild haemophilia A and high titre inhibitors, and offer suggestions for the management of these children.     

Efficacy and inhibitor development in previously treated patients with haemophilia A switched to a B domain-deleted recombinant factor VIII

There have been recent reports of unexpected poor efficacy of a B-domain-deleted recombinant factor VIII (BDD-rFVIII) in haemophiliacs, and inhibitor development in previously treated patients (PTPs) switched to BDD-rFVIII. The results of a 6-month prospective study of 25 PTPs and of a retrospective survey of 94 PTPs, all switched to BDD-rFVIII, were used to evaluate efficacy and inhibitor development. The prospective study showed that 89% of 362 bleeds were controlled by one to two infusions, reproducing the efficacy profiles of other recombinant products (rFVIIIs). One patient, previously treated with plasma-derived FVIII only, developed a high titre inhibitor (30 BU) after 5 days of exposure. The retrospective survey, carried out in the total Italian PTP population switched to BDD-rFVIII, involved 19 PTPs at higher inhibitor risk due to previous exposure of < or = 50 days and 75 PTPs at lower inhibitor risk due to previous exposure of > 50 days. One patient developed an inhibitor: he was a high-risk, severe PTP previously exposed to another rFVIII for 3 days only. Among the entire low-risk population of severe Italian PTPs switched to BDD-rFVIII (25 in the prospective study, 49 in the retrospective cohort) only one developed an inhibitor (1.3%). These data indirectly support the views that BDD-rFVIII is equivalent to other rFVIIIs in term of efficacy and inhibitor development.     

Severe acquired haemophilia A treated with recombinant factor VIIa

Acquired haemophilia can be associated with various conditions including pregnancy, autoimmune diseases and lymphoproliferative disorders, though often no underlying cause is found. It often presents with a rapid onset of muscle bleeding and involves the IgG antibody. It may be treated with human or porcine factor VIII (FVIII), prothrombin complex concentrates, factor IX (FIX) complex concentrates, factor VIIa (FVIIa) or by immunosuppression. We report a case of acquired haemophilia in a 40-year-old woman diagnosed following laparotomy. She was treated unsuccessfully using human FVIII and cryoprecipitate, porcine FVIII and FIX complex concentrate, before being treated with recombinant FVIIa (NovoSeven, Novo Nordisk). On treatment with recombinant FVIIa, bleeding stopped rapidly with no side-effects and the abdominal haematoma was evacuated with minimal post-operative bleeding.