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.     

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.     

Use of recombinant factor VIIa (NovoSeven) in a haemophilia A patient with inhibitor in Kuwait

Development of inhibitors is a known complication in some haemophiliacs receiving coagulation factor replacement therapy. We report on the successful management of a young boy with haemophilia A with inhibitor using recombinant factor VIIa. We had failed to control bleeding in this patient following his circumcision, despite infusion with high doses of factor VIII concentrate for 2 weeks. Recombinant factor VIIa is a useful 'factor VIII bypassing agent' for the control of bleeding in patients with haemophilia A and B who develop inhibitors. We suggest that severely affected haemophiliacs should be absolved of ritual circumcision as a protective measure against what might become a life-threatening haemorrhage - especially in those with inhibitors.     

Obstetrical and gynaecological bleeding: a common presenting symptom

Excessive haemorrhage is one of the commonest symptom when women present to obstetricians and gynaecologists. In the majority of cases the cause is related to the primary obstetric and gynaecological pathology and is easily identified. However, less commonly, the bleeding is unexpected and due to an undiagnosed underlying coagulation defect, the commonest of which is von Willebrand (vWD) disease. Menorrhagia is a common, and may be the only, clinical manifestation of an inherited bleeding disorder. Screening 150 women with menorrhagia, vWD was diagnosed in 13% of patients and other hereditary haemorrhagic disorders in another 4%. Menorrhagia with onset at the menarche was predictive of an inherited bleeding disorder in 65% of vWD and 67% of FXI deficient patients. Therefore, testing for bleeding disorders should be considered in women with menorrhagia especially those with early onset and no obvious pelvic pathology. Childbirth and puerperium present a special risk for excessive haemorrhage. The risk of postpartum haemorrhage is very high in women with inherited bleeding disorders. In our centre, the incidence of primary and secondary postpartum haemorrhage was 22% and 11% in carriers of haemophilia 18.5% and 20% in vWD and 16% and 24% in FXI deficient women, respectively. Acquired haemophilia can be an unusual cause of severe and unexpected postpartum haemorrhage with a very high mortality rate. Unexplained postpartum and postoperative haemorrhage that does not respond to general measures should alert clinicians to the possibility of bleeding disorders as a causative factor. In addition, increased awareness among obstetricians and gynaecologists of these less common causes and close collaboration with the local haemophilia centre and availability of management guidelines are essential for optimal outcome.     

Gross hematuria due to acquired haemophilia in hereditary hemorrhagic telangiectasia

Hereditary haemorrhagic telangiectasia (HHT, Osler-Weber-Rendu syndrome) is a rare inherited disease; acquired haemophilia, caused by factor VIII inhibitors, is a rare autoimmune disorder. Both diseases cause bleeding manifestations. We report a case of a young woman affected by hereditary haemorrhagic telangiectasia who was admitted to our unit because of gross hematuria. The prolonged activated partial thromboplastin time suggested us the possibility of a bleeding cause other than hereditary haemorrhagic telangiectasia. The test result for factor VIII inhibitors resulted positive and a diagnosis of acquired haemophilia was made. The patient was treated with frozen fresh plasma and with activated eptacog alpha and a steroid therapy was started. After she received steroid, factor VIII inhibitor titre decreased and activated partial thromboplastin time gradually recovered. After 2 weeks a complete normalization of activated partial thromboplastin time was obtained. Acquired haemophilia is a life-threatening disorder. Measuring factor VIII activity and its inhibitor in patients with bleeding and a prolonged activated partial thromboplastin time are recommended even in patients affected by other known hemorrhagic disease.     

Protein A sepharose immunoadsorption: immunological and haemostatic effects in two cases of acquired haemophilia

Acquired haemophilia is a life-threatening disorder caused by circulating auto-antibodies that inhibit factor VIII coagulant activity (FBIII:C). Immunoadsorption on protein A sepharose (IA-PA) was performed in two bleeding patients with acquired haemophilia: we observed a dramatic and quick decrease in the anti-FVIII:C inhibitor titre leading to a normal, albeit transient, haemostatic status. In one case, IA-PA was the only procedure which succeeded in stopping massive haemorrhage. In the second case, IA-PA reinforced the haemostatic effect of recombinant activated factor VII by increasing the endogenous plasma factor VIII level. The efficacy of IA-PA was sustained with immunosuppressive treatment introduced, respectively, 10 and 15 d before the IA-PA procedures. Our experience with IA-PA suggests that this extracorporeal anti-FVIII:C removal procedure is a valuable therapeutic tool for acquired haemophilia and can alleviate life-threatening haemorrhages.     

Acute intestinal obstruction due to intramural haemorrhage in small intestine in a patient with severe haemophilia A and inhibitor

Patients with severe haemophilia A usually present with joint, gastrointestinal and urinary tract haemorrhage. Bleeding elsewhere is often precipitated by pre-existing pathology or trauma. We report a patient with severe haemophilia A, who presented with symptoms of acute intestinal obstruction. He has a factor VIII inhibitor and receives recombinant factor VIIa on demand at home. The CT scan of abdomen showed dilated small intestine with fluid filled loops and a long segment in the jejunum with marked transmural thickening. There was no other pathology in the small intestine. These appearances were consistent with intramural haemorrhage in the small intestine as the cause of acute obstruction. He was managed conservatively with recombinant factor VIIa and this resulted in resolution of his symptoms. This case highlights an unusual presentation of bleeding in a haemophilia patient. Intestinal obstruction due to haemorrhage in the small intestinal wall is extremely rare and only previously reported in a few haemophilia patients. It also highlights the effectiveness of conservative management with recombinant factor VIIa as opposed to immediate exploratory surgery.     

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.     

Pregnancy in carriers of haemophilia

Summary.  The aim of the study was to review the complications, management and outcome of pregnancy in carriers of haemophilia over a 10-year period following the introduction of a multidisciplinary management guideline. Comparison was made to a 10-year cohort prior to implementation of the guidelines. A retrospective review of case notes of carriers of haemophilia (41 haemophilia A, 12 haemophilia B) who had received obstetric care at the Royal Free Hospital between 1995 and 2005 was conducted. There were 90 pregnancies (65 live births, 13 miscarriages, 12 terminations). Prenatal testing was taken up in 97% (63/65) of pregnancies where the mother was known to be a carrier of haemophilia. The majority (71%; 46/65) chose only to have non-invasive fetal sex determination. Seventeen (26%) had invasive testing (13 primarily for haemophilia and four primarily for chromosomal abnormalities). Termination of pregnancy was opted for in 67% (6/9) of pregnancies affected with haemophilia. Pregnancy was accompanied by a marked rise in factor VIII levels compared to only a small rise in factor IX levels. Invasive intrapartum monitoring techniques and instrumental deliveries were avoided in all pregnancies known to be at risk of haemophilia. Regional block was performed in 25 pregnancies for labour/delivery with no complications. The caesarean section rate was 47%. The incidence of primary and secondary postpartum haemorrhage was 19% and 2%, respectively. There were two neonatal head bleeding complications associated with prolonged labour or instrumental delivery. Availability of management guideline and care provided in a multidisciplinary approach can help to minimize bleeding complications in carriers of haemophilia and their newborns.     

Factor VIII inhibitors in mild and moderate-severity haemophilia A

Summary. Inhibitors are an uncommon complication of mild haemophilia, occurring in 3–13% of patients and usually arising during adulthood. The risk of inhibitor development in this group appears to be associated with relatively few high-risk factor VIII genotypes clustered in the A2 and C2 domains, especially the Arg⁵⁹³-Cys and the Trp²²²⁹-Cys mutations. Kindreds with these mutations have an inhibitor incidence of up to 40%. These mutations may induce a stable conformational change in the factor VIII molecule rendering it antigenically distinct from wild-type factor VIII. Inhibitors in mild haemophilia usually cross-react with endogenous factor VIII reducing the basal VIIIC to <0.01 IU/ml, and causing spontaneous bleeding. This bleeding is sometimes severe and life-threatening, two-thirds of patients developing a pattern of soft tissue, gastrointestinal (GI) and urinogenital bleeding reminiscent of acquired haemophilia. Bleeding has been treated with human and porcine factor VIII, bypass therapy and DDAVP. Recombinant factor VIIa and DDAVP have the advantage that they do not induce an anamnestic rise in inhibitor titre. About 60% of these inhibitors disappear in the remainder over a median of 9 months. Few of these inhibitors recur, suggesting that most such patients have become tolerant. The inhibitors persist long-term and remain troublesome in about 40% of patients. The limited data available on immune tolerance induction in this group indicate a generally poor response to this approach. Two of nine achieved tolerance, with a partial response in a further four. Inhibitors are an uncommon but life-threatening complication of haemophilia. This complication should be considered when selecting the treatment modality for patients with a family history of inhibitors, and DDAVP used whenever possible.     

Factor VIII Inhibitor Postpartum

Acquired factor VIII deficiency in women postpartum due to a factor VIII inhibitor is rare and the etiology is unknown. In this study a case report and a review of the literature are given. The haemorrhagic diathesis resembles classic haemophilia, with the exception that ecchymoses and tissue bleeding occur more frequently. The potency of the inhibitor may vary from weak to strong and the inactivation of factor VIII coagulant activity (factor VIII-C) by the inhibitor is of a non-linear type. Severe bleeding has been fatal in a few cases, but factor VIII concentrate substitution has usually been successful without anamnestic response of inhibitor activity. There is no convincing evidence that immunosuppression is effective, also because the natural history of the disease is characterised by a spontaneous disappearance of the factor VIII-C inhibitor. Treatment of bleeding symptoms with factor VIII concentrate should therefore not be reserved for life threatening haemorrhages only.     

Iliopsoas haemorrhage in patients with bleeding disorders – experience from one centre

Iliopsoas haemorrhage in patients with bleeding disorders is a potentially life-threatening condition, with significantly associated morbidity. Despite its clinical importance, little has been published on the frequency, complications or outcomes of this entity since the advent of modern therapies for haemophilia. In a retrospective review of 297 patients with bleeding disorders followed at our centre, we identified 46 episodes of iliopsoas haemorrhage in 31 patients. Patients presented primarily with thigh, hip and/or groin pain, and frequently had flexion hip contracture, femoral nerve paresthesia, and >2 g dL(-1) haemoglobin drop. The duration of symptoms prior to seeking medical attention was 3.8 +/- 4 days. Nineteen of 155 patients (12.3%) with haemophilia A had 28 episodes of iliopsoas bleed; 52.6% of these patients had severe haemophilia. Of these 19 patients with haemophilia A who had iliopsoas haemorrhage, seven (36.8%) had an inhibitor to factor VIII (FVIII), and accounted for one-half of the bleeding episodes. Nine of 66 patients (13.6%) with haemophilia B had 15 episodes of iliopsoas haemorrhage; 22.2% of these patients had severe haemophilia, including one patient with an inhibitor to FIX who had two iliopsoas bleeds. The mean duration of therapy was 18.7 +/- 11.9 days, and the duration of hospitalization was 12.3 +/- 9.1 days. The length of hospital stay was significantly longer in patients with inhibitors, when compared with patients without inhibitors (19.1 +/- 5.8 days vs. 7.6 +/- 7.8 days; P<0.0001) with higher factor consumption, although the total duration of therapy was not significantly different. Patients with inhibitors were over-represented in the cohort of haemophiliacs with iliopsoas bleed. Patients with inhibitors who had iliopsoas bleeds remained hospitalized longer, although the duration of therapy was the same as patients with no inhibitors. There was a low frequency of recurrent bleed (2.8%).     

Acquired haemophilia: experiences with a standardized approach

Acquired haemophilia is a rare, life-threatening, acquired bleeding diathesis. No general consensus exists on the best therapeutic approach. We report on the standardized approach at our institution evaluated in ten patients with acquired haemophilia. Factor VIII inhibitors were found in all patients, activities ranging from 1 to 648 Bethesda units (BU). Eight of the ten patients presented with severe bleeding. Two patients died during the acute phase, one from intracranial bleeding and one due to Mycoplasma pneumonia. One patient with mild bleeding was treated with immunosuppression alone. Two patients with factor VIII inhibitor activities below 5 BU were started on factor VIII concentrate therapy. Therapy was successful in one and was changed to recombinant human activated factor VII infusion (rFVIIa) in the other, owing to insufficient factor VIII recovery. Six patients with factor VIII inhibitor activities above 5 BU were started on activated prothrombin complex concentrate (APCC) therapy. APCC treatment was successful initially in all six patients and was changed to rFVIIa infusion in one for rebleeding. One patient did not receive any specific therapy. Immunosuppression with prednisolone (2 mg kg(-1)) was begun in nine patients and was continued with cyclophosphamide (2 mg kg(-1)) in six. A complete remission of the acquired haemophilia was found in seven of the eight patients surviving the acute phase, one had a partial remission. All patients with acquired haemophilia could be managed effectively following our standardized approach. Routine administration of immunosuppression was associated with high inhibitor elimination rates.     

Surreptitious bleeding in surgery: a major challenge in coagulation

Apart from inadequate surgical haemostasis, postoperative bleeding can be related to acquired disorders of platelet number, platelet function or coagulation proteins (e.g. Vitamin K deficiency, DIC or liver injury). We highlight our experience with three patients who suffered life-threatening bleeding in the postoperative setting. The three patients - a 47-year-old man and 70- and 74-year-old women -- all had negative histories for excessive bleeding with prior surgeries, and all had normal preoperative PT and aPTT tests. Surgeries were resection of ischaemic bowel, cholecystectomy and coronary artery bypass grafting. All patients experienced unexpected bleeding within the first few postoperative days requiring multiple red cell transfusions and surgical re-explorations. Evaluations within the first 4--7 days after surgery revealed that these three patients had developed prolonged aPTT due to demonstrable factor VIII antibodies initially at low titre. One patient was treated with high doses human factor VIII, corticosteroids, intravenous gammaglobulin and plasma exchanges. The inhibitor was no longer demonstrable after 6 weeks of such therapy, and he has remained in remission without therapy. The second patient was initially treated with high-dose human factor VIII infusions. Five months later, prednisone and 6-mercaptopurine were begun for worsening inhibitor titre and diffuse purpura and subcutaneous haematomas. The factor inhibitor remitted, but the patient died from liver failure related to post-transfusion hepatitis. The third patient was initially managed with high-dose human factor VIII. Two months later, worsening inhibitor titre and tongue haematoma was treated with activated prothrombin complex, corticosteroids and cyclophosphamide. Eight years later, she is on no therapy, demonstrates a mild bleeding tendency and has a stable low-titre inhibitor. There have been a few case reports of inhibitors to coagulation factors including factor VIII becoming manifest in the postoperative setting but surgery has not been widely recognized as an underlying cause for acquired haemophilia. This paper speculates on pathogenesis and reviews treatment options. This syndrome is remarkable for its abrupt onset in the first few postoperative days and for its substantial morbidity. The problem is potentially reversible with immunosuppressive therapy. Clinicians should be aware of this syndrome, considering acquired haemophilia in patients with unexpected postoperative bleeding.     

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.     

Polymyalgia rheumatica/arteritis temporalis and acquired factor VIII inhibitor

Acquired haemophilia is a rare, but often life-threatening bleeding disorder caused by autoantibodies, mostly directed against factor VIII (FVIII inhibitor). The incidence of acquired haemophilia, which most commonly affects patients over 50 years of age, is estimated between 0.2 and 1 million per year. Although its aetiology remains obscure, 40–50% of cases are associated with other conditions, such as pregnancy, malignancies, drugs and autoimmune disorders as rheumatoid arthritis, systemic lupus erythematosus and Sjögren's disease. We report the case of a 69-year-old patient with spontaneously acquired FVIII inhibitor secondary to polymyalgia rheumatica (PMR)/arteritis temporalis (AT). Our case illustrates that PMR/AT can be added to the list of autoimmune disorders associated with acquired haemophilia due to FVIII inhibitor.     

Treatment options for bleeding episodes in patients undergoing immune tolerance therapy

Inhibitors to factor VIII develop in 4–20% of haemophilia A patients, with the percentage rising to 52% in certain subpopulations. The management of inhibitor patients is directed toward stopping acute haemorrhages, providing short-term haemostasis before and after surgery, and inducing immune tolerance to factor VIII (immune tolerance therapy or ITT). Several different protocols have been used for ITT, but they are all centred around ongoing exposure to high doses of factor VIII. High responders (those patients with a large increase in inhibitor level after exposure to factor VIII) are the prime candidates for ITT, but low responders may also benefit from this treatment. It is often necessary to treat bleeding episodes during ITT, because elimination of inhibitors may require many years of therapy. Treatment of haemorrhages in inhibitor patients is reviewed for both low and high responders during ITT and in the absence of ITT. The choice of clotting agent for inhibitor patients who have not yet responded to ITT depends on current and past inhibitor levels, the severity of the haemorrhage, the site of the haemorrhage or the setting in which it occurs (e.g. surgical), and the extent of inhibitor cross-reactivity with porcine factor VIII. Patients with high-titre inhibitors experiencing a critical haemorrhage are generally best managed with bypassing agents (AUTOPLEX® T or FEIBA® VH), porcine factor VIII or rFVIIa.     

Primary postpartum haemorrhage in women with von Willebrand disease or carriership of haemophilia despite specialised care: a retrospective survey

Pregnant women with bleeding disorders require specialised peripartum care to prevent postpartum haemorrhage (PPH). If third trimester coagulation factor levels are <0.50 IU mL^?1, prophylactic treatment is indicated and administered according to international guidelines. However, optimal dose and duration are unknown and bleeding may still occur. The aim of this study was to investigate the outcome in women with von Willebrand disease (VWD) or haemophilia carriership treated according to current practice guidelines. From the period 2002–2011, 185 deliveries in 154 VWD women or haemophilia carriers were retrospectively included. Data on blood loss, bleeding disorder characteristics and obstetric risk factors were obtained. The outcome was primary PPH, defined as blood loss ≥500 mL within 24 h postpartum and severe PPH as blood loss ≥1000 mL. Primary PPH was observed in 62 deliveries (34%), 14 (8%) of which resulted in severe PPH. In 26 deliveries prophylactic treatment was administered due to factor levels below the 0.50 IU mL^?1 cut‐off in the third trimester, 14 of which (54%) were complicated by PPH. We found an increased PPH risk in deliveries given prophylactic treatment compared with deliveries without (OR 2.7, 95% CI 1.2–6.3). In conclusion, PPH incidence was highest in deliveries with the lowest factor levels in the third trimester. Currently, delivery outcome in women with bleeding disorders is unsatisfactory, given the high PPH incidence despite specialised care. Future studies are required to optimise management of deliveries in this patient population.     

Recombinant factor VIIa treatment for life-threatening haemoptysis

Diffuse alveolar haemorrhage is a severe clinical disorder that may be life-threatening. The early diagnosis of diffuse alveolar haemorrhage and prompt intervention is crucial. Recombinant factor VIIa has been used extensively for the treatment of haemophilia A and B patients. More recently, recombinant factor VIIa has been used successfully for the treatment of bleeding in patients without pre-existing coagulopathy. We describe the successful use of recombinant factor VIIa in a patient with diffuse alveolar haemorrhage secondary to pulmonary-renal syndrome.     

Desmopressin is not always effective in mild haemophilia Apatients undergoing urological surgery: the need of standardized protocols

Desmopressin may be an efficient haemostatic treatment for mild A haemophiliacs because its infusion raises plasma factor VIII level. We report the use of desmopressin in five mild haemophilia A patients undergoing urological surgery. They all received a preoperative infusion (0.3 microg kg(-1), i.v.) 1 h before incision followed by repeated injections at 12- or 24-h intervals according to the severity of the procedure. Nevertheless, four patients presented a postoperative bleeding requiring again surgery performed for 3 of them under clotting factor concentrate instead of desmopressin. The occurrence of haemorrhage was not always correlated with particularly low plasma factor VIII level. Surgical management of urological procedures with desmopressin in mild haemophilia A patients requires standardized protocols.