Epidemiology, spectrum of clinical manifestations and diagnostic issue of acquired haemophilia: A case series

@#Introduction: Acquired haemophilia A (AHA) is a rare acquired bleeding disorder caused by polyclonal immunoglobulin G autoantibodies against clotting factor VIII (FVIII). The incidence was reported to be rare occurring in 0.2- 4 cases/million/year. Patients may present with different clinical manifestations to various specialties. Early recognition of the disease contributes to favourable clinical outcome. Case Series: Here, we reported five cases of this disorder with different clinical presentations from two tertiary hospitals in Kelantan state, Malaysia within a two year-period. Most of them were elderly, except for one who presented at the age of 36 years old. No direct or secondary cause was identified except for one patient who had developed from pregnancy-related at 3 weeks postpartum. These patients presented with spontaneous bleeding typically into skin, muscles, and mucous membranes but also at rare site in the epidural space. All patients denied previous history of bleeding or family history of bleeding disorder. FVIII activities were recorded between <1% to 19%, while the inhibitor titre levels were between 3.9 BU to 340 BU. The treatment approaches especially at presentation were complicated by unfamiliarity of managing this rare condition but all these patients received appropriate medical attention. Discussion: Prompt diagnosis and management in the right hand are critical. Awareness of this disorder by medical personnel at all levels in the community and in various specialties is important.

A Case of Acquired Hemophilia A Complicating Gastric Carcinoma: A Rare Hemorrhagic Condition That Palliative Care Physicians May Encounter

Abstract: We report a case of acquired hemophilia A diagnosed after hospitalization in a palliative care unit. Case: The patient was an 86-year-old man diagnosed with gastric carcinoma one-year prior, who declined treatment but whose progress was being monitored. He was admitted to our hospital due to multiple, systemic, and subcutaneous bleeding and exacerbation of anemia. Blood testing revealed prolonged activated partial thromboplastin time (APTT), but the cause was unknown. Subcutaneous bleeding persisted after hospitalization, accompanied by pain. After admission to a palliative care unit, blood testing revealed only prolonged APTT; hence, a coagulation study was performed, resulting in a diagnosis of acquired hemophilia A. Immunosuppressive therapy was considered but was not performed as the patient’s progress was complicated by aspiration pneumonia for which antibiotics were ineffective, and the patient’s prognosis was determined to be short. The patient died on the 20th day after admission to the palliative care unit. Conclusion: Acquired hemophilia A is a rare hemorrhagic condition, but it is important to suspect it in cases involving prolonged APTT and spontaneous bleeding with no medical history or family history.

Incidence of factor VIII inhibitory antibodies in patients with hemophilia A seen at HEMOCE, Ceará, Brazil / Prevalência de inibidores do fator VIII em pacientes com hemofilia A atendidos no HEMOCE, Ceará, Brasil

ABSTRACT Introduction: Hemophilia A is an inherited disease caused by a deficiency of factor VIII, which results from a genetic inheritance located on the X chromosome. During treatment of patients with this disorder, factor VIII inhibitors may be present, which are primarily antibodies type immunoglobulin G (IgG), and interfere with the activation of factor VIII. Objectives: The present study aims to investigate and quantify the presence of antibodies against factor VIII:C in patients with hemophilia A, treated at the Ceará Hematology Center (HEMOCE). Material and methods: Screening for the inhibitor against factor VIII was performed according to the original Bethesda method or the Nijmegen modified assay. Results: One hundred eighty-four patients with hemophilia A were evaluated, from November 2012 to February 2015. From the patients evaluated, 149 (80.98%) showed no inhibitor presence, while in 35 patients (19.02%) the presence of the inhibitor was detected. Among inhibitor carriers, most hemophilia patients had high titers of the inhibitor (57.2%). Conclusion: The high incidence of factor VIII inhibitor in the study population can be explained by the type of treatment used at HEMOCE, which is based on the factor VIII in its recombinant form. The results should be evaluated carefully, so that the treatment and monitoring of these patients are conducted in the safest way possible.

RESUMO Introdução: A hemofilia A é uma doença hereditária causada pela deficiência do fator VIII, resultante de uma herança genética ligada ao cromossomo X. Durante o tratamento de pacientes com essa doença, pode ocorrer presença de inibidores do fator VIII, os quais são, em sua maioria, anticorpos do tipo imunoglobulina da classe G (IgG), que interferem na ativação do fator VIII. Objetivos: O presente estudo tem como objetivo pesquisar e quantificar a presença de anticorpos contra o fator VIII:C em pacientes com hemofilia A, atendidos no Hemocentro Ceará (HEMOCE). Material e métodos: A pesquisa para detecção do inibidor do fator VIII foi realizada de acordo com a modificação do método de Nijmegen Bethesda original. Foram avaliados 184 pacientes com hemofilia A entre novembro de 2012 e fevereiro de 2015. Resultados: Dos pacientes avaliados, 149 (80,98%) não revelaram presença do inibidor, enquanto em 35 (19,02%) essa presença foi detectada. Entre os portadores dos inibidores, a maioria dos pacientes hemofílicos apresentaram títulos elevados do inibidor (57,2%). Conclusão: A incidência elevada de inibidor do fator VIII na população em estudo pode ser explicada pelo tipo de tratamento utilizado no HEMOCE, o qual se baseia no fator VIII na sua forma recombinante. Os resultados devem ser avaliados com critério para que o tratamento e o acompanhamento desses pacientes sejam realizados da maneira mais segura possível.

Hemofilia adquirida (inhibidor adquirido del factor VIII) / Acquired haemophilia (acquired factor VIII inhibitor)

La hemofilia adquirida es una enfermedad de muy poco frecuente presentación. El paciente habitualmente consulta con equimosis y hematomas extensos en la piel y tejido celular subcutáneo, anemia y en algunas oportunidades un sangrado grave, que si no se controla puede ser fatal hasta en el 20% de los casos. Se produce por un autoanticuerpo dirigido contra el factor VIII de la coagulación y suele ocurrir en pacientes añosos sin historia de sangrados, pero también puede presentarse asociado a neoplasias, enfermedades autoinmunes, medicamentos y en mujeres jóvenes asociado al embarazo. Tiene un perfil de laboratorio característico con un tiempo de tromboplastina parcial activada (aPTT) prolongado, que no corrige con plasma normal, y niveles de factor VIII disminuidos. El tratamiento recomendado es muy específico, ya que para controlar el sangrado se utilizan agentes de puenteo (productos que sortean el efecto del inhibidor), factor VII recombinante activado o concentrado de complejo de protrombina activada, y medicación inmunosupresora para erradicar el autoanticuerpo.

Acquired haemophilia is a rare disorder. The clinical picture ranges from mild ecchymosis and anaemia to life threatening bleeding in up to 20% of patients. The disease is produced by an antibody against Factor VIII and it usually occurs in the elderly, with no previous history of a bleeding disorder. It can be associated to an underlying condition such as cancer, autoimmune disorders, drugs or pregnancy. It has a typical laboratory pattern with isolated prolonged activated partial thromboplastin time (aPTT) that fails to correct upon mixing tests with normal plasma and low levels of factor VIII. Treatment recommendations are based on controlling the acute bleeding episodes with either bypassing agent, recombinant activated factor VII or activated prothrombin complex concentrate, and eradication of the antibody with immunosuppressive therapy.

Two Cases of Infant Hemophilia A Patients with Inhibitors / 임상소아혈액종양

Development of inhibitors is currently one of the most serious complications of hemophilia treatment. Typically, the propensity to develop an inhibitor is likely influenced by both genetic and non-genetic factors. Hemophilia patients with inhibitors are partially or completely refractory to traditional replacement of the deficient clotting factors and are at increased risk of bleeding as compared to patients without inhibitors. Several cases of infant hemophilia A with inhibitor have been reported in other countries, but no such patient has so far been reported in South Korea. We report two infants affected by hemophilia A with inhibitors, both of whom had bleeding episodes that were successfully treated with recombinant activated factor VII. Clinicians should remain aware of potential inhibitor development in infant hemophilia A patients and such patients should be carefully monitored.

Unexpected Bleeding Following Endoscopic Sinus Surgery Leading to the Rare Diagnosis of Acquired Haemophilia A / 대한이비인후과학회지

We report a case of acquired hemophilia A following endoscopic sinus surgery. The patient was a 64-year-old man whose preoperative activated partial thromboplastin time (aPTT) was slightly prolonged. He underwent endoscopic sinus surgery for chronic rhinosinusitis with nasal polyp. Nasal bleeding occurred spontaneously on the postoperative day 3. The aPTT was prolonged at 58.9 s, with factor VIII activity of 21% and a positive factor VIII inhibitor. Treatment with factor VIII and methylprednisolone resulted in remission within 1 month. This is the first of such case reported in Korea; the patient was treated by recombinant factor VIII replacement and steroid therapy.

Two Cases of Infant Hemophilia A Patients with Inhibitors / 임상소아혈액종양

Development of inhibitors is currently one of the most serious complications of hemophilia treatment. Typically, the propensity to develop an inhibitor is likely influenced by both genetic and non-genetic factors. Hemophilia patients with inhibitors are partially or completely refractory to traditional replacement of the deficient clotting factors and are at increased risk of bleeding as compared to patients without inhibitors. Several cases of infant hemophilia A with inhibitor have been reported in other countries, but no such patient has so far been reported in South Korea. We report two infants affected by hemophilia A with inhibitors, both of whom had bleeding episodes that were successfully treated with recombinant activated factor VII. Clinicians should remain aware of potential inhibitor development in infant hemophilia A patients and such patients should be carefully monitored.

Acquired Hemophilia: Successfully Treated with Plasma Exchange in a Patient with Hightiter Inhibitors / 대한수혈학회지

Acquired hemophilia is an extremely rare but life threatening hemorrhagic disease caused by autoantibodies directed coagulation factor VIII. Estimated management guidelines include rapid diagnosis, suppression of bleeding, and elimination of inhibitors by use of immunosuppressants. Plasma exchange is used restrictively as an adjuvant in order to lower the level of inhibitor. We report on a successful therapeutic experience with plasma exchange in a patient with refractory acquired hemophilia. After performance of the plasma exchange procedure, bleeding was controlled and results of coagulation tests showed improvement according to the decrease in levels of factor VIII inhibitor.

The First Case of Postpartum Acquired Hemophilia A in Korea

Acquired hemophilia A (AHA) is a rare coagulopathy caused by autoantibodies to coagulation factor VIII (FVIII). Most patients with AHA have been previously healthy; however, a variety of morbidities have been associated with the condition including pregnancy. A 40-yr-old woman visited our institution with extensive hematoma on the right hip area. Her medical history revealed no personal or familial history of bleeding diathesis. Her coagulation tests showed markedly prolonged aPTT (117 sec), markedly decreased level of FVIII activity (0.4%) and high-titer FVIII inhibitor (77 BU). Collectively, she was diagnosed as having postpartum AHA and was treated with bypassing agents and corticosteroids. Her aPTT was normalized on the 174th postpartum day and FVIII inhibitor showed negative conversion on the 224th postpartum day. This is the first case of postpartum AHA with high-titer FVIII inhibitor in Korea. Timely diagnosis and management can reduce morbidity and mortality of this potentially life-threatening condition.

Acquired factor VIII deficiency after consuming the dried gallbladder of a cobra, Naja naja

Acquired factor VIII deficiency is very rare, often fatal. It is associated with pregnancy, autoimmune diseases, malignancy, and drugs, although no underlying cause is found in 50%. A 49-year-old male was referred with right shoulder bruising. The coagulation test showed a prolonged activated partial thromboplastin time. The factor VIII level was less than 1%, and the factor VIII inhibitor antibody titer was 246 Bethesda units/mL. The findings were compatible with acquired factor VIII deficiency. He had consumed the dried gallbladder of a cobra, Naja naja, for two weeks, it contained venom. After the initial treatment with factor VIII, he did not take supplemental coagulation factor VIII. The patient was readmitted with left forearm swelling. He lost consciousness suddenly and brain computed tomography (CT) revealed a subdural hematoma. Despite administering recombinant factor VII, his bleeding was not controlled and he died.

Acquired hemophilia associated with rheumatoid arthritis / Hemofilia A adquirida associada à artrite reumatoide

O aparecimento do anticorpo contra fator VIII é um fenômeno bem estabelecido na hemofilia A, ocorrendo em 5 a 15 por cento dos pacientes hemofílicos dos Estados Unidos, Inglaterra, Suécia e França. Nos pacientes não-hemofílicos o seu aparecimento é raro, podendo ocorrer em indivíduos saudáveis, principalmente idosos e mulheres no puerpério, pacientes com neoplasia maligna ou doenças autoimunes, como lúpus eritematoso sistêmico, artrite reumatoide e síndrome de Sjõgren. Descrevemos o caso de uma paciente de 64 anos de idade, portadora de artrite reumatoide soropositiva há 23 anos, que há 10 dias desenvolveu equimoses e hematomas progressivos cuja investigação foi compatível com a presença de anticorpo contra fator VIII. Foi instituída terapia com metilprednisolona, ciclofosfamida endovenosa, imunoglobulina e reposição de complexo protrombínico, com remissão do quadro hemorrágico e negativação do anticorpo contra o fator VIII. Concluímos com esse caso que, apesar de ser rara, a presença de inibidores adquiridos do fator VIII deve ser pesquisada quando pacientes portadores de doença autoimune desenvolvem manifestações hemorrágicas associadas ao prolongamento do TTPA com TAP e contagem plaquetária normais.

The occurrence of the antibody against factor VIII is a well-known phenomenon in hemophilia A, occuring in 5 to 15 percent of the hemophilic patients in the United States, England, Sweden and France. The development of factor VIII in non-hemophilic patients is rare and may occur in healthy individuals, mostly elderly and women in postpartum period, and in patients with malignant neoplasia or autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and Sjõgren's syndrome. We described the case of a 64-year-old female patient who has had seropositive rheumatoid arthritis for 23 years and presented with a ten-day history of progressive ecchymosis. Therapy with methylprednisolone, intravenous cyclophosphamide, immunoglobulin and factor VIII reposition was instituted, resulting in a remission of the bleeding and negativity for antibodies against factor VIII titers. We concluded that, despite its rarity, the presence of acquired factor VIII inhibitors should be investigated when patients with autoimmune diseases develop bleeding manifestations.

Transient Acquired Hemophilia Associated with Mycoplasma Pneumoniae Pneumonia

Acquired hemophilia is a rare disorder caused by autoantibodies to factor VIII (FVIII) (also referred to as factor VIII inhibitors or anti-FVIII) and may be associated with pregnancy, underlying malignancy, or autoimmune disorders. A 33-month-old girl who presented with hematochezia and ecchymotic skin lesions was diagnosed with Mycoplasma pneumoniae pneumonia by serology and polymerase chain reaction. Hematologic studies showed a prolonged activated partial thromboplastin time (aPTT), partially corrected mixing test for aPTT, reduced levels of FVIII, and the presence of antibodies against FVIII. She was treated conservatively with prednisone and intravenous immunoglobulin (IVIG) without FVIII transfusion and recovered without sequelae. This report provides the first description of acquired hemophilia due to anti-FVIII in association with M. pneumoniae in Korea. We discuss this case in the context of the current literature on acquired hemophilia in children.

Two Cases of Acquired Hemophilia A Successfully Treated with Oral Steroid or Danazol

Acquired Hemophilia A is a rare and considerably life-threatening coagulopathy, which is caused by the development of autoantibodies against factor VIII (FVIII) in non-hemophilic adults. Acquired FVIII inhibitors can be associated with diverse conditions, such as malignant disorders, medications, autoimmune diseases, postpartum states and others. These autoantibodies inhibit normal coagulation, had results in bleeding complications, which can contribute to mortality in a high percentages of cases. Effective control of the disorder can be achieved by prompt diagnosis and appropriate managements. Generally, the managements of acquired hemophilia A are aimed at treating the acute bleeding and eliminating inhibitors by immunosuppression. Although a range of treatment options exists for patients with acquired hemophilia A, there is no consensus with regard to the optimal therapies for this disorder. Herein, two cases, an 82-year-old man and a 78-year-old man who were successfully treated by steroid or danazol, which is a relatively mild immunosuppressive agent, are reported.

Laparoscopic Cholecystectomy in a Hemophiliac Patient with Factor VIII Inhibitor

Hemophilia A is a severe bleeding disorder resulting from the lack of functional blood coagulation factor VIII. Accordingly, operations on patients with hemophilia A, except in a few cases, are performed with the administration of factor VIII. However, in those hemophilia A patients administered factor VIII inhibitor, factor VIII replacement therapy is ineffective. The treatment of hemophilic patients with factor VIII inhibitor is undertaken to utilize the hemostatic capacity of the activated forms of FVII, FIX and FX contained within prothrombin complex concentrates, which are purposely manufactured to contain Factor Eight Inhibitor Bypassing Activity (FEIBA) during surgery. Further, in the last few years, a new product, recombinant activated FVII (FVIIa, Novo-VII), which is thought to ensure hemostasis by binding, directly or in complex with tissue factor, to negatively charged phospholipids on the surface of activated platelets, has been licensed. Recently, we experienced a GB stone, with acute cholecystitis, in a fifty year old hemophilia A man treated with factor VIII inhibitor. Under medication with FEIBA and Novo-VII, a laparoscopic cholecystectomy was performed. Here, this case is reported, with a review of the literature.

A Case of Acquired Hemophilia A / 임상검사와정도관리

Acquired hemophilia is a rare acquired bleeding disorder. It occurs most frequently in elderly patients and in patients with associated underlying diseases such as autoimmune disorders, rheumatoid arthritis, malignancies, and so on. It is caused by autoantibodies to factor VIII which deplete circulating factor VIII. We report a 78-year-old man with acquired hemophilia A who underwent subtotal gastrectomy for stomach cancer 7 years ago with no current evidence of recurrence. He has no bleeding tendency in the past nor family history for bleeding. On admission he had blood clots in both renal pelvis and sustaining hematuria. Laboratory tests revealed prolonged activated partial thromboplastin time(aPTT), decreased activity of factor VIII and evidence of factor VIII inhibitor.

Acquired hemophilia successfully treated with oral immunosuppressive therapy

Acquired hemophilia is a rare disorder associated with serious bleeding in nonhemophilic patients. We had a 40-year-old woman who was diagnosed as acquired hemophilia with a factor VIII inhibitor level of 27.5 BU/mL. She was presented with gross hematuria and severe right shoulder pain, and was successfully treated with daily oral cyclophosphamide and prednisone for 2 weeks. After the remission, the doses of prednisone and cyclophosphamide were slowly decreased and she remained in complete remission without further bleeding episodes.