Acquired Hemophilia A associated with bullous pemphigoid: A rare combination

Acquired Hemophilia A (AHA) is a rare autoimmune disorder, caused by the development of circulating autoantibodies against coagulation factor VIII (FVIII). AHA is associated with bullous pemphigoid in 2% of patients. We report a case of a 74-year-old man admitted with anemia and a tense subcutaneous and muscular hematoma in the right thigh. Blood analysis confirmed AHA. The patient had a recent diagnosis of bullous pemphigoid. Response to bypass agents and corticosteroids was good with bleeding control and normalization of FVIII and negative autoantibodies, respectively. In a 3-month follow-up period after tapering and stopping prednisolone, a relapse occurred, and immunosuppression was reinitiated. An early diagnosis and effective treatment in AHA are essential to reduce morbimortality. A careful tapering of immunosuppression is important to minimize FVIII inhibitor recurrence, as observed in this case.     

Management of acquired hemophilia A: Review of current evidence

Acquired hemophilia A (AHA) is a rare acquired bleeding disorder caused by autoantibodies against autologous factor VIII (FVIII). It is a disease that most commonly affects the elderly, but it has been described in children and during the post-partum period. It is idiopathic in 50% of cases and is associated with autoimmune disease, malignancy, pregnancy, infection or certain medications in the other 50%. The diagnosis should be suspected in patients with an isolated prolonged aPPT without previous personal or familial bleeding history. Treating the bleeding and eradication of the inhibitor is the mainstay of treatment. The first line of treatment for acute bleeding is the use of bypassing agents. The most commonly used method for eradicating the inhibitor is immunosuppression, namely corticosteroids alone or in combination with cyclophosphamide. This review summarises current knowledge and reviews management options and guidelines.     

Acquired hemophilia a: a current review of autoantibody disease

Acquired hemophilia A (AHA) is a rare, potentially life-threatening hemorrhagic disorder that presents a complex clinical challenge. The immune-mediated production of autoantibodies, known as factor VIII inhibitors, often results in clinically significant soft tissue or post-procedural bleeding episodes in patients without a previous diagnosis of a bleeding disorder. Acquired antibodies against factor VIII are associated with an extensive list of conditions, including pregnancy, autoimmune disease, and malignancy. There is great potential for morbidity and mortality resulting from autoantibody development. Death is more frequent within the first few weeks after symptomatic manifestation, making prompt recognition and treatment vitally important. Treatment focuses on stabilization of initial bleeding and long-term eradication of the acquired inhibitor. As no randomized clinical trials have been conducted regarding treatment in this patient population, clinical expertise and experience continue to guide treatment recommendations. This report provides an algorithm for the diagnosis of AHA and outlines potential treatment recommendations, most notably concomitant use of recombinant factor VIIa (rF7a) and factor VIII inhibitor bypassing agent to control bleeding in patients not responsive to single-agent therapy, and use of rituximab and prednisone for inhibitor eradication therapy.     

Acquired hemophilia A in solid cancer: Two case reports and review of the literature

Acquired hemophilia A (AHA) is a rare, hemorrhagic autoimmune disease, whose pathogenesis involves reduced coagulation factor VIII (FVIII) activity related to the appearance of inhibitors against FVIII. Common etiological factors include autoimmune diseases, malignancy, and pregnancy. We report two cases of AHA in solid cancer. The first case is a 63-year-old man who developed peritoneal and intestinal bleeding after gastrectomy for gastric cancer. He was diagnosed with AHA, and was treated with prednisone, followed by cyclophosphamide. In the second case, a 68-year-old man developed a subcutaneous hemorrhage. He was diagnosed with AHA in hepatocellular carcinoma on CT imaging, and treated with rituximab alone. Hemostasis was achieved for both patients without bypassing agents as the amount of inhibitors was reduced and eradicated. However, both patients died within 1 year due to cancer progression. Successful treatment for AHA in solid cancer can be difficult because treatment of the underlying malignancy is also required.     

The IgG autoimmune response in postpartum acquired hemophilia A targets mainly the A1a1 domain of FVIII

Summary. Background: Acquired hemophilia A (AHA) is a severe life‐threatening autoimmune disease due to the development of autoantibodies that neutralize the procoagulant activity of factor VIII (FVIII). In rare cases, AHA occurs in the postpartum period as a serious complication of an otherwise normal pregnancy and delivery. Due to its rarity, little is known about the features of the antibody response to FVIII in AHA. Objectives: Our study wanted to (i) determine the epitope specificity and the immunoglobulin (Ig) subclasses of anti‐FVIII autoantibodies in plasma samples from a large cohort of AHA patients, and (ii) compare the epitope specificity of anti‐FVIII autoantibodies in plasma samples from postpartum AHA and other AHA patients. Patients/Methods: Seventy‐three plasma samples from patients with postpartum AHA (n = 10) or associated with malignancies (n = 16) or autoimmune diseases (n = 11) or without underlying disease (n = 36) were analyzed with three multiplexed assays. Results and Conclusions: Our results showed a stronger response against the A1a1‐A2a2‐B fragments of FVIII and more specifically against the A1a1 domain in patients with postpartum AHA than in the other AHA groups (P < 0.01). Moreover, although IgG₄ was the predominant IgG subclass in all groups, anti‐A1a1‐A2a2‐B and anti‐A1a1 domain autoantibodies of the IgG₁ and IgG₃ subclasses were more frequently detected in postpartum AHA than in the other AHA groups. These findings support the involvement of the Th1‐driven response in the generation of autoantibodies in women with postpartum AHA compared with the other groups of AHA patients in whom production of Th2‐driven IgG₄ was predominant.     

The tipping point: The critical role of therapeutic apheresis in a case of refractory acquired hemophilia

Acquired hemophilia A (AHA) is a rare autoimmune disorder that leads to factor VIII (FVIII) deficiency via autoantibody formation. Standard treatment options include FVIII bypassing factors and immunosuppression. However, the role of therapeutic plasma exchange (TPE) is not clear in the treatment of AHA. We present a case of idiopathic AHA in a 66 year old female with severe bleeding and a FVIII inhibitor of 17.6 Bethesda units (BU). She failed to respond to standard treatment including maximum dose of recombinant FVIIa (rFVIIa), rituximab, and other immunosuppressive agents. Her FVIII inhibitor rapidly increased to 140 BU and FVIII was below 5%. TPE was initiated 3 weeks after admission and her bleeding stabilized after the first treatment and completely stopped after three treatments. Repeat testing revealed increased FVIII to 15% and FVIII inhibitor decreased to 2.0 BU. After an additional TPE treatment, her FVIII increased to 27% and FVIII inhibitor decreased to 0.6 BU and she was discharged without bleeding 40 days after admission. In this case, TPE played a critical role in reducing FVIII inhibitor, which resulted in a recovery of FVIII activity and hemostasis. Therefore, TPE should be initiated early in AHA patients with bleeding and high titer of FVIII inhibitor.     

Utilization of emicizumab in acquired hemophilia A: A case report

BackgroundAcquired Hemophilia A (AHA) is a rare autoimmune disorder associated with the development of autoantibodies against factor VIII (FVIII). Although obtaining hemostatic control through the use of recombinant factor VIIa, activated prothrombin complex concentrate and recombinant porcine FVIII are cornerstones in the clinical management of AHA, these therapies have several disadvantages, including a higher risk for the development of thromboembolic events, unpredictable efficacy and short half-lives. While emicizumab has been FDA licensed for use in bleeding prophylaxis for patients with Congenital Hemophilia A (CHA) with and without inhibitors, it has not been approved for use in AHA, with only a few reports describing its use in this context.Case reportWe report our experience with the use of emicizumab in an 83-year old male with AHA, complicated by the onset of atrial fibrillation following admission, drug-induced thrombocytopenia, infectious complications, and the identification of a low-grade lymphoproliferative disorder, in which emicizumab prophylaxis was used for bleeding prophylaxis in the context of persistently elevated inhibitor titers without evidence of thrombotic events or thrombotic microangiopathy.     

山东济宁地区270例矮小症病因及诊断线索分析

目的探讨山东济宁地区270例矮小症病因及早期诊断线索。 方法回顾性分析2013年4月至2014年4月济宁医学院附属医院内分泌科收治的270例(男性179例,女性91例)矮小症患者的临床资料,均采用统一的调查问卷进行详细的病史采集、体格检查及相关实验室检查。本研究仅对矮小症患者不同发病原因构成比及不同年龄段发病原因构成比进行了分析。 结果270例矮小症患者中,有18种病因,排名前5位分别是,生长激素缺乏症(GHD)150例,占55.56%;特发性身材矮小(ISS)81例,占30.00%;甲状腺功能减退症11例,占4.07%;小于胎龄儿(SGA)7例,占2.59%;先天性卵巢发育不全7例,占2.59%。此外,垂体柄阻断2例,占0.74%;神经纤维瘤病、家族性矮小、体质性青春期发育延迟、性早熟、佝偻病、巴特综合征、Russell-Silver综合征、促性腺激素分泌不足的性腺功能减退伴嗅觉丧失征(Kallmann征)及垂体占位性病变各1例,共占3.33%;合并其他慢性病者共3例,占1.11%。7岁以下(男性37例,女性12例)患儿矮小的主要原因为GHD、ISS、SGA;7～13岁(男性82例,女性64例)及13～18岁(男性60例,女性15例)患儿矮小的病因均为GHD、ISS以及甲状腺功能减退症。 结论山东济宁矮小症病因谱复杂多样;矮小症临床表现各异,正确诊断并及时给予恰当治疗尤为重要。     

Auto‐ and alloantibodies against factor XIII: laboratory diagnosis and clinical consequences

Summary

Acquired FXIII deficiencies caused by autoantibodies against FXIII subunits represent rare but very severe bleeding diatheses. Alloantibodies in FXIII‐deficient patients also cause life‐threatening bleeding complications, but they develop extremely rarely. In this review we provide an overview of the diagnosis and classification of anti‐FXIII antibodies and analyze 48 patients with autoimmune FXIII deficiency and four additional FXIII‐deficient patients who developed anti‐FXIII alloantibody. The patients were collected from peer‐reviewed publications from which relevant data could be extracted. With the exception of two cases the antibodies were directed against FXIII‐A. The difficulties in the diagnosis of FXIII deficiency in the presence of anti‐FXIII antibodies are discussed and a scheme for the functional classification of the anti‐FXIII antibodies is recommended. The three main categories are neutralizing and non‐neutralizing antibodies and antibodies with combined effect. The methods being used for detecting and quantifying the inhibitory effect on FXIII activation and on the transglutaminase activity of activated FXIII are summarized and techniques for the classification of neutralizing anti‐FXIII antibodies are outlined. The importance of clearance studies in these cases is emphasized. Binding assays, useful for the identification of non‐neutralizing and combined type antibodies, were collected from the literature and their informative power is demonstrated by examples. The most frequently occurring bleeding symptoms in patients with anti‐FXIII antibodies were soft tissue bleeding; intracranial bleedings also occurred, but less frequently than in inherited FXIII deficiency. Treatment of such patients is extremely challenging; the main aim should be eradication of the antibody.

     

获得性血友病A合并静脉血栓形成一例并文献复习

目的通过分析1例获得性血友病A(AHA)合并静脉血栓形成患者的临床资料并复习相关文献,提高对该病的认识。方法结合1例胃印戒细胞癌患者相关的AHA合并下肢深静脉血栓形成的临床资料及文献报道,对本病的病因学、发病机制、临床表现、诊断和治疗进行讨论。结果 AHA是由针对凝血因子Ⅷ的自身抗体导致的罕见出血性疾病,多见于老年人;与其相关的常见疾病是自身免疫性疾病、恶性肿瘤,约50%的AHA患者既往身体健康。出血最常累及软组织。AHA患者存在的各种促血栓形成因素(先天性、获得性)均有助于静脉血栓形成。AHA患者的治疗包括凝血因子替代止血治疗和抗体清除治疗,静脉血栓的抗凝治疗则有可能加重患者出血倾向。本例患者为一66岁男性胃癌患者,术前APTT延长,术后软组织血肿,血浆凝血因子Ⅷ活性(FⅧ:C)下降,FⅧ抗体滴度128BU,予糖皮质激素、丙种球蛋白、环磷酰胺(CTX)抑制抗体生成、输注FⅧ、凝血酶原复合物(PCC)止血;此后,出现右下肢静脉血栓形成;停用PCC,并予胃癌联合化疗,出血和血栓症状消失,凝血功能恢复正常。结论 AHA合并静脉血栓形成临床罕见,治疗相互矛盾。及时识别这两种疾病同时存在并采取综合性、个体化治疗措施是成功治疗的关键。     

Advances in Acquired Hemophilia A

Acquired Hemophilia A (AHA) is a rare, life-threatening bleeding disorder from autoantibodies against clotting factor VIII. These autoantibodies occur with increasing incidence with advanced age and are often associated with other medical conditions such as autoimmune diseases and malignancy. Not uncommonly, AHA presents as a new bleeding disorder in a person with prior thrombosis or thrombotic risk. Treatment of AHA focuses on managing and preventing bleeding, as well as immunosuppression with the goal to eradicate the autoantibody. Despite current treatment approaches, morbidity, and mortality are high due to complications from bleeding, immunosuppression, and underlying comorbidities. The most pressing needs to improved outcome for this disease are better bleeding prophylaxis in the outpatient setting and reduction of the need for intense immunosuppression. Because of the rare nature of this disease, there is limited prospective data and most treatment standards have been based on case series. The field has recently focused on improved diagnostics and advanced risk stratification, with a potential of tailoring the need and intensity of immunosuppression. Case reports of off label use of emicizumab, a factor FVIII mimetic approved for congenital hemophilia A, suggest emicizumab may provide effective and safe bleeding prophylaxis in the outpatient setting; this could permit reducing immunosuppression and decreasing the risk of treatment related infections. Two ongoing prospective clinical trials of emicizumab will help clarify the safety and efficacy in AHA.     

超声在颈动脉血栓诊断及鉴别诊断中的应用价值

目的分析颈动脉血栓超声特点及其与动脉硬化斑块的鉴别诊断。方法颈部动脉超声检查的患者41417例,颈动脉血栓患者行CT或MRI检查,并超声随访。结果41417例中,检出血栓870例,检出率2．10％。其中血栓呈无回声2例,低回声393例,等回声195例,混合回声280例。附壁血栓9例,血栓性闭塞或近闭塞42例,颈动脉硬化斑块合并血栓性闭塞或近闭塞819例。颈动脉血栓和血栓合并斑块的男性患者均较女性患者少,附壁血栓组和血栓性闭塞组的患者年龄较血栓合并斑块组小,差异均有统计学意义（P〈0．01）。结论超声检查可以用于颈动脉血栓的诊断,并与颈动脉硬化斑块鉴别,为临床的诊治提供依据。     

Acquired von Willebrand disease

Acquired von Willebrand disease (AvWD) is a relatively rare acquired bleeding disorder that usually occurs in elderly patients, in whom its recognition may be delayed. Patients usually present predominantly with mucocutaneous bleeding, with no previous history of bleeding abnormalities and no clinically meaningful family history. Various underlying diseases have been associated with AvWD, most commonly hematoproliferative disorders, including monoclonal gammopathies, lymphoproliferative disorders, and myeloproliferative disorders. The pathogenesis of AvWD remains incompletely understood but includes autoantibodies directed against the von Willebrand factor (vWF), leading to a more rapid clearance from the circulation or interference with its function, adsorption of vWF by tumor cells, and nonimmunologic mechanisms of destruction. Laboratory evaluation usually reveals a pattern of prolonged bleeding time and decreased levels of vWF antigen, ristocetin cofactor activity, and factor VIII coagulant activity consistent with a diagnosis of vWD. Acquired vWD is distinguished from the congenital form by age at presentation, absence of a personal and family history of bleeding disorders, and, often, presence of a hematoproliferative or autoimmune disorder. The severity of the bleeding varies considerably among patients. Therapeutic options include desmopressin and certain factor VIII concentrates that also contain vWF. Successful treatment of the associated illness can reverse the clinical and laboratory manifestations. Intravenous immunoglobulins have also shown some efficacy in the management of AvWD, especially cases associated with monoclonal gammopathies. Awareness of AvWD is essential for diagnosis and appropriate management.     

Low seroprevalence of Helicobacter pylori infection in patients with stress ulcer bleeding

OBJECTIVE: The pathogenesis of stress ulceration in seriously ill patients is uncertain and the pathogenic role of Helicobacter pylori infection is unknown. We therefore assessed the seroprevalence of patients of a cardiosurgical intensive care unit (ICU) with clinically important stress ulcer bleeding. We compared this prevalence with a control group matched for this kind of surgical intervention, missing history of peptic ulcer disease, age and gender. DESIGN: Prospective survey. SETTING: Cardiosurgical ICU in a university teaching hospital. Patients and participants: Two thousand five hundred seventy cardiosurgical patients with intravenous ranitidine stress ulcer prophylaxis were screened for clinically important stress ulcer bleeding. Helicobacter pylori seropositivity was measured in all patients with a clinically important bleeding and in a control group of 245 consecutive cardiosurgical patients, matched for the kind of cardiosurgical intervention, age and gender. RESULTS: In 56 of 2,570 (2.1%) patients signs of clinically important bleeding were seen. Endoscopical examination revealed stress ulcer bleeding in 42 cases. The incidence of stress ulcer bleeding was 1.6%. The seropositivity of the group with ulcer bleeding was 45.2 % whereas 62.4 % of the patients in the control group were Helicobacter pylori positive (p = 0.08). CONCLUSIONS: Our results suggest that the Helicobacter pylori infection does not play a pathogenic role in stress ulcer bleeding. Prophylactic cure of Helicobacter pylori can not be recommended in this setting.     

175例急性肾功能衰竭病因分析

目的 :分析ARF的病因、转归 ,探讨其发生的危险因素。方法 :通过观察 175例ARF患者的临床表现、肾功能、肾脏B超形态等 ,分析统计ARF发病情况、病因与预后关系。结果 :ARF近年发病有增高趋势 ;病因中内科源性ARF最多见 ,占 81.14 % ;总死亡率为 17.14 % ,70岁以上死亡率高达 36 .3%。结论 :ARF大多是多因素联合致病 ,而药物性ARF最为多见 ,且渐成为医源性ARF的主要动向 ,因此临床医师谨慎用药是预防ARF的关键     

电视宫腔镜检查妇科疾病499例临床分析

目的 在宫腔镜直视下对宫内疾病进行诊断及治疗，探讨其临床应用价值。 方法 对本院2005年9月至2006年1月间499例因子宫异常出血，不孕症，宫内异物等进行宫腔镜检查的临床资料进行回顾性分析。 结果 正常宫腔102例，镜下发现不同疾病共397例，阳性检出率为79．5％。 结论 应用宫腔镜能在直视下检查宫腔内病变，对异常子宫出血，宫腔粘连，宫腔占位病变以及宫腔异物等是一种较好的诊断手段，而且能同时进行相关的治疗，具有较高的临床应用价值。     

深度手烧伤的治疗及功能康复

目的 :探讨深度手烧伤早期创面修复及功能康复最好的治疗方法。方法 :应用中厚皮、异体去细胞真皮基质作支架加自体刃厚皮片移植 ,腹部真皮血管网皮片及超薄皮瓣移植等手术方式 ,进行深度手烧伤早期切削痂。结果 :2 94例 4 6 2只手功能良好者 138例 2 32只手 (5 0 % ) ,功能较好者 79例 134只手 (2 9% ) ,功能障碍者 77例 96只手 (2 1% )。结论 :应用早期切削痂植皮的方法可减少瘢痕增生和畸形 ,使深度手烧伤后获得满意的外形和功能     

甲状腺癌的高频声像图中钙化的意义

目的：评估甲状腺癌高频声像图中钙化的意义。方法：对２７１例甲状腺结节的高频声像图进行回顾性分析, 将其中的钙化分为三种类型： （１） 微钙化; （２） 粗钙化; （３） 弧形钙化。结果： １４４例恶性组中, 检出钙化６２例 （４３．０６％ ）, 其中微钙化４６ 例, 粗钙化１６ 例, 有微钙化的甲状腺癌中３７例为乳头状癌。１２７例良性组中, 检出钙化１１例（８．６７％ ）, 微钙化５ 例, 粗钙化５例, 弧形钙化１ 例。两组钙化率有显著性差异。但粗钙化与微钙化在两组中无显著性差异。钙化在甲状腺癌诊断中的敏感性和特异性分别为４３．０６％ 及９１．３３％ 。结论： 高频声像图中的钙化是诊断甲状腺癌的一个特异性指标。钙化的形状对甲状腺结节的良恶性鉴别帮助不大,而微钙化是乳头状癌的一个特征性表现。     

Risk factors for sedation‐related events during procedural sedation in the emergency department

Objective: To determine the nature, incidence and risk factors for sedation‐related events during ED procedural sedation, with particular focus on the drugs administered. Methods: Eleven Australian EDs enrolled consecutive adult and paediatric patients between January 2006 and December 2008. Patients were included if a sedative drug was administered for an ED procedure. Data collection was prospective and employed a specifically designed form. Multivariate logistic regression was employed to determine risk factors for sedation‐related events. Results: Two thousand, six hundred and twenty‐three patients were enrolled (60.3% male, mean age 39.2 years). Reductions of fracture/dislocations of shoulders, wrists and ankles were most common. Four hundred and sixty‐one (17.6%) cases experienced at least one airway event that required intervention. Airway obstruction, hypoventilation and desaturation occurred in 12.7%, 6.4% and 3.7% of all patients, respectively. Two thousand, one hundred and forty‐six cases had complete datasets for further analyses. Increasing age and level of sedation, pre‐medication with fentanyl, and sedation with propofol, midazolam or fentanyl were risk factors for an airway event (P < 0.05). Ketamine was a protective factor. Hypotension (systolic pressure <80 mmHg) occurred in 34 (1.6%) cases with midazolam being a significant risk factor (P < 0.001). Vomiting also occurred in 34 (1.6%) cases, 12 of whom required an intervention. One patient aspirated. Vomiting occurred after administration of all drugs but was not associated with fasting status. Other events were rare. Conclusions: Sedation‐related events, especially airway events, are common but very rarely have an adverse outcome. Elderly patients, deeply sedated with short‐acting agents, are at particular risk. The results will help tailor sedation to individual patients.