Family History Of Bleeding Research Articles

Review of patients studied for coagulopathy in a haematology/oncology unit

Abstract Introduction Symptoms/signs suggestive of coagulopathy is a frequent complaint in Paediatric Haematology units. Both the clinical and family history are essential for diagnosis. Patients and methods Retrospective and descriptive study of patients referred to a Paediatric Haematology unit of a tertiary hospital for possible coagulopathy during 2012. Results A total of 47 children were studied, of whom 61.7% had not previously presented bleeding. The most frequent reason for referral was a prolonged activated partial thromboplastin time without any haemorrhage (42.5%), of these, 25% were diagnosed with coagulopathy with a real risk of bleeding. Patients referred due to a prolonged activated partial thromboplastin time with bleeding more frequently (41.7%) present coagulopathy with a real risk of bleeding. Children with a family history of bleeding are diagnosed more frequently with coagulopathy with real risk of bleeding: 37.5% (family history) vs. 14.3% (no family history). The most frequent diagnoses were: healthy children (48.9%), von Willebrand type 1 disease (19.1%), factor xii deficiency (19.1%), factor xi deficiency (4.2%), prekalikrein/high molecular weight kininogen deficiency (2.1%), acquired deficiency of factor x (2.1%), and factor ix deficiency (2.1%). Conclusions A thorough personal and family bleeding history and physical examination are the first steps for a correct differential diagnosis. The reason for referral should be based more on clinical bleeding and not just on an abnormal coagulation time. The most frequent diagnoses were type 1 von Willebrand disease and factor xii deficiency.

Assessing Bleeding Risk in Pediatric Patients Undergoing Major Spinal Surgery

Preoperative screening for bleeding disorders in pediatric patients is problematic due to children's limited exposures to significant hemostatic challenges and the inherent difficulty in obtaining blood samples from young patients. Overcoming these challenges is of particular importance for surgical procedures that carry a significant bleeding risk, such as spinal surgeries. Many pediatric surgeons, including the Pediatric Orthopedic team at our Institution, rely on an unfocused history and measurement of general markers of hemostasis for preoperative screening. In order to improve preoperative screening of pediatric patients undergoing spinal procedures, we instituted the use of a detailed semi-quantitative questionnaire based on the ISTH Bleeding Assessment Tool (BAT), in combination with evaluation of PT, aPTT, platelet count, and PFA. The BAT gives positive points for a personal or family history of bleeding, and negative points for significant hemostatic challenges that did not result in bleeding complications. It was decided a priori that a BAT score of ≥3 would result in referral to Pediatric Hematology. A total of 212 patients presenting for major spinal surgeries (e.g., spinal fusion, growth rod placement) ranging in age from 3 to 25 years were prospectively evaluated in this fashion. A total of 41 patients (19.3%) had a prolongation of the PT and/or aPTT, none of which had a high BAT score. The majority of the abnormal PT/aPTT values were minimal prolongations that were not reproducible on repeat testing. Prolongation of the PT and/or aPTT revealed 3 patients with mild deficiencies of either factors VII, X, or XI, none of which were felt to be clinically significant. Prolonged PFAs were observed in 32 patients (16%), 1 of which was diagnosed with type I VWD (BAT score = 1), and the other with "possible VWD" based on a borderline VWF antigen level (BAT score = 0). Both were treated with Humate P. The remainder of the patients with a prolonged PFA were determined not to have a significant bleeding disorder after further testing. A total of 15 patients were referred to Hematology based on a high BAT score. Of these, 2 had a history of thrombocytopenia (1 with known DiGeorge syndrome and 1 with Depakote-related thrombocytopenia). Neither required platelet transfusion. One patient with a high BAT score was known to have type I VWD and was treated with Humate P, another was diagnosed with low expression of glycoprotein GP1b and was treated with Humate P and platelet transfusion. The remainder of the patients with high BAT scores were not felt to have a clinically significant bleeding disorder based on a Hematologist's assessment. None of the 212 patients evaluated were felt to have excessive intraoperative bleeding by the surgical team, suggesting that none of the patients had a significant undiagnosed hemostatic defect. Together, these results suggest that reliance on history or screening labs alone may not be sufficient for many pediatric surgery patients. While the PFA identified 2 patients with mild/possible VWD that would have been missed by the BAT, the PFA also had a significant number of apparent false positives. The combination of a BAT and a platelet count, as well as assessment of VWF activity for patients without previous hemostatic system challenges, may provide a more effective screening methodology for institutions with ready access to VWF activity measurement. DisclosuresNo relevant conflicts of interest to declare.

Evaluation of a Standardized Approach to the Diagnosis of Mild Platelet Function Defects: Recommendation for a Targeted Approach to the Diagnosis of Mild Platelet Function Defects and Identification of a Subset of Children with a "Developmental" Form

Mild platelet function defects (MPFD) are a variable group of common inherited disorders characterized by mucocutaneous bleeding and excessive bleeding with trauma, surgery and procedures. The diagnosis is often based on subjective interpretations of expensive platelet function tests that require a substantial volume of blood. Furthermore, the diagnosis of MPFD can significantly limit participation in contact sports and physically demanding careers. To explore these issues, a retrospective chart review of patients from the Comprehensive Center for Bleeding Disorders of the BloodCenter of Wisconsin with a diagnosis of MPFD, and who had at least one follow-up evaluation was undertaken. The majority of patients had been evaluated by a two-step process; initially screened with CBC, PT, PTT, TT and a von Willebrand factor (VWF) panel. If these tests were normal, platelet function was assessed with light transmission aggregometry and chemiluminesence detection of ATP release in platelet rich plasma by the agonists TRAP, arachidonic acid (0.5 nM), ADP (10 uM), collagen (2.5 ug/mL) and high and low dose ristocetin.One hundred forty-eight patients diagnosed with a primary MPFD between 1982-2014 and with at least one recorded follow-up were identified. Bleeding scores were assigned by a system incorporating principles developed for the ISTH bleeding assessment tool. Patients ranged in age from 2 months to 57 years. For assessment of age on platelet function, patients were grouped as follows: Group A <2 years (N=23), Group B 2-4 years (N=33), Group C 5-8 years (N=36), Group D 9-16 years (N=30), and group E >16 years (N=26).At diagnosis, median bleeding score was 3 (range 0-12). Bleeding scores increased with age (p<.0001); the median (range) score was 2 (0-8) for A, 2 (0-5) for B, 3 (0-9) for C, 3 (0-7) for D and 4 (0-12) for E. There was no difference in gender by age group except group E with 23 females and 1 male; twenty of the 23 females reported menorrhagia. One hundred twenty eight (86%) of the patients had abnormal ATP release (122) or platelet aggregation (6) in the presence of ADP, the most common defect identified. Of those with abnormal release of ATP, 50% had another platelet function abnormality; there was no difference in bleeding scores between those with either single or multiple abnormalities. Of those who did not have abnormal aggregation or release with ADP, 8 had an abnormal response(s) with collagen alone and 1 had abnormal ATP release with arachidonic acid alone. At the most recent follow-up visit, (median 97 months, range 1-368 ) after the initial evaluation, the interim median bleeding scores were lower; for each age group the bleeding score (range) was 2 (0-8) for A, 1 (0-6) for B, 3 (0-7) for C, 2 (0-8) for D and 3.5 (0-10) for E. When compared to the oldest group (E), groups B and D showed a statistically significant difference (p <0.05).Twenty-nine of the patients had follow-up platelet function studies; of these, 13 (all were children) had a significant decrease in bleeding score and normalization of platelet function studies. There were no differences in age, gender, or family history of bleeding between those with persistent MPFD and those with normal follow-up platelet function tests. The persistent group had higher initial (p<0.03) and follow-up (p<0.02) bleeding scores. Those with normalization had a significant decrease in bleeding scores from diagnosis to follow-up (p<0.01) while the persistent MPFD group had no difference.These results suggest that a more targeted approach utilizing the analysis of ATP release by ADP, with TRAP release to confirm the presence of granules, will identify the majority of patients with mild platelet function defects. For those with suspected MPFD and normal ATP release with ADP, a full panel of agonists followed by additional step-wise evaluation as recommended by the ISTH should be undertaken. Limiting initial platelet function testing will reduce the volume of blood required and the cost. The reassessment of platelet function studies in patients with MPFD whose bleeding symptoms subside will identify a subset of these patients with normalization of platelet function. This group will no longer require treatment for procedures and restrictions of career choices or athletic pursuits. Thus, by utilizing a standard approach, patients with MPFD can be diagnosed and managed more efficiently and effectively with less cost to both the patient and healthcare system. DisclosuresFriedman:Alexion: Speakers Bureau; Novo Nordisk: Consultancy; CSL-Behring: Consultancy; Instrumentation Laboratories: Consultancy. Flood:Baxter: Consultancy; CSL Behring: Consultancy. Jobe:Bayer: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Membership on an entity's Board of Directors or advisory committees. Gill:Bayer: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Membership on an entity's Board of Directors or advisory committees.

Acquired factor VIII inhibitor and subsequent development of non-Hodgkin's lymphoma

Acquired hemophilia A (AHA) is a rare disorder caused by the development of factor VIII autoantibodies. It can induce acute and major hemorrhages in patients with negative personal and family history of bleeding. AHA is frequently associated with hematologic malignancies. This study describes the first case of AHA in a patient who developed a mantle cell lymphoma after a year and half of complete remission. It also provides an example of an initial wrong approach in terms of diagnosis and treatment, as well as of a very long course of the disease. Further, a review of AHA-associated lymphomas from 1974 to 2014 is also presented.Clinical and laboratory staff should be alert to the possibility of such an event when the medical history of patients is enriched with new symptoms or signs. A follow-up of at least 2 years might therefore be required.

Acquired haemophilia: an overview for clinical practice.

Acquired haemophilia is a potentially life-threatening bleeding disorder caused by the development of autoantibodies against coagulation factors, most commonly against factor (F) VIII (acquired haemophilia A; AHA). In around half of patients, an underlying disorder is associated with AHA; the remaining cases are idiopathic. Typically, the disorder presents with bleeding, ranging from mild to life- and limb-threatening, in patients with no personal or family bleeding history. Diagnosis involves an isolated prolongation of the activated partial thromboplastin time, without correction in mixing studies, low FVIII activity levels and evidence of a FVIII inhibitor. As AHA is rare, a lack of familiarity of the condition may result in delayed diagnosis, and prompt haemostatic control is required to reduce morbidity and mortality. Bypassing agents (recombinant activated factor VII or activated prothrombin complex concentrates) can be used to control acute bleeding, and immunosuppression is necessary to eradicate the inhibitor. As clinical trials in this rare and heterogeneous disease are difficult, current evidence comes from observational studies, including registries. This review will focus on the diagnostic and therapeutic challenges of AHA and summarise how understanding of this complex condition has increased based on recent registry data.

Revisión de los pacientes estudiados por coagulopatía en una unidad de Oncohematología

IntroductionSymptoms/signs suggestive of coagulopathy is a frequent complaint in Pediatric Hematology units. Both the clinical and family history are essential for diagnosis. Patients and methodsRetrospective and descriptive study of patients referred to a Pediatric Hematology unit of a tertiary hospital for possible coagulopathy during 2012. ResultsA total of 47 children were studied, of whom 61.7% had not previously suffered bleeding. The most frequent reason for referral was an eloganted activated partial thromboplastin time without any hemorrhage (42.5%), of these, 25% were diagnosed of a coagulopathy with a real risk of bleeding. While patients referred due to an eloganted activated partial thromboplastin time with bleeding more frequently (41.7%) have a coagulopathy with a real risk of bleeding. Children with a family history of bleeding are diagnosed more frequently with a coagulopathy with a real risk of bleeding: 37.5% (family history) vs. 14.3% (without). The most frequent diagnoses were: healthy children (48.9%), von Willebrand type 1 disease (19.1%), factor xii deficiency (19.1%), factor xi deficiency (4.2%), prekalikrein/high molecular weight kininogen deficiency (2.1%), acquired deficiency of factor x (2.1%), and factor ix deficiency (2.1%). ConclusionsA thorough personal and family bleeding history and physical examination are the first steps for a correct differential diagnosis. The reason for referral should be based more on clinical bleeding and not just on an abnormal coagulation time. The most frequent diagnoses were type 1 von Willebrand disease and factor xii deficiency.

Strong lupus anticoagulant (LA) as a cause for prolonged prothrombin time (PT), activated partial thromboplastin time (APTT) and abnormally low intrinsic factor (IF) levels

We report the case of a previously healthy 53-year-old male who presented with an incidental finding of both prolonged PT (57 seconds) and APTT (41 seconds) whilst being investigated for acute abdominal pain. There was no personal or family history of bleeding or thrombosis. Partial correction of both PT and APTT was demonstrated on mixing studies, with presence of heparin excluded. Intrinsic factor assays showed universal reduction, with Bethesda assay failed to identify an inhibitor. Extrinsic factors and von Willebrand assays were normal. LA testing showed a moderate strength LA, confirmed by a strongly positive IgM anticardiolipin (ACL) and moderately positive IgG ACL antibody. PT is normally relatively insensitive to LA. Nevertheless, falsely increased PT has been reported, likely from interference of LA with the phospholipid component of the PT reagent, particularly where recombinant tissue factor and purified phospholipids are used. This can result in difficulties with INR monitoring in warfarinised patients. This case also illustrates how the presence of a potent LA can also interferes with factor assays interpretations. Therefore all diagnostic laboratories should develop a robust policy to detect and monitor this unique group of patients.

Acquired Haemophilia a after Allogeneic Stem Cell Transplant for Acute Myeloid Leukemia: Occurred during Cyclosporin a Used for Chronic Graft Versus Host Disease and Tolerance Induction with Rituximab

Background: 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. AHAs occurring after autologous hematopoietic stem cell transplantation (auto-HSCT) HSCT for an autoimmune disease have been reported by the EBMT Autoimmune Disease Working Party, but AHA secondary to allogeneic (allo-) HSCT was rarely reported, except for a literature by Lozier JN, et al reported a AHA occurred after allo-HSCT for sickle cell disease. Here we reported a AHA secondary to allo-HSCT for acute myeloid leukemia (AML).Case report: A 54 years old female patient was diagnosed as having AML on March 7th 2011 in Nanfang Hospital, Guangzhou, China. She acquired complete remission after induction therapy with IA protocol, and then she received consolation therapy with IA and high dose cytarabine. As having HLA 10/10 loci matched sibling donor, she underwent allo-HSCT on July 4th 2011. The conditioning regimen consisted of fludarabine and busulfan, and standard short term methotrexate and cyclosporin A (CsA) was used to prevent acute graft versus host disease. She acquired hematopoietic reconstitution on day 11 after transplantation. She had no acute GVHD, but she acquired limited chronic GVHD 11 months after transplantation. CsA, prednisone and azathioprine was given to treat chronic GVHD. After chronic GVHD was gradually controlled, azathioprine and prednisone were stopped, CsA was tapered step by step. On October 5th 2013, she experienced onset of severe soft tissue haemorrhage (left upper arm, right gluteal and lower right leg) associated with a long aPTT and low FVIII activity (1.3%). Other pertinent coagulation studies were normal. The Bethesda assay showed a factor VIII inhibitor at 2.8 Bethesda units (BU)/ml, confirming a diagnosis of acquired AHA. Autoimmune and viral screens were negative. Considering of AHA happened during CsA used for chronic GVHD treatment, CsA was stopped, cyclophosphamide (CTX) and prednisone were given to treat AHA. The patients underwent 3 episodes of severe soft tissue haemorrhage during treatment, and factor VIII inhibitor increased to 1587.2 Bu/ml. Rituximab were started concomitant with prednisone treatment. After one dose of 375 mg/m2 and 4 doses of low dose Rituximab 100mg per week treatment, the inhibitor titre to human FVIII declined, and the patient had no signs of haemorrhage, Concomitantly, the patient’s FVIII activity rose to >100%, and remained normal after completion of 2 doses of rituximab and a complete taper of prednisone over the next 3 months.Conclusions: This is rarely AHA case emerged after allo-HSCT for AML. Prednisone and CTX were ineffective for this patient. Low dose Rituximab combined with prednisone may be a useful choice for the treatment of AHA occurring after allo-HSCT. DisclosuresLiu:National Natural Science Foundation of China (81270647, 81300445, 81200388): Research Funding; National High Technology Research and Development Program of China (863 Program) (2011AA020105): Research Funding; National Public Health Grand Research Foundation (201202017): Research Funding; Natural Science Foundation of Guangdong Province (S2012010009299): Research Funding; the project of health collaborative innovation of Guangzhou city (201400000003-4, 201400000003-1): Research Funding; the Technology Plan of Guangdong Province of China (2012B031800403): Research Funding; the project of the Zhujiang Science & Technology Star of Guangzhou city (2013027): Research Funding.

Acquired Von Willebrand Syndrome Associated with B Cell Chronic Lymphoproliferative Disorders. Results from a Prospective Observational Study

▪Introduction. Whereas von Willebrand disease is the most common constitutional bleeding disorder, acquired von Willebrand syndrome (AVWS) is rare with an estimated prevalence between 0.04 to 0.5%(1). AVWS has been related in various pathophysiological conditions including cardiovascular diseases such as aortic stenosis, autoimmune and lymphoproliferative disorders. To our knowledge, the prevalence of AVWS in lymphoproliferative disorders has never been investigated.Methods. We conducted an observational monocentric prospective study in Caen university hospital to evaluate the incidence of AVWS in B cell chronic lymphoproliferative disorders (B-CLPD) and characterize its phenotype. Inclusion criteria were the presence of a BCLPD in patients with no personal or family history of bleeding. Every enrolled patients was tested for Biological parameters were measured including closure time, von Willebrand Antigen (VWF:Ag), ristocetin cofactor activity (VWF:RCo) and factor VIII procoagulant activity (FVIII:C). The bleeding phenotype was evaluated using Tossetto bleeding score(2). AVWS was suspected when patients presented a decrease of VWF:Ag and VWF:RCo and/or a VWF:RCo/VWF:Ag below 0.7.Results. A total of 147 patients were included with the following diagnosis: fifty five patients (37%) with chronic lymphocytic leukemia, 48 patients (33%) with monoclonal gammopathies of undetermined significance (MGUS), 22 patients (15 %) with non hodgkin B cell lymphoma, 9 patients (6 %) with multiple myeloma, 4 patients (3 %) with Waldenstrom macroglobulinemia and 9 patients with other B-CLPD. Closure times, with epinephrine and ADP, were prolonged for six patients (6/147, 4.1%) with median levels of VWF:Ag, VWF:RCo, FVIII:C and VWF:RCo/VWF:Ag ratio at 29.5 IU/dL [9-284], 11.4 IU/dL [1-140] , 42.5 [6-204] and 0.3 [0.04-0.84], respectively. Five of these 6 patients had MGUS and 1 patient presented a follicular lymphoma. Serum protein electrophoresis revealed a monoclonal component in 5 patients with a median concentration at 8.45 g/L [4.4-9.1]. Four out of these 6 patients presented mucocutaneous bleedings including menorragia, ecchymoses, epistaxis, gingival bleedings, post-operative bleedings and gastro intestinal bleedings. The median bleeding score of these six patients was 4.5 [-1 – 12]. In four patients, the biological phenotype was a type 2 von Willebrand disease, with decreased VWF:RCo/VWF:Ag ratio (<0.7), loss of high and intermediate molecular weight multimers and a decrease of von Willebrand binding to collagen (VWF:CB) (VWF:CB/VWF:Ag<0.6). Anti-von Willebrand factor inhibitor screening was negative for the six patients. Four of these 6 patients presented an accelerated clearance of VWF with increased von willebrand factor propeptide/VWF:Ag ratios.Table 1Different proposed cutoffs with their prospective sensitivity, specificity, and likelihood ratios (LR).Cutoff >Sensitivity %95% CISpecificity %95% CILR +LR -503.50100.0066.37% to 100.0%0.300.007557% to 1.652%1.000.002514.0088.8951.75% to 99.72%75.2270.24% to 79.76%3.590.155020.0077.7839.99% to 97.19%85.6781.46% to 89.24%5.430.26Conclusion: In this original prospective study, we observed AVWS for 4.1% of patients with B-CLPD. Monoclonal gammopathies of undetermined significance (MGUS) were associated with AVWS in 5 of 6 patients with AVWS. For patients with type 2 phenotypes, an increased clearance of VWF was the main mechanism of AVWS. The annual follow-up of these patients will give informations regarding the time of appearance and clinical informations for AVWS.Tiede A et al. Blood 2011.Tosetto A et al. Blood Rev 2007. DisclosuresNo relevant conflicts of interest to declare.

Dusky bullae on the abdomen

A 61-year-old woman presented to the emergency department with the sudden, recent onset of 2 large, painful “black blisters” on her abdomen. She was otherwise healthy and felt well. Six weeks earlier, she had undergone a total right knee replacement and had since been administering subcutaneous enoxaparin daily on her abdomen. She had no personal or family history of bleeding, clotting, or immune disorders. The physical examination revealed 2 dark brown to black bullae with surrounding erythema and induration on her lower abdomen (Fig 3).

Hemostatic Abnormalities in Young Females with Heavy Menstrual Bleeding

ObjectiveTo study the prevalence of hemostatic abnormalities, including bleeding disorders and risk factors, in young females referred to a multidisciplinary clinic for evaluation of heavy menstrual bleeding (HMB). MethodsRetrospective chart review was undertaken for 131 post-menarchal girls with HMB, 7 to 17 years of age, enrolled in the institutional ‘Menorrhagia Data Registry’ protocol. The diagnostic approach included: (1) complete blood count, prothrombin time, partial thromboplastin time, fibrinogen, von Willebrand panel (2) platelet aggregometry, specific clotting factor assay, fibrinolytic pathway analysis, and factor XIII level as needed. The prevalence of hemostatic abnormalities and the prognostic significance of clinical variables associated with hemostatic abnormalities in young girls with HMB were evaluated. ResultsA hemostatic abnormality was identified in 69 (53%) young girls with HMB. Of these, 27 (21%) had an underlying bleeding disorder and 42 (32%) had a risk factor for bleeding, namely low von Willebrand factor activity. A larger number of girls with underlying bleeding disorder had personal history of other bleeding symptoms (48% vs 31%) and bleeding after surgical or dental procedure (25% vs 8%) when compared to females without hemostatic abnormality. Furthermore, girls with risk factor for bleeding (low vWF activity) were more likely to have bleeding after surgical or dental procedure (15% vs 8%) and family history of bleeding (79% vs 60%) than patients without hemostatic abnormality. ConclusionsThere is high prevalence of hemostatic abnormalities, including bleeding disorders and risk factors, in young girls with HMB. These findings support comprehensive and systematic hemostatic evaluation in this group of patients.

Diagnostic Outcome of Preoperative Coagulation Testing in Children

The value of routine coagulation testing instead of bleeding history alone in children, to predict bleeding risk prior to tonsillectomy and adenoidectomy has been questioned. Our objectives are to identify the causes of abnormal PT and/or aPTT in these patients, and to determine whether routine preoperative coagulation testing is effective in identifying children with a clinically significant coagulation abnormality prior to undergoing a procedure. In this study, data were extracted by chart review for 854 patients referred to the pediatric hematology service at Stony Brook University for the evaluation of an elevated PT and/or aPTT on preoperative testing. Seven hundred and ninety two of 854 reviewed charts (92.7%) contained sufficient data for analysis. On repeat testing, 393 (49.6%) had a laboratory abnormality identified. A potentially significant coagulation abnormality was identified in 32 of 792 patients (4%). For the remaining 760 patients, the most common diagnosis was a lupus anticoagulant (n = 98, 24.6%) or a “presumed” lupus anticoagulant (n = 166, 41.6%). A positive personal or family bleeding history was documented in 268 patients (268/792 = 33.8%). Of these patients, only 107 (39.9%) had an abnormality identified on further work-up. Seventeen of the 32 patients with clinically significant bleeding disorders identified were found to have a positive bleeding history (17/32 = 53.1%). Routine preoperative coagulation testing identifies only a small number of children at increased risk for surgical bleeding. However, a “positive” bleeding history identifies only 60% of children found to have a clinically significant coagulation abnormality. Routine preoperative coagulation testing may serve as a useful adjunct to clinical history.

Von Willebrand Disease

Von Willebrand Disease

Clinical Profile of Haemophilia In Children in A Tertiary Care Hospital

Introduction : Haemophilias are the most common inherited coagulation disorders transmitted by X- linked recessive fashion affecting the males and females are the carriers of the disease. Haemophilias are distributed worldwide and have heterogeneous presentation depending upon its severity starting from neonatal period. Knowledge of spectrum of presentation of haemophilia helps in early diagnosis and planning of management. Objectives : To observe the clinical presentation of haemophilia in children Methodology : This observational study was carried out in the Department of Pediatric Hematology and Oncology, Bangabandhu Sheikh Mujib Medical University for a period of one year from 1st July 2007 to 30th June 2008. Clinical profile of 50 diagnosed cases of haemophilia &lt;15 years of age was analyzed. Result: All the 50 cases of haemophilia were male. Mean age of the patients was 6.62±3.87 years with an age range of 6 months to 14 years. Forty (80%) cases were haemophilia A and 10 (20%) cases were Haemophilia B. Only 40% cases had family history of bleeding. Among the Haemophilia A, 52.5% cases had mild, 47.5% cases had moderate disease and among the Haemophilia B, 40% cases had mild, 50% cases had moderate and 10% cases had severe disease. Heamarthrosis of knee joint was the major presentation followed by oral cavity bleeding, bleeding following tooth extraction and circumcision. Sixty two percent cases had initial bleeding episode before 1 year of age and by 5 years of age 94% of cases had produced symptoms. No patient had history of bleeding during neonatal period. Bruises and hematoma were the most common initial manifestation followed by joint bleeding, cut injury of lips and chin, scalp and facial hematoma. Conclusion: Bruises, hematoma and joint bleeding either spontaneous or after trauma were the main feature at initial presentation of haemophilia in children, so presence of these features in an otherwise normal child should be considered for evaluation of haemophilia. More vigilance is to be needed for detection of haemophilia in newborn. DOI: http://dx.doi.org/10.3329/bjch.v37i2.17266 BANGLADESH J CHILD HEALTH 2013; VOL 37 (2) : 90-96

Severe Acquired Bleeding Tendency Secondary To An Anti-Thrombin Antibody In a Patient With Monoclonal Gammapathy Of Unknown Significance: Direct In Vivo evidence

IntroductionAnti-thrombin antibodies are a rare cause of acquired bleeding disorder. We report a case of a patient with a monoclonal gammapathy of unknown significance (MGUS) referred to us for an acquired bleeding tendency. We found that he had an isolated anti-thrombin antibody and showed that this antibody inhibit platelet accumulation and fibrin generation in vivo in a mouse model of arterial thrombus formation. PatientA 40-year-old man with no personal or familial history of bleeding was referred to us for multiple bleeding episodes (rectal bleeding, hematoma) for 18 years. He was diagnosed 12 years previously with an IgG Kappa MGUS which was stable. Complete blood counts were normal. Activated partial thromboplastin time (APTT) and thrombin time (TT) were prolonged at 76 seconds (control 35) and > 120 seconds (control 18) respectively. The prolonged TT was observed using human and bovine thrombin. A TT mixing study was performed by measuring the TT of serial dilutions of patient's plasma in normal pooled plasma. This study confirmed an acquired anti-thrombin activity of patient's plasma, as TT of the mix was prolonged from dilutions 1:1 to 1:16 (>120 to 25 seconds). Other coagulation factors were normal. No other auto-antibodies were detected except an isolated lupus anticoagulant. Thrombin generation in patient's platelet rich plasma measured using the Calibrated Automated Thrombogram (CAT) showed a prolonged lag time (15.5 versus 4.7 minutes) associated with a decreased endogenous thrombin potential (ETP, 834 versus 1730 nmol/L min). The diagnosis of an acquired anti-thrombin antibody associated with a MGUS was proposed. The patient received multiple treatments, including immunosuppressive agents, anti-CD20 monoclonal antibody therapy and bortezomib, in order to eradicate the antibody with no success. MethodsAnti-thrombin IgG antibodies were affinity purified from the patient's plasma using activated agarose beads covalently coupled to human alpha thrombin (Aminolink, ThermoScientific). A mouse model of thrombosis was used to test the effect of the infusion of the purified anti-thrombin IgG on thrombus formation in vivo. Platelet accumulation and fibrin generation at the site of injury was imaged after laser-induced injury of cremaster arterioles using intravital microscopy in wild type mice. Platelet and fibrin labeling were performed using anti-CD42 antibody conjugated to DyLight 488 (Emfret) and an anti-fibrin antibody conjugated with AlexaFluor 647 (Sekisui). ResultsImmunoblotting using human and bovine alpha-thrombin thrombin confirmed the purified IgG from the patient's plasma (yield 86 µg/ml) to be anti-thrombin antibodies. At a concentration of 2.45 mg/mL, these anti-thrombin IgG were able to prolong APTT and TT (59 versus 33 seconds and >120 versus 19 seconds, respectively). Control IgG (2.5 mg/mL) purified from healthy individuals had no effect on APTT and TT. Using the mouse model of laser-induced arteriolar injury, we found that patient-derived anti-thrombin IgG (690 microg) caused a significant inhibition of platelet accumulation and fibrin generation of more than 70% at the site of vessel wall injury. ConclusionWe report a case of severe acquired bleeding tendency secondary to an anti-thrombin antibody in a patient with an IgG Kappa MGUS. Anti-thrombin IgG antibodies purified from the patient's plasma retain the anti-thrombin activity in vitro. Additionally, infusion of purified anti-thrombin IgG from the patient induced a dramatic decrease in platelet thrombus accumulation and fibrin generation at the site of injury in a mouse model of arterial injury, proving the etiology of patient's bleeding tendency. This is the first description of the anti-thrombotic effect of anti-thrombin antibodies directly in vivo. Disclosures:Turhan:BMS, Novartis: Honoraria, Research Funding.

Gestion du péri-partum de la patiente conductrice d’une hémophilie

Women who are carriers for hemophilia are usually considered as safe carriers. However, they can present hemorragic symptoms associated with low factor VIII or IX levels. During pregancy, factor VIII increases whereas factor IX does not. The peripartum period is at risk of increased bleeding in these women. Here are presented reports of clinical data concerning two hemophilia carriers with low factor VIII or IX (30–40%) during the peripartum period. They received remifentanil and ketamine for labor pain management because of contraindication of epidural and spinal analgesia. Delivery occured quickly but they presented immediate moderate postpartum haemorrage. They did not necessitate blood transfusion. The one with hemophilia A received desmopressin just after delivery and the other one received factor IX when she arrived in delivery room. Blood factor VIII or IX has to be assessed in these women with familial history of hemophilia and bleeding. During pregnancy, factor VIII increases and can be assessed many times during pregnancy expecting a level over 50%. Factor IX does not really increase during pregancy and hemorrage can occur. Epidural and spinal anesthesia seem to be contraindicated as far as recommandations are concerned. Coagulation factor substitution is a mean of increasing factor level before these anaesthesias and can be discussed for each case.

Congenital Factor V Deficiency: Moroccans Cases

Background and Objective: The congenital factor V deficiency, known as Owren's disease or parahemophilia is a rare autosomic recessive haemorrhagic disease of coagulation, identified for the first time in Norway in 1943. In Morocco, there is no national registry including cases of congenital coagulopathy. This study highlights the rarity of inherited factor V deficiency deficiency and the importance of coagulation testing in the diagnosis of condition. Patients and Methods: We report twelve cases of factor V deficiency at our institution. Results: Of the 12 cases, seven were followed at the haematology department; the remaining five were discovered during a family survey. The average age of our patients is 16 years old [1 - 40 years], with a female dominance (Sex ratio F/M: 2). Parental consanguinity was found in three patients, bleeding family history were found in 5 patients. The concept of bleeding was found in 6 of 7 cases of patients followed, in 1 patient’s case the discovery was fortuitous. Conclusion: Inherited factor V deficiency is a rare inherited disorder. The diagnosis is mainly based on coagulation tests; however, the bleeding tendency may be severe and occurs early in life with immeasurable factor II levels.

Occurrence of Thrombosis in Rare Bleeding Disorders

Paradoxically, there are reports of thrombotic events for some rare bleeding disorders associated with significant bleeding tendency. Afibrinogenemia, factor (F) VII, or FXI deficiencies are those most commonly associated with venous or arterial thrombosis. Pathogenesis is multifactorial and the main conditions associated with this complication relate to the coexistence of inherited or acquired thrombotic risk factors linked to certain specific characteristics of the underlying defect. Patients with afibrinogenemia can develop severe, spontaneous, or recurrent thromboembolic disease. Up to 20% of congenital dysfibrinogenemia patients show predisposition to thrombosis. Thrombotic episodes, particularly deep vein thrombosis, have been reported in 3 to 4% FVII deficient patients, even those who were severely affected. These events have been reported either after infusion of plasma derived FXI concentrate or recombinant activated FVII in FXI deficient patients. So, in addition to factor level, replacement therapy must be individualized and should take into account past personal or family history of bleeding and thrombosis, and other prothrombotic risk factors. Treatment of thrombosis represents a challenge. For mild factor deficiencies, antithrombotic prophylaxis must be considered with or without concomitant use of replacement therapy. For all patients, it is also recommended to control known cardiovascular disease risk factors.

Screening Bleeding Disorders in Adolescents and Young Women with Menorrhagia

Objective: Chronic menorrhagia causes anemia and impairment of life quality. In this study the aim was the screening of bleeding disorders in adolescents and young women with menorrhagia. Materials and Methods: The study was performed prospectively by pediatric hematologists. A form including demographic characteristics of the patients, bleedings other than menorrhagia, familial bleeding history, characteristics of the menorrhagia, and impairment of life quality due to menorrhagia was filled out by the researcher during a face-to-face interview with the patient. A pictorial blood assessment chart was also used for evaluation of blood loss. All patients underwent pelvic ultrasound sonography testing and women also received pelvic examination by gynecologists. Whole blood count, peripheral blood smear, blood group, serum transaminases, urea, creatinine, ferritin, PFA-100, PT, aPTT, INR, TT, fibrinogen, VWF:Ag, VWF:RCo, FVIII, and platelet aggregation assays were performed. Platelet aggregations were studied by lumiaggregometer. Results: Out of 75 patients enrolled, 60 patients completed the study. The mean age was 20.68±10.34 (range: 10-48) years and 65% (n=39) of the patients were younger than 18 years. In 18 (46%) of the adolescents, menorrhagia subsided spontaneously. In 20% (n=12) of the patients, a bleeding disorder was detected (1 case of type 3 von Willebrand disease, 2 patients with low VWF:Ag, 1 case of probable von Willebrand disease, 3 cases of Bernard-Soulier syndrome, 2 cases of Glanzmann thrombasthenia, 2 cases of immune thrombocytopenic purpura, 1 case of congenital factor VII deficiency). Conclusion: In patients with menorrhagia, at least complete blood count, peripheral smear, aPTT, PT, VWF:Ag, VWF:RCo, FVIII, and fibrinogen assays must be performed. When there is history of nose and gum bleeding, platelet function assay by lumiaggregometer must also be performed. In nearly 50% of adolescents, menorrhagia is dysfunctional and transient. Detailed coagulation assays can be postponed in adolescents if bleeding history other than menorrhagia and/or family history of bleeding and/or parental consanguinity is absent. All subjects with menorrhagia must consult with gynecologists and hematologists.Conflict of interest:None declared.

Molecular testing for disorders of hemostasis

The investigation of inherited bleeding disorders with routine tests of hemostasis will yield clear diagnostic information in the majority of subjects with an unequivocal history of bleeding and especially in those where the phenotypic severity is severe and where an obvious family history of bleeding is present. Nevertheless, a significant minority of subjects with obvious bleeding symptoms will remain without a definite diagnosis after extensive hemostatic testing. With these facts in mind, the role of molecular testing for inherited disorders of hemostasis now includes the following: confirmation of a phenotypic diagnosis through targeted genetic analysis, the distinction of bleeding phenocopies by molecular analysis, and provision of genetic testing as the investigation of choice in situations such as prenatal diagnosis and detection of the carrier state for inherited bleeding traits. In addition, molecular testing can sometimes be used to provide supplementary knowledge that can be used to enhance clinical care. Finally, the utility of genome-wide approaches to identify novel genetic associations may provide new information to explain the cause of bleeding in the population of bleeders without established diagnoses.