A Unique Case of Acquired Hemophilia A Presenting with Transient Ischemic Attack.

Acquired hemophilia A (AHA) is a rare but serious condition, usually associated with significant spontaneous or traumatic bleeding and a high mortality rate. In this report, we describe the case of an elderly patient presenting a transient ischemic attack concurrently with AHA. A thrombotic event in AHA is occasionally associated with the use of bypassing agents for treatment, but a spontaneous thrombotic event has not ever been described.

[Angiology and haemostasis. Highlights on some new data in 2017]. / Angiologie et hémostase. Quelques nouvelles données en 2017.

New data support the fact that prophylactic anticoagulation with direct oral anticoagulants is effective and safe for the long-term prevention of venous thromboembolism. This type of treatment is dedicated for a subgroup of patients only, which is described in this article. With regard to major bleedings occurring with these anticoagulants, new data have been added to those already available for idarucizumab, a specific antagonist of dabigatran. Finally, we summarize the data regarding a breakthrough molecule, emicizumab, which could potentially open a new era in the management of people with haemophilia A.

De nouvelles données viennent conforter le fait qu'une anticoagulation prophylactique avec des anticoagulants oraux directs est efficace et sûre pour la prévention au long cours de la maladie thromboembolique veineuse. Ce type de traitement ne s'adresse cependant qu'à un sous-groupe de patients, décrit dans cet article. Concernant les hémorragies majeures survenant sous anticoagulants oraux directs, de nouvelles données viennent compléter celles que l'on avait déjà sur l'idarucizumab pour contrer l'effet du dabigatran. Finalement, nous effectuons un point de situation concernant un médicament qui pourrait potentiellement révolutionner la prise en charge des personnes avec hémophilie A, l'émicizumab.

Patient-derived anti-ß2GP1 antibodies recognize a peptide motif pattern and not a specific sequence of residues.

Antiphospholipid antibody syndrome is an autoimmune disease characterized by the presence of so-called antiphospholipid antibodies and clinical manifestations such as recurrent thromboembolic or pregnancy complications. Although the main antigenic determinant for antiphospholipid antibodies has been identified as the ß-2-glycoprotein 1 (ß2GP1), the precise epitope recognized by antiphospholipid antibodies still remains largely unknown. In the study herein, we wanted to identify a sequence in domain I of ß2GP1 able to induce the proliferation of CD4+ T cells isolated from antiphospholipid antibody syndrome patients, but not from healthy donors, and to interact with antiphospholipid antibodies. We have characterized a sequence in domain I of ß2GP1 that triggers CD4+ T-cell proliferation. A comparison of this sequence with the previously reported binding of antiphospholipid antibodies to discontinuous epitope R39-R43 reveals the presence of an indeterminate motif in ß2GP1, in which the polarity determines the characteristics and specificity of antiphospholipid antibodies-interacting motifs. Using point mutations, we characterized the main antiphospholipid antibodies-interacting motif as ϕϕϕζζFxC, but also established ϕϕϕζζFxϕ-related motifs as potential antiphospholipid antibodies epitopes, in which ϕ represents nonpolar residues and ζ polar residues, with charges of the residues not being involved. Of specific importance, these different motifs are present at least once in all antiphospholipid antibodies-related receptors described so far. We have further demonstrated, in vitro, that peptides and domains of ß2GP1 containing these motifs were able to interact with antiphospholipid antibodies and inhibit their monocyte activating activity. These results established that the antiphospholipid antibodies-interacting motifs are determined by the polarity, but not by the sequence or charge, of amino acids. These data could also contribute to the future development of more sensitive and specific diagnostic tools for antiphospholipid antibody syndrome determination and potential peptide- or ß2GP1 domain-based clinical therapies.

[News in Angiology and Hemostasis]. / Angiologie et hémostase.

Several themes were selected from those that marked the year 2016. The analysis of registries with «real life¼ data regarding the use of direct oral anticoagulants is reassuring and overall confirm the data of the pivotal studies. We also present the validation of a prediction rule for risk stratification of thromboembolism recurrence and duration of anticoagulation after an unprovoked event. In addition, new data shed light on the treatment of distal vein thrombosis. We also address the issue of venous thromboembolism risk related to oral contraceptives and the issue of genetic testing prior prescription, and finally present a new factor VIII recently available for the treatment of patients with acquired hemophilia A.

Plusieurs thèmes ont été choisis parmi ceux qui ont marqué l'année 2016. L'analyse des registres de patients de la «vraie vie¼ concernant l'utilisation des anticoagulants oraux directs permet dans l'ensemble de confirmer les données des études pivots. Concernant la maladie thromboembolique veineuse, nous présentons la validation d'une règle de prédiction pour la stratification du risque de récidive et la durée d'anticoagulation après un événement idiopathique. De plus, des données nouvelles apportent un éclairage sur la prise en charge des thromboses veineuses distales. Finalement, nous abordons le risque d'événement thromboembolique veineux en relation avec la contraception orale et l'arrivée sur le marché de tests de dépistage génétique de même que d'un nouveau facteur VIII pour la prise en charge des patients avec une hémophilie A acquise.

The first Team Haemophilia Education meeting, 2015, Amsterdam, The Netherlands.

Haemophilia remains a complex disorder to diagnose and manage, requiring close cooperation between multidisciplinary healthcare professionals. There are still many unmet challenges in haemophilia care. The first Team Haemophilia Education (THE) meeting, held on 7-8 May 2015 in Amsterdam, The Netherlands, aimed to promote the optimal care of haemophilia patients through education of the multidisciplinary treatment team. This was achieved by reviewing the latest developments in haemophilia management, considering how these can be implemented in the clinic to improve patient care and providing a platform for networking and debate for all haemophilia treatment team members. Haemophilia treatment centres from several countries were asked to complete a premeeting online questionnaire to establish the biggest challenges that they face when managing patients. The concerns expressed were used to develop the agenda, which comprised a combination of formal presentations, case studies and informal workshops covering such topics as pharmacokinetics, laboratory assays and tailoring of treatment to individual patients. This report is a summary of the key developments in haemophilia care presented by various investigators and healthcare professionals at THE meeting 2015.

Preoperative hemostatic assessment: a new and simple bleeding questionnaire.

PURPOSE: Current recommendations for the assessment of the risk of perioperative bleeding limit coagulation testing to patients with a personal and/or family history of bleeding. As no simple preoperative screening questionnaire is currently available, we assessed the performance of a novel screening questionnaire for its ability to detect bleeding disorders. METHODS: A dichotomized, seven-point questionnaire named HEMSTOP (Hematoma, hEmorrhage, Menorrhagia, Surgery, Tooth extraction, Obstetrics, Parents) was applied to three groups of subjects: patients referred to hemostasis specialists for bleeding symptoms for whom any kind of perioperative hemostatic precautions were subsequently recommended (n = 38); patients referred to hemostasis specialists for whom precautions were not required (n = 75); healthy volunteers (n = 70). We calculated the sensitivity and specificity of HEMSTOP scores and compared them with the discriminative performances of standard blood coagulation assays (prothrombin time, activated partial thromboplastin time). RESULTS: Patients requiring perioperative hemostatic precautions had greater median [interquartile range] HEMSTOP scores (2 [2-3]) than patients not requiring precautions (1 [1-2]) and healthy controls (0 [0-0]); P < 0.001. A HEMSTOP score ≥ 2 had a specificity of 98.6% [95% confidence interval (CI), 92.3 to 100] and a sensitivity of 89.5% (95% CI, 75.2 to 97.1). The 26.3% (95% CI, 13.4 to 43.1) sensitivity of the standard coagulation times was much lower. CONCLUSION: The HEMSTOP score discriminates patients at an elevated risk for bleeding with recommended perioperative precautions from those without such recommendations as well as from healthy participants. Further evaluation of the HEMSTOP score is required for a better evaluation of its definitive usefulness to predict the risk of perioperative bleeding.

[News in angiology and hemostasis]. / Angiologie et hémostase.

This update describes contemporary studies of clinical relevance in angiology and hemostasis. We discuss newer developments for the treatment of haemophilia, with a focus on drugs with longer-half lives. Direct anticoagulants (DOAC: rivaroxaban, apixaban, edoxaban and dabigatran) and their approved prescription in Switzerland are summarized, with a description of antidotes that will be available in the near future. We will present new data on the utility of cancer screening at the diagnosis of idiopathic venous thromboembolism (VTE) and on the evaluation of DOAC in patients with cancer-related VTE. Finally, new studies evaluating the clinical risk-benefit of anticoagulation bridging for patients with vitamin K antagonists undergoing procedures do not support the use of such bridging in the majority of patients.

[Direct oral anticoagulants (DOAC) : practical guidance for daily prescription]. / Anticoagulants oraux directs (ACOD) : une aide à la prescription dans la pratique quotidienne.

The widespread introduction of direct oral anticoagulants (DOAC) represents a major step forward in the therapeutic management of patients with venous thromboembolic disease and atrial fibrillation, accompanied by new challenges. A thorough knowledge of the available evidence needs to be associated with pragmatism in order to address patients' individual issues. Access to documents containing practical guidance will certainly contribute to increase the efficacy and safety of prescription of these drugs for patients. The aim of this article is to present suggestions based on scientific data and international recommendations for the prescription and further management of DOACs in everyday clinical practice, based of frequently asked questions to the authors.

L'introduction des anticoagulants oraux directs (ACOD) à large échelle représente une avancée majeure dans la prise en charge des patients présentant une maladie thromboembolique veineuse ou une fibrillation auriculaire, accompagnée de nouveaux défis. Ceux-ci doivent être relevés en se basant sur les données scientifiques associées à des considérations pragmatiques. L'acquisition d'une connaissance croissante de ces médicaments et la possibilité d'avoir recours à des documents d'aide pratique permettent certainement d'augmenter la sécurité de prescription de ces médicaments pour les patients. Le but de cet article est de présenter des suggestions fondées sur les données scientifiques et les recommandations internationales pour la prescription des ACOD dans la pratique clinique, sur la base des questions fréquemment posées aux auteurs.

[Hereditary haemorrhagic telangiectasia: importance of a multidisciplinary approach]. / Maladie de Rendu-Osler-Weber: importance d'une prise en charge multidisciplinaire.

The Rendu-Osler-Weber disease, also known as hereditary haemorrhagic telangiectasia, is an autosomal dominant inherited disease. Its main manifestations are nosebleeds and digestive tract bleeding due to angiodysplasia. The presence of arteriovenous malformations in organs such as lung, liver, brain, etc. can cause serious complications (haemorrhage, stroke, brain abscess, hypoxemia, increased cardiac output, pulmonary arterial hypertension). Diagnosis is based on clinical criteria and can be confirmed by genetic analysis. The prevalence of this rare disease is 1/5,000 to 1/10,000 and its expression varies widely, even in the same family. The management must be multidisciplinary and based on prevention and treatment of bleeding complications as well as screening and treatment of arteriovenous malformations.

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A.

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.

Suspicion of heparin-induced thrombocytopenia in internal medicine: How appropriate is the ordering of anti-PF4/heparin antibody testing?

Thrombocytopenia is frequent in hospitalized patients, and heparin-induced thrombocytopenia (HIT) is often suspected when a decrease in platelet count is concomitant with heparin treatment. ELISA tests used for anti-PF4/heparin antibodies detection usually have high sensitivity but only fair specificity for HIT. Pre-test probability scores (such as 4 Ts or HEP scores) have been validated and a low probability score rules out HIT without anti-PF4/heparin testing. The aims of this study are to evaluate the appropriateness of anti-PF4/heparin testing according to pre-test probabilities of HIT and to compare the abilities of the 4 Ts and HEP scores to avoid inappropriate anti-PF4/heparin testing. This retrospective observational study included 74 consecutive patients hospitalized in a general internal medicine division who had anti-PF4/heparin testing for suspicion of HIT. 4 Ts and HEP scores were computed retrospectively. About 73% of patients who had ordering of an anti-PF4/heparin were at low risk according to the 4 Ts score, and 46% according to the HEP score. Heparin was discontinued in 61% and 62% of low-risk patients according to 4 Ts and HEP scores and switched to alternative anticoagulant in 31% and 32% of them, respectively. No case of HIT was diagnosed in patients with a low-risk score. One major bleeding and no thrombosis were observed. For the 4 Ts score, the sensitivity was 100%, the negative predictive value (NPV) was 100%, the specificity was 77%, and the positive predictive value (PPV) was 20% (95% CI: 7-44). For the HEP score, the sensitivity was 100%, the NPV was 100%, the specificity was 49%, and the PPV was 10%. In conclusion, pre-test probability scores were vastly underused in this internal medicine population despite their ability to rule out HIT without laboratory testing in a large proportion of patients. Appropriate use of those instruments should be actively promoted.

Felty's syndrome and hypofibrinogenemia: an unusual target for anti-cyclic citrullinated peptide antibodies?

BACKGROUND: Rheumatoid arthritis (RA) is a risk factor for the development of Felty's syndrome and large granular lymphocyte (LGL) leukemia. Anti-cyclic citrullinated peptide (CCP) antibodies are considered highly specific for RA and are directed against various citrullinated antigens, including citrullinated fibrinogen. Anti-CCP antibodies may interfere with the detection of citrullinated proteins and their function. In this article, we describe the possible inhibition of fibrinogen by anti-CCP antibodies with clinical consequences which have never been reported in the literature to our best knowledge. CASE REPORT: We present the case of a 79-year-old Caucasian woman with a longstanding history of untreated seropositive RA and who had been investigated for severe neutropenia since several months. The association of splenomegaly led to suspicion of Felty's syndrome. Flux cytometry was compatible with T-cell LGL leukemia. In addition, severe hypofibrinogenemia was detected. The later finding has not been consistently associated with the former clinical entities. Further investigations demonstrated that the anti-CCP antibodies of the patient also recognized the P41 peptide of citrullinated fibrinogen. The patient deceased of intracranial hemorrhage. CONCLUSION: It is likely, yet not definite, that high anti-citrullinated fibrinogen titers may contribute to low fibrinogen levels and could have contributed to the fatal hemorrhagic event.

MYH10 protein expression in platelets as a biomarker of RUNX1 and FLI1 alterations.

RUNX1 gene alterations are associated with acquired and inherited hematologic malignancies that include familial platelet disorder/acute myeloid leukemia, primary or secondary acute myeloid leukemia, and chronic myelomonocytic leukemia. Recently, we reported that RUNX1-mediated silencing of nonmuscle myosin heavy chain IIB (MYH10) was required for megakaryocyte ploidization and maturation. Here we demonstrate that runx1 deletion in mice induces the persistence of MYH10 in platelets, and a similar persistence was observed in platelets of patients with constitutional (familial platelet disorder/acute myeloid leukemia) or acquired (chronic myelomonocytic leukemia) RUNX1 mutations. MYH10 was also detected in platelets of patients with the Paris-Trousseau syndrome, a thrombocytopenia related to the deletion of the transcription factor FLI1 that forms a complex with RUNX1 to regulate megakaryopoiesis, whereas MYH10 persistence was not observed in other inherited forms of thrombocytopenia. We propose MYH10 detection as a new and simple tool to identify inherited platelet disorders and myeloid neoplasms with abnormalities in RUNX1 and its associated proteins.

Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia.

Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 × 10(9)/L.

[Aspirin: once or twice a day?]. / Hémostase. Aspirine: une ou deux fois par jour?

Aspirin is a cornerstone in the prevention of ischemic events and guidelines usually recommend a once-daily dosing. This dosing is based at least in part on the platelet renewal rate, which is of only 10-15% a day. A once-daily dosing is now challenged by several studies demonstrating that when platelet turnover is increased, such as in patients with diabetes or essential thrombocytemia, the inhibition of platelet function provided by aspirin is no longer homogeneous between dosing with a significant recovery of platelet function within a day that is blunted by a twice-daily dosing. This review addresses the issue of aspirin dosing in selected patients in the controversial era of personalized antiplatelet therapy.

Toll-like receptor 2 mediates the activation of human monocytes and endothelial cells by antiphospholipid antibodies.

The presence of antiphospholipid antibodies (aPLAs) is associated with arterial or venous thrombosis and/or recurrent fetal loss. The proposed pathogenic mechanisms for aPLA effects include the inflammatory activation of monocytes and endothelial cells. Toll-like receptors (TLRs) are candidate signaling intermediates. The aim of this study was to investigate the relative contribution of TLR2 and TLR4 in cell activation by aPLAs. Of 32 patient-derived aPLAs, 19 induced an inflammatory activation of human monocytes and umbilical vein endothelial cells (HUVECs). In HUVECs, inflammatory responses to these aPLAs were increased by TNF pretreatment, which increases the expression of TLR2 but not TLR4. Anti-TLR2 but not anti-TLR4 antibodies reduced the aPLA-induced activation of monocytes and HUVECs. aPLAs activated TLR2-expressing human embryonic kidney 293 (HEK293) cells but not TLR4-expressing cells. Binding studies demonstrated an interaction between aPLAs and TLR2 but not TLR4. A role for CD14, a coreceptor for TLR2 and TLR4, can be inferred by observations that anti-CD14 antibodies reduced responses to aPLAs in monocytes, and that responses in HEK293 cells expressing TLR2 and CD14 were greater than in HEK293 cells expressing TLR2 alone. Our results demonstrate a role for TLR2 and CD14 in human endothelial cell and monocyte activation by aPLAs.

Predicting deep venous thrombosis in pregnancy: external validation of the LEFT clinical prediction rule.

The assessment of clinical probability represents an important step in the diagnostic strategy of patients with suspected deep vein thrombosis. The recently derived LEFt clinical prediction rule for pregnant women combines three variables: symptoms in the left leg (L), calf circumference difference of 2 centimeters or over (E for edema) and first trimester presentation (Ft) but is lacking an external validation. The LEFt rule was computed among pregnant women with suspected deep vein thrombosis who were included in a multicenter prospective diagnostic management outcome study. We calculated the proportion of women and the prevalence of deep vein thrombosis in each probability group, along with the diagnostic performances of the LEFt rule. All variables needed to compute the rule could be retrieved in 157 of the 167 pregnant women with suspected deep vein thrombosis. The prevalence of confirmed deep vein thrombosis was 13 of 157 (8.3%). The LEFt rule was negative in 46 (29%) women. A deep vein thrombosis was diagnosed in 13 of 111 (11.7%, 95% Confidence Interval (CI): 8.3-20.9%) of women with at least one of the LEFt criteria, as compared with none of 46 (0.0%, 95%CI: 0.0-7.9%) of women with none of the LEFt criteria. These results suggest that a negative LEFt rule accurately identifies pregnant women in whom the proportion of confirmed deep vein thrombosis appears to be very low. The rule should not be used as stand-alone test for excluding DVT during pregnancy, but might rather be implemented in a diagnostic strategy in association with D-dimer measurement and compression ultrasonography.

Management of antithrombotic therapies in patients scheduled for eye surgery.

The large majority of patients undergoing ophthalmic surgery are elderly and take systemic medications on a regular basis, including antiplatelet and anticoagulant treatments. It is current practice for many physicians to discontinue antithrombotic treatment prior to surgery to reduce bleeding complications that may lead to retrobulbar haemorrhage and, ultimately, to loss of vision. However, discontinuation of antithrombotic treatment in such patients may lead to thromboembolic events with serious consequences. The present narrative review highlights the risk of thrombosis when discontinuing antithrombotic drugs and the risk of bleeding when continuing them. The published literature on this topic shows that discontinuation of antiplatelet or anticoagulant treatment leads to a substantially increased risk of arterial or venous thromboembolic events and related complications, especially in patients with atrial fibrillation, prosthetic heart valves or recent coronary stenting. This risk is distinctly higher than the risk of significant local haemorrhage. Ophthalmic bleeding events reported in the literature are usually minor, without serious consequences, even if antiplatelet or anticoagulant treatments are continued, provided that the anticoagulation level is within the therapeutic range. Thus, the current data are in favour of maintaining antiplatelet and anticoagulant drugs for most ophthalmic procedures, regardless of the anaesthetic techniques.

Anaesthetic management for caesarean section in a patient with hereditary haemorrhagic telangiectasia and severe epistaxis during pregnancy.

A primigravida patient, with a history of hereditary haemorrhagic telangiectasia (HHT) manifesting as nasal angiodysplasia and hepatic arteriovenous malformations (AVM), presented for delivery planning and anaesthetic evaluation at 29 weeks of gestation. She was hospitalised several times during the second and third trimester for serious recurrent epistaxis, leading to severe anaemia. In total, she required the transfusion of 20 units of packed red blood cells during her pregnancy as well as surgical nasal haemostasis under general anaesthesia (GA). The patient was referred to our tertiary centre for delivery. In the context of recurrent severe epistaxis and high cardiac output (due to hepatic AVM) in the third trimester, a multidisciplinary decision was made to plan an elective caesarean section at 35 4/7 weeks combined with nasal packing under GA. This report discusses the implications of HHT, the multidisciplinary planning of the caesarean section, intraoperative anaesthetic management and patient follow-up.

[Management of thrombocytopenia during pregnancy]. / Prise en charge des thrombopénies au cours de la grossesse.

Thrombocytopenia defined as a platelet count < 150 G/l is found in about 10% of pregnancies. The differential diagnosis is similar to that of non-pregnant women but some specific causes related to pregnancy need to be considered. Even if the so-called gestational thrombocytopenia is the most common etiology, a careful history and simple laboratory tests are needed in order not to miss a serious condition that may require specific and sometimes urgent treatment. However in most cases detailed investigations are not required during pregnancy and a pragmatic attitude can be proposed, including monitoring of platelet count in the mother and platelet count in the newborn.