Management of antiplatelet therapy for non elective invasive procedures of bleeding complications: proposals from the French working group on perioperative haemostasis (GIHP), in collaboration with the French Society of Anaesthesia and Intensive Care Medicine (SFAR).

The French Working Group on Perioperative Haemostasis (GIHP) and the French Study Group on Haemostasis and Thrombosis (GFHT) in collaboration with the French Society of Anaesthesia and Intensive Care Medicine (SFAR) drafted up-to-date proposals on the management of antiplatelet therapy for non-elective invasive procedures or bleeding complications. The proposals were discussed and validated by a vote; all proposals could be assigned with a high strength. Emergency management of oral antiplatelet agents (APA) requires knowledge on their pharmacokinetic/pharmacodynamics parameters, evaluation of the degree of the alteration of haemostatic competence and the associated bleeding risk. Platelet function testing may be considered. When APA-induced bleeding risk may worsen the prognosis, measures should be taken to neutralise antiplatelet therapy by considering not only the efficacy of available means (which can be limited for prasugrel and even more for ticagrelor) but also the risks that these means expose the patient to. The measures include platelet transfusion at the appropriate dose and haemostatic agents (tranexamic acid; rFVIIa for ticagrelor). When possible, postponing non-elective invasive procedures at least for a few hours until the elimination of the active compound (which could compromise the effect of transfused platelets) or if possible a few days (reduction of the effect of APA) should be considered.

Intravenous thrombolysis for acute ischaemic stroke in patients on direct oral anticoagulants.

BACKGROUND AND PURPOSE: Whereas intravenous thrombolysis (IVT) is allowed for acute ischaemic stroke in patients on vitamin K antagonists with international normalized ratio ≤1.7, there are no similar recommendations for patients on direct oral anticoagulants (DOACs), notably due to the lack of coagulation tests to assess the therapeutic effects. Although the literature is scarce, consisting of small case series and retrospective studies, considering the frequency of this situation the French Vascular Neurology Society and the French Study Group on Haemostasis and Thrombosis have worked on a joint position paper to provide a practical position regarding the emergency management of ischaemic stroke in patients on DOACs. METHOD: Based on a review of the literature, the authors wrote a first text that was submitted to a broad panel of members from the two societies. The text was then amended by the authors to address experts' comments and to reach a consensus. RESULTS: In patients with normal renal function and who stopped the DOAC for at least 48 h, the management should not differ from that in patients without oral anticoagulant. In patients who are still on DOACs, mechanical thrombectomy is encouraged preferentially when applicable in first line. Otherwise, when specific tests are available, values <50 ng/ml indicate that IVT is allowed. In the absence of specific tests, standard tests (thrombin time, prothrombin time and activated partial thromboplastin time) can be used for dabigatran and rivaroxaban, although interpretation of these tests may be less reliable. In some patients on dabigatran, idarucizumab may be used before IVT. CONCLUSIONS: In this expert opinion paper, it is suggested that IVT can be performed in patients selected according to the time elapsed since the drug was last taken, renal function, type of hospital where the patient is admitted and plasma concentration of DOAC.

Postauthorization safety study of Clottafact® , a triply secured fibrinogen concentrate in acquired fibrinogen deficiency: a prospective observational study.

BACKGROUND AND OBJECTIVES: A postauthorization safety study was performed between 2009 and 2012 to describe the use of Clottafact® in acquired fibrinogen deficiency in real-life medical practice in France. MATERIALS AND METHODS: One hundred and fifty patients were planned for 28 days of prospective follow-up after infusion. The analysis of this observational study was descriptive and performed according to the type of treatment (curative or preventive) and the origin of the bleed. RESULTS: One hundred and fifty-six patients (16-87 years) were included in 13 centres and treated in five different medical bleeding situations: postpartum (59), other gynaecological/obstetrical (6), trauma (34), liver (13), cardiovascular (23) and other various bleeding situations (21). The mean follow-up time was 18·9 ± 12·3 days. Two patients presented adverse drug reactions: one a pulmonary embolism and the other a four-site venous thromboembolic episode. All were serious with a dubious causal relationship with the study treatment. Efficacy data were collected as a secondary objective. In 150 patients receiving curative treatment, 117 of 159 infusions (73·6%) were considered as successful by the investigators, 35 as moderate (22%) and seven as no response (4·4%). CONCLUSION: The Clottafact® safety profile observed during the study matched the known profile of fibrinogen during use.

[Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors. Proposals of the Working Group on Perioperative Haemostasis (GIHP) - March 2013]. / Prise en charge des complications hémorragiques graves et de la chirurgie en urgence chez les patients recevant un anticoagulant oral anti-IIa ou anti-Xa direct. Propositions du Groupe d'intérêt en Hémostase Périopératoire (GIHP) - mars 2013.

New direct oral anticoagulants (NOAC), inhibitors of factor IIa or Xa, are expected to be widely used for the treatment of venous thromboembolic disease, or in case of atrial fibrillation. Such anticoagulant treatments are known to be associated with haemorrhagic complications. Moreover, it is likely that such patients on long-term treatment with NOAC will be exposed to emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose management for optimal safety as regards the risk of bleeding in such emergency conditions. In this article, only dabigatran and rivaroxaban were discussed. For emergency surgery at risk of bleeding, we propose to dose the plasmatic concentration of drug. Levels inferior or equal to 30ng/mL for both dabigatran and rivaroxaban, should enable the realization of a high bleeding risk surgery. For higher concentration, it was proposed to postpone surgery by monitoring the evolution of the drug concentration. Action is then defined by the kind of NOAC and its concentration. If the dosage of the drug is not immediately available, proposals only based on the usual tests, PT and aPTT, also are presented. However, these tests do not really assess drug concentration or bleeding risk. In case of severe haemorrhage in a critical organ, it is proposed to reduce the effect of anticoagulant therapy using a nonspecific procoagulant drug (activated prothrombin concentrate, FEIBA, 30-50U/kg, or non-activated 4-factors prothrombin concentrates 50U/kg). For any other type of severe haemorrhage, the administration of such a procoagulant drug, potentially thrombogenic in these patients, will be discussed regarding concentration of NACO and possibilities for mechanical haemostasis.

Successful management of heparin-induced thrombocytopenia using argatroban in a very old woman: a case report.

Thrombosis due to heparin-induced thrombocytopenia (HIT) is rare but has a severe prognosis. Its management is not always easy, particularly in old patients with renal insufficiency. A 95-year-old woman was hospitalized for dyspnea. Curative treatment with unfractionated heparin was started because pulmonary embolism was suspected. Disseminated intravascular coagulation was then suspected because of thrombocytopenia, hypoprothrombinemia, hypofibrinogenemia, and a positive ethanol gelation test. The first immunoassay for HIT was negative. On the 12th day of hospitalization, bilateral cyanosis of the toes occurred associated with recent deep bilateral venous and arterial thrombosis at duplex ultrasound. New biological tests confirmed HIT and led us to stop heparin and to start argatroban with a positive clinical and biological evolution. Venous and arterial thrombosis associated with thrombocytopenia during heparin treatment must be considered HIT whatever the biological test results are. Argatroban is a good alternative treatment in the elderly.

Prestroke antiplatelet therapy and early prognosis in stroke patients: the Dijon Stroke Registry.

BACKGROUND AND PURPOSE: Previous antiplatelet therapy (APT) in cardiovascular prevention is common in patients with first-ever stroke. We aimed to evaluate the prognostic value of APT on early outcome in stroke patients. METHODS: All first-ever strokes from 1985 to 2011 were identified from the population-based Stroke Registry of Dijon, France. Demographic features, risk factors, prestroke treatments and clinical information were recorded. Multivariate analyses were performed to evaluate the associations between pre-admission APT and both severe handicap at discharge, and mortality at 1 month and 1 year. RESULTS: Among the 4275 patients, 870 (20.4%) were previously treated with APT. Severe handicap at discharge was noted in 233 (26.8%) APT users and in 974 (28.7%) non-users. Prestroke APT use was associated with lower odds of severe handicap at discharge [adjusted odds ratio (OR): 0.79; 95% confidence interval (CI): 063-1.00; P = 0.046], non-significant better survival at 1 month [adjusted hazard ratio (HR): 0.87; 95% CI: 0.70-1.09; P = 0.222] and no effect on 1-year mortality (HR: 0.94; 95% CI 0.80-1.10; P = 0.429). In stratum-specific analyses, APT was associated with a lower risk of 1-month mortality in patients with cardioembolic ischaemic stroke (HR: 0.65; 95% CI: 0.43-0.98; P = 0.040). CONCLUSIONS: APT before stroke was associated with less severe handicap at discharge, with no significant protective effect for mortality at 1 month except in patients with cardioembolic stroke. No protective effect of APT was observed for mortality at 1 year. Further studies are needed to understand the mechanisms underlying the distinct effects of prior APT observed across the ischaemic stroke subtypes.

Increased risk for heart valve disease associated with antiphospholipid antibodies in patients with systemic lupus erythematosus: meta-analysis of echocardiographic studies.

BACKGROUND: Heart valve disease (HVD) is frequent in patients with systemic lupus erythematosus (SLE), and the role of antiphospholipid antibodies (aPL) is controversial. Thus, our objective was to estimate the risk of HVD, including Libman-Sacks endocarditis, associated with aPL in patients with SLE. METHODS AND RESULTS: Studies were selected if they investigated the association between aPL and HVD in SLE patients and if aPL-negative patients were included for comparison. Data sources were MEDLINE, Embase, Cochrane Library, hand search, contact with investigators, and reference lists of studies, without language restrictions. Data on study and patient characteristics, risk estimates, and study quality were independently extracted by 2 investigators. Pooled effect estimates were obtained by using the DerSimonian-Laird method. Of 234 identified abstracts, 23 primary studies (15 cross-sectional, 7 cohort, 1 case-control) met inclusion criteria, including 1656 SLE patients and 508 cases of HVD. Compared with SLE patients without aPL (n=988), the overall pooled odds ratios for HVD and Libman-Sacks endocarditis in aPL-positive patients (n=668) were 3.13 (95% confidence interval, 2.31 to 4.24) and 3.51 (95% confidence interval, 1.93 to 6.38), respectively. The risk of HVD depending on aPL subtypes was the highest for lupus anticoagulant at 5.88 (95% confidence interval, 2.92 to 11.84) and IgG anticardiolipin antibodies at 5.63 (95% confidence interval, 3.53 to 8.97). CONCLUSIONS: Overall, the presence of aPL in SLE patients is significantly associated with an increased risk for HVD including Libman-Sacks endocarditis. The risk conferred by IgG anticardiolipin antibodies is as strong as by lupus anticoagulant. Systematic echocardiographic examinations in SLE patients with aPL should be performed.

[A case of cutaneous and mucous haemorrhage secondary to vitamin K deficiency in hyperemesis gravidarum]. / Un cas d'hémorragie cutanéomuqueuse secondaire à un déficit d'apport en vitamine K dans le syndrome d'hyperemesis gravidarum.

The frequency of the syndrome of hyperemesis gravidarum (HG) varies from 0.1 to 2% according to the literature. The complications are generally benign. Some of them can compromise the life outcome. Only two cases of HG with bleeding disorder (major epitasis) related to a vitamin K deficiency were previous reported. Here is described a third case related to a vitamin deficiency K. It is characterized by a skin and mucosa haemorrhage (gingivorrhagias; bleeding in urine; bruises at the points of puncture) and by the necessity to treat her in emergency with fresh frozen plasma before intravenous vitamin K as soon as the diagnosis of vitamin K deficiency was done. The indication of the use of frozen fresh plasma is discussed.

[Multiple osteonecroses and venous thrombosis: one case of patient with a novel mutation of protein C (N102S) and heterozygous for FV Leiden]. / Ostéonécroses et thromboses veineuses multiples : un cas de patient porteur d'une nouvelle mutation de la protéine C (N102S) et hétérozygote pour le facteur V Leiden.

The association of a thrombo-embolic venous disease and multiple osteonecroses occurring in the presence of biological risk factors for thrombosis is rarely described in the literature. We report here the case of a 35-year old patient with such clinical manifestations. This patient is heterozygous for a novel mutation of the protein C gene (N102S) and for FV Leiden polymorphism. The clinical history is characterized by numerous thrombo-embolic venous episodes associated with several episodes of epiphysis osteonecrosis requiring two hip total prostheses and two knee total prostheses. The particular clinical features here are the multiple osteonecroses and the unusual localisation of brain and genital thromboses. The absence of both venous thromboembolic and osteonecrosis events in the relatives presenting the same genetic pattern suggests broad phenotype variations in the clinical expression of these genetic abnormalities. In osteonecrosis associated with thrombophilia, some authors have proposed treatment with stanazolol, which increase circulating protein C concentration. The effectiveness of this drug among such patients should be evaluated by clinical studies.

[Discrepancy between two methods of D-dimers measurement: one case of human anti-mouse antibody interference]. / Incohérence entre deux méthodes de dosage des D-dimères: un cas d'interférence d'anticorps humain anti-souris.

Quantification of D-dimers is the major biometry step in the diagnostic of an episode of the venous thromboembolic disease. The measurement of D-dimers can be performed with ELISA or immunoturbidimetric methods suited to emergency, using a mouse monoclonal antibody as capture and/or revelation antibody. Therefore, the presence in patient's plasma of human antibody mouse (HAMA) that binds the mouse antiglobulin used in immunoassays can lead to false negative or false positive results. In a young woman presenting repetitive thoracic pain suggestive of a pulmonary embolism, a major discrepancy was found between one result of D-dimers above the cut-off with an immunoturbidimetric method (STA Liatest D-DI; Diagnostica Stago) and one result below the cut-off with a sandwich method (Vidas D-Dimer Exclusion; bioMérieux). HAMA, which is known to be responsible for this type of discrepancy, was detected in the patient serum. The false positive result probably impaired with the management of patient. Taking in charge the patient should take into account the possible presence of this antibody. Interference by heterophilic antibodies is not easily detected by the laboratory. Even if their frequency is low, it remains a difficult problem for the biologist. Suspicion generally arises from inconsistency between the clinical data and immunoassay results. A good communication between physician and biologist should avoid to providing false negative or positive results.

[Willebrand factor deficiency and septorhinoplasty]. / Déficit en facteur Willebrand et septorhinoplastie.

INTRODUCTION: Willebrand disease can be diagnosed late, sometimes only when hemorrhage complicates surgery. French guidelines do not recommend investigation before surgery when no personal or familial hemorrhagic diathesis is reported. OBJECTIVE: To consider the advantages of Willebrand factor dosage before septorhinoplasty. METHOD: Three cases of septorhinoplasty and Willebrand factor deficiency complicated with hemorrhage compromising the functional result are reported. The routine tests (platelet count, bleeding time, and activated partial thromboplastin time) and Willebrand factor dosage were done before or after surgery. RESULTS: In the three cases, no personal or familiar hemorrhagic diathesis was found. For two cases, a hemorrhage occurred during surgery. One of them had prolonged and repeated nose bleedings after surgery. In this case, iterative packings damaged the result of surgery and a new rhinoplasty had to be done. In one case, a prolonged activated partial thromboplastin time before surgery revealed a Willebrand factor deficiency, leading to prophylactic treatment (desmopressin) of bleeding. CONCLUSION: The cases described suggest that systematic dosage of Willebrand factor before septorhinoplasty could be advantageous and that functional prognosis can be impaired by uncontrolled epistaxis.

[Thrombocytopenia: clinicobiologic validation and classification]. / Validation et classification clinicobiologique d'une thrombopénie.

Thrombocytopenia occurs frequently. We will illustrate, through the presentation of a clinical case, the difficulties encountered to identify and characterize thrombocytopenia. The clinicobiological validation of a low platelet count implies, at the same time, the biologist, who must assume the validation of numeration while mentioning the morphological characteristics of the platelets and other blood cells, as well as the clinician who must interpret these data according to the clinical context. Firstly, we will detail the basic rules to correctly ensure this validation. Secondly, we will see which are the arguments which that make it possible to direct the diagnosis towards an acquired or inherited thrombocytopenia. Lastly, we will approach the classification of inherited thrombocytopenias.

[Labour epidural analgesia for a woman with hereditary macrothrombocytopenia]. / Analgésie péridurale obstétricale chez une patiente présentant une macrothrombocytopénie familiale.

Epidural analgesia is often considered as risk of epidural haematoma in a patient with thrombocytopenia. In this observation, uncomplicated epidural analgesia was performed in a pregnant woman with hereditary macrothrombocytopenia. She received continuous epidural labour analgesia for a vaginal delivery with a platelet count at 63x10(9)/l but platelets with high mean platelet volume (20fL) and normal function. No neurological sequelae or excessive bleeding occurred.

[Use of ecarin clotting time in whole blood for monitoring recombinant hirudine treatment during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia]. / Utilisation du temps de coagulation par l'écarine en sang total pour la surveillance d'un traitement anticoagulant par lépirudine (Refludan au cours de circulation extracorporelle dans un contexte de thrombopénie induite par l'héparine.

Lepirudin (Refludan is a recombinant hirudin, approved for anticoagulation treatment of heparin-induced thrombocytopenia patients with thrombosis. We report here our method for laboratory monitoring with ecarin clotting time (ECT) of hirudin therapy as anticoagulation for cardiac surgery. Ecarin is extracted from the Echis carinatus snake venom and directly converts prothrombin to its intermediate, meizothrombin. This one binds in a stoechiometric way to hirudin to be proportioned in whole blood. The activation of coagulation starts up only when the totality of the hirudin is bound to the meizothrombin. To minimize the effect of dilution related to the CEC on the prothrombin and fibrinogen levels, thus lengthening the ECT, the specimen to be tested is diluted with normal whole blood. In 1997, when we have performed our first surgery with cardiopulmonary bypass, only one team (Pötzsch et al., 1997) had described the use of the ECT in whole blood. We describe in this work our assay to dose hirudin with ECT after dilution in whole blood. This assay was used during 8 CEC among 7 patients affected with HIT (n = 6) or potentially sensitized with heparin (n = 1). Experimental conditions and interpretation of the assay are reported here. This test is fast enough to provide useful information for adjusting the dose during cardiopulmonary bypass.

[A case of celiac disease with late diagnosis by very long prothrombin and activated partial prothrombin times]. / Un cas de maladie coeliaque révélée tardivement par un temps de Quick et un temps de céphaline avec activateur très allongés.

Coeliac disease is usually revealed by intestinal symptoms, but less frequently by deficiency symptoms. Early screening is very important to avoid with appropriate diet an intestinal lymphoma or epidermoid cancer. We report here the case of a 68-year old woman where coeliac disease was pointed out by very long Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT). Clinical examination was strictly normal except for leanness, a small height, and several diarrhoea episodes 3 or 4 times a year. Other blood tests showed a macrocytic anemia, a fibrinogen level slightly above the upper limit, a decreased proteinaemia and albuminaemia, and a sideraemia at the lower normal limit. Liver tests pointed to a cytolysis. Vitamin K-dependent factors were decreased. A perfusion of vitamin-K allowed getting a normal PT. Duodenofiberscopy with biopsy allowed the diagnosis of coeliac disease. Neither lymphoma nor epidermoid cancer were detected. A gluten-free diet allowed the disappearing of digestive symptoms, weight rising and return to a normal PT. Searching for a coeliac disease is therefore relevant in aged patients even when very faint clinical or biological symptoms of malabsorption appear, particularly when PT is longer than the control with decreased vitamin-K dependant factors.

[Peri-operative anticoagulation with danaparoid for a patient with Budd-Chiari syndrome and heparin-induced thrombocytopenia]. / Anticoagulation péri-opératoire par danaparoïde (Orgaran) chez un patient ayant un syndrome de Budd-Chiari et une thrombopénie induite par l'héparine.

We report a case of Budd-Chiari syndrome revealing a polycythemia vera and complicated by heparin-induced thrombocytopenia. A surgical porto-caval shunt was inserted with danaparoid as anticoagulant during the peri-operative period. The doses of danaparoid were as follows: a continuous intravenous infusion of 200 U/h with a target between 0.5 et 0.8 U/ml antifactor Xa activity during the preoperative period, followed by 100 U/h with a target of 0.3 U/ml during the peroperative period; an increase in doses of danaparoid to 150 and 200 U/h with a target above 0.5 U/ml was used during the postoperative period. This case report is a rare situation of hypercoagulable state, in a surgical context, treated with danaparoid.

[Delayed diagnosis of homocystinuria by major deficiency in cystathionine beta synthase]. / Diagnostic tardif d'homocystinurie par déficit majeur en cystathionine beta synthase.

INTRODUCTION: Homocystinuria due to cystathionine beta synthase (CBS) deficiency is a special type of hyperhomocysteinemia because of its clinical expression (thrombotic events, ectopic lens and mental retardation). It's a rare, hereditary recessive autosomic disease generally diagnosed during childhood. EXEGESIS: Thrombophilia examination in a 50-year-old man found a dramatically increase homocysteinemia. Homocystinuria, profile of plasmatic amino acids and reduced CBS activity, (0.05 microkat/kg protein; N = 1.5 +/- 0.8) confirmed homocystinuria's diagnosis. Family study demonstrates that three siblings suffer from homocystinuria. Vitamin enriched diet with pyridoxin, vitamin B12 and folates induced reducing hyperhomocysteinemia and homocystinuria. CONCLUSION: This case report, original because of the diagnosis age, suggests a hyperhomocysteinemia's screening in patients with recurrent thrombotic events.