French lyophilized plasma versus fresh frozen plasma for the initial management of trauma-induced coagulopathy: a randomized open-label trial.

Essentials An immediate supply of plasma in case of trauma-induced coagulopathy is required. The Traucc trial compared French Lyophilised Plasma (FLyP) and Fresh Frozen Plasma (FFP). FLyP achieved higher fibrinogen concentrations compared with FFP. FLyP led to a more rapid coagulopathy improvement than FFP. SUMMARY: Background Guidelines recommend beginning hemostatic resuscitation immediately in trauma patients. We aimed to investigate if French lyophilized plasma (FLyP) was more effective than fresh frozen plasma (FFP) for the initial management of trauma-induced coagulopathy. Methods In an open-label, phase 3, randomized trial (NCT02750150), we enrolled adult trauma patients requiring an emergency pack of 4 plasma units within 6 h of injury. We randomly assigned patients to receive 4-FLyP units or 4-FFP units. The primary endpoint was fibrinogen concentration at 45 min after randomization. Secondary outcomes included time to transfusion, changes in hemostatic parameters at different time-points, blood product requirements and 30-day in-hospital mortality. Results Forty-eight patients were randomized (FLyP, n = 24; FFP, n = 24). FLyP reduced the time from randomization to transfusion of first plasma unit compared with FFP (median[IQR],14[5-30] vs. 77[64-90] min). FLyP achieved a higher fibrinogen concentration 45 min after randomization compared with FFP (baseline-adjusted mean difference, 0.29 g L-1 ; 95% confidence interval [CI], 0.08-0.49) and a greater improvement in prothrombin time ratio, factor V and factor II. The between-group differences in coagulation parameters remained significant at 6 h. FLyP reduced fibrinogen concentrate requirements. Thirty-day in-hospital mortality rate was 22% with FLyP and 29% with FFP. Conclusion FLyP led to a more rapid, pronounced and extended increase in fibrinogen concentrations and coagulopathy improvement compared with FFP in the initial management of trauma patients. FLyP represents an attractive option for trauma management, especially when facing logistical issues such as combat casualties or mass casualties related to terror attacks or disasters.

Antithrombotic therapy in diabetic patients with coronary artery disease.

In case of coronary artery disease (CAD), diabetic patients are at higher risk than their non-diabetic counterparts. Antithrombotics are therefore of key importance to decrease the risk of ischemic complications. A careful assessment of the benefit-risk balance is however needed to limit the risk of bleeding. Diabetic CAD patients are characterized by a pro-thrombotic milieu and by an impaired response to both aspirin and P2Y12 receptor inhibitors, especially to clopidogrel. When combined with aspirin, the new P2Y12 receptor inhibitors prasugrel and ticagrelor provide superior efficacy for the diabetic patients with acute coronary syndromes. In stable CAD, antiplatelet monotherapy (aspirin) remains for the time being the reference treatment for diabetic as well as for non-diabetic patients; further studies are however ongoing to test whether the antithrombotic strategy should be reinforced, particularly in case of diabetes mellitus. Finally, although chronic oral anticoagulation is rarely indicated for CAD management in itself, it is often prescribed for the concomitant treatment of atrial fibrillation. The combination of anticoagulation and antiplatelet therapy is associated with a high risk of bleeding and should only be prescribed for limited periods of time when the estimated benefits exceed the risks.

Gallium nitrate induces fibrinogen flocculation: an explanation for its hemostatic effect?

A novel hemostatic effect of gallium nitrate has recently been discovered. Our aim was to perform a preliminary investigation into its mode of action. Thromboelastography® showed no effect on coagulation but pointed instead to changes in fibrinogen concentration. We measured functional fibrinogen in whole blood after addition of gallium nitrate and nitric acid. We found that gallium nitrate induces fibrinogen precipitation in whole blood to a significantly higher degree than solutions of nitric acid alone. This precipitate is not primarily pH driven, and appears to occur via flocculation. This behavior is in line with the generally observed ability of metals to induce fibrinogen precipitation. Further investigation is required into this novel phenomenon.

Danaparoid cross-reactivity with heparin-induced thrombocytopenia antibodies: report of 12 cases.

PURPOSE: Danaparoid is a safe and effective drug for the treatment of heparin-induced thrombocytopenia (HIT). We describe an uncommon complication: danaparoid cross-reactivity with HIT antibodies. DESIGN AND SETTING: A retrospective observational multicenter study on HIT was conducted in France. In this study concerning HIT patients treated with lepirudin, 12 patients were treated with lepirudin because danaparoid cross-reacted with the heparin-dependent antibodies. RESULTS: Three groups of situations can be separated. In a first group, four patients received a short course of danaparoid until their initial functional HIT assay showed a cross-reactivity between danaparoid and HIT antibodies. One patient presented a fatal thrombotic complication but the relationship between this thrombotic complication and danaparoid cross-reactivity cannot be certain. In a second group, four patients received for 4 days at least a danaparoid treatment while the initial functional test did not show any danaparoid cross-reactivity. During danaparoid treatment, no significant increase of platelet count was observed and two patients presented a fatal thrombotic complication. In a third group, cross-reactivity between danaparoid and HIT antibodies was not checked before danaparoid therapy. During danaparoid treatment, no significant increase of platelet count was observed and the four patients developed a venous thromboembolic complication. CONCLUSION: Absence of any increase in platelet count after 3 to 5 days of danaparoid therapy and/or the occurrence of a new thrombotic event should lead to danaparoid cross-reactivity suspicion. However, before attributing thrombotic complications to danaparoid cross-reactivity, it is crucial to verify that the patients received the recommended danaparoid dosage regimen.

Hemostasis and Thrombosis: Clinical Usefulness of Combined use of Platelet Aggregation Test and Anti PF4-H. Antibodies Elisa test for the Diagnosis of Heparin Induced Thrombocytopenia.

Background. Heparin is the most commonly used drug in patients requiring therapeutic anticoagulation. But the use of heparin has serious side effects such as heparin-induced thrombocytopenia (HIT). The diagnosis of HIT is often difficult. This study was designed to test the diagnosis value of 2 laboratory tests: the platelet aggregation test and the ELISA test (Enzym Linked Immuno-Sorbent Assay). Methods and Results. In order to evaluate the diagnostic value of these 2 tests, we prospectively performed both tests in all patients referred to our laboratory with suspected type II HIT, and compared their results with clinical outcome. Plasmas from 60 patients suspected of HIT, were tested for heparin-dependent platelet-reactive antibodies with a platelet agregation test (PAT) and with an ELISA which detects anti heparin platelet factor 4 antibodies (Anti PF4-H Ab). Among the 60 explored patients, the clinical diagnosis of HIT was confirmed in 27 patients by clinical criteria. In 16 of these 27 patients, PAT and anti PF4-H. Ab were both positive, and in the 11 other patients, one of the 2 tests was negative. In 29 of the 33 patients with no clinical HIT, PAT and anti PF4-H. Ab were both negative, in the 4 remaining patients, one of the 2 tests was positive. Conclusion. For 75% of patients, biological results were concordant with the final clinical diagnosis. The combination of both tests is more reliable than the use of a single test; in the present series, all patients with positive results on both tests had clinically confirmed HIT, and all patients with negative results on both tests had not clinically confirmed HIT.

[Management of hemoptysis in invasive pulmonary aspergillosis]. / Prise en charge des hémoptysies au cours de l'aspergillose pulmonaire invasive.

Invasive pulmonary aspergillosis is an opportunistic infection occurring in a background of severe immune depression. The majority of cases occur in patients who have malignant hematologic disease, particularly during chemotherapy induction or consolidations phases for acute non-lymphocytic leukemia. The principal risk factors are profound (PN < 500 per mm3) and prolonged (very high risk beyond 20 days) neutropenia, perturbed phagocyte function and cellular immune deficiency (AIDS, immunosuppressive treatment in organ and bone marrow recipients). Clinically, invasive pulmonary aspergillosis presents as acute non-specific pneumonia with cough, chest pain and fever. The severe infection rapidly becomes life-threatening. The development of massive hemoptysis is a major risk. We report four cases of invasive pulmonary aspergillosis in patients who had hemoptysis. All four patients developed non-specific pneumonia resistant to broad-spectrum antibiotics during post-chemotherapy aplasia. Computed tomography of the thorax and bronchoscopy with bronchoalveolar lavage was performed due to the occurrence of hemoptysis. In the first two cases, the patients were recovering from aplasia. The thoracic CT scan showed evidence of a cavitating mass with peripheral vessels. Bronchoscopy findings suggested mucosal lesions. The patients were managed surgically. Pathology confirmed the diagnosis of invasive pulmonary aspergillosis with the presence of ischemic necrosis of the pulmonary parenchyma harboring numerous aspergillus filaments. Outcome was favorable and chemotherapy was re-initiated in one case. These two patient died from their hematological disease a few months later. The other two patients remained in aplasia. A CT of the thorax showed multifocal infiltration with vascular contact. Bronchoscopy was again suggestive. One patient developed massive hemoptysis with respiratory distress. Embolization was performed but the patient died two days after onset of hemoptysis. In the last case, embolization was successful and outcome was favorable enabling a bone marrow allograft; the patient died a few months later from the hematological disease. The potential gravity of hemoptysis in the course of invasive pulmonary aspergillosis should lead to early treatment with emergency CT scan and, if possible, bronchoscopy with bronchoalveolar lavage to establish the therapeutic strategy based on surgical excision or embolization of the pulmonary or bronchial arteries.

Effects of coronary angioplasty on monocyte tissue factor response in patients with stable or unstable angina.

Balloon coronary angioplasty is a revascularization procedure which increases the luminal diameter at a site of arterial stenosis, leading to mechanical disruption of the atherosclerotic plaque and to stretching of the vascular wall (1). This procedure can be complicated by thrombosis or restenosis, which occur in 5% and 30% of the cases respectively (2). These complications probably result from exposure of blood to components of atherosclerotic plaque, subendothelium and components of vascular wall, leading to activation of coagulation (thrombin generation) and platelets (3,4). Recent data point to simultaneous increase of leukocyte adhesive receptors, indicating an additional process of leukocyte activation, which could play a key role in the vascular healing process after angioplasty (5). These elements could also play a role in the thrombotic and stenotic complications.

Homozygous variant of antithrombin with lack of affinity for heparin: management of severe thrombotic complications associated with intrauterine fetal demise.

Patients with homozygous heparin-binding-site (HBS) qualitative antithrombin deficiencies are at significant risk of venous and arterial thrombosis. We report on the eighth case of homozygous HBS deficiency, and the fourth case concerning the Arg 47-Cys mutation. The proposita is a 25 year old, without known thrombotic antecedent, despite an oral contraceptive therapy for 7 years. After 25 weeks of a first pregnancy, she presented an intrauterine fetal demise complicated with deep vein thrombosis and pulmonary embolism. Heparin therapy was inefficient (no clinical nor angiographic improvement, no biological hypocoagulability). Heparin cofactor activity was < 10%, antigen concentration was normal. The crossed immunoelectrophoresis of patient's plasma, with and without heparin, showed a typical profile of qualitative HBS antithrombin deficiency. The molecular analysis revealed an homozygous Arg 4-Cys mutation. Antithrombotic therapy was achieved with continuous infusion of antithrombin concentrates (80 IU/kg/day) and unfractionated heparin (500 IU/kg/day) during 12 days, leading to clinical improvement, and followed by treatment with vitamin K antagonists. This observation emphasizes the risk of intrauterine fetal demise and the inefficiency of heparin therapy without antithrombin infusion in type II HBS homozygous deficiency. The management of a future pregnancy will probably require repeated infusions of antithrombin.