Annie Bezeaud

Coagulation disorders in patients with cirrhosis and severe sepsis

Background: In patients with cirrhosis, severe sepsis may stimulate the extrinsic coagulation pathway resulting in thrombin generation and fibrin formation.

Bleeding in patients with Budd–Chiari syndrome

BACKGROUND & AIMS Anticoagulation therapy is recommended for patients with Budd-Chiari syndrome (BCS). This study aimed to assess the incidence, severity, and risk factors of major bleeding in patients with Budd-Chiari syndrome (BCS) receiving anticoagulation therapy. METHODS We evaluated 94 consecutive BCS patients. Major bleeding required hospitalization, and/or transfusion of ≥ 2 red blood cell units, and/or was located intracranially, and/or retroperitoneally, and/or was fatal. RESULTS After a median follow-up of 43 months, 47 patients had 92 major bleeding episodes (22.8 per 100 patient-years). Forty episodes were related to invasive therapy for BCS. The origin of the 52 other episodes was gastrointestinal in 26 (including 15 related to portal hypertension) and genital in 10; 26 were spontaneous and 26 provoked. Excess anticoagulation was identified in 13 (27%) out of 49 documented episodes. Bleeding was managed by interrupting or reducing anticoagulation in 34 episodes, surgery in 18, endoscopy in 12, and radiological intervention in 8. The presence of esophageal varices was an independent predictor of bleeding unrelated to invasive therapy for BCS. Bleeding contributed to death in five patients and caused neurological complications in two. These poor outcomes were associated with more severe liver disease at baseline. CONCLUSIONS Major bleeding is common in BCS patients receiving anticoagulation therapy. Invasive procedures and portal hypertension are major factors, while excess anticoagulation plays a secondary role. Baseline BCS severity is the main determinant of prognosis at bleeding. Reducing anticoagulation intensity during invasive therapy and reinforced prophylaxis for portal hypertension could improve the benefit-risk ratio of anticoagulation.

Sickle cell disease : relation between procoagulant activity of red blood cells from different phenotypes and in vivo blood coagulation activation

In the present study we examined if, among other mechanisms, the abnormal exposure of phosphatidylserine at the surface of sickle red blood cells (RBCs) contributes to the hypercoagulability which characterizes homozygous sickle cell disease (SCD). The question was addressed by comparison of the procoagulant properties of RBCs from subjects with various phenotypes (SS, SC and AS) that differ in clinical presentation. As previously reported, SS‐RBCs accelerated the prothrombin activation by factor Xa, by decreasing the Km of the reaction compared to normal RBCs. SC‐RBCs and AS‐RBCs also promoted prothrombin activation although their procoagulant properties were milder compared to SS‐RBCs. A significant increase of the thrombin–antithrombin complexes was observed in SS subjects. Prothrombin fragment 1+2 (F1+2) was elevated in half of the SS subjects, but the difference with controls did not reach significance. Elevated levels of thrombin–antithrombin complexes were observed in a number of SC (4/11) and AS (3/12) subjects, but the difference with controls was not significant. A significant correlation was observed between the plasma levels of thrombin–antithrombin complexes in the subjects with SS, AS and AA phenotypes, and the procoagulant properties of RBCs. Our results strongly suggest that the procoagulant properties which characterize SS‐RBCs also affect SC‐RBCs and AS‐RBCs, and that exposure of phosphatidylserine by RBCs contributes to the hypercoagulable state observed in SCD.

Prothrombin Saint-Denis: a natural variant with a point mutation resulting in Asp to Glu substitution at position 552 in prothrombin.

A new prothrombin variant, with a point mutation at nucleotide 20 029 resulting in Asp 552 to Glu substitution (prothrombin numbering), has been identified in a male newborn. Plasma prothrombin level was <3%, 16% and 60% when measured by clotting, chromogenic and immunological assays respectively. The substitution did not affect the rate of prothrombin conversion to thrombin but altered thrombin activity. Amino acid 552 has been reported to be involved in the allosteric transition, which is induced by sodium binding to thrombin. This is the first known amino acid substitution at this site to result in dysprothrombinaemia.

Red blood cells from patients with homozygous sickle cell disease provide a catalytic surface for factor Va inactivation by activated protein C

Summary.  The structure of red blood cell (RBC) membranes in homozygous sickle cell disease (SCD) is significantly disturbed, with an increased exposure of aminophospholipids (phosphatidylserine and phosphatidylethanolamine) at the outer surface, responsible for a procoagulant activity of SS RBCs. Aminophospholipids are known not only to promote procoagulant reactions, but also to support inhibition of blood coagulation by the protein C system. The aim of the present study was to examine whether SS RBCs could serve as a catalytic surface for the inactivation of factor Va by activated protein C (APC). Venous blood was obtained from 19 consecutive SS patients and 13 controls (AA). In all SS patients, the amount of phosphatidylserine exposed at the outer surface of RBCs was increased compared with controls, as demonstrated by a prothrombinase assay. In addition, SS RBCs significantly (P < 0·0001) increased the rate of FVa inactivation by APC: the mean values (and ranges) of the factor Va inactivation rates were 30 (0–57) vs 9·5 (0–32) mmol Vai/min/mol APC for SS RBCs and normal RBCs respectively. Our results indicate that SS RBCs provide a catalytic surface for the negative control of blood coagulation, which may partially control the procoagulant activity of these cells.