Characterization of an autosomal dominant bleeding disorder caused by a thrombomodulin mutation.

We describe a family with an autosomal dominant disorder characterized by severe trauma- and surgery-related bleeding. The proband, who experienced life-threatening bleeding during a routine operation, had normal clotting times, but markedly reduced prothrombin consumption. Plasma levels of all coagulation factors and of the main coagulation inhibitors were normal. Thrombin generation at low triggers was severely impaired and mixing experiments suggested the presence of a coagulation inhibitor. Using whole exome sequencing, the underlying genetic defect was identified as the THBD c.1611C>A mutation (p.Cys537Stop), which predicts a truncated form of thrombomodulin that is shed from the vascular endothelium. The patient had decreased expression of endothelium-bound thrombomodulin, but extremely elevated levels of soluble thrombomodulin in plasma, impairing the propagation phase of coagulation via rapid activation of protein C and consequent inactivation of factors Va and VIIIa. The same thrombomodulin mutation has been recently described in an unrelated British family with strikingly similar features.

Pregnancy-related thrombosis risk in patients with protein C deficiency and comparison with pregnant women with heterozygous factor V Leiden mutation.

: The risk of pregnancy-related venous thromboembolism is high in patients with inherited thrombophilia. The aim of this study was to compare the risk of pregnancy related-venous thromboembolism of women with protein C (PC) deficiency to patients with heterozygous factor V Leiden mutation. 145 consecutive pregnant women with confirmed PC deficiency or heterozygous factor V Leiden mutation were prospectively enrolled in the study. Lyon venous thromboembolism-risk score was used to individually tailor antithrombotic prophylaxis. The use of a validated clinical score presents the advantage to have a homogenous management of the venous thromboembolism risk in patients having similar risk factors. 53 pregnancies with PC deficiency were compared with 190 pregnancies in heterozygous factor V Leiden mutation carriers. 50% of the patients with PC deficiency and 64% of the heterozygous factor V Leiden mutation carriers were asymptomatic. According to the Lyon-venous thromboembolism risk score, 50% of patients with PC deficiency and 51% of heterozygous factor V Leiden carriers did not received any antepartum heparin prophylaxis. 34 and 37% of patients respectively received heparin prophylaxis during the third trimester only. No venous thromboembolism was observed in patients with PC deficiency and one postpartum venous thromboembolism occurred in a patient with heterozygous factor V Leiden. In the absence of randomized controlled clinical studies, we report here a large prospective series of pregnant women with PC deficiency. In our cohort, no difference of outcome, in terms of venous thromboembolism, was observed between pregnant women with PC deficiency and those with heterozygous factor V Leiden. Based on our results, low-molecular-weight heparin prophylaxis should not be mandatory in all pregnant women with PC deficiency. Similar prophylaxis strategies may be applied to women with factor V Leiden mutation or PC deficiency.

An unusual clinical presentation of factor XIII deficiency and issues relating to the monitoring of factor XIII replacement therapy.

Congenital factor XIII deficiency is a very rare bleeding disorder. Patients with severe FXIII deficiency usually exhibit severe bleeding diatheses. Factor XIII is also involved in maintaining pregnancy, and women with factor XIII deficiency have a high risk of spontaneous abortions. We report here the case of a patient with a mild bleeding history before her pregnancy but who had three spontaneous haemorrhagic miscarriages. The patient was homozygous for G 501 R mutation of the factor XIII A subunit gene. We also detected a coinherited heterozygous factor V Leiden mutation, probably leading to a milder bleeding tendency. The patient had successful factor XIII replacement therapy throughout her fourth pregnancy. The efficacy of the factor XIII infusions was monitored using thromboelastometry and routine factor XIII measurements. This case report shows that factor XIII deficiency should be ruled out in patients with recurrent fetal loss but with a normal miscarriage workup, even in the absence of a history of severe bleeding since childhood. We also showed that thromboelastometry could be a valuable tool for the monitoring of factor XIII replacement therapy.

Evaluation of thrombin generating capacity in plasma from patients with haemophilia A and B.

In haemophilia patients, a relationship is usually observed between the clinical expression of the disease and plasmatic factor VIII/factor IX (FVIII/FIX) activity. However, it is known from clinical experience, that some haemophilia patients, despite similar FVIII/FIX plasma levels, could exhibit different bleeding phenotype. After determining preanalytical test conditions, we evaluated the thrombin generation capacity from haemophilia plasma samples in various conditions and the potential usefulness of thrombin generation test (TGT) in haemophilia patients. In a series of 46 haemophilia patients (34 haemophilia A and 12 haemophilia B patients), we found a significant correlation between plasmatic FVIII/FIX levels and endogenous thrombin potential (ETP), peak and time to peak obtained by thrombin generation measurement. In addition, a correlation was found between severe clinical bleeding phenotype and ETP. Our results suggest that TGT could be a promising tool to evaluate haemostasis capacity in patients with haemophilia. Our ex vivo results, obtained 24 hours after FVIII concentrate administration, showed that in patients presenting similar plasmatic FVIIII levels, thrombin generation capacity may be significantly different. These results suggest that in patients with haemophilia, TGT could be useful for individually tailoring prophylactic regimens as well as for adapting clotting factors infusions in surgical situations, in addition to FVIII/FIX plasma clotting activities.