Point of care management of heparin administration after heart surgery: A randomized, controlled trial

Objectives: Determination of activated partial thromboplastin time (aPTT) is used in coagulation management after heart surgery. Results from the central laboratory take long to be obtained. We sought to shorten the time to obtain coagulation results and the desired coagulation state and to reduce blood loss and transfusions using point of care (POC) aPTT determination. Design: Randomized, controlled trial. Setting: University-affiliated 20-bed surgical ICU. Patients and participants: Forty-two patients planned for valve surgery (Valves) and 84 for coronary artery bypass grafting (CABG) with cardiopulmonary bypass. Interventions: Valves and CABG were randomized to postoperative coagulation management monitored either by central laboratory aPTT (Lab group) or by POC aPTT (POC group). Heparin was administered according to guidelines. Measurements and results: POC aPTT results were available earlier than Lab aPTT after venipuncture in Valves (3 ± 2 vs. 125 ± 68 min) and in CABG (3 ± 4 vs. 114 ± 62 min). Heparin was introduced earlier in the POC group in Valves (7 ± 23 vs. 13 ± 78 h, p = 0.01). Valves of the POC group bled significantly less than Valves in the Lab group (647 ± 362 ml vs. 992 ± 647ml, p < 0.04), especially during the first 8 h after ICU admission. There was no difference in bleeding in CABG (1074 ± 869 ml vs. 1102 ± 620, p = NS). In Valves, fewer patients in the POC group than in the Lab group needed blood transfusions (1/21 vs. 8/21; p = 0.03). No difference was detected in CABG. Conclusions: In Valves in the POC group the time to the desired coagulation state was reduced, as was the thoracic blood loss, reducing the number of patients transfused. This improvement was not observed in CABG. Side effects were similar in the two group

Quality control of fibrinogen secretion in the molecular pathogenesis of congenital afibrinogenemia

Congenital afibrinogenemia is a rare bleeding disorder characterized by the absence in circulation of fibrinogen, a hexamer composed of two sets of three polypeptides (Aα, Bβ and γ). Each polypeptide is encoded by a distinct gene, FGA, FGB and FGG, all three clustered in a region of 50 kb on 4q31. A subset of afibrinogenemia mutations has been shown to specifically impair fibrinogen secretion, but the underlying molecular mechanisms remained to be elucidated. Here, we show that truncation of the seven most C-terminal residues (R455-Q461) of the Bβ chain specifically inhibits fibrinogen secretion. Expression of additional mutants and structural modelling suggests that neither the last six residues nor R455 is crucial per se for secretion, but prevent protein misfolding by protecting hydrophobic residues in the βC core. Immunofluorescence and immuno-electron microscopy studies indicate that secretion-impaired mutants are retained in a pre-Golgi compartment. In addition, expression of Bβ, γ and angiopoietin-2 chimeric molecules demonstrated that the βC domain prevents the secretion of single chains and complexes, whereas the γC domain allows their secretion. Our data provide new insight into the mechanisms accounting for the quality control of fibrinogen secretion and confirm that mutant fibrinogen retention is one of the pathological mechanisms responsible for congenital afibrinogenemi

Can the phenotype of inherited fibrinogen disorders be predicted?

Congenital fibrinogen disorders are rare diseases affecting either the quantity (afibrinogenaemia and hypofibrinogenaemia) or the quality (dysfibrinogenaemia) or both (hypodysfibrinogenaemia) of fibrinogen. In addition to bleeding, unexpected thrombosis, spontaneous spleen ruptures, painful bone cysts and intrahepatic inclusions can complicate the clinical course of patients with quantitative fibrinogen disorders. Clinical manifestations of dysfibrinogenaemia include absence of symptoms, major bleeding or thrombosis as well as systemic amyloidosis. Although the diagnosis of any type of congenital fibrinogen disorders is usually not too difficult with the help of conventional laboratory tests completed by genetic studies, the correlation between all available tests and the clinical manifestations is more problematic in many cases. Improving accuracy of diagnosis, performing genotype, analysing function of fibrinogen variants and carefully investigating the personal and familial histories may lead to a better assessment of patients' phenotype and therefore help in identifying patients at increased risk of adverse clinical outcomes. This review provides an update of various tests (conventional and global assays, molecular testing, fibrin clot analysis) and clinical features, which may help to better predict the phenotype of the different types of congenital fibrinogen disorders

How I treat dysfibrinogenemia

Congenital dysfibrinogenemia (CD) is caused by structural changes in fibrinogen that modify its function. Diagnosis is based on discrepancy between decreased fibrinogen activity and normal fibrinogen antigen levels and is confirmed by genetic testing. CD is caused by monoallelic mutations in fibrinogen genes that lead to clinically heterogenous disorders. Most patients with CD are asymptomatic at the time of diagnosis, but the clinical course may be complicated by a tendency toward bleeding and/or thrombosis. Patients with a thrombosis-related fibrinogen variant are particularly at risk, and, in such patients, long-term anticoagulation should be considered. Management of surgery and pregnancy raise important and difficult issues. The mainstay of CD treatment remains fibrinogen supplementation. Antifibrinolytic agents are part of the treatment in some specific clinical settings. In this article, we discuss 5 clinical scenarios to highlight common clinical challenges. We detail our approach to establishing a diagnosis of CD and discuss strategies for the management of bleeding, thrombosis, surgery, and pregnancy