Hereditary combined deficiency of vitamin K-dependent factors is a rare entity. We report a 7-year-old girl of Arab origin with hereditary deficiency of the procoagulants factors II, VII, IX and X and the natural anticoagulants proteins C and S. The patient is the tenth offspring of a consanguinous marriage and presented at 6 weeks with spontaneous intracerebral haemorrhage. Symptoms improved following plasma infusion. A sibling died at 5 d from uncontrollable umbilical bleeding. Blood coagulation work-up at 6 years showed: factor II:C (activity) 12 U/dl, factor II:Ag (antigen) 40 U/dl; factor VII:C 12 U/dl; factor IX:C 36 U/dl, factor IX:Ag 57 U/dl; factor X:C 17 U/dl, factor X:Ag 54 U/dl; protein C activity 43 U/dl; protein C:Ag 45 U/dl; protein S:Ag 34 U/dl; levels of factors V:C and VIII:C were normal. Assays of coagulation factors in the parents and five of the siblings were within the normal range. Following acute infection and dilantin therapy procoagulant activity levels were reduced further and were partially increased after vitamin K infusion. Crossed immunoelectrophoresis of prothrombin in the presence of calcium lactate revealed a population of des-carboxyprothrombin. Serum vitamin K epoxide levels were undetectable. The data suggest that the defect in our patient stems from abnormal carboxylation of the vitamin K-dependent proteins and that the mode of inheritance is autosomal recessive.
SummaryTo account for the lack of correlation between the level of factor XI (FXI) in deficient patients and haemorrhagic manifestations, we correlated the prevalence of combined FXI and von Willebrand’s factor (vWF) deficiency in 212 FXI-deficient patients. Fifty-four patients had a combined FXI and vWF deficiency: 16 patients had severe and 38 patients had mild FXT deficiency. In a group of 28 patients with comparably mild FXI deficiency, 14 bleeders had significantly lower mean vWF, Ag, ristocetin cofactor and ristocetin induced platelet aggregation than 14 non-bleeders selected on the basis of comparable FXI levels. These findings suggest that the combination of FXI and vWF deficiency is common and may affect the bleeding tendency in mild FXI deficiency.
Previous preliminary data and case reports have suggested an association of von Willebrand's disease (vWD) with factor XI deficiency and platelet abnormalities. We have analyzed the prevalence of factor XI deficiency and thrombocytopathy in a cohort of Israeli patients with vWD. Decreased factor XI levels (<67 U/dl) were documented in 35 of 63 (36%) vWD subjects; factor XI levels were <30 U/dl in five of 60 (8%). A significant decline in ADP-induced platelet aggregation (<30% of control) was found in 48% of vWD patients. Likewise, epinephrine-induced aggregation was reduced in 41%, and collagen-induced aggregation was decreased in 7% of vWD patients. Logistic regression analysis showed that while Ivy bleeding time, ristocetin cofactor, and ristocetin-induced platelet aggregation did not predict bleeding, both von Willebrand factor antigen and factor XI activity levels predict bleeding in patients with vWD. These findings suggest that mild factor XI deficiency and thrombocytopathy are common in Israeli subjects with vWD and that associated factor XI deficiency can result in clinical bleeding in these patients. Key Words: Von Willebrand' s disease—Factor XI deficiency—Thrombocytopathy.
Fibrinogen is composed of six polypeptide chains, 2 Aα, 2 Bβ and 2 γ chains, covalently linked at their amino termini by disulfide bonds. Fibrinogen is activated to α,β-fibrin by thrombin which cleaves 2 A (FPA) and 2B (FPB) fibrinopeptides from the N-termini. Release of FPA and FPB exposes'A'and'B' polymerization sites, respectively. The resulting fibrin self-associates into a branched 3-dimensional matrix. Two other types of fibrin can be formed in vitro: ct-fibrin [FPA release]and β-fibrin [FPB reelease). Fibrinogen Haifa is a congenital abnormal fibrinogen variant characterized by normal fibrinopeptide release, abnormal fibrin polymerization and replacement of γ275 Arg by His. The propositus has experienced thrombotic episodes. In this study the ultrastructure of fibrin formed from fibrinogen Haifa was compared to that of normal fibrin in order to better define the effect of the γ275 Arg → His substitution on its molecular function.
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