Summary.  von Willebrand disease (VWD) is a commonly encountered inherited bleeding disorder affecting both males and females, causing mucous membrane and skin bleeding symptoms, and bleeding with surgical or other haemostatic challenges. VWD may be disproportionately symptomatic in women of child‐bearing age. It may also occur less frequently as an acquired disorder (acquired von Willebrand syndrome). VWD is caused by deficiency or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates platelet haemostatic function and stabilizes blood coagulation factor VIII. The pathophysiology, classification, diagnosis and management of VWD are relatively complex, but understanding them is important for proper diagnosis and management of patients with VWD. These evidence‐based guidelines for diagnosis and management of VWD from the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel (USA) review relevant publications, summarize current understanding of VWD pathophysiology and classification, and present consensus diagnostic and management recommendations based on analysis of the literature and expert opinion. They also suggest an approach for clinical and laboratory evaluation of individuals with bleeding symptoms, history of bleeding or conditions associated with increased bleeding risk. This document summarizes needs for further research in VWF, VWD and bleeding disorders, including clinical research to obtain more objective information about bleeding symptoms, advancements in diagnostic and therapeutic tools, and enhancement in the education and training of clinicians and scientists in bleeding and thrombotic disorders. The NHLBI Web site (http://www.nhlbi.nih.gov/guidelines/vwd) has a more detailed document, a synopsis of these recommendations, and patient education information.

Von Willebrand factor (VWF) mediates blood platelet adhesion and accumulation at sites of blood vessel injury, and also carries coagulation factor VIII (FVIII) that is important for generating procoagulant activity. Von Willebrand disease (VWD), the most common inherited bleeding disorder, affects males and females, and reflects deficiency or defects of VWF that may also cause decreased FVIII. It may also occur less commonly as an acquired disorder (acquired von Willebrand syndrome). This article briefly summarizes selected features of the March 2008 evidence-based clinical and laboratory diagnostic recommendations from the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel for assessment for VWD or other bleeding disorders or risks. Management of VWD is also addressed in the NHLBI guidelines, but is not summarized here. The VWD guidelines are available at the NHLBI Web site (http://www.nhlbi.nih.gov/guidelines/vwd).

Six different substitution mutations were identified in four different amino acid residues of antithrombin strand 1C and the polypeptide leading into strand 4B (F402S, F402C, F402L, A404T, N405K, and P407T), and are responsible for functional antithrombin deficiency in seven independently ascertained kindreds (Rosny, Torino, Maisons-Laffitte, Paris 3, La Rochelle, Budapest 5, and Oslo) affected by venous thromboembolic disease. In all seven families, variant antithrombins with heparin-binding abnormalities were detected by crossed immunoelectrophoresis, and in six of the kindreds there was a reduced antigen concentration of plasma antithrombin. Two of the variant antithrombins, Rosny and Torino, were purified by heparin-Sepharose and immunoaffinity chromatography, and shown to have greatly reduced heparin cofactor and progressive inhibitor activities in vitro. The defective interactions of these mutants with thrombin may result from proximity of s1C to the reactive site, while reduced circulating levels may be related to siC proximity to highly conserved internal ft strands, which contain elements proposed to influence serpin turnover and intracellular degradation. In contrast, siC is spatially distant to the positively charged surface which forms the heparin binding site of antithrombin; altered heparin binding properties of siC variants may therefore reflect conformational linkage between the reactive site and heparin binding regions of the molecule. This work demonstrates that point mutations in and immediately adjacent to strand 1C have multiple, or pleiotropic, effects on this serpin, leading ultimately to failure of its regulatory function. (J.

This case-control study examined the prevalence of a prothrombin gene mutation in the 3'-untranslated region (UTR) first reported by Poort et al in Dutch subjects with a history of venous thrombosis and in matched control subjects without a history of thrombosis. We tested the hypothesis that the presence of the 3'UTR prothrombin mutation would convey a higher risk of venous or arterial thrombosis and therefore would be found in a higher-than-normal percentage of subjects with a history of thrombosis. Our study included 100 subjects: 50 with a history of thrombosis (21 with venous thrombosis and 29 with arterial thrombosis, who had been recruited from an anticoagulation clinic) and 50 control subjects without a history of thrombosis. DNA from these subjects was analyzed by polymerase chain reaction and agarose gel electrophoresis. We found a statistically significant increase in the prevalence of the 3'UTR mutation in subjects with a history of venous thrombosis compared with subjects without thrombosis. The prevalence of the 3'UTR prothrombin mutation was 19% (4/21;3 heterozygous and 1 homozygous) in subjects with a history of venous thrombosis, 0% (0/29) in subjects with a history of arterial thrombosis, and 2% (1/50) in control subjects (P < .0245, by Fisher's exact test for comparison of subjects with versus those without a history of venous thrombosis). The G-->A mutation at nucleotide 20,210 in the 3'UTR was confirmed by direct DNA sequencing. The similar increased prevalence of the 3'UTR mutation in subjects with venous thrombosis in our population and in the Dutch population studied by Poort et al suggests that this mutation is an important risk factor for venous thrombosis in the general white population.

The plasma level of factor VII activity was a risk factor for the development of ischemic heart disease (IHD) in a prospective epidemiological study of hemostatic factors. We have previously reported significant correlations between factor VII clotting activity or antigen and lipid fractions in a group of 132 young men (<30 years old) at low risk for IHD and concluded that control of the plasma factor VII level may be linked to lipid metabolism in normal male physiology. Because factor VII is one of four vitamin K-dependent procoagulant proteins, we hypothesized that plasma levels of all these proteins would be similarly controlled in normal physiology. In an extension of this study, we have measured two additional vitamin K-dependent clotting factors (prothrombin [factor II] and factor X activity), as well as factor VII activity and antigen and fasting serum lipid fractions in healthy young men and women (<30 years old) at low risk for T he Northwick Park Heart Study identified elevated plasma factor VII clotting activity as a predictive risk factor for ischemic heart disease (EHD) in a prospective study of 1511 middle-aged men.1 -2 Other investigators have reported a positive correlation between factor VII levels and total serum cholesterol, 2 -3 triglycerides, 3 7 and the large, trigryceride-rich lipoproteins, especially very-low-density lipoproteins (VLDL). 48 The correlations of factor VII activity with lipid fractions in these studies may have reflected pathophysiological changes related to the presence of silent or subclinical arteriosclerosis in the middle-aged and older subjects in the studies.We have previously demonstrated that young adults (mean age, 35 years) at high risk for IHD had significantly higher plasma factor VII activity and antigen levels than comparable young adults at low risk. 9 We subsequently found that a similar group of high-risk young adults (mean age, 34.8 years) also had significant elevations of prothrombin, factor IX, and factor X clotting activities, as well as factor VII, compared with young adults at low risk. 10 We have also found a strong positive correlation of factor VII activity and antigen with fasting levels of total serum cholesterol, serum triglycerides, high-density lipoprotein cholesterol (HDL-C), or low-density lipoprotein cholesterol IHD. In the women, we found significant positive correlations of factor VII antigen with total or HDL cholesterol and of prothrombin or factor X with total or LDL cholesterol. In the men, factor VII activity or antigen correlated with total cholesterol, triglycerides, HDL cholesterol, or LDL cholesterol; prothrombin or factor X correlated with total cholesterol, triglycerides, or LDL cholesterol. In contrast, we found no significant correlations of fibrinogen with any of the lipid fractions in our groups of men or women. Our data support the hypothesis that control of the levels of the vitamin K-dependent procoagulant proteins is linked to lipid metabolism in the normal physiology of both men and women. (Arterioscler Thro...

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The Northwick Park Heart Study found that elevation of factor VII in middle-aged subjects was an independent risk factor for subsequent ischemic heart disease. The present study was designed to determine whether factor VII elevation is present at a younger age and whether zymogen or activated factor VII is responsible for this elevation. A group of 20 asymptomatic first degree relatives (mean age 34.9 years) of patients with premature ischemic heart disease were compared with 15 age-matched normal subjects at low risk of ischemic heart disease and 15 older subjects with established ischemic heart disease (mean age 49.7 years). Factor VII procoagulant, coupled amidolytic and antigenic assays, as well as fasting serum triglyceride and cholesterol assays, were performed on all three groups. Factor VII antigen and coagulant activity was significantly elevated in first degree relatives, as was factor VII antigen in the patients with ischemic heart disease. The increased factor VII level in these subjects was caused by elevated factor VII zymogen, not activated factor VII. The results of this study, combined with those of previous studies, suggest that factor VII may be a useful additional marker of the risk for ischemic heart disease and merits further investigation.

Antithrombin III (Human) (AT III) was administered to 18 patients with documented hereditary AT III deficiency. In eight patients with no ongoing clinical symptoms of thrombosis, the percent increase per unit AT III infused per kilogram of body weight ranged from 1.56% to 2.74%, and the half-life from 43.3 to 77.0 hours. No significant difference was noted between patients receiving and those not receiving coumarin therapy. In clinically ill patients, the in vivo recovery was significantly lower and ranged from 0.64% to 1.90% increase per unit AT III infused/kg. Efficacy of AT III was evaluated in 13 patients for the prevention or treatment of thrombosis. AT III was efficacious as assessed by the absence of thrombotic complications after surgery and/or parturition, and the nonextension and nonrecurrence of thrombosis in patients exhibiting an acute thrombotic episode. No side effects were noted. Follow-up studies indicated no hepatitis B seroconversion and no alanine aminotransferase elevations in patients who were not transfused with other blood products.