Mae B. Hultin

von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA)†

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.

Increased factor VIII/von Willebrand factor antigen and von Willebrand factor activity in renal failure☆

Factor VIII/von Willebrand factor antigen and von Willebrand factor activity (ristocetin assay) were studied in 12 patients in renal failure. A dramatic increase in both activities was observed (antigen 315 +/- 30 per cent in patients verus 104 +/- 9 per cent in control subjects; activity 402 +/- 48 per cent in patients versus 111 +/- 5 per cent in control subjects; p less than 0.001 for both). Since von Willebrand factor is thought to play at least a facilitative role in the development of arteriosclerosis, these increased activities may contribute to the premature arteriosclerosis reported in patients with chronic renal failure undergoing dialysis.

Elevation of factor VII activity and mass in young adults at risk of ischemic heart disease

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.

Correlation of vitamin K-dependent clotting factors with cholesterol and triglycerides in healthy young adults.

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 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.

Acquired inhibitors in malignant and nonmalignant disease states

Acquired inhibitors against factor VIII:C (FVIII:C) arise in nonhemophilic patients who have many associated disease states, both malignant and benign. This review emphasizes knowledge of the association with malignant diseases and places particularly close attention on the hematologic malignancies, including plasma cell dyscrasias and lymphoproliferative disorders. Characteristics of postpartum inhibitors are examined, as well as the association of inhibitor with certain drugs and dermatologic conditions. Also discussed is the experience amassed by one center over the past decade in the treatment of patients with inhibitors against FVIII:C.

Clinical and laboratory diagnosis of von Willebrand disease: A synopsis of the 2008 NHLBI/NIH guidelines

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). Am. J. Hematol. 2009.

Postprandial Elevation of Activated Factor VII in Young Adults

The Northwick Park Heart Study found that factor VII (FVII) activity was a risk factor for ischemic heart disease, and other studies based on indirect assays of activated factor VII (FVIIa) found an elevation of FVIIa postprandially. We hypothesized that postprandial elevation of FVIIa would produce intermittent activation of factor X to Xa and, subsequently, prothrombin to thrombin. We chose to study postprandial activation of coagulation with a new assay specific for FVIIa that uses soluble tissue factor and with a prothrombin fragment 1 + 2 (F1 + 2) assay to detect the activation of prothrombin by factor Xa. We fed a high-fat breakfast (30 g/m2) to 30 healthy volunteer subjects (30.8 +/- 9.8 years; range, 20 to 49 years) on no medication. Fasting blood samples were collected for FVIIa, FVII antigen (FVIIag). and F1 + 2 as well as triglycerides and total and HDL cholesterol. A significant difference was found between fasting (2.82 +/- 1.49 ng/mL. mean +/- SD) and 6-hour postprandial (3.45 +/- 2.08 ng/mL) FVIIa levels (P < .004); FVIIag did not change significantly (mean, 0.89 U/mL fasting and 0.90 U/mL at 6 hours). In contrast, F1 + 2 levels were slightly lower 6 hours postprandially than fasting (median, 0.39 versus 0.44 nmol/L, P < .02). Four-hour postprandial triglyceride levels correlated significantly (p = 0.51, P < .02) with 6-hour postprandial FVIIag but not with 6-hour postprandial FVIIa. Postprandial F1 + 2 levels (at 6 hours) correlated significantly (p = 0.39, P < .04) with fasting FVIIag levels but not with 6-hour postprandial FVIIa levels. Thus, the basal FVIIag level, in the fasting state, may be involved in control of the generation of F1 + 2. We found a postprandial increase in FVIIa levels after a dietary fat load but did not find a concomitant postprandial burst of activation of factor X and prothrombin as measured by F1 + 2. Further studies are to test whether postprandial FVIIa generation leads to enhanced activation of coagulation.

Lipoprotein(a) Level Does Not Predict Restenosis After Percutaneous Transluminal Coronary Angioplasty

The serum lipoprotein(a) [Lp(a)] level is a known risk factor for arteriosclerotic coronary artery disease. However, its association with restenosis after percutaneous transluminal coronary angioplasty (PTCA) is controversial. We hypothesized that the Lp(a) level is a significant risk factor for restenosis after angioplasty through a pathophysiological mechanism leading to excess thrombin generation or inhibition of fibrinolysis. We designed a prospective study of the relation of Lp(a) to outcome after PTCA, in which we measured selected laboratory variables at entry and collected clinical, procedural, lesion-related, and outcome data pertaining to restenosis. Restenosis was defined as >50% stenosis of the target lesion by angiography or as ischemia in the target vessel distribution by radionuclide-perfusion scan. Before the patients underwent PTCA, blood was obtained by venipuncture for measurement of Lp(a), total cholesterol, thrombin-antithrombin (TAT) complex, alpha2-antiplasmin-plasmin (APP) complex, and plasminogen activator inhibitor-1 (PAI-1). Evaluable outcome data were obtained on 162 subjects, who form the basis of this report. Restenosis occurred in 61 subjects (38%). The Lp(a) level was not correlated significantly with TAT, APP, PAI-1, or the TAT-APP ratio. Levels of TAT, APP, and PAI-1 were not statistically different in the patients with versus those without restenosis. The median ratio of TAT to APP was 2-fold higher in the restenosis group, and this difference approached statistical significance (P=0.07). Univariate analysis was performed for the association of clinical, lesion-related, and procedural risk factors with restenosis. Lp(a) levels did not differ significantly in the restenosis versus no-restenosis group, whether assessed categorically (>25 mg/dL versus <25 mg/dL) or as a continuous variable by Mann-Whitney U test. The number of lesions dilated and the lack of family history of premature heart disease were significantly associated with restenosis (P=0.002 and P=0.008, respectively). A history of diabetes mellitus was of borderline significance (P=0.055). By multiple logistic regression analysis, the number of lesions dilated was the only variable significantly associated with restenosis (P=0.03). We conclude that the number of lesions dilated during PTCA is a significant risk factor for restenosis, whereas the serum Lp(a) level was not a significant risk factor for restenosis in our patient population. The TAT to APP ratio merits further study as a possible risk factor for restenosis.

Intravenous gammaglobulin therapy in the management of a patient with idiopathic thrombocytopenic purpura and a warm autoimmune erythrocyte panagglutinin during pregnancy.

Intravenous gammaglobulin (IVIgG) was recently introduced for the treatment of idiopathic thrombocytopenic purpura (ITP). Reported is a previously splenectomized patient who had a severe exacerbation of her ITP during pregnancy and was managed with large doses of IVIgG throughout the second half of her pregnancy. She also had an autoimmune IgG erythrocyte panagglutinin on her red blood cells and in her serum, but only minimal evidence of hemolysis. There was little or no transplacental passage of her autoimmune antibodies since she delivered a normal fetus after 34 weeks of gestation who had a normal platelet count and no evidence of an antierythrocyte antibody. Interestingly, at the time of delivery the mothers serum IgG was dramatically elevated, but the cord serum IgG was normal for the length of gestation, indicating the presence of a dramatic and abnormal difference in IgG between maternal and fetal blood. This raises the possibility that the IVIgG therapy may have actually prevented transplacental passage of the pathological antibodies.