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

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.

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.

A prothrombin gene mutation is significantly associated with venous thrombosis.

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.

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.

Vitamin K-dependent clotting factors are elevated in young adults who have close relatives with ischemic heart disease.

An increase in factor VII was found to be a risk factor for ischemic heart disease. The present study was designed to test the hypothesis that this increase in factor VII is part of a general increase in vitamin K-dependent clotting factors. Initially, a prospective analysis of factor VII antigen and prothrombin activity was performed in two groups of young subjects without symptoms who differed in their risk of ischemic heart disease based on a history (or lack thereof) of premature heart disease in a first-degree relative. A statistically significant increase in prothrombin activity and factor VII antigen was found in the high-risk group of subjects when compared with the low-risk group. In a second series of subjects, factor IX and X activity assays were also performed, and all four of the vitamin K-dependent clotting factors were found to be significantly higher in high-risk subjects when compared with low-risk subjects. A second goal of the study was to explore whether correlations between factor VII and cholesterol and triglycerides might be due to binding of factor VII with apolipoprotein B. Although a significant correlation of factor VII antigen with apolipoprotein B (rho = 0.523, p < 0.025) was found in our high-risk group of subjects, the correlation between factor VII and triglycerides (rho = 0.641, p < 0.005) was even stronger statistically, suggesting a probable interaction of factor VII with very-low-density lipoproteins in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma fibrinogen level is not elevated in young adults from families with premature ischemic heart disease.

Several epidemiological studies have found that the plasma fibrinogen level is a risk factor for ischemic heart disease (IHD), similar in importance to the serum cholesterol level. A family history of IHD is also a significant risk factor for IHD, statistically independent of the serum cholesterol level. Whether the familial risk for IHD is related to genetic control of the fibrinogen level is unknown. Estimates of the genetic contribution to the variance in plasma fibrinogen levels vary markedly. We previously found elevated levels of cholesterol and factor VII in young subjects with a familial history of premature IHD. In the present study we chose to measure fibrinogen, factor VII antigen, and total cholesterol levels in 43 asymptomatic first-degree relatives (< 50 years old) of patients with premature IHD and in 43 age- and sex-matched asymptomatic young adults at low risk of IHD. No subjects in either group were smokers. The mean plasma fibrinogen level of the high-risk group (259 mg/dL) did not differ significantly from that of the low-risk group (250 mg/dL; p > 0.4). In contrast, the high-risk group had significantly higher mean factor VII antigen (p < 0.001) and mean serum cholesterol (p < 0.0001) than the low-risk group. These data argue against the hypothesis that genetic determination of the plasma fibrinogen level is a common pathophysiological mechanism responsible for familial risk of IHD.

Dibucaine elicits platelet procoagulant activity in factor VIII and factor X activation by a mechanism involving a sulfhydryl-dependent enzyme.

Dibucaine, a potent inhibitor of platelet aggregation and platelet release, was found to enhance the ability of fresh gel-filtered or washed human platelets to support factor VIII activation and factor X activation. Dibucaine-treated platelets increased the peak of factor VIII clotting activity by 2-fold compared to activity with untreated platelets. Similarly platelets optimally stimulated by dibucaine (1.0-1.5 mM for 5 min at 37 degrees C) supported as much factor X activation by factors IXa and VIII (measured in a chromogenic assay) as platelets optimally stimulated by ionophore A23187 (15 microM). An assay of platelet calcium-dependent sulfhydryl proteases was devised and used to test the effect of various inhibitors on these platelet proteases. The membrane-permeable sulfhydryl inhibitor Thiolyte MB inhibited platelet calcium-dependent protease activity; whereas, membrane-impermeable Thiolyte MQ did not. Thiolyte MB also blocked the ability of dibucaine-stimulated platelets to support factor X activation. Incubation of fresh, gel-filtered platelets with calpain inhibitor II (N-Ac-L-L-Normethioninal) completely inhibited the calcium-dependent sulfhydryl protease activity of these platelets but did not affect their ability to support factor X activation after subsequent incubation with dibucaine. These data support the interpretation that an intracellular SH-dependent enzyme, which may not be calpain, is involved in the expression of platelet procoagulant activity in dibucaine-treated platelets.

Correlation of factor VII activity and antigen with cholesterol and triglycerides in healthy young adults.

Prospective epidemiological studies found that the plasma level of factor VII activity was a risk factor for ischemic heart disease (IHD). Our laboratory previously demonstrated that young adults (mean age, 35 years) at high risk of IHD had significantly higher plasma factor VII activity and antigen levels than did comparable young adults at low risk. To study the relation of factor VII with lipid metabolism in even younger adults (less than 30 years), using standard techniques we measured plasma factor VII activity and antigen, plasma fibrinogen, and fasting serum lipid fractions in healthy male and female subjects who were at low risk of IHD and who were not on medication. Factor VII antigen correlated significantly with total serum cholesterol, fasting serum triglycerides, and high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol (p less than 0.01), and factor VII activity correlated with total and HDL cholesterol (p less than 0.05) in the men (n = 132); however, fibrinogen level did not correlate significantly with any lipid level in this group. We found no significant correlation of factor VII activity or antigen with any lipid levels in the women (n = 65). Our data support the hypothesis that control of plasma factor VII level is linked to lipid metabolism in normal physiology in men. Thus, factor VII level may reflect the mechanism by which male gender imparts added risk for IHD, independent of other established risk factors. This study also supports the use of the factor VII antigen assay, a highly reproducible method, in studies of the relation of factor VII to the risk of IHD.

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.

Effective therapy of human immunodeficiency virus-associated anemia with recombinant human erythropoietin despite high endogenous erythropoietin.

A 32-year-old woman with human immunodeficiency virus (HIV) infection and progressive anemia presented to University Hospital with a hemoglobin of 3.4 g/dl. Because of her religious beliefs, she refused transfusion, and no iron or vitamin deficiency was found. She responded to recombinant human erythropoietin 150 U/kg intramuscularly thrice weekly with a rise in hemoglobin to 9.3 g/dl by 3 months of treatment. The serum erythropoietin level before treatment was markedly elevated at 1,340 mU/ml.

Postoperative thrombocytopenia in type IIB von Willebrand disease.

We report studies of a large kindred with type IIb von Willebrand disease and manifestations of thrombocytopenia. While only one member of the family was thrombocytopenic routinely, three members of the family who underwent various surgical procedures demonstrated thrombocytopenia and platelet clumping postoperatively. Platelet clumps were found on peripheral blood smear only in the immediate postoperative specimens and did not appear to be a technical artifact. In the one patient who received no preoperative prophylactic therapy, postoperative plasma specimens showed the transient appearance of high molecular weight von Willebrand factor multimers. These results support the hypothesis that surgery, or some related aspect such as stress, led to the release of high molecular weight multimers, resulting in platelet clumping and removal from the circulation, and subsequent thrombocytopenia. Thrombocytopenia under conditions of stress may be a more common manifestation of type IIb vWd than is currently appreciated.

Evaluation of the safety, recovery, half-life, and clinical efficacy of antithrombin III (human) in patients with hereditary antithrombin III deficiency. Cooperative Study Group.

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.

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.

The use of polyelectrolyte-fractionated porcine factor VIII in the treatment of a spontaneously acquired inhibitor to factor VIII.

Polyelectrolyte-fractionated porcine factor VIII concentrate is a recent addition to the therapeutic choices for treatment of factor VIII inhibitor patients, but cross-reactivity of the inhibitor with porcine factor VIII limits its usefulness in some cases. Hemophilic patients with inhibitor titers greater than or equal to 50 Bethesda units/micromilligrams often demonstrate sufficient cross-reactivity (10-20%) to prevent the achievement of a satisfactory plasma factor VIII level and a therapeutic response with porcine factor VIII. We have studied plasma from five women with high-titer, spontaneously acquired factor VIII inhibitors to determine the degree of cross-reactivity with porcine factor VIII. Four of the five had little or no detectable inhibitor to porcine factor VIII despite high titers to human factor VIII (26-143 Bethesda units/micromilligrams). One of these patients, with a titer of 53 Bethesda units/micromilligrams against human factor VIII, was treated successfully with porcine factor VIII concentrate, given for serious hemorrhagic complications. These studies and other reports support the conclusion that the majority of high-titer spontaneous factor VIII inhibitors exhibit little cross-reactivity with porcine factor VIII and can be treated successfully with this product.

Controlled prospective study of factor IX concentrate therapy and immunodeficiency.

In 1983, six patients who were exclusively treated with factor IX (FIX) concentrate (greater than 40,000 units/yr) were prospectively matched for age and dosage to six patients treated exclusively with factor VIII (FVIII) concentrate and to six normal male controls. At baseline evaluation between October 1983 and May 1984, both groups had significantly decreased absolute T helper cell counts (mean of 452/microliters and 505/microliters for FIX- and FVIII-treated groups, respectively) compared to normal (1,157/microliters). By August 1988, three of the six FIX-treated group have developed AIDS and two are seropositive for antibody to the human immunodeficiency virus (HIV). Four of the six FVIII-treated group have HIV seropositivity or disease. The other three patients (1/6 for FIX and 2/6 for FVIII) declined HIV antibody testing. Our results support other studies showing a dose-related risk of HIV exposure for FIX concentrate-treated patients and do not support the view that FIX concentrate was intrinsically safer than FVIII concentrate.

Antithrombin Oslo: type Ib classification of the first reported antithrombin-deficient family, with a review of hereditary antithrombin variants.

Patients with classical antithrombin deficiency (Type I) from seven unrelated kindreds were studied by crossed immunoelectrophoresis of plasma in the presence and absence of heparin. The only abnormal pattern was found in the kindred first reported by Egeberg in 1965. An abnormal cathodal peak of antithrombin antigen was found in the presence, but not the absence, of heparin in the first dimension gel. We have named this variant antithrombin Oslo. Such evidence of an abnormal protein, despite equivalent low levels of antithrombin antigen and activity, has been denoted previously by Sas as Type Ib deficiency. In the context of this new report, we review the literature to date on 33 other variants of the Types Ib, II and III subclassifications with a discussion of the value of the classification scheme.

Factor VII activity state in coronary artery disease.

In a recent study, Dalaker et al. (Br J Haematol 1985; 61:315-22) reported that men at high risk for cardiovascular disease had an increased mean level of factor VII procoagulant activity that was apparently attributable to an increase of a phospholipase C-sensitive form of factor VII in their plasma. We chose to investigate this phenomenon further by observing patients at high risk of coronary artery disease with assays that reflect the activity state of factor VII. We measured factor VII levels in patients before coronary arteriography and in normal subjects by an amidolytic assay (FVIIam assay) and by a standard clotting assay (FVIIc-A assay), both of which reflect the total amount of factor VII and are insensitive to activated factor VII, and by the method of Seligson et al. (Blood 1978;52:978-88) (FVIIc-B assay), which is sensitive to the presence of activated factor VII. In the FVIIc-A and FVIIam assays, the patients had a significantly higher mean value than the normal subjects; in the FVIIc-B assay, the patients had a significantly lower mean value than did the normal subjects. Moreover, the ratio of FVIIc-B to FVIIam, which is an indicator of the factor VII activity state, was much lower for the patients (0.70) than for the normal subjects (0.99). Thus, patients at high risk for coronary artery disease have an increased mean level of total factor VII that is not associated with an increase in activated factor VII and therefore presumably reflects an increase in zymogen factor VII.