Screening of female family members of von Willebrand disease patients: utility of a modified screening tool in a high-risk population.

INTRODUCTION: Family members of Von Willebrand disease (VWD) patients may have low levels of VWF without major bleeding episodes and often remain undiagnosed. AIM: The purpose of this study was to assess the utility of a modified Screening Tool in identifying previously untested reproductive age female family members of VWD patients for haemostatic evaluation. METHODS: Ninety-four reproductive age women including 41 previously untested family members of VWD patients, 26 previously diagnosed VWD patients and 27 healthy controls were administered a modified Screening Tool and had blood drawn for CBC, ferritin, and VWF testing. Participants completed a pictorial blood assessment chart (PBAC) with menses. RESULTS: The modified Screening Tool was positive in 32% family members, 77% VWD patients, and 19% controls (P < 0.001). Combined with low ferritin, the modified Screening Tool was positive in 66% family members, 92% VWD patients, and 44% controls (P = 0.001). In family members, incorporating low ferritin with the modified Screening Tool resulted in a sensitivity of 86% (95% CI, 42-100) and negative predictive value of 93% (95% CI, 66-100). In the control group, NPV was between 92% and 95% for the modified Screening Tool and also for the modified Screening Tool combined with low ferritin or a positive PBAC. CONCLUSION: These data in a racially diverse population suggest the usefulness of a simple, easy to administer modified Screening Tool. In conjunction with ferritin it could be used in a primary care setting to stratify reproductive age women with a family history of VWD for haemostatic evaluation.

Von Willebrand factor for menorrhagia: a survey and literature review.

BACKGROUND: von Willebrand disease (VWD) is the most common congenital bleeding disorder. In women, menorrhagia is the most common bleeding symptom, and is disabling with iron deficiency anaemia, high health cost and poor quality of life. Current hormonal and non-hormonal therapies are limited by ineffectiveness and intolerance. Few data exist regarding von Willebrand factor (VWF), typically prescribed when other treatments fail. The lack of effective therapy for menorrhagia remains the greatest unmet healthcare need in women with VWD. Better therapies are needed to treat women with menorrhagia. METHODS: We conducted a survey of US haemophilia treatment centres (HTCs) and a literature review using medical subject heading (MeSH) search terms 'von Willebrand factor,' 'menorrhagia' and 'von Willebrand disease' to assess the use of VWF in menorrhagia. Analysis was by descriptive statistics. RESULTS: Of 83 surveys distributed to HTC MDs, 20 (24.1%) provided sufficient data for analysis. Of 1321 women with VWD seen during 2011-2014, 816 (61.8%) had menorrhagia, for which combined oral contraceptives, tranexamic acid and desmopressin were the most common first-line therapies for menorrhagia, whereas VWF was third-line therapy reported in 13 women (1.6%). Together with data from 88 women from six published studies, VWF safely reduced menorrhagia in 101 women at a dose of 33-100 IU kg(-1) on day 1-6 of menstrual cycle. CONCLUSIONS: This represents the largest VWD menorrhagia treatment experience to date. VWF safely and effectively reduces menorrhagia in women with VWD. A prospective clinical trial is planned to confirm these findings.

Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis.

The aim of this study was to elucidate the fall in von Willebrand factor (VWF) and factor VIII activity (FVIII) after childbirth in women with and without von Willebrand disease (VWD). VWF:RCo, VWF:Ag, and FVIII were obtained in the third trimester of pregnancy, on admission for childbirth, and 10 times postpartum. Specimens were processed within 4 h and analysed centrally. Means were calculated at each time point. Forty women (40 pregnancies) without VWD and 32 women (35 pregnancies) with VWD were enrolled. 15/32 with VWD were treated (30% of those with type 1 and all of those with type 2) in 17 pregnancies. Treatments prior to delivery consisted of desmopressin (2/17), VWF concentrate (15/17) and after delivery VWF concentrate (16/17). Duration of treatment was 0-21 days (median 6). VWF levels peaked at 250% of baseline--4 h postpartum in women with VWD and 12 h postpartum in women without VWD. Thereafter, VWF levels fell rapidly, approached baseline at 1 week and reached baseline at 3 weeks. Except immediately postpartum, when the levels among treated cases were higher, levels among women with VWD appeared to parallel, but were lower than those among women without VWD. Levels were lowest among those who received treatment. VWF levels fall rapidly after childbirth. Except immediately postpartum, current treatment strategies do not raise VWF levels to the levels of women without VWD or even to the levels of women with milder, untreated VWD. Consequently, women with VWD may be at risk of postpartum haemorrhage despite treatment.

The spectrum of haemostatic characteristics of women with unexplained menorrhagia.

While an estimated 13% of women with unexplained menorrhagia have von Willebrand disease (VWD), the frequency of other potential bleeding disorders has been uncertain. This study describes the relatively wide range of laboratory characteristics of women with unexplained menorrhagia and presents issues affecting diagnosis in this population. Women with pictorial blood assessment chart (PBAC) score > 100 were identified at six U.S. sites and asked to remain drug free for 10 days prior to testing. Blood was collected on one of the first four menstrual cycle days and tested at a central laboratory for procoagulant factors, VWD and fibrinolytic factors. Platelet function testing by PFA-100® (PFA) and platelet aggregation with ATP release (PAGG/ATPR) were performed locally using standardized methods. Among 232 subjects, a laboratory abnormality was found in 170 (73.3%), including 124 of 182 White (68.1%) and 34 of 37 Black (91.9%) subjects; 6.0% had VWD, 56.0% had abnormal PAGG/ATPR, 4.7% had a non-VWD coagulation defect (NVCD) and 6.5% had an abnormal PFA only. AGG/ATPR was reduced in 58.9% of subjects, with multiple agonists in 28.6%, a single agonist in 6.1% and ristocetin alone in 24.2%. Frequencies of PAGG/ATPR defects varied by study site and race; frequencies of VWD and NVCD were similar. Laboratory abnormalities of haemostasis, especially platelet function defects, were common among women with unexplained menorrhagia across multiple U.S. sites. To what degree these abnormalities are clinically significant requires further study.

Surveillance of female patients with inherited bleeding disorders in United States Haemophilia Treatment Centres.

Inherited bleeding disorders are especially problematic for affected girls and women due to the monthly occurrence of menstrual periods and the effects on reproductive health. Although heavy menstrual bleeding (HMB) is the most common manifestation, females with inherited bleeding disorders (FBD) experience other bleeding symptoms throughout the lifespan that can lead to increased morbidity and impairment of daily activities. The purpose of this article is to describe the utility of a female-focused surveillance effort [female Universal Data Collection (UDC) project] in the United States Haemophilia Treatment Centres (HTCs) and to describe the baseline frequency and spectrum of diagnoses and outcomes. All FBD aged 2 years and older receiving care at selected HTCs were eligible for enrollment. Demographic data, diagnoses and historical data regarding bleeding symptoms, treatments, gynaecological abnormalities and obstetrical outcomes were analysed. Analyses represent data collected from 2009 to 2010. The most frequent diagnoses were type 1 von Willebrand's disease (VWD) (195/319; 61.1%), VWD type unknown (49/319; 15.4%) and factor VIII deficiency (40/319; 12.5%). HMB was the most common bleeding symptom (198/253; 78.3%); however, 157 (49.2%) participants reported greater than four symptoms. Oral contraceptives were used most frequently to treat HMB (90/165; 54.5%), followed by desmopressin [1-8 deamino-D-arginine vasopressin (DDAVP)] (56/165; 33.9%). Various pregnancy and childbirth complications were reported, including bleeding during miscarriage (33/43; 76.7%) and postpartum haemorrhage (PPH) (41/109; 37.6%). FBD experience multiple bleeding symptoms and obstetrical-gynaecological morbidity. The female UDC is the first prospective, longitudinal surveillance in the US focusing on FBD and has the potential to further identify complications and reduce adverse outcomes in this population.

Laboratory response to intranasal desmopressin in women with menorrhagia and platelet dysfunction.

Intranasal desmopressin (IN-DDAVP) is used for home treatment of menorrhagia in women with inherited bleeding disorders. The effect of IN-DDAVP on laboratory haemostatic parameters in women with menorrhagia related to platelet dysfunction is unknown. We evaluated the effects of IN-DDAVP on haemostatic parameters in women with menorrhagia and platelet dysfunction and correlated them with menstrual flow. Eleven women (aged 18-45) with menorrhagia and haemostatic abnormalities had determination of von Willebrand factor antigen (VWF:Ag), von Willebrand factor ristocetin cofactor (VWF:RCo) activity, factor VIII coagulant activity (FVIII:C), platelet aggregation and platelet adenosine tri-phosphate (ATP) release pre-IN-DDAVP and 60-min post-IN-DDAVP. Eight of eleven women underwent platelet function analyzer (PFA-100) closure time determination with collagen/adrenaline and collagen/adenosine diphosphate cartridges pretreatment and post-treatment. IN-DDAVP was administered during two consecutive menstrual cycles. Menstrual flow was assessed during each cycle using a pictorial blood assessment chart. Treatment with IN-DDAVP resulted in elevated VWF levels and shortened PFA-100 closure time with significant inverse correlation between shortening of PFA-100 closure times and increases in VWF levels. There were also significant inverse correlations between changes in menstrual flow and changes in VWF:Ag (P = 0.02), VWF:RCo (P = 0.04) and FVIII:C (P = 0.006), following treatment. In vitro platelet aggregation and platelet ATP release response did not correct and did not correlate with changes in menstrual flow. Our results demonstrate a correlation between haemostatic parameters and menstrual flow following IN-DDAVP in women with menorrhagia and platelet dysfunction.

Venous thrombosis and breast cancer in older women: Racial differences in risk factors and mortality.

BACKGROUND: Risk factors for venous thromboembolism (VTE) in women with breast cancer are not known by race. OBJECTIVES: The purpose of our study was to determine risk factors for VTE and VTE associated mortality in white and black women with breast cancer. PATIENTS AND METHODS: The SEER-Medicare merged database (2000 to 2011) was used for women 65 years and older diagnosed with breast cancer. Stratified by race, logistic regression was used to examine risk factors for VTE and Cox proportional hazards regression was used to evaluate the effect of VTE on mortality. RESULTS: There were 276,028 women 65 years and older with breast cancer. Of those, 6.4% white and 10.1% black women with breast cancer had a diagnosis of VTE. In adjusted analyses by race, risk of VTE increased with each year of age in both white and black cohorts. VTE was independently associated with distant metastasis and coexisting medical conditions in white women and in black women, hypertension, heart failure and hyperlipidemia were determinants of VTE. VTE was not associated with distant metastasis in black women. Tumor size, grade, and receptor status were also not independently associated with VTE risk in either white or black women. VTE accorded a higher risk of death in both white (HR = 1.49, 95% CI, 1.34-1.65) and black women (HR = 1.57, 95% CI, 1.23-2.00) with breast cancer. CONCLUSION: The study identified VTE risk factors and effect of VTE on mortality in white and black older women with breast cancer.

Platelet functional defects in women with unexplained menorrhagia.

Menorrhagia is a common clinical problem and is unexplained in more than 50% of women. Although studies suggest that von Willebrand's Disease (VWD) is found in a substantial number of women with unexplained menorrhagia, the prevalence of platelet defects in women with menorrhagia is unknown. To determine the prevalence of platelet and other hemostatic defects, we evaluated women ages 17-55 diagnosed with unexplained menorrhagia. Seventy-four women (52 white, 16 black, six other) were studied. Bleeding time was prolonged in 23 women (31.5%). Maximal percent platelet aggregation was decreased with one or more agonists in 35 (47.3%) women. The most commonly found platelet function defects were reduced aggregation responses to ristocetin in 22 women and to epinephrine in 16 women. Sixteen of 22 women with reduced ristocetin aggregation had von Willebrand ristocetin cofactor (VWF:RCo) and von Willebrand factor antigen (VWF:Ag) > 60%. Platelet ATP release was decreased with one or more agonists in 43 (58.1%) women. Of the black women studied, 11/16 (69%) had abnormal platelet aggregation studies compared with 20/52 white women (39%) (P = 0.06). Black women with menorrhagia had a higher prevalence of decreased platelet aggregation in response to ristocetin and epinephrine than did white women (P = 0.0075, P = 0.02). Ten women (13.5%) had VWF:RCo and/or VWF:Ag < 60%. Using race and blood group specific ranges, 5 (6.8%) women had decreased VWF:RCo, VWF:Ag and/or collagen binding (VWF:CB). Mild factor XI deficiency was found in two women and one woman with mild factor V deficiency and one hemophilia A carrier were identified. We conclude that the prevalence of platelet function defects and other inherited bleeding disorders is substantial in a multiracial US population of women with unexplained menorrhagia.

The effects of Mpl-ligand, interleukin-6 and interleukin-11 on megakaryocyte and platelet alpha-granule proteins.

Thrombopoietin (Mpl ligand), interleukin-6 (IL-6), and interleukin-11 (IL-11) differ in their effects on megakaryocyte maturation and development. In the present study, the impact of these thrombocytopoietic cytokines on biochemical and structural granule and membrane components was examined. Western blotting was performed on equivalent amounts of isolated megakaryocyte or platelet protein and the relative intensities of the enhanced chemiluminescent-visualized bands were quantitated by densitometry. Megakaryocyte growth and development factor (MGDF), a recombinant thrombopoietin-related molecule, significantly increased megakaryocyte fibronectin (72%), thrombospondin (55%), von Willebrand factor (28%) and p-selectin (CD62p) (37%) when compared to equivalent amounts of protein from saline-treated controls (p<0.01). Megakaryocyte fibrinogen was not increased. Ultrastructurally, there was a marked increase in ribosomes and rough endoplasmic reticulum even in mature-appearing megakaryocytes. Platelets from MGDF-treated mice showed small increases in fibronectin (8%), and CD62p (18%), but did not show increases in other measured alpha-granule proteins. Neither IL-6 nor IL-11 increased megakaryocyte or platelet alpha-granule proteins over levels observed in saline controls. IL-11 treated megakaryocytes, while also exhibiting an increase in ribosomes, were characterized by prominent cytoplasmic fragmentation. The study demonstrates the impact of Mpl ligand in increasing synthesized megakaryocyte alpha-granule proteins and of IL-11 in promoting megakaryocyte fragmentation.

Deletion polymorphism in the angiotensin-converting enzyme gene as a thrombophilic risk factor after hip arthroplasty.

Despite thromboprophylaxis, deep vein thrombosis is a common complication of major orthopedic surgery. Predisposing genetic risk factors are unknown. In this case-control study, we investigated the association of the insertion (I)/deletion (D) angiotensin converting enzyme (ACE) gene polymorphism, Factor V Leiden (R506Q) mutation, and 5,10 methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with post-operative venous thrombosis in 85 patients who underwent elective total hip arthroplasty. The odds of a thrombotic event following hip surgery among subjects with the DD genotype of the ACE gene was increased more than 10-fold compared to subjects with the II genotype (odds ratio 11.7 [95% confidence interval 2.3-84.5]); it was increased 5-fold in subjects with the ID genotype compared to the II genotype (odds ratio 5.0 [95% confidence interval 1.1-34.9]). Mean plasma ACE level in control subjects not on ACE inhibitors at the time of study (n=43) was lowest in persons homozygous for the I allele (18.9+/-7.95 U/l), intermediate in patients with the ID genotype (31.6+/-10.8 U/l) and highest in subjects homozygous for the D allele (44.0+/-7.14 U/l). Mean plasma ACE level among cases was higher (33.0 U/l, n=25) than among controls (29.4 U/l, n=43) but this difference was not statistically significant. Neither the Factor V Leiden mutation nor MTHFR gene polymorphism increased the risk of thrombosis following hip replacement. These results demonstrate that the I/D ACE gene polymorphism is a potent risk factor for thrombosis in subjects undergoing total hip arthroplasty.

Effect of niacin supplementation on fibrinogen levels in patients with peripheral vascular disease.

This study demonstrates that niacin supplementation decreases plasma fibrinogen and low-density lipoprotein cholesterol in subjects with peripheral vascular disease randomized to receive niacin, warfarin, antioxidants, or placebo. Changes in fibrinogen levels are highly correlated with changes in low-density lipoprotein cholesterol (r = 0.61; p < 0.009) in subjects taking niacin.

The U.S. Thrombosis and Hemostasis Centers pilot sites program.

Venous thromboembolism (VTE) is a common disorder associated with significant morbidity and mortality. Despite important advances in understanding the etiology of VTE, delivery of care to patients with thrombosis and thrombophilia is frequently incomplete and highly variable. A comprehensive model of health care has been used successfully to treat and prevent complications for people with hemophilia and other chronic disorders. The effectiveness of an integrated healthcare model for patients with all coagulation disorders has yet to be evaluated. The Division of Hereditary Blood Disorders of the Centers for Disease Control and Prevention (CDC) is collaborating with eight Thrombosis and Hemostasis Centers (pilot sites) to provide health-related services and conduct research directed toward the reduction or prevention of complications of thrombosis and thrombophilia. The initial objectives of the collaboration are to (1) determine the efficacy of integrated multidisciplinary care and prevention services for people with hemostatic disorders, (2) assess unmet needs for service delivery and identify outreach strategies to improve access to care, (3) develop effective messages aimed at disease management and prevention, and (4) foster the development of training programs to enhance provider skills for the delivery of patient care. To address these objectives, the investigators and CDC have developed and implemented a web-based patient registry to follow prospectively service allocation and patient outcomes. Funding for the program began in October 2001. All eight funded centers are affiliated with U.S. medical schools. Principal investigators at the centers are hematologists (five adult, two pediatric) or cardiologists. Faculty in obstetrics-gynecology, surgery, and multiple other specialties are integral to the model of care at the centers. Other critical components at the centers are clinical laboratory services, training programs, research networks, and education and outreach programs. From August 2003 to March 2006, over 2,600 patients were enrolled in the registry, accounting for a total of more than 5,000 visits to the centers. Immediate goals of the data collection at the centers are to characterize patients receiving care at centers and document the state of health services provided. Long-term goals are to evaluate prospectively clinical outcomes for patients receiving multidisciplinary care and prevention services at centers. The network of data collection across centers will facilitate future collaborative clinical and epidemiologic investigations and enhance collective expertise in hemostasis and coagulation disorders.

Screening women with menorrhagia for underlying bleeding disorders: the utility of the platelet function analyser and bleeding time.

Menorrhagia is a very common clinical problem among women of reproductive age and recent studies have suggested that underlying bleeding disorders, particularly von Willebrand's deficiency and platelet function defects, are prevalent in women presenting with menorrhagia. The objective of this study was to determine the utility of the platelet function analyser (PFA-100) and bleeding time (BT) as initial screening tests for underlying bleeding disorders in women with menorrhagia. In this study, 81 women with a physician diagnosis of menorrhagia underwent PFA-100 testing, BT and comprehensive haemostatic testing. The effectiveness of the PFA-100 and BT as screening tools in women with menorrhagia was assessed using results of haemostatic testing for von Willebrand's disease (VWD) and platelet dysfunction. In women presenting with menorrhagia, the PFA-100 had a sensitivity 80%, specificity 89%, positive predictive value (PPV) 33%, negative predictive value (NPV) 98% and efficiency 88% for VWD. For platelet aggregation defects, the PFA-100 closure time had a sensitivity 23%, specificity 92%, PPV of 75%, NPV of 52% and efficiency 55%. The data suggest that the PFA-100 may be useful in stratifying women with menorrhagia for further von Willebrand testing; however, neither the PFA-100 nor the BT tests are effective for purposes of classifying women for standard platelet aggregometry testing in women presenting with menorrhagia.

Viral safety of a pasteurized, monoclonal antibody-purified factor VIII concentrate in previously untreated haemophilia A patients.

The efficacy and viral safety of a pasteurized, immunoaffinity-purified procoagulant factor VIII protein (FVIII:C; Monoclate-P) was studied in two multicentre, prospective, open-label trials in 30 previously untreated patients, 18 with severe (< 1% FVIII:C activity), and 12 with moderate (1% to 5% FVIII:C activity) haemophilia A. Clinical assessments, performed at screening and regularly thereafter for 6 to > 24 months (maximum 34 months), showed that none of 24 assessable patients acquired illnesses consistent with monitored transfusion-transmissible diseases. No patients acquired hepatitis B surface antigen, or antibodies against hepatitis B core antigen, hepatitis C, or human immunodeficiency virus. Likewise, no patients acquired treatment-related hepatitis A antibodies or sustained elevations of alanine aminotransferase levels. The safety profile for Monoclate-P is brought about by a multi-step safety system that incorporates viral inactivation (through a combination of immunoaffinity chromatography and pasteurization) plus donor screening, plasma testing, and quality assurance. The inhibitor development rate (13% low titre, 10% high titre) was similar to that reported in the literature for other FVIII concentrates (24% to 52%). The most frequently reported adverse events were related to typical infant and childhood diseases. Monoclate-P was effective in all patients treated according to protocol, except in two, who developed inhibitors.

Platelet production in the pulmonary capillary bed: new ultrastructural evidence for an old concept.

Although there is substantial evidence indicating that platelets are released from megakaryocytes in the capillary bed of the lung, this concept has not been universally accepted because much of the evidence has been indirect. To more definitively substantiate that platelet production takes place in the lungs, megakaryocyte and platelet production was accelerated in mice by phlebotomy or by administration of thrombopoietin, and ultrastructural analysis was performed on lung specimens. Intact megakaryocytes, megakaryocyte fragments with numerous demarcated platelet fields, dissociating intact platelets, and denuded megakaryocyte nuclei were seen in the pulmonary capillaries of mice. In addition, some megakaryocyte nuclei exhibited the morphological counterpart of apoptosis. These observations provide evidence for platelet release in the capillary bed of the lungs during stimulated as well as reactive thrombocytosis without precluding observations that some "proplatelets" form in the sinusoids of the bone marrow before transmigration of intact megakaryocytes into the circulation.

Plasma tissue factor antigen levels in capillary whole blood and venous blood: effect of tissue factor on prothrombin time.

To measure the amount of tissue factor released during specimen collection and its potential effect of shortening the prothrombin time, we measured tissue factor and prothrombin time in twenty-three paired venous and capillary blood samples from anticoagulated patients and in ten paired samples from controls. We also compared venous prothrombin time determined by a plasma-based assay with venous and capillary prothrombin time determined with a whole blood assay. Venous specimens were obtained using a two-syringe technique; capillary specimens were obtained by fingerstick after wiping the first drop of blood. Plasma tissue factor was determined by an enzyme-linked immunoabsorbant assay. The patients' mean venous tissue factor (235 +/- 101 pg/ml) and capillary tissue factor (268 +/- 106 pg/ml) were higher than those of the controls (161 +/- 42 pg/ml and 187 +/- 63 pg/ml, respectively, P < 0.05). These differences disappeared after adjusting for age. Capillary tissue factor levels were higher than venous tissue factor (244 +/- 102 pg/ml vs. 213 +/- 93 pg/ml), with a mean difference of 31 pg/ml (P = 0.0001). In addition, whole blood prothrombin time was lower in the capillary than in the venous samples (17.7 +/- 5 sec vs. 18.3 +/- 5.4 sec, P = 0.004). However, there was no correlation between capillary-venous differences in tissue factor and capillary-venous differences in the whole blood prothrombin time. Whole blood capillary and venous prothrombin times highly correlated with the plasma-based venous prothrombin time (r = 0.98, P < 0.0001). These results demonstrate that obtaining blood by fingerstick does not result in a clinically significant release of tissue factor. In addition, we did not observe any interference of plasma tissue factor with the whole blood prothrombin time assay. A direct relationship between tissue factor and age was observed.

Association of hemostatic factors with peripheral vascular disease.

Hemostatic risk factors have been well established in coronary artery disease but less well studied in peripheral vascular disease. The relationship of coagulation and fibrinolytic proteins to lower limb arterial occlusive disease and other vascular risk factors remains poorly defined. Fibrinogen, factor VII coagulant activity, von Willebrand factor (vWf) antigen, and plasminogen activator inhibitor-1 (PAI-1) activity were measured in 46 adult participants in the Arterial Disease Multiple Intervention Trial (ADMIT) and in 76 control subjects and related to ankle-brachial systolic pressure index (ABI), a measure of lower limb arterial stenosis. The primary inclusion criterion for the ADMIT study population was an average of two ABIs <0.85. Fibrinogen and PAI-1 in ADMIT subjects were significantly higher than in control subjects (331 +/- 52 mg/dl vs 273 +/- 46 mg/dl, p < 0.0001; 18.7 +/- 10 units/ml vs 13.5 +/- 8.9 units/ml, p < 0.04). There were significant correlations of fibrinogen with ABI, factor VII coagulant activity, and systolic and diastolic blood pressures; PAI-1 with body mass index and age; and factor VII coagulant activity with cholesterol levels. Logistic regression analysis, considering hemostatic variables and several known nonhemostatic risk factors of peripheral arterial disease, showed that fibrinogen and systolic blood pressure were independently associated with ABI status in this population. The results demonstrate a strong independent correlation between fibrinogen levels and the presence of lower limb arterial stenosis. PAI-1 levels were elevated in ADMIT participants, but multivariate analysis did not demonstrate an independent relationship between PAI-1 and ABI.

Replication of Colorado tick fever virus within human hematopoietic progenitor cells.

Significant neutropenia, as well as thrombocytopenia and a mild anemia, occurs in patients infected with Colorado tick fever virus. In this study, human bone marrow CD34+ cells and KG-1a cells, a human hematopoietic progenitor cell line, were infected in vitro with Colorado tick fever virus. The time course and morphological appearance of viral replication in human progenitor cells were similar to those seen in erythroblasts and in HEL cells and suggest one possible mechanism for the clinical hematologic findings.