Paula L. Bockenstedt

Comparison of characteristics from White‐ and Black‐Americans with venous thromboembolism: A cross‐sectional study

When compared with Whites, Black‐Americans may have a 40% higher incidence venous thromboembolism (VTE) incidence. However, whether other VTE characteristics and risk factors vary by race is uncertain. To compare demographic and baseline characteristics among White‐ and Black‐Americans with VTE, we used data prospectively collected from consecutive consenting adults enrolled in seven Centers for Disease Control (CDC) Thrombosis and Hemostasis Centers from August 2003 to March 2009. These characteristics were compared among Whites (n = 2002) and Blacks (n = 395) with objectively diagnosed VTE, both overall, and by age and gender. When compared with Whites, Blacks had a significantly higher proportion with pulmonary embolism (PE), including idiopathic PE among Black women, and a significantly higher proportion of Blacks were women. Blacks had a significantly higher mean BMI and a significantly lower proportion with recent surgery, trauma or infection, family history of VTE, and documented thrombophilia (solely from reduced factor V Leiden and prothrombin G20210A prevalence). Conversely, Blacks had a significantly higher proportion with hypertension, diabetes mellitus, chronic renal disease and dialysis, HIV, and sickle cell disease. When compared with White women, Black women had a significantly lower proportion with recent oral contraceptive use or hormone therapy. We conclude that Whites and Blacks differ significantly regarding demographic and baseline characteristics that may be risk factors for VTE. The prevalence of transient VTE risk factors and idiopathic VTE among Blacks appears to be lower and higher, respectively, suggesting that heritability may be important in the etiology of VTE among Black‐Americans. Am. J. Hematol. 85:467–471, 2010

Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the antiphospholipid syndrome.

Antiphospholipid antibodies (aPL), especially those targeting β2‐glycoprotein I (β2GPI), are well known to activate endothelial cells, monocytes, and platelets, with prothrombotic implications. In contrast, the interaction of aPL with neutrophils has not been extensively studied. Neutrophil extracellular traps (NETs) have recently been recognized as an important activator of the coagulation cascade, as well as an integral component of arterial and venous thrombi. This study was undertaken to determine whether aPL activate neutrophils to release NETs, thereby predisposing to the arterial and venous thrombosis inherent in the antiphospholipid syndrome (APS).

A study of prospective surveillance for inhibitors among persons with haemophilia in the united states

Inhibitors are a rare but serious complication of treatment of patients with haemophilia. Phase III clinical trials enrol too few patients to adequately assess new product inhibitor risk. This project explores the feasibility of using a public health surveillance system to conduct national surveillance for inhibitors. Staff at 17 U.S. haemophilia treatment centres (HTC) enrolled patients with haemophilia A and B into this prospective study. HTC staff provided detailed historic data on product use and inhibitors at baseline, and postenrolment patients provided monthly detailed infusion logs. A central laboratory performed inhibitor tests on blood specimens that were collected at baseline, annually, prior to any planned product switch or when clinically indicated. The central laboratory also performed genotyping of all enrolled patients. From January 2006 through June 2012, 1163 patients were enrolled and followed up for 3329 person‐years. A total of 3048 inhibitor tests were performed and 23 new factor VIII inhibitors were identified, 61% of which were not clinically apparent. Infusion logs were submitted for 113 205 exposure days. Genotyping revealed 431 distinct mutations causing haemophilia, 151 of which had not previously been reported elsewhere in the world. This study provided critical information about the practical issues that must be addressed to successfully implement national inhibitor surveillance. Centralized testing with routine monitoring and confirmation of locally identified inhibitors will provide valid and representative data with which to evaluate inhibitor incidence and prevalence, monitor trends in occurrence rates and identify potential inhibitor outbreaks associated with products.

Interactions of von Willebrand factor on mica studied by atomic force microscopy

Abstract Three-dimensional molecular level images of uncoated human von Willebrand factor (vWF), a plasma glycoprotein, have been obtained using atomic force microscopy (AFM). However, the structural detail obtained by AFM was found to depend on the interactive forces between the hydrophilic mica surface and the vWF, relative to the tracking force of the probe tip acting on the protein. vWF on mica was characterized by AFM in air, under two deposition conditions, which differed with respect to the amount of vWF on the surface and the degree of sample hydration. Under hydrated conditions, the vWF had weak adhesion to the mica and was moved easily by the AFM probe tip. This resulted in tip-induced organization of vWF into molecular aggregates oriented approximately perpendicular to the fast scanning direction. In contrast, under dehydrated conditions, three-dimensional images of individual vWF molecules were observed at approximately 10 nm lateral resolution. Extended vWF molecules up to 600 nm in length were imaged, but most molecules were in the 50–300 nm range with 15–45 nm globular subunits. AFM images obtained using the constant force imaging mode indicated height measurements of 3–5 nm for most of the vWF molecules.

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.

Immune thrombocytopenic purpura following liver transplantation: a case series and review of the literature.

Thrombocytopenia is common among liver transplant candidates and recipients. The aim of our study was to determine the incidence and outcome of new‐onset immune‐mediated thrombocytopenic purpura (ITP) following liver transplantation at a single center. Among the 256 liver transplant recipients with an International Classification of Diseases, Ninth Edition code for thrombocytopenia, 8 cases of new‐onset ITP were identified, leading to an overall incidence of 0.7% in 1,105 consecutive liver transplant recipients over a 15‐year period. All 8 patients were Caucasian, 5 (63%) were male, and the median age at ITP onset was 54 years (range, 15‐63). The median platelet count at presentation was 3,500 cells/mL (range, 1,000‐12,000) and liver disease was due to hepatitis C (38%), primary sclerosing cholangitis (38%), and cryptogenic cirrhosis (25%). The median time from transplant to ITP onset was 53.5 months (range, 1.9‐173). Three of the 6 patients tested (50%) had cell‐bound antiplatelet antibodies, 1 patient had an underlying hematological malignancy, and none of the organ donors had a history of ITP. Corticosteroids and/or immunoglobulin infusions were effective in 4 patients. However, serial rituximab infusions were required in 4 patients with persistent thrombocytopenia, and 3 of them eventually required splenectomy to induce disease remission. At a median follow‐up of 19.7 months, 7 long‐term survivors remain in remission with a median platelet count of 267,000 cells/mL. In conclusion, new‐onset ITP is an infrequent but important cause of severe thrombocytopenia in liver transplant recipients. Corticosteroids and immunoglobulin infusions were effective in 50% while the remainder of patients required rituximab infusions or eventual splenectomy for long‐term disease remission. Liver Transpl 12:781–791, 2006.

Endothelial progenitor dysfunction associates with a type I interferon signature in primary antiphospholipid syndrome

Objectives Patients with antiphospholipid syndrome (APS) are at risk for subclinical endothelial injury, as well as accelerated atherosclerosis. In the related disease systemic lupus erythematosus, there is a well-established defect in circulating endothelial progenitors, which leads to an accrual of endothelial damage over time. This defect has been at least partially attributed to exaggerated expression of type I interferons (IFNs). We sought to determine whether these pathways are important in APS. Methods We studied 68 patients with primary APS. Endothelial progenitors were assessed by flow cytometry and functional assay. Type I IFN activity was determined by a well-accepted bioassay, while peripheral blood mononuclear cells were scored for expression of IFN-responsive genes. Results Endothelial progenitors from patients with APS demonstrated a marked defect in the ability to differentiate into endothelial cells, a phenotype which could be mimicked by treating control progenitors with APS sera. Elevated type I IFN activity was detected in the circulation of patients with APS (a finding that was then replicated in an independent cohort). While IgG depletion from APS sera did not rescue endothelial progenitor function, the dysfunction was successfully reversed by a type I IFN receptor-neutralising antibody. Conclusions We describe, for the first time to our knowledge, an IFN signature in primary APS and show that this promotes impaired endothelial progenitor function. This work opens the door to novel approaches that may mitigate vascular damage in APS, such as anti-IFN drugs.

Differences in thrombotic risk factors in black and white women with adverse pregnancy outcome

INTRODUCTION Black women have an increased risk of adverse pregnancy outcomes and the characteristics of thrombotic risk factors in this population are unknown. The objective of this study was to examine the racial differences in thrombotic risk factors among women with adverse pregnancy outcomes. METHODS Uniform data were collected in women with adverse pregnancy outcomes (pregnancy losses, intrauterine growth restriction (IUGR), prematurity, placental abruption and preeclampsia) referred to Thrombosis Network Centers funded by the Centers for Disease Control and Prevention (CDC). RESULTS Among 343 white and 66 black women seen for adverse pregnancy outcomes, protein S and antithrombin deficiencies were more common in black women. The prevalence of diagnosed thrombophilia was higher among whites compared to blacks largely due to Factor V Leiden mutation. The prevalence of a personal history of venous thromboembolism (VTE) did not differ significantly by race. A family history of VTE, thrombophilia, and stroke or myocardial infarction (MI) was higher among whites. Black women had a higher body mass index, and a higher prevalence of hypertension, while the prevalence of sickle cell disease was approximately 27 fold higher compared to the general US black population. CONCLUSIONS Thrombotic risk factors differ significantly in white and black women with adverse pregnancy outcomes. Such differences highlight the importance of considering race separately when assessing thrombotic risk factors for adverse pregnancy outcomes.

Coagulation Status During Aortic Aneurysm Surgery: Comparison of Thrombelastography with Standard Tests

A prospective comparison of thrombelastography to standard coagulation tests was undertaken in ten patients undergoing routine, uncomplicated abdominal aortic aneurysm surgery in order to explore potential clinical utility and establish normal patterns of change. Thrombelastograph k values increased (7.1 vs 5.4 min baseline, P < or = .01), and alpha angle (43 vs 52 degrees baseline, P < or = .001) and ma (39 vs 52 mm baseline, P < or = .01) values decreased following graft placement, while r values remained unaffected (6.4 vs 7.5 min baseline, P > .05). Weak correlations were observed between alpha angle and fibrinogen, prothrombin time, and partial thromboplastin time (aPTT), as well as between k and aPTT (0.70 < r < 0.79 for all). Systemic fibrinolysis was suggested by thrombelastography in 25% of samples, although euglobulin lysis times were abnormal in only 5% (chi 2 = 4.80, P < or = .05). Fibrin degradation product detection increased through the fifth postoperative day in all patients. Variations in thrombelastographic parameters and their correlation to standard coagulation tests in patients undergoing uncomplicated abdominal aortic aneurysm repair were documented. In such a setting, no clear advantages to thrombelastography were defined. Further observations will be necessary to establish the role for thrombelastography in the management of patients experiencing clinically significant perioperative coagulation disorders.

Uncomplicated stereotactic and open neurosurgical procedures in patients with factor vii deficiency

Factor VII deficiency is characterized by epistaxis, bruising, hemarthrosis, menorrhagia, gastrointestinal bleeding, hematuria, and intracranial hemorrhage during infancy. Causes of acquired factor VII deficiency include liver disease, Vitamin K deficiency, and warfarin administration. Congenital factor VII deficiency is an autosomal recessive disorder, with the homozygotes having a severe deficiency and the heterozygotes a moderate deficiency of factor VII. Orthopedic, gynecological, cardiothoracic, and abdominal surgical procedures have been successfully performed in patients with factor VII deficiency both with and without factor VII replacement. We present two patients with moderate and moderately severe factor VII deficiency who successfully underwent intracranial procedures using plasma during the perioperative period for factor VII replacement. One patient successfully underwent stereotactic placement of mesial temporal lobe depth electrodes and subdural strip electrodes followed by anterior temporal lobectomy for medically refractory seizures. The second patient successfully underwent craniotomy for an olfactory groove meningioma. No bleeding complications were encountered with any of the three intracranial procedures performed. These cases represent the first reported cases of successful intracranial procedures in patients with factor VII deficiency, other than shunting procedures performed for intraventricular hemorrhage during infancy.