Suman L. Sood

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.

Cancer-associated thrombosis

Purpose of reviewVenous thromboembolic disease (VTE) is an important source of morbidity and mortality in patients with cancer. Activation of coagulation pathways may be a central mechanism for tumor spread and development of aggressive disease. This review will focus on novel risk factors and predictors for the development of VTE in patients with malignancies, as well as approaches for the treatment and prevention of cancer-associated thrombosis. Recent findingsIndividual patient comorbidities, cancer-specific factors such as site and stage, and therapies including angiogenesis inhibitors associated with higher risk of VTE are increasingly being identified. Novel risk stratification approaches focus on the use of predictive biomarkers including P-selectin and markers of coagulation activation such as D-dimer, as well as predictive modeling. Thromboprophylaxis and treatment of VTE with low-molecular-weight heparin, unfractionated heparin, or fondaparinux in hospitalized medical and surgical cancer patients has been found to be well tolerated and effective; the appropriate role of thromboprophylaxis in ambulatory cancer patients, especially those with central venous catheters, remains to be explored. SummaryRoutine thromboprophylaxis in all patients with cancer cannot be recommended because only a subgroup of patients develop VTE, and the use of anticoagulants may be associated with unacceptably high risk of bleeding complications. Identification of patients at highest risk for VTE or bleeding who would benefit from careful prophylaxis is an important next step.

Similarity in joint function limitation in Type 3 von Willebrand's disease and moderate haemophilia A.

Type 3 von Willebrands disease (VWD) is a rare bleeding diathesis with complete or near complete deficiency of von Willebrand factor (VWF) and low factor VIII (FVIII) levels. In contrast, only FVIII is decreased in haemophilia A (HA). Both disorders are complicated by arthropathy. The purpose of this study was to further clarify the roles of FVIII and VWF: Antigen (VWF:Ag) in joint range of motion (ROM) loss over time. We compared joint ROM loss and other bleeding manifestations in 100 Type 3 VWD subjects (FVIII<5%) and 1814 moderate HA subjects (FVIII 1–5%) within the U.S. Universal Data Collection (UDC) database. High rates of bleeding were reported at baseline. During follow‐up, moderate HA patients reported a joint (46% vs. 34%, P < 0.0001) or muscle bleed (27% vs. 16%, P < 0.0001) in a higher proportion of visits than VWD patients. Other bleeds, including mucosal, were reported in a greater proportion of visits among patients with Type 3 VWD than among those with HA (49% vs. 32%, P < 0.0001). Multivariate analysis revealed no difference in joint ROM loss over time in the Type 3 VWD vs. moderate HA populations. A higher FVIII level was protective in both VWD and HA (P < 0.001). Our findings support the hypothesis of primacy of the FVIII level in determining risk of joint haemorrhage, and may help target therapy in Type 3 VWD and moderate HA to prevent joint disability.

Aging among persons with hemophilia: Contemporary concerns

The life expectancy of persons with hemophilia (PWH) has increased almost 10-fold over the past seven decades, largely due to access to safe factor replacement products. Concomitant with this success, however, comes the burden of aging. Older PWH are developing similar comorbidities as the general population, including increasing rates of hypertension, obesity, and diabetes, which predispose them to chronic diseases such as cardiovascular disease (CVD) and chronic kidney disease (CKD). How their coagulopathy affects the expression of these conditions remains unclear. In addition, the elderly hemophilia population must cope with chronic joint arthropathy, which provokes falls and fractures, and complications related to human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, which greatly impact the incidence of cancer and liver disease. With a dearth of evidence-based guidelines to direct therapy, a new challenge has arisen for hematologists to optimally manage these complex age-related issues. This review will focus on common complications affecting the older hemophilia population, including joint disease, CVD, malignancy, renal insufficiency, and liver disease.

Managing older patients with hemophilia

With access to safe factor products, the life expectancy of persons with hemophilia (PWHs) has increased almost 10-fold over the past 7 decades. Unfortunately, hand in hand with this success comes the burden of aging. As PWHs age, they are subject to develop many of the same risk factors as the general population, including increasing rates of hypertension, obesity, and diabetes. Such comorbidities predispose them to chronic diseases, such as cardiovascular disease and chronic kidney disease, although how their coagulopathy affects the expression of these conditions remains unclear. The older hemophilia population faces additional challenges, such as chronic joint arthropathy, which provokes falls and fractures, and complications related to HIV and hepatitis C infections, which greatly affect the incidence of cancer and liver disease. In light of the paucity of evidence-based guidelines to direct therapy, a new challenge has arisen for hematologists to optimally manage these complex age-related issues. In general, elderly PWHs should be treated similarly to their peers without hemophilia, with the addition of factor replacement therapy as appropriate. Primary prevention of risk factors should be emphasized, and close coordination between specialties is essential. This review will focus on common complications affecting the older hemophilia population, including cardiovascular disease, malignancy, liver disease, renal insufficiency, and joint disease.

E-selectin inhibition with GMI-1271 decreases venous thrombosis without profoundly affecting tail vein bleeding in a mouse model

Selectins, such as E-selectin (CD62E), function in venous thrombosis by binding and activating immune cells to initiate the coagulation cascade. GMI-1271 is a small molecule antagonist that inhibits E-selectin activity. Here we determine whether inhibition of E-selectin is sufficient to decrease acute venous thrombosis and associated inflammatory events in both prophylactic and treatment protocols without significantly affecting haemostasis. Male C57BL/6 mice underwent surgery for experimental thrombosis induction and were harvested at peak thrombus formation in our animal model, two days post induction. Groups included non-thrombosed true controls, shams, controls, and prophylactic or treatment groups of GMI-1271 (10 mg/kg intraperitoneal BID (twice a day) and low-molecular-weight heparin (LMWH, Lovenox 6 mg/kg subcutaneously (SC), once a day (SID). Compared with control animals, prophylaxis or treatment with LMWH and GMI-1271 in a dose-dependent manner significantly decreased thrombosis. GMI-1271 significantly lowered tail bleeding times when compared to LMWH. GMI-1271 and LMWH prophylactically administered significantly decreased vein wall neutrophil cell extravasation. However, all treatment and prophylactic therapies significantly decreased vein wall monocyte extravasation versus controls. GMI-1271 prophylactic therapy significantly decreased intra-thrombus cell counts versus control animals and other treatment groups. Immunohistochemistry confirmed that both treatments with GMI-1271 and LMWH significantly decreased activated leukocyte migration. GMI-1271 therapy significantly decreased thrombus weight and resulted in significantly lower bleeding times than LMWH. GMI-1271 treated mice showed decreased local and systemic inflammatory effects while modulating neutrophil activation, suggesting that GMI-1271 is a viable therapeutic candidate for venous thrombosis prophylaxis and treatment.

New biomarkers and imaging approaches for the diagnosis of deep venous thrombosis

Purpose of review Symptoms suggestive of deep vein thrombosis (DVT) are extremely common in clinical practice, but unfortunately nonspecific. In both ambulatory and inpatient settings, clinicians are often tasked with evaluating these concerns. Here, we review the most recent advances in biomarkers and imaging to diagnose lower extremity DVT. Recent findings The modified Wells score remains the most supported clinical decision rule for risk stratifying patients. In uncomplicated patients, the D-dimer can be utilized with risk stratification to reasonably exclude lower extremity DVT in some patients. Although numerous biomarkers have been explored, soluble P-selectin has the most promise as a novel marker for DVT. Imaging will be required for many patients and ultrasound is the primary modality. Nuclear medicine techniques are under development, and computed tomography (CT) and magnetic resonance venography are reasonable alternatives in select patients. Summary D-dimer is the only clinically applied biomarker for DVT diagnosis, with soluble P-selectin a promising novel biomarker. Recent studies have identified several other potential biomarkers. Ultrasound remains the imaging modality of choice, but CT, MRI, or nuclear medicine tests can be considered in select scenarios.

A prospective study of von Willebrand factor levels and bleeding in pregnant women with type 1 von Willebrand disease.

S. L. SOOD,* A. H. JAMES,† M. V. RAGNI,‡ A. D. SHAPIRO,§ C. WITMER,¶** R. VEGA,** D. BOLGIANO†† and B. A. KONKLE††‡‡ *Hematology/Oncology, University of Michigan, Ann Arbor, MI; †Department of OB/GYN, Duke University Medical Center, Durham, NC; ‡Department of Medicine, Division Hematology/Oncology, University of Pittsburgh and Hemophilia Center of Western Pennsylvania, Pittsburgh, PA; §Indiana Hemophilia and Thrombosis Center, Indianapolis, IN; ¶Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA; **University of Pennsylvania, Philadelphia, PA; ††Bloodworks Northwest, Seattle, WA; and ‡‡Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA

A cross-sectional analysis of cardiovascular disease in the hemophilia population

Men with hemophilia were initially thought to be protected from cardiovascular disease (CVD), but it is now clear that atherothrombotic events occur. The primary objective of the CVD in Hemophilia study was to determine the prevalence of CVD and CVD risk factors in US older men with moderate and severe hemophilia and to compare findings with those reported in age-comparable men in the Atherosclerosis Risk in Communities (ARIC) cohort. We hypothesized if lower factor levels are protective from CVD, we would see a difference in CVD rates between more severely affected and unaffected men. Beginning in October 2012, 200 patients with moderate or severe hemophilia A or B (factor VIII or IX level ≤ 5%), aged 54 to 73 years, were enrolled at 19 US hemophilia treatment centers. Data were collected from patient interview and medical records. A fasting blood sample and electrocardiogram (ECG) were obtained and assayed and read centrally. CVD was defined as any angina, any myocardial infarction by ECG or physician diagnosis, any self-reported nonhemorrhagic stroke or transient ischemic attack verified by physicians, or any history of coronary bypass graft surgery or coronary artery angioplasty. CVD risk factors were common in the population. Compared with men of similar age in the ARIC cohort, patients with hemophilia had significantly less CVD (15% vs 25.8%; P < .001). However, on an individual patient level, CVD events occur and efforts to prevent cardiovascular events are warranted. Few men were receiving secondary prophylaxis with low-dose aspirin, despite published opinion that it can be used safely in this patient population.

Sociodemographic factors in patients continuing warfarin vs those transitioning to direct oral anticoagulants

Clinical factors and patient preferences are important for selecting oral anticoagulants for venous thromboembolism (VTE) and atrial fibrillation (AF). The relative association of sociodemographic factors with anticoagulant use is unknown. We evaluated a prospective cohort to compare sociodemographic variables in patients who continued on warfarin for AF or VTE to those who transitioned to 1 of the direct oral anticoagulants (DOACs). Adult patients, newly started on warfarin, were enrolled through 6 anticoagulation clinics across Michigan. Of 8468 patients, 53.3% had AF, 45.6% had VTE, and 1.1% had both. Of these, 696 (8.2%) switched from warfarin to a DOAC. There were no significant differences between switchers and nonswitchers for percentage of time with a therapeutic international normalized ratio on warfarin, urban-rural residence status, or health insurance. Switchers were more often white (83.3% vs 77.7%; P < .001), partnered (67.3% vs 59.2%; P < .001), or resided in a zip code with a higher median household income (P < .001). The results show that sociodemographic factors, such as race, partnered status, and income are associated with a patients likelihood of switching to a DOAC vs remaining on warfarin therapy. Although clinical factors predominate, the reason for, and impact of, these observed variations in care requires further investigation.