Von Willebrand Factor Levels Research Articles

Genetic Variation in ADAMTS13 is Related to VWF Levels, Atrial Fibrillation and Cerebral Ischemic Events.

ADAMTS13 cleaves von Willebrand factor (VWF) multimers into less active fragments. Both markers have been related to cardiovascular disease (CVD). We aimed to investigate the influence of ADAMTS13 single nucleotide polymorphisms (SNPs) on levels of ADAMTS13 and VWF, and CVD. The c.1342C>G, g.41635A>G and c.2699C>T polymorphisms were determined in patients with chronic coronary syndrome (n = 1000). VWF and ADAMTS13 were analyzed. Clinical endpoints after 2 years (n = 106) were unstable angina pectoris, myocardial infarction, non-hemorrhagic stroke and death. The SNPs did not affect ADAMTS13 levels. The 41635A-allele associated with higher VWF levels (P < .001). Patients with the 1342G-allele had significantly higher frequency of previous atrial fibrillation (n = 26, P = .016) and cerebral ischemic events (n = 47, P = .030). Heterozygous of the 1342CG variant experienced more clinical endpoints compared to homozygous (CC and GG) (P = .028). The association between the 41635A-allele and VWF indicates a role for this polymorphism in VWF regulation. ADAMTS13 has previously been linked to atrial fibrillation and ischemic stroke, and our findings suggest that the 1342G-allele may be of significance. The association between the 1342CG genotype and endpoints needs further investigations.Clinicaltrials.gov, ASCET, NCT00222261. https://clinicaltrials.gov/ct2/show/NCT00222261?term=NCT00222261&draw=2&rank=1.

Relationships Between Transcranial Doppler Velocity, Von Willebrand Factor, Factor VIII, and Hematological Parameters in Children with Sickle Cell Anemia: A Comparative Cross-Sectional Study

Background and Objectives Sickle cell anemia (SCA) is associated with recurrent acute inflammatory processes. These inflammatory processes could lead to elevation of Factor VIII and Von Willebrand Factor levels, thereby increasing the risk of stroke in SCA children. This study aims to determine vWF/FVIII levels in children with SCA and their association with abnormal transcranial Doppler (TCD). Subjects and Methods This study enrolled 75 children, including 24 SCA cases with normal TCD, 27 SCA cases with abnormal TCD, and 24 Hb AA controls, all aged between 2 and 16 years. Transcranial Doppler (TCD) ultrasound was performed to measure the cerebral blood velocity. Venous blood drawn from each participant was used to determine the levels of von Willebrand Factor Antigen (vWF: Ag) and Factor VIII (FVIII) and the complete blood count (CBC). Relationships among the measured parameters were determined using SPSS version 25. Statistical significance was set at P &lt; .05. Results FVIII and vWF levels were significantly higher among children with SCA compared to the Hb AA controls ( P &lt; .001). Although SCA patients with abnormal TCD tended to have higher levels of FVIII and vWF, this result did not attain statistical significance ( P &gt; .05). There was a moderate negative correlation between the left middle cerebral artery and FVIII, (r = −0.332; P = .017). Children with SCA showing an abnormal TCD velocity had significantly higher platelet count compared to those with normal TCD ( P = .018). Conclusion Children with SCA have elevated levels of FVIII and vWF, and an abnormal TCD velocity is associated with elevated platelet count.

Ageing and women with bleeding disorders

Abstract As life expectancy increases, women with bleeding disorders can expect to live for decades after their menopause – potentially with a range of comorbidities including cardiovascular (CV) disease, cancer and osteoporosis. Menstrual bleeding around the menopause may be heavy and unpredictable for women with bleeding disorders (WBD). Hormone replacement therapy (HRT) remains the gold standard for those with debilitating menopausal symptoms and for osteoporosis prevention. Levels of endogenous von Willebrand factor (VWF) increase with age in the general population without bleeding disorders, with an associated rise in levels of Factor VIII (FVIII). Evidence also suggests age-related increases in VWF in people with von Willebrand disease (VWD), with limited but potentially associated evidence for increases in FVIII in those with mild or moderate haemophilia A. However, it appears that age-related changes in factor levels do not correlate completely with bleeding episodes, and more data are needed to fully understand the picture. New models of comprehensive care are needed that take account of age-related comorbidities in both women and men with bleeding disorders, including the impact of polypharmacy and its potential for causing adverse effects and impaired treatment adherence. Consideration will also be needed for bleeding cover during interventions such as surgery, radiotherapy and chemotherapy that become more likely with age. Protocols and care pathways need to be updated as the implications of ageing in women and men with bleeding disorders become better understood.

Examining international practices in the management of pregnant women with von Willebrand disease

BackgroundThe management of pregnant women with von Willebrand disease (VWD) is complex as physiological pregnancy‐induced increases in plasma von Willebrand factor (VWF) may be blunted or absent. Women with VWD experience a heightened risk of postpartum hemorrhage (PPH) and special consideration must be given regarding neuraxial anesthesia (NA) and the need for prophylaxis at time of delivery. These challenges are compounded by a lack of robust evidence to guide clinical decision‐making. Objectives and MethodsTo determine the current international clinical practices in the management of pregnancy for women with VWD, the International Society on Thrombosis and Haemostasis (ISTH) conducted an international survey of health‐care providers (HCP). ResultsOne hundred thirty‐two respondents from 39 countries were included in the final analysis. Variations in clinical practice were identified in antenatal (monitoring of plasma VWF and ferritin levels), peripartum (optimal plasma VWF target at delivery) and postpartum management (definitions used for PPH and postpartum monitoring). A key area of divergence was suitability for NA for women with type 2 and type 3 VWD, with many respondents advising against the use of NA even with VWF supplementation (29% type 2 VWD, 37% type 3 VWD) but others advising use once plasma VWF activity was >50 IU/dL (57% type 2 VWD; 50% type 3 VWD). ConclusionsThis survey highlighted areas of uncertainty surrounding common management issues for pregnant women with VWD. These data underscore the need for international collaborative research efforts focused on peripartum management to improve care for pregnant women with VWD.

Von Willebrand Factor Multimer Patterns in People Living with Human Immunodeficiency Virus Infection.

Endothelial dysfunction contributes to hypercoagulability in people with HIV (PWH). A surrogate marker of this is elevated von Willebrand factor (VWF) which has been documented in PWH. This study compared VWF multimer patterns in PWH who were anti-retroviral therapy (ART) naive and immune reconstituted on ART. VWF multimer analysis was performed with a semi-quantitative electrophoresis assay on plasma from 79 PWH (39 ART-naive and 40 virally suppressed on ART) and 25 normal control samples. The total optical density mean VWF level was significantly increased in PWH and higher in ART-naive versus ART-exposed, virally suppressed patients (p < 0.0001). No quantitative difference was demonstrated in the multimer distribution pattern between the groups. Our findings suggest that there is no difference in multimer distribution between ART-naive and virally suppressed PWH. Due to a small sample size, confirmation in a larger study is required.

Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis.

Hepatopulmonary syndrome affects 10-30% of patients with cirrhosis and portal hypertension. We evaluated the serum angiogenic profile of hepatopulmonary syndrome and assessed the clinical impact of hepatopulmonary syndrome in patients evaluated for liver transplantation. The Pulmonary Vascular Complications of Liver Disease 2 study was a multicentre, prospective cohort study of adults undergoing their first liver transplantation evaluation. Hepatopulmonary syndrome was defined as an alveolar-arterial oxygen gradient ≥15 mmHg (≥20 mmHg if age >64 years), positive contrast-enhanced transthoracic echocardiography and absence of lung disease. We included 85 patients with hepatopulmonary syndrome and 146 patients without hepatopulmonary syndrome. Patients with hepatopulmonary syndrome had more complications of portal hypertension and slightly higher Model for End-Stage Liver Disease-Na score compared to those without hepatopulmonary syndrome (median (interquartile range) 15 (12-19) versus 14 (10-17), p=0.006). Hepatopulmonary syndrome patients had significantly lower 6-min walk distance and worse functional class. Hepatopulmonary syndrome patients had higher circulating angiopoietin 2, Tie2, tenascin C, tyrosine protein kinase Kit (c-Kit), vascular cell adhesion molecule 1 and von Willebrand factor levels, and lower E-selectin levels. Patients with hepatopulmonary syndrome had an increased risk of death (hazard ratio 1.80, 95% CI 1.03-3.16, p=0.04), which persisted despite adjustment for covariates (hazard ratio 1.79, 95% CI 1.02-3.15, p=0.04). This association did not vary based on levels of oxygenation, reflecting the severity of hepatopulmonary syndrome. Hepatopulmonary syndrome was associated with a profile of abnormal systemic angiogenesis, worse exercise and functional capacity, and an overall increased risk of death.

Prognostic value of the ADAMTS13-vWF axis in disseminated intravascular coagulation: Platelet count/vWF:Ag ratio as a strong prognostic marker.

ADAMTS13 deficiency increases the circulating level of von Willebrand factor (vWF). Low ADAMTS13 and high vWF can provide a milieu for microthrombosis, including disseminated intravascular coagulation (DIC). This study investigated the prognostic values of ADAMTS13-vWF axis markers and their correlation with DIC severity. ADAMTS13-vWF axis markers (vWF antigen (vWF:Ag), vWF ristocetin cofactor (vWF:Rco), ADAMTS13 activity, and anti-ADAMTS13 antibody) were measured in patients (n=152) suspected of having DIC along with the well-known DIC markers including antithrombin and protein C. The vWF:Ag level was significantly increased, and ADAMTS13 activity was significantly decreased in overt DIC. The vWF:Ag level (hazard ratio 7.365, p=.009), ADAMTS13 activity/vWF:Ag ratio (hazard ratio 3.777, p=.037), ADAMTS13 activity/vWF:Rco ratio (hazard ratio 3.027, p=.028), and platelet count/vWF:Ag ratio (hazard ratio 8.538, p<.001) were significant prognostic markers in Cox regression analysis and correlated well with DIC score and antithrombin and protein C levels. The platelet count/vWF:Ag was the strongest prognostic marker among ADAMTS13-vWF axis markers. The measurement of vWF:Ag may improve prognostic insights of DIC in clinical practice.

Impact of obesity on factor VIII and von Willebrand factor levels in patients with Type 1 von Willebrand disease and low von Willebrand factor: An analysis of the ATHNdataset.

Obesity is associated with endothelial dysfunction, haemostatic and fibrinolytic disturbances, however the impact of obesity on von Willebrand factor (VWF) is unclear. The aim of this study was to test our hypothesis that the prevalence of obesity is higher among participants with low VWF (LVWF) compared to type 1 von Willebrand disease (T1VWD). A retrospective review of the ATHNdataset as of March 2018 was performed. Participants were categorized as T1VWD if their VWF ristocetin cofactor activity was 30IU/dL and LVWF if the values were 30-50IU/dL, and by the NIH definitions for body mass index (BMI) for adult participants (≥18 years of age) or BMI z-score for paediatric participants (<18 years). The prevalence of obesity was not significantly different between adults with T1VWD (n=186) and LVWF (n=362) (32%vs 36%; p=.345). The mean factor VIII (FVIII) increased with increasing BMIs in both groups. In the paediatric cohort (T1VWD, n=583; LVWF, n=1702), there was no difference in the prevalence of obesity, but BMI was positively correlated with mean FVIII (p<.001). Children<10 years were 27.6% more likely to be diagnosed with T1VWD compared to>10 years. Among participants in the ATHNdataset, the prevalence of obesity was similar among those with LVWF and T1VWD. However, higher BMI levels were associated with elevated FVIII. Further research is needed to evaluate the impact of obesity on bleeding phenotype and treatment practices.

Hemophilia: The Past, the Present, and the Future.

Hemophilia: The Past, the Present, and the Future.

Relationship between the D-dimer and von Willebrand factor levels and the development of gastrointestinal bleeding in patients with stable coronary artery disease: data from the registry of long-term antithrombotic therapy REGATTA-1

Aim. To study the role of von Willebrand factor (VWF) and D-dimer (DD) as predictors of upper gastrointestinal bleeding (GIB) in patients with stable coronary artery disease (CAD).Material and methods. The study included patients with stable CAD who are members of the prospective registry of long-term antithrombotic therapy (REGATTA-1) (ClinicalTrials.gov Identifier: NCT04347200). The primary endpoints were actionable GIBs (Bleeding Academic Research Consortium type 2-5). Cut-off points for DD and VWF were determined by ROC analysis. The predictive significance of an increase in VWF and DD was assessed by the logistic regression.Results. The study included 408 patients (men, 77,5%; mean age, 61,3±10,8 years). The median follow-up period was 2,5 [1,1-14,7] years. DD was determined in all patients, including 36 patients with GIB, while VWF — in 169 patients (28 patients with GIB). An increase in DD &gt;928 ng/ml was an independent predictor of GIB, including taking into account clinical risk factors (odds ratio (OR), 3,26 [95% confidence interval (CI), 1,43-7,42] (p=0,0047), or the previously developed REGATTA scale score (OR, 3,73, 95% CI: 1,65-8,43 (p=0,0015)). VWF &gt;105% was also an independent predictor of GIB (OR, 14,02; 95% CI: 1,41-139,42 (p=0,023)); in the REGATTA scale model — OR 11,3, 95% CI: 1,43-88,83 (p=0,021). The increase in both markers was most unfavorable, since the proportion of those with GIB was 41,4%, while among patients with normal DD and increased VWF — 14,9%, and with low values of both markers — 0%. OR of GIB in patients with an increase in both markers was 4,1 (95% CI: 1,6-10,3 (p=0,003)).Conclusion. In patients with stable CAD, an increase in VWF and DD was associated with an increase in GIB risk regardless of the presence of clinical risk factors.

Serum levels of laminin and von Willebrand factor in COVID-19 survivors 6 months after discharge

ObjectivesThe aim of this study was to evaluate the clinical characteristics, pulmonary diffusion function, chest computed tomography (CT), and serum lung cell damage indicators of coronavirus disease 2019 (COVID-19) survivors 6 months after discharge. MethodsData of COVID-19 survivors discharged from hospital between January 21, 2020 and January 11, 2021 and healthy controls were collected. Serum levels of surfactant protein D (SP-D), the receptor for advanced glycation end products (RAGE), laminin, and von Willebrand factor (vWF) were measured in the healthy controls and COVID-19 survivors 6 months after discharge. The relationships between serum lung cell damage indicator levels and various parameters were explored. ResultsFifty-two COVID-19 survivors (31 with non-severe disease and 21 with severe disease) and 30 controls were included. Serum levels of laminin in COVID-19 survivors 6 months after discharge were significantly higher than those in the controls. The increase was more significant in elderly and female patients. Serum levels of RAGE and vWF were not statistically different from those of the controls. However, 6 months after discharge, COVID-19 survivors with abnormal chest CT and those in the severe group had higher vWF levels. ConclusionsCOVID-19 patients had abnormal lung injury indicators 6 months after discharge. The recovery time after infection is currently unknown, and long-term observation is required.

The von Willebrand factor A-1 domain binding aptamer BT200 elevates plasma levels of von Willebrand factor and factor VIII: a first-in-human trial.

von Willebrand factor (VWF) and factor VIII (FVIII) circulate in a noncovalent complex in blood and promote primary hemostasis and clotting, respectively. A new VWF A1-domain binding aptamer, BT200, demonstrated good subcutaneous bioavailability and a long half-life in non-human primates. This first-in-human, randomized, placebo-controlled, double-blind trial tested the hypothesis that BT200 is well tolerated and has favorable pharmacokinetic and pharmacodynamic effects in 112 volunteers. Participants received one of the following: a single ascending dose of BT200 (0.18-48 mg) subcutaneously, an intravenous dose, BT200 with concomitant desmopressin or multiple doses. Pharmacokinetics were characterized, and the pharmacodynamic effects were measured by VWF levels, FVIII clotting activity, ristocetin-induced aggregation, platelet function under high shear rates, and thrombin generation. The mean half-lives ranged from 7-12 days and subcutaneous bioavailability increased dose-dependently exceeding 55% for doses of 6-48 mg. By blocking free A1 domains, BT200 dose-dependently decreased ristocetin-induced aggregation, and prolonged collagen-adenosine diphosphate and shear-induced platelet plug formation times. However, BT200 also increased VWF antigen and FVIII levels 4-fold (P<0.001), without increasing VWF propeptide levels, indicating decreased VWF/FVIII clearance. This, in turn, increased thrombin generation and accelerated clotting. Desmopressin-induced VWF/FVIII release had additive effects on a background of BT200. Tolerability and safety were generally good, but exaggerated pharmacology was seen at saturating doses. This trial identified a novel mechanism of action for BT200: BT200 dose-dependently increases VWF/FVIII by prolonging half-life at doses well below those which inhibit VWF-mediated platelet function. This novel property can be exploited therapeutically to enhance hemostasis in congenital bleeding disorders.

Whole-exome analysis of adolescents with low VWF and heavy menstrual bleeding identifies novel genetic associations

AbstractAdolescents with low von Willebrand factor (VWF) levels and heavy menstrual bleeding (HMB) experience significant morbidity. There is a need to better characterize these patients genetically and improve our understanding of the pathophysiology of bleeding. We performed whole-exome sequencing on 86 postmenarchal patients diagnosed with low VWF levels (30-50 IU/dL) and HMB and compared them with 660 in-house controls. We compared the number of rare stop-gain/stop-loss and rare ClinVar “pathogenic” variants between cases and controls, as well as performed gene burden and gene-set burden analyses. We found an enrichment in cases of rare stop-gain/stop-loss variants in genes involved in bleeding disorders and an enrichment of rare ClinVar “pathogenic” variants in genes involved in anemias. The 2 most significant genes in the gene burden analysis, CFB and DNASE2, are associated with atypical hemolytic uremia and severe anemia, respectively. VWF also surpassed exome-wide significance in the gene burden analysis (P = 7.31 × 10−6). Gene-set burden analysis revealed an enrichment of rare nonsynonymous variants in cases in several hematologically relevant pathways. Further, common variants in FERMT2, a gene involved in the regulation of hemostasis and angiogenesis, surpassed genome-wide significance. We demonstrate that adolescents with HMB and low VWF have an excess of rare nonsynonymous and pathogenic variants in genes involved in bleeding disorders and anemia. Variants of variable penetrance in these genes may contribute to the spectrum of phenotypes observed in patients with HMB and could partially explain the bleeding phenotype. By identifying patients with HMB who possess these variants, we may be able to improve risk stratification and patient outcomes.

Multimer Analysis of Von Willebrand Factor in Von Willebrand Disease with a Hydrasys Semi-Automatic Analyzer-Single-Center Experience.

von Willebrand disease (VWD) is reportedly the most common inherited bleeding disorder. This disorder develops as a result of defects and/or deficiency of the plasma protein von Willebrand factor (VWF). Laboratory testing for VWF-related disorders requires the assessment of both VWF level and VWF activity, the latter requiring multiple assays. As an additional step, an evaluation of VWF structural features by multimer analysis is useful in selective investigations. Multimer analysis is also important for the selection of a suitable VWF therapy preparation (desmopressin, VWF/FVIII concentrate, recombinant VWF) and the determination of the correct dose for the patient. Based on clinical and laboratory findings, including the analysis of VWF multimers, we classified our patients into individual types of VWD. Our study group included 58 patients. The study group consisted of 66% (38 patients) with VWD type 1, 5% (3 patients) with VWD type 2, 7% (4 patients) with VWD type 3, 5% (3 patients) with mixed type 1/2A VWD, and 17% (10 patients) comprising an unclassified group. In this article, we provide an overview of our practical experience using a new complementary method—the analysis of von Willebrand factor multimers with a semi-automatic analyzer Hydrasys 2 scan. We explain the principle, procedure, advantages, and pitfalls associated with the introduction of the VWF multimer analysis methodology into standard VWD diagnostics.

Biomarkers of thromboinflammation correlate to COVID-19 infection and admission status in emergency department patients

BackgroundCOVID-19-associated coagulopathy is incompletely understood. ObjectivesTo characterize thrombin generation, Von Willebrand Factor (VWF), neutrophil extracellular traps (NETs), and their role in COVID-19 risk stratification in the emergency department (ED). Patients/methodsPlasma samples from 67 ED COVID-19 patients were compared to 38 healthy volunteers (HVs). Thrombin generation (calibrated automated thrombogram, CAT) was expressed as lag time (LT, min), peak height (PH, min), and time to peak (ttPeak, min). Citrullinated nucleosomes and histones were quantified with ELISA, VWF antigen and activity (IU/dL) through latex immunoassay, Factor VIII (IU/dL) through one-stage optical clot detection, and VWF multimers with Western blot densitometry. Wilcoxon testing and multivariable logistic regression were performed. Results presented as median [Q1, Q3]; p < 0.05 significant. ResultsCOVID-19 patients had longer LT (4.00 [3.26, 4.67]; 2.95 [2.67, 3.10], p < 0.001) and ttPeak (7.33 [6.33, 8.04]; 6.45 [6.00, 7.50], p = 0.004), greater VWF antigen (212 [158, 275]; 110 [91, 128], p < 0.001) and Factor VIII levels (148 [106, 190]; 106 [86, 129], p < 0.001), with decreased high molecular weight multimers (Normalized multimer ratio 0.807 [0.759, 0.869]; 0.891 [0.858, 0.966], p < 0.001), than HVs. COVID-19 patients requiring admission from the ED had longer LT and ttPeak with greater VWF antigen and Factor VIII levels than those not admitted. Two and three variable models of CAT parameters and VWF correlated with COVID-19 and admission status (C-statistics 0.677 to 0.922). ConclusionsThrombin generation kinetics and VWF levels, independent of NETs, may have a role in predicting admission need for COVID-19 patients.

TEG®, Microclot and Platelet Mapping for Guiding Early Management of Severe COVID-19 Coagulopathy.

An important component of severe COVID-19 disease is virus-induced endothelilitis. This leads to disruption of normal endothelial function, initiating a state of failing normal clotting physiology. Massively increased levels of von Willebrand Factor (VWF) lead to overwhelming platelet activation, as well as activation of the enzymatic (intrinsic) clotting pathway. In addition, there is an impaired fibrinolysis, caused by, amongst others, increased levels of alpha-(2) antiplasmin. The end result is hypercoagulation (proven by thromboelastography® (TEG®)) and reduced fibrinolysis, inevitably leading to a difficult-to-overcome hypercoagulated physiological state. Platelets in circulation also plays a significant role in clot formation, but they themselves may also drive hypercoagulation when they are overactivated due to the interactions of their receptors with the endothelium, immune cells or circulating inflammatory molecules. From the literature it is clear that the role of platelets in severely ill COVID-19 patients has been markedly underestimated or even ignored. We here highlight the value of early management of severe COVID-19 coagulopathy as guided by TEG®, microclot and platelet mapping. We also argue that the failure of clinical trials, where the efficacy of prophylactic versus therapeutic clexane (low molecular weight heparin (LMWH)) were not always successful, which may be because the significant role of platelet activation was not taken into account during the planning of the trial. We conclude that, because of the overwhelming alteration of clotting, the outcome of any trial evaluating an any single anticoagulant, including thrombolytic, would be negative. Here we suggest the use of the degree of platelet dysfunction and presence of microclots in circulation, together with TEG®, might be used as a guideline for disease severity. A multi-pronged approach, guided by TEG® and platelet mapping, would be required to maintain normal clotting physiology in severe COVID-19 disease.

Abstract 17234: Cisplatin Induced Coronary Artery Atherosclerosis Leading To St-elevation Myocardial Infarction: A Case Report

Introduction: Cisplatin-based chemotherapeutic regimen (CBCR) is known for increasing risk of venous thromboembolic (TE) disease. We report a unique case of STEMI associated with CBCR which we believe was caused by coronary artery thrombosis. Case description: A 31-yo man with a past history of germ cell tumor presented with chest pain radiating to back and left arm. It started this morning and intensity did not worsen with exertion. He denied any dyspnea, diaphoresis or palpitations. He was non-smoker and non-obese. He denied any family history of premature coronary artery disease. He had undergone unilateral orchiectomy a year ago, and was currently receiving chemotherapy with bleomycin, etoposide and cisplatin; the last dose of his 3 rd cycle was given the day before. EKG showed ST elevation in leads I, aVL, V4 and V5. Troponin I was high to 6.9 ng/ml (ULN 0.045 ng/ml). He received intravenous infusion of thrombolytic. An angiogram done the next day showed moderate mid-LAD disease with residual clot. A CT scan and an echocardiogram later showed left ventricular thrombus (LVT). He was kept on therapeutic enoxaparin along with aspirin. Follow up echocardiogram showed resolution of the thrombus. His chemotherapy was stopped, and he has been kept on active surveillance since then. Discussion: Most cases of CBCR-associated myocardial infarction that have been reported have been seen in the older population with other risk factors for coronary artery disease. Cases where angiographic data was available, coronary artery vasospasm appeared to be the culprit rather than a true plaque rupture. While the presence of LVT raises possibility of thromboembolism to coronaries causing MI, the angiographic findings support accelerated plaque formation to be the cause of infarction. In earlier reports, elevated pre-treatment level of von Willebrand factor has been postulated to have some role in the disease pathogenesis. Other possible mechanisms for pathogenesis include endothelial cell damage, platelet activation, and imbalance between thromboxane-prostacyclin levels. This case emphasizes the need to keep cardiac etiologies of chest pain in the differential when evaluating patients on CBCR as timely intervention is life saving and prevent morbidity.

Antithrombin protects against Plasmodium falciparum histidine-rich protein II-mediated inflammation and coagulation

AbstractPlasmodium falciparum-derived histidine-rich protein II (HRPII) has been shown to inhibit heparin-dependent anticoagulant activity of antithrombin (AT) and induce inflammation in vitro and in vivo. In a recent study, we showed that HRPII interacts with the AT-binding vascular glycosaminoglycans (GAGs) not only to disrupt the barrier-permeability function of endothelial cells but also to inhibit the antiinflammatory signaling function of AT. Here we investigated the mechanisms of the proinflammatory function of HRPII and the protective activity of AT in cellular and animal models. We found that AT competitively inhibits the GAG-dependent HRPII-mediated activation of NF-κB and expression of intercellular cell adhesion molecule 1 (ICAM1) in endothelial cells. Furthermore, AT inhibits HRPII-mediated histone H3 citrullination and neutrophil extracellular trap (NET) formation in HL60 cells and freshly isolated human neutrophils. In vivo, HRPII induced Mac1 expression on blood neutrophils, MPO release in plasma, neutrophil infiltration, and histone H3 citrullination in the lung tissues. HRPII also induced endothelial cell activation as measured by increased ICAM1 expression and elevated vascular permeability in the lungs. AT effectively inhibited HRPII-mediated neutrophil infiltration, NET formation, and endothelial cell activation in vivo. AT also inhibited HRPII-meditated deposition of platelets and fibrin(ogen) in the lungs and circulating level of von Willebrand factor in the plasma. We conclude that AT exerts protective effects against pathogenic effects of P falciparum-derived HRPII in both cellular and animal models.

The Von Willebrand Disease Aging and Bleeding Correlation (VWD ABC) Study

The Von Willebrand Disease Aging and Bleeding Correlation (VWD ABC) Study

Bleeding Outcomes in People with Von Willebrand Disease Receiving Antithrombotic Therapy

▪Aging brings additional challenges in the management of people with von Willebrand Disease (VWD). Plasma von Willebrand Factor (VWF) levels may increase but the impact on bleeding phenotype is unclear. With the development of age-related comorbidities, the use of antiplatelet (AP) or anticoagulant (AC) therapies may be warranted. As highlighted in the 2021 international VWD guidelines, limited evidence exists regarding the bleeding risk and safety of AP/AC use in people with VWD. 1 We sought to address this knowledge gap through a retrospective review of a large cohort of people with VWD attending a tertiary referral center.The records of all patients aged >50 years (y) attending our center registered with VWD were retrospectively reviewed. We identified all individuals treated with AP and/or AC, recording the indication for and duration of therapy. We also recorded disease subtype, baseline and most recent plasma VWF levels and bleeding on AP and/or AC. Bleeding episodes were stratified according to the World Health Organization (WHO) Bleeding Scale.From 255 eligible patients, 18 patients (7 male, 11 female) were identified who received AP and/or AC over a period of 22y. The median age at commencement was 60.2 years (range 40.0-74.5). 15 patients had Type 1 with baseline levels 30-50 IU/dL, (median VWF antigen, VWF:Ag, 57.5, range 39-87 IU/dL; median VWF ristocetin cofactor levels, VWF:RCo, 43, range 35-54 IU/dL). 3 patients had type 2 VWD (median VWF:Ag 64, range 27-90 IU/dL; median VWF:RCo of 16, range 10-66 IU/dL). The type of AP/AC used and indications for treatment are outlined in Table 1.Overall, 12 patients were treated with AP and 7 with AC therapy (19 therapies in total as one patient received first aspirin then warfarin therapy). The cumulative exposure to AP therapy was 61.9y with a median exposure time of 3.2y/patient (range 0.3-14.1y). Duration of AC therapy was shorter, with a cumulative exposure of 17.6y and a median of 1.5 y/patient (range 0.3-6.3y).Overall, 85.7% of patients on AC therapy had at least one episode of bleeding (6/7; 10 episodes total) in contrast to 58.3% of patients on AP (7/12; 12 episodes total). Of these 22 episodes, 5 (22.7%) were grade 1 bleeding. Grade 2 bleeding (iron deficiency or gastrointestinal (GI), gynecological or genitourinary bleeding) occurred in 5 patients (41.7%) treated with AP and 4 patients (57.1%) on AC (total of 14 episodes). 1 episode of grade 3 bleeding occurred in both the AP (8.3%) and AC (14.3%) group (GI bleeding requiring transfusion and abdominal hematoma respectively). The single grade 4 bleed was an intracranial hemorrhage (ICH) and occurred in a patient with type 2 VWD (VWF:RCo 10 IU/dL) on warfarin for atrial fibrillation; this required prothrombin complex concentrate, VWF concentrate, neurosurgical intervention and cessation of AC.Bleeding complications resulted in discontinuation of therapy in 2 patients (11.1%) treated; the individual with ICH and a patient with type 1 VWD on warfarin (baseline VWF:RCo 43 IU/dL) due to recurrent GI bleeding. No patients treated with AP therapy required discontinuation of use. The overall rate of major bleeding (WHO grade >/=3) in our study was 11.4 events/100 patient-years in VWD patients receiving AC therapy, in comparison to the rate of bleeding in the general population using AC of 7.2 events per 100 patient-years. 2For patients with type 1 VWD, plasma VWF levels were seen to increase during follow up (median 8.5y, VWF:Ag median +13 IU/dL, VWF:RCo +18 IU/dL), resulting in plasma VWF levels >50 IU/dL for 66.6% of patients in this cohort. Despite this, bleeding while on AP and/or AC was still experienced in 8/10 patients whose levels had normalized, necessitating cessation in one instance.In conclusion, this study provides important insights into the use of AP and/or AC in patients with VWD. Bleeding rates were higher in patients treated with AC therapy than AP resulting in cessation of therapy in 28.6% of those on AC. Bleeding events still occurred despite normalization of plasma VWF levels in patients with type 1 VWD. These data highlight the need for close follow up of patients with VWD whilst on antithrombotic therapy, particularly AC.1. Connell NT et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv 2021;5(1):301-325.2. Shoeb M, Fang M. Assessing Bleeding Risk in Patients Taking Anticoagulants. J Thromb Thrombolysis 2013;35(3):312-319. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.