Publications by authors named "Cihan Ay"

186 Publications

Extended anticoagulation treatment for cancer-associated thrombosis - rates of recurrence and bleeding beyond 6 months: A systematic review.

J Thromb Haemost 2021 Nov 24. Epub 2021 Nov 24.

Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria.

Background: Patients with cancer-associated venous thromboembolism (VTE) are recommended to receive treatment with therapeutic anticoagulation for at least 3-6 months. Little data exists on extended treatment beyond 6 months.

Objective: To comprehensively summarize the best available evidence on incidence of recurrent VTE and major bleeding 6-12 months after the index event in patients with cancer-associated VTE.

Patients/methods: We systematically screened biomedical databases (Medline, Embase, Central) to identify studies reporting recurrent VTE and/or bleeding events between 6-12 months after a diagnosis of cancer-associated VTE. Based on the observed heterogeneity in study design, setting, patient cohort characteristics, anticoagulation strategies, and outcome rates, no overall quantitative estimate of outcome rates was calculated.

Results: We screened 2,597 publications and identified 11 eligible studies matching pre-defined in-/exclusion criteria, reporting on 3,019 patients specifically during the 6-12-month period post index VTE. Overall rates of recurrent VTE in this timeframe varied substantially (1-12%), with the highest risk observed in the patient subgroup with residual vein thrombosis present at 6 months randomized to receive no anticoagulation (13%-15%). Reported rates of major bleeding between 6-12 months were between 2% and 5%.

Conclusions: In this systematic review, we provide a comprehensive and structured summary of the best available evidence on recurrence and bleeding risk between 6-12 months after cancer-associated VTE. VTE recurrence remains common beyond 6 months and continuation of different anticoagulation strategies has an acceptable safety profile indicated by lower bleeding rates. These findings support guideline recommendations to continue anticoagulation treatment beyond 6 months in patients with active cancer.
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http://dx.doi.org/10.1111/jth.15599DOI Listing
November 2021

The path of uncovering a prothrombotic thrombocytopenic syndrome after viral vector-based COVID-19 vaccination: Where there is much light, the shadow is deep.

Res Pract Thromb Haemost 2021 Oct 2;5(7):e12609. Epub 2021 Nov 2.

Clinical Division of Haematology and Haemostaseology Department of Medicine I Medical University of Vienna Vienna Austria.

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http://dx.doi.org/10.1002/rth2.12609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563919PMC
October 2021

Thrombomodulin in patients with mild to moderate bleeding tendency.

Haemophilia 2021 Nov 10;27(6):1028-1036. Epub 2021 Oct 10.

Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Introduction: A massive increase of soluble thrombomodulin (sTM) due to variants in the thrombomodulin gene (THBD) has recently been identified as a novel bleeding disorder.

Aim: To investigate sTM levels and underlying genetic variants as a cause for haemostatic impairment and bleeding in a large number of patients with a mild to moderate bleeding disorder (MBD), including patients with bleeding of unknown cause (BUC).

Patients And Methods: In 507 MBD patients, sTM levels, thrombin generation and plasma clot formation were measured and compared to 90 age- and sex-matched healthy controls. In patients, genetic analysis of the THBD gene was performed.

Results: No difference in sTM levels between patients and controls was found overall (median ([IQR] 5.0 [3.8-6.3] vs. 5.1 [3.7-6.4] ng/ml, p = .762), and according to specific diagnoses of MBD or BUC, and high sTM levels (≥95th percentile of healthy controls) were not overrepresented in patients. Soluble TM levels had no impact on bleeding severity or global tests of haemostasis, including thrombin generation or plasma clot formation. In the THBD gene, no known pathogenic or novel disease-causing variants affecting sTM plasma levels were identified in our patient cohort.

Conclusion: TM-associated coagulopathy appears to be rare, as it was not identified in our large cohort of patients with MBD. Soluble TM did not arise as a risk factor for bleeding or altered haemostasis in these patients.
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http://dx.doi.org/10.1111/hae.14433DOI Listing
November 2021

Long-term follow-up after successful treatment of vaccine-induced prothrombotic immune thrombocytopenia.

Thromb Res 2021 Oct 4;207:126-130. Epub 2021 Oct 4.

Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Austria.

Background: Cases of ChAdOx1 nCoV-19 (AstraZeneca) vaccinated patients with thrombocytopenia, elevated D-dimer, and elevated platelet factor 4 (PF4) antibody levels with- and without thrombosis have been reported. No recommendations regarding the duration of anticoagulation have been made, because data on the long-term course beyond the first weeks is lacking.

Objective: To report on the treatment, medical course, and longitudinal follow-up of laboratory parameters in patients with vaccine-induced prothrombotic immune thrombocytopenia (VIPIT).

Patients: We followed VIPIT patients with- (n = 3) and without (n = 3) venous thromboembolism fulfilling the aforementioned laboratory criteria.

Results: Elevated D-dimer (median: 35.10 μg/ml, range: 17.80-52.70), thrombocytopenia (42 G/l, 20-101), and strong positivity in the platelet factor 4 (PF4)/heparin-enzyme-immunoassay (2.42 optical density [OD], 2.06-3.13; reference range < 0.50) were present in all patients after vaccination (10 days, 7-17). Routine laboratory parameters rapidly improved upon initiation of treatment (comprising therapeutic non-heparin anticoagulation in all patients and high dose immunoglobulins ± corticosteroids in 5 patients). PF4 antibody levels slowly decreased over several weeks. Patients were discharged in good physical health (8 days, 5-13). VIPIT did not recur during follow-up (12 weeks, 8-17). Five of 6 patients fully recovered (in 2 patients thrombosis had resolved, in 1 patient exertional dyspnea persisted).

Conclusions: Remissions without sequelae can be achieved upon rapid initiation of treatment in patients with VIPIT. Platelet factor 4 antibody levels slowly decreased over several weeks but VIPIT did not recur in any of our patients. Continuation of anticoagulation in VIPIT patients at least until PF4 antibody negativity is reached seems reasonable.
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http://dx.doi.org/10.1016/j.thromres.2021.09.017DOI Listing
October 2021

Estimating Bleeding Risk in Patients with Cancer-Associated Thrombosis: Evaluation of Existing Risk Scores and Development of a New Risk Score.

Thromb Haemost 2021 Sep 20. Epub 2021 Sep 20.

Department of Acute Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

Background:  Bleeding risk is highly relevant for treatment decisions in cancer-associated thrombosis (CAT). Several risk scores exist, but have never been validated in patients with CAT and are not recommended for practice.

Objectives:  To compare methods of estimating clinically relevant (major and clinically relevant nonmajor) bleeding risk in patients with CAT: (1) existing risk scores for bleeding in venous thromboembolism, (2) pragmatic classification based on cancer type, and (3) new prediction model.

Methods:  In a posthoc analysis of the Hokusai VTE Cancer study, a randomized trial comparing edoxaban with dalteparin for treatment of CAT, seven bleeding risk scores were externally validated (ACCP-VTE, HAS-BLED, Hokusai, Kuijer, Martinez, RIETE, and VTE-BLEED). The predictive performance of these scores was compared with a pragmatic classification based on cancer type (gastrointestinal; genitourinary; other) and a newly derived competing risk-adjusted prediction model based on clinical predictors for clinically relevant bleeding within 6 months after CAT diagnosis with nonbleeding-related mortality as the competing event ("CAT-BLEED").

Results:  Data of 1,046 patients (149 events) were analyzed. Predictive performance of existing risk scores was poor to moderate (C-statistics: 0.50-0.57; poor calibration). Internal validation of the pragmatic classification and "CAT-BLEED" showed moderate performance (respective C-statistics: 0.61; 95% confidence interval [CI]: 0.56-0.66, and 0.63; 95% CI 0.58-0.68; good calibration).

Conclusion:  Existing risk scores for bleeding perform poorly after CAT. Pragmatic classification based on cancer type provides marginally better estimates of clinically relevant bleeding risk. Further improvement may be achieved with "CAT-BLEED," but this requires external validation in practice-based settings and with other DOACs and its clinical usefulness is yet to be demonstrated.
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http://dx.doi.org/10.1055/s-0041-1735251DOI Listing
September 2021

Extended Anticoagulant Treatment with Full- or Reduced-Dose Apixaban in Patients with Cancer-Associated Venous Thromboembolism: Rationale and Design of the API-CAT Study.

Thromb Haemost 2021 Sep 17. Epub 2021 Sep 17.

INNOVTE-FCRIN, Saint-Etienne, France.

Cancer-associated thrombosis (CT) is associated with a high risk of recurrent venous thromboembolic (VTE) events that require extended anticoagulation in patients with active cancer, putting them at risk of bleeding. The aim of the API-CAT study (NCT03692065) is to assess whether a reduced-dose regimen of apixaban (2.5 mg twice daily [bid]) is noninferior to a full-dose regimen of apixaban (5 mg bid) for the prevention of recurrent VTE in patients with active cancer who have completed ≥6 months of anticoagulant therapy for a documented index event of proximal deep-vein thrombosis and/or pulmonary embolism. API-CAT is an international, randomized, parallel-group, double-blind, noninferiority trial with blinded adjudication of outcome events. Consecutive patients are randomized to receive apixaban 2.5 or 5 mg bid for 12 months. The primary efficacy outcome is a composite of recurrent symptomatic or incidental VTE during the treatment period. The principal safety endpoint is clinically relevant bleeding, defined as a composite of major bleeding or nonmajor clinically relevant bleeding. Assuming a 12-month incidence of the primary outcome of 4% with apixaban and an upper limit of the two-sided 95% confidence interval of the hazard ratio <2.0, 1,722 patients will be randomized, assuming an up to 10% loss in total patient-years (β = 80%; α one-sided = 0.025). This trial has the potential to demonstrate that a regimen of extended treatment for patients with CT beyond an initial 6 months, with a reduced apixaban dose, has an acceptable risk of recurrent VTE recurrence and decreases the risk of bleeding.
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http://dx.doi.org/10.1055/a-1647-9896DOI Listing
September 2021

New Inhibitors in the Ageing Population: A Retrospective, Observational, Cohort Study of New Inhibitors in Older People with Hemophilia.

Thromb Haemost 2021 Sep 10. Epub 2021 Sep 10.

Van Creveldkliniek, UMC Utrecht, Utrecht, The Netherlands.

Introduction:  A second peak of inhibitors has been reported in patients with severe hemophilia A (HA) aged >50 years in the United Kingdom. The reason for this suggested breakdown of tolerance in the aging population is unclear, as is the potential impact of regular exposure to the deficient factor by prophylaxis at higher age. No data on hemophilia B (HB) have ever been reported.

Aim:  The ADVANCE Working Group investigated the incidence of late-onset inhibitors and the use of prophylaxis in patients with HA and HB aged ≥40 years.

Methods:  A retrospective, observational, cohort, survey-based study of all patients aged ≥40 years with HA or HB treated at an ADVANCE hemophilia treatment center.

Results:  Information on 3,095 people aged ≥40 years with HA or HB was collected. Of the 2,562 patients with severe HA, the majority (73% across all age groups) received prophylaxis. In patients with severe HA, the inhibitor incidence per 1,000 treatment years was 2.37 (age 40-49), 1.25 (age 50-59), and 1.45 (age 60 + ). Overall, the inhibitor incidence was greatest in those with moderate HA (5.77 [age 40-49], 6.59 [age 50-59], and 4.69 [age 60 + ]) and the majority of inhibitor cases were preceded by a potential immune system challenge. No inhibitors in patients with HB were reported.

Conclusion:  Our data do not identify a second peak of inhibitor development in older patients with hemophilia. Prophylaxis may be beneficial in older patients with severe, and possibly moderate HA, to retain a tolerant state at a higher age.
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http://dx.doi.org/10.1055/a-1642-4067DOI Listing
September 2021

Management of Cancer-Associated Thrombosis: Unmet Needs and Future Perspectives.

TH Open 2021 Jul 31;5(3):e376-e386. Epub 2021 Aug 31.

Department of Obstetrics and Gynecology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia.

Patients with cancer are at a high risk of symptomatic venous thromboembolism (VTE), which is a common cause of morbidity and mortality in this patient population. Increased risk of recurrent VTE and bleeding complications are two major challenges associated with therapeutic anticoagulation in these patients. Long-term therapy with low-molecular-weight heparins (LMWHs) has been the standard of care for the treatment of cancer-associated VTE given its favorable risk-benefit ratio in comparison with vitamin K antagonists. Direct oral anticoagulants (DOACs), which offer the convenience of oral administration and have a rapid onset of action, have recently emerged as a new treatment option for patients with cancer-associated thrombosis (CT). Randomized clinical trial data with head-to-head comparisons between DOACs and LMWHs showed that overall, DOACs have a similar efficacy profile but a higher risk of bleeding was observed in some of these studies. This review aims to identify unmet needs in the treatment of CT. We discuss important considerations for clinicians tailoring anticoagulation (1) drug-drug interactions, (2) risk of bleeding (e.g., gastrointestinal bleeding), (3) thrombocytopenia, hematological malignancies, (4) metastatic or primary brain tumors, and (5) renal impairment. Additional research is warranted in several clinical scenarios to help clinicians on the best therapeutic approach.
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http://dx.doi.org/10.1055/s-0041-1736037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407937PMC
July 2021

Hemostatic Biomarkers and Venous Thromboembolism Are Associated With Mortality and Response to Chemotherapy in Patients With Pancreatic Cancer.

Arterioscler Thromb Vasc Biol 2021 11 2;41(11):2837-2847. Epub 2021 Sep 2.

Clinical Division of Haematology and Haemostaseology (F.M., J.T., S.W., T.S., C.E., I.P., C.A.), Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria.

Objective: Pancreatic cancer activates coagulation and increases risk of venous thromboembolism (VTE). We aimed at characterizing the association of hemostatic biomarkers and VTE with mortality and chemotherapy response.

Approach And Results: Pancreatic cancer patients (N=145) were included in a prospective, observational cohort study (CATS [Vienna Cancer and Thrombosis Study]). Hemostatic biomarkers (D-dimer, extracellular vesicle-tissue factor activity, prothrombin fragment 1+2, fibrinogen, factor VIII, PAI-1 [plasminogen activator inhibitor 1], sP-selectin [soluble P-selectin], thrombin generation assay) were measured at inclusion. The impact of VTE on overall survival/progression-free survival (OS/PFS) was evaluated by multistate modeling. The association of biomarkers with OS was analyzed by Cox-regression and with PFS and disease control rate in patients initiating palliative chemotherapy (n=95) by Cox-regression and logistic regression. Multivariable analysis included stage, grade, sex, age, performance status, VTE (time-dependent), vascular infiltration/compression, and tumor marker levels (carbohydrate-antigen 19-9, carcinoembryonic antigen). VTE occurrence was associated with shorter OS (transition hazard ratio, 3.40 [95% CI, 2.05-5.64]) and shorter PFS (transition hazard ratio, 2.10 [1.16-3.79]). Median post-VTE OS/PFS in months was 5.5 [2.2-6.5] and 3.0 [1.5-3.9], compared with 13.4 [9.7-16.6] and 7.5 [5.9-9.8] in patients without VTE (both P<0.001). D-dimer, extracellular vesicle-tissue factor activity, PAI-1, and sP-selectin were associated with increased mortality (hazard ratio per doubling, 1.27 [1.00-1.61]; 1.63 [1.14-2.36]; 1.25 [1.06-1.47]; 1.52 [1.05-2.20]). In patients initiating palliative chemotherapy, higher D-dimer predicted shorter PFS (hazard ratio per doubling, 1.27 [1.01-1.60]) and lower disease control rate (odds ratio per doubling, 0.59 [0.36-0.98]).

Conclusions: VTE diagnosis is associated with shorter OS and PFS. Higher baseline levels of D-dimer, extracellular vesicle-tissue factor activity, PAI-1, and sP-selectin were independently prognostic for increased mortality, and D-dimer predicted response to palliative chemotherapy.
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http://dx.doi.org/10.1161/ATVBAHA.121.316463DOI Listing
November 2021

Anticoagulation use and the risk of stroke and major bleeding in patients on hemodialysis: From the VIVALDI, a population-based prospective cohort study.

J Thromb Haemost 2021 Dec 5;19(12):2984-2996. Epub 2021 Sep 5.

Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Background: Evidence supporting the use of anticoagulation for the prevention of stroke and thromboembolism in patients with kidney failure on hemodialysis (HD) and atrial fibrillation (AF) is limited. We prospectively assessed the incidences of stroke and major bleeding, as well as anticoagulation strategies in patients on HD with AF.

Methods: We recruited 625 prevalent HD patients into a population-based observational cohort study. The primary prospective outcomes were thromboembolic events (stroke, transient ischemic attack, systemic embolism) and major bleeding. Secondary outcomes included a composite of thromboembolic events, major bleeding, and cardiovascular death to determine net clinical harm.

Results: A total of 238 patients (38.1%) had AF, 165 (26.4%) already at baseline and 73 (15.9%) developed AF during a median follow up of 870 days. Forty (6.4%) thromboembolic events and 89 (14.2%) major bleedings occurred. Overall, 256 patients died (41.0%). In AF patients, use of vitamin K antagonists (VKAs) in 61 patients (25.6%) was not significantly associated with reduced risk of the primary thromboembolic outcome (subdistribution hazard ratio [SHR] 1.41 adjusted for age, sex, congestive heart failure, hypertension, stroke/transient ischemic attack/thromboembolism, vascular disease, and diabetes history score and antiplatelet co-medication (95% CI, 0.49-4.07), but with increased risk of major bleeding (SHR: 2.28; 95% CI, 1.09-4.79) compared with AF patients without anticoagulation (N = 139, 58.4%). Use of VKAs was associated with net clinical harm (adjusted SHR: 2.07; 95% CI, 1.25-3.42).

Conclusions: Although the nonrandomized nature of the study is prone to bias, anticoagulation with VKAs was not associated with decreased thromboembolic risk, but rather with increased risk of major bleeding and may be net harmful to patients with AF on HD.
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http://dx.doi.org/10.1111/jth.15508DOI Listing
December 2021

[Title: Covid-19-associated coagulopathy].

Dtsch Med Wochenschr 2021 Aug 3;146(15):944-949. Epub 2021 Aug 3.

Klinische Abteilung für Hämatologie und Hämostaseologie, Universitätsklinik für Innere Medizin I, Medizinische Universität Wien, Österreich.

COVID-19, primarily a respiratory disease, is considered a multi-systemic disease as symptom severity increases. Blood coagulation abnormalities are key features of patients with severe symptoms and indicative of the high risk of both venous and arterial thromboembolism in COVID-19. This prothrombotic condition caused by an interplay of the infectious agent, inflammation, and the blood coagulation system is referred to as COVID-19-associated coagulopathy and characterized by greatly increased D-dimer, high fibrinogen, an extended prothrombin time, and a reduced number of platelets. Due to this high thrombotic potential, prophylactic anticoagulation is recommended in all hospitalized patients. However, the optimal dosage of anticoagulation is still debated. In this article, we provide an overview of the current state of knowledge about COVID-19-associated coagulopathy and discuss clinical therapeutic consequences.
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http://dx.doi.org/10.1055/a-1497-9028DOI Listing
August 2021

Peri-interventional Triple Therapy With Dabigatran Improves Vasomotion and Promotes Endothelialization in Porcine Coronary Stenting Model.

Front Cardiovasc Med 2021 2;8:690476. Epub 2021 Jul 2.

Department of Cardiology, Medical University of Vienna, Vienna, Austria.

We evaluated the short and long-term effect of peri-interventional dabigatran therapy on vasomotion, endothelialization, and neointimal formation in a porcine coronary artery stenting model. Stenting of coronary arteries induces local inflammation, impairs vasomotion and delays endothelialization. Twenty-eight animals underwent percutaneous coronary intervention (PCI) with drug eluting stents. Sixteen pigs started dabigatran therapy 4 days prior to PCI and continued for 4 days post-stenting, while 12 animals served as controls. Post-stenting dual antiplatelet therapy (75 mg clopidogrel and 100 mg aspirin) was continued in both groups until termination. Immediately post-stenting and at day 3 optical coherence tomography (OCT) was performed in all animals, followed by euthanasia of 8 dabigatran and 4 control animals. The remaining pigs (8 of each group) were followed up for 1 month, with control angiography and OCT. Tissue burden (degree of peri-strut structure-thrombus and/or fibrin) was evaluated. After euthanasia coronary arteries were harvested for myometry and histology. Thrombin generation was lower ( < 0.001) and tissue burden (0.83 ± 0.98 vs. 3.0 ± 2.45; = 0.031) was significantly decreased in dabigatran treated animals. After 3 days post-PCI endothelium-dependent vasodilation was significantly improved (77 ± 40% vs. 41 ± 31%, = 0.02) in dabigatran animals. Neither quantitative angiography nor histomorphometry showed differences between the groups. Endothelialization was faster in the dabigatran group as compared with controls ( = 0.045). Short-term peri-interventional triple therapy with dabigatran, aspirin, and clopidogrel led to an enhanced endothelium dependent vasodilation and faster endothelialization. However, neointimal formation 1-month after stent implantation was comparable between groups.
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http://dx.doi.org/10.3389/fcvm.2021.690476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300015PMC
July 2021

Patterns of Thromboembolism in Patients with Advanced Pancreatic Cancer Undergoing First-Line Chemotherapy with FOLFIRINOX or Gemcitabine/nab-Paclitaxel.

Thromb Haemost 2021 Jul 12. Epub 2021 Jul 12.

IIIrd Medical Department of Hematology, Medical Oncology, Hemostaseology, Rheumatology and Infectious Disease, Salzburg Cancer Research Institute, Paracelsus Medical University, Salzburg, Austria.

Introduction:  Recent advances in prophylactic anticoagulation and antineoplastic treatment for advanced pancreatic cancer (aPC) warrant an updated reassessment of thromboembolic risk in this population. This multicenter retrospective cohort study aims to comprehensively characterize incidence, risk factors, and outcomes of venous (VTE) and arterial thromboembolism (ATE) in homogenously treated patients with aPC.

Methods:  Four hundred and fifty-five patients with aPC undergoing palliative first-line chemotherapy (Gemcitabine/nab-Paclitaxel (GN) or FOLIRINOX) were included. Primary outcomes were objectively confirmed VTE and/or ATE.

Results:  Over a median follow-up of 26 months, 86 VTE (cumulative incidence: 20.0%; 95% confidence interval [CI]: 16.3-24.0) and 11 ATE events (cumulative incidence: 2.8%; 95% CI: 1.5-4.9) were observed. VTE diagnosis was associated with increased mortality (transition hazard ratio [THR]: 1.59 [95% CI: 1.21-2.09]) and increased risk of cancer progression (THR: 1.47 [95% CI: 1.08-2.01]), while the impact of ATE on mortality was numerically but not statistically significant (THR: 1.85 [95% CI: 0.87-3.94]). The strongest predictor of increased VTE risk was history of cancer-associated VTE (subdistribution hazard ratio [SHR]: 3.29 [95% CI: 2.09-5.18]), while the Khorana score (SHR: 0.78 [0.57-1.06]) failed to predict VTE risk. A history of cerebrovascular disease was associated with markedly increased ATE risk (SHR: 22.05 [95% CI: 6.83-71.22],  < 0.001), especially ischemic stroke. Risk of VTE/ATE did not significantly differ according to type of first-line chemotherapy.

Conclusion:  Patients with aPC undergoing palliative first-line chemotherapy with FOLFIRINOX or GN face a high risk for VTE/ATE and its diagnosis is linked to worse clinical outcomes. VTE-risk prediction models have limited ability to sub-stratify thrombotic events in this high-risk scenario.
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http://dx.doi.org/10.1055/a-1548-4847DOI Listing
July 2021

Bleeding outcomes and factor utilization after switching to an extended half-life product for prophylaxis in haemophilia A in Austria.

Sci Rep 2021 06 21;11(1):12967. Epub 2021 Jun 21.

Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

To prevent bleeding in severe haemophilia A [SHA, defined as factor VIII (FVIII) activity < 1%] regular prophylactic FVIII replacement therapy is required, and the benefits of factor products with extended half-life (EHL) over traditional standard half-life (SHL) are still being debated. We performed a multi-centre, retrospective cohort study of persons with SHA in Austria aiming to compare clinical outcomes and factor utilization in patients with SHA, who switched from prophylaxis with SHL to an EHL. Data were collected from haemophilia-specific patient diaries and medical records. Twenty male persons with SHA (median age: 32.5 years) were included. The most common reason for switching to the EHL was a high bleeding rate with SHL. Switch to rFVIII-Fc resulted in a significantly decreased annualized bleeding rate (ABR; median difference (IQR): - 0.3 (- 4.5-0); Wilcoxon signed-rank test for matched pairs: Z = - 2.7, p = 0.008) and number of prophylactic infusions per week (- 0.75 (- 1.0-0.0); Z = - 2.7, p = 0.007). Factor utilization was comparable to prior prophylaxis with SHL (0.0 (- 15.8-24.8) IU/kg/week; Z = - 0.4, p = 0.691). In summary, switch to EHL (rFVIII-Fc) was associated with an improved clinical outcome, reflected by ABR reduction, and less frequent infusions, without significantly higher factor usage.
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http://dx.doi.org/10.1038/s41598-021-92245-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217178PMC
June 2021

Alterations of the Platelet Proteome in Lung Cancer: Accelerated F13A1 and ER Processing as New Actors in Hypercoagulability.

Cancers (Basel) 2021 May 8;13(9). Epub 2021 May 8.

Centre for Physiology and Pharmacology, Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, 1090 Vienna, Austria.

In order to comprehensively expose cancer-related biochemical changes, we compared the platelet proteome of two types of cancer with a high risk of thrombosis (22 patients with brain cancer, 19 with lung cancer) to 41 matched healthy controls using unbiased two-dimensional differential in-gel electrophoresis. The examined platelet proteome was unchanged in patients with brain cancer, but considerably affected in lung cancer with 15 significantly altered proteins. Amongst these, the endoplasmic reticulum (ER) proteins calreticulin (CALR), endoplasmic reticulum chaperone BiP (HSPA5) and protein disulfide-isomerase (P4HB) were significantly elevated. Accelerated conversion of the fibrin stabilising factor XIII was detected in platelets of patients with lung cancer by elevated levels of a coagulation factor XIII (F13A1) 55 kDa fragment. A significant correlation of this F13A1 cleavage product with plasma levels of the plasmin-α-2-antiplasmin complex and D-dimer suggests its enhanced degradation by the fibrinolytic system. Protein association network analysis showed that lung cancer-related proteins were involved in platelet degranulation and upregulated ER protein processing. As a possible outcome, plasma FVIII, an immediate end product for ER-mediated glycosylation, correlated significantly with the ER-executing chaperones CALR and HSPA5. These new data on the differential behaviour of platelets in various cancers revealed F13A1 and ER chaperones as potential novel diagnostic and therapeutic targets in lung cancer patients.
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http://dx.doi.org/10.3390/cancers13092260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125802PMC
May 2021

Fibrinolysis and bleeding of unknown cause.

Res Pract Thromb Haemost 2021 May 7;5(4):e12511. Epub 2021 Apr 7.

Clinical Division of Hematology and Hemostaseology Department of Medicine I Medical University of Vienna Vienna Austria.

Patients with bleeding of unknown cause (BUC) present with a variety of mild to moderate bleeding symptoms, but no hemostatic abnormalities can be found. Hyperfibrinolysis is rarely evaluated as the underlying cause for bleeding in clinical practice, and well-established global assays for abnormal fibrinolysis are lacking. Few patients with definitive fibrinolytic disorders, including α2-antiplasmin deficiency, plasminogen activator inhibitor 1 deficiency, or Quebec platelet disorder, have been reported. This review aims to summarize data on established fibrinolytic disorders and to discuss assessments of fibrinolysis in prior bleeding cohorts. Furthermore, we review available global tests with the potential to measure fibrinolysis, such as turbidity fibrin clot assays and rotational thromboelastometry, and their relevance in the workup of patients with BUC. We conclude that, due to the lack of adequate global tests, hyperfibrinolysis might be an underdiagnosed cause for a bleeding disorder. The diagnosis of hyperfibrinolytic bleeding disorders would improve patient care as effective treatment with antifibrinolytic agents is available.
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http://dx.doi.org/10.1002/rth2.12511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117813PMC
May 2021

Intraperitoneal Activation of Coagulation and Fibrinolysis in Patients with Cirrhosis and Ascites.

Thromb Haemost 2021 May 21. Epub 2021 May 21.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Development of ascites is the most common form of decompensation of cirrhosis. We aimed to investigate the coagulation system in ascitic fluid and plasma of patients with cirrhosis. We determined coagulation parameters and performed clotting and fibrinolysis experiments in ascitic fluid and plasma of thoroughly characterized patients with cirrhosis and ascites ( = 25) and in plasma of patients with cirrhosis but without ascites ( = 25), matched for severity of portal hypertension. We also investigated plasma D-dimer levels in an independent cohort of patients ( = 317) with clinically significant portal hypertension (HVPG ≥ 10 mmHg), grouped according to ascites severity. Ascitic fluid was procoagulant in a clotting assay. The procoagulant potential of ascitic fluid was abolished by depletion of extracellular vesicles from ascitic fluid by filtration or by addition of a tissue factor-neutralizing antibody. Compared with plasma, extracellular vesicle-associated tissue factor activity was high in ascitic fluid, while activities of other coagulation factors were low. The extracellular vesicle-depleted fraction of ascitic fluid induced fibrinolysis, which was prevented by aprotinin, indicating the presence of plasmin in ascitic fluid. Plasma peak thrombin generation and parameters reflecting fibrinolysis were independently associated with the presence of ascites. Finally, plasma D-dimer levels were independently linked to ascites severity in our second cohort comprising 317 patients. In conclusion, coagulation and fibrinolysis become activated in ascites of patients with cirrhosis. While tissue factor-exposing extracellular vesicles in ascitic fluid seem unable to pass the peritoneal membrane, fibrinolytic enzymes get activated in ascitic fluid and may re-enter the systemic circulation and induce systemic fibrinolysis.
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http://dx.doi.org/10.1055/a-1515-9529DOI Listing
May 2021

Successful treatment of vaccine-induced prothrombotic immune thrombocytopenia (VIPIT).

J Thromb Haemost 2021 07 11;19(7):1819-1822. Epub 2021 Jun 11.

Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

Cases of unusual thrombosis and thrombocytopenia after administration of the ChAdOx1 nCoV-19 vaccine (AstraZeneca) have been reported. The term vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) was coined to reflect this new phenomenon. In vitro experiments with VIPIT patient sera indicated that high-dose intravenous immunoglobulins (IVIG) competitively inhibit the platelet-activating properties of ChAdOx1 nCoV-19 vaccine induced antibodies. Here, we report a case of a 62-year-old woman who had received this vaccine and developed VIPIT. She visited the emergency ward because of petechiae and hematomas. In the laboratory work-up, thrombocytopenia, low fibrinogen, elevated D-dimer, and positivity in the platelet factor 4/heparin-enzyme-immunoassay were present. Signs and symptoms of thrombosis were absent. Upon immediate therapy with non-heparin anticoagulation, high-dose IVIG, and prednisolone, laboratory parameters steadily improved and the patient was discharged from hospital without thrombotic complications. We conclude that early initiation of VIPIT treatment results in a swift response without thrombotic complications.
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http://dx.doi.org/10.1111/jth.15346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362082PMC
July 2021

Diagnosis and Management of Vaccine-Related Thrombosis following AstraZeneca COVID-19 Vaccination: Guidance Statement from the GTH.

Hamostaseologie 2021 Jun 1;41(3):184-189. Epub 2021 Apr 1.

Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald, Greifswald, Germany.

The COVID-19 pandemic is an ongoing global healthcare crisis. Based on reports of atypically located thromboses following vaccination with the AstraZeneca COVID-19 vaccine, the Society of Thrombosis and Haemostasis Research (GTH) has issued guidance statements on the recognition, diagnosis, and treatment of this rare complication. It shares pathophysiological features with heparin-induced thrombocytopenia (HIT) and is referred to as vaccine-induced prothrombotic immune thrombocytopenia (VIPIT).
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http://dx.doi.org/10.1055/a-1469-7481DOI Listing
June 2021

Extracellular Vesicle-Associated Tissue Factor Activity in Prostate Cancer Patients with Disseminated Intravascular Coagulation.

Cancers (Basel) 2021 Mar 24;13(7). Epub 2021 Mar 24.

Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.

Patients with advanced prostate cancer may develop fulminant disseminated intravascular coagulation (DIC). Circulating extracellular vesicles (EVs)-exposing tissue factor (TF), the initiator of the coagulation cascade, may play an important role. We included 7 prostate cancer patients with DIC, 10 age- and stage-matched cancer controls without DIC, and 10 age-matched healthy male individuals. EV-TF activity was highly elevated in prostate cancer patients with DIC (11.40 pg/mL; range: 4.34-27.06) compared with prostate cancer patients without DIC (0.09 pg/mL; range: 0.00-0.30, = 0.001) and healthy controls (0.18 pg/mL; range: 0.09-0.54; = 0.001). Only EVs from patients with DIC reduced fibrin clot formation time of pooled plasma in a TF-dependent manner. Next, we performed in vitro co-culture experiments including EVs derived from a prostate cancer cell line with high (DU145) and low (LNCaP) TF expression, peripheral blood mononuclear cells (PBMCs), and platelets. Co-incubation of DU145 EVs with PBMCs and platelets significantly increased EV-TF activity in conditioned medium and induced TF activity on monocytes. No such effects were seen in co-culture experiments with LNCaP EVs. In conclusion, the findings indicate that elevated EV-TF activity plays a role in the development of prostate-cancer-related DIC and may result from interactions between tumor-derived EVs, monocytes, and platelets.
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http://dx.doi.org/10.3390/cancers13071487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036918PMC
March 2021

Relative risk of arterial and venous thromboembolism in persons with cancer vs. persons without cancer-a nationwide analysis.

Eur Heart J 2021 06;42(23):2299-2307

Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria.

Aims: An interrelation between cancer and thrombosis is known, but population-based studies on the risk of both arterial thromboembolism (ATE) and venous thromboembolism (VTE) have not been performed.

Methods And Results: International Classification of Disease 10th Revision (ICD-10) diagnosis codes of all publicly insured persons in Austria (0-90 years) were extracted from the Austrian Association of Social Security Providers dataset covering the years 2006-07 (n = 8 306 244). Patients with a history of cancer or active cancer were defined as having at least one ICD-10 'C' diagnosis code, and patients with ATE and/or VTE as having at least one of I21/I24 (myocardial infarction), I63/I64 (stroke), I74 (arterial embolism), and I26/I80/I82 (venous thromboembolism) diagnosis code. Among 158 675 people with cancer, 8559 (5.4%) had an ATE diagnosis code and 7244 (4.6%) a VTE diagnosis code. In contrast, among 8 147 569 people without cancer, 69 381 (0.9%) had an ATE diagnosis code and 29 307 (0.4%) a VTE diagnosis code. This corresponds to age-stratified random-effects relative risks (RR) of 6.88 [95% confidence interval (CI) 4.81-9.84] for ATE and 14.91 (95% CI 8.90-24.95) for VTE. ATE proportion was highest in patients with urinary tract malignancies (RR: 7.16 [6.74-7.61]) and lowest in patients with endocrine cancer (RR: 2.49 [2.00-3.10]). The corresponding VTE proportion was highest in cancer of the mesothelium/soft tissue (RR: 19.35 [17.44-21.47]) and lowest in oropharyngeal cancer (RR: 6.62 [5.61-7.81]).

Conclusion: The RR of both ATE and VTE are significantly higher in persons with cancer. Our population-level meta-data indicate a strong association between cancer, ATE and VTE, and support the concept of shared risk factors and pathobiology between these diseases.Relative risk of ATE and VTE in persons with a cancer diagnosis code versus persons without a cancer diagnosis code.
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http://dx.doi.org/10.1093/eurheartj/ehab171DOI Listing
June 2021

Platelet activation and aggregation in different centrifugal-flow left ventricular assist devices.

Platelets 2021 Mar 24:1-8. Epub 2021 Mar 24.

Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.

Left-ventricular assist devices (LVADs) improve outcomes in end-stage heart failure patients. Two centrifugal-flow LVAD systems are currently approved, HeartMate 3 (HM3) and Medtronic/Heartware HVAD (HVAD). Clinical findings suggest differences in thrombogenicity between both systems. We compared markers of platelet activation and aggregation between HM3 and HVAD. We prospectively included 59 LVAD patients (40 HM3, 19 HVAD). Platelet -selectin expression, activated glycoprotein (GP) IIb/IIIa and monocyte-platelet aggregates (MPA) were assessed by flow-cytometry. Platelet aggregation was measured by light-transmission aggregometry (LTA) and multiple-electrode aggregometry (MEA). Von-Willebrand factor (VWF) antigen (VWF:Ag), VWF activity (VWF:Ac), and VWF multimer pattern analysis were determined. Soluble -selectin (sP-selectin) was measured with an enzyme-linked immunoassay. -selectin, GPIIb/IIIa and MPA levels and in response to arachidonic acid, adenosine diphosphate, and thrombin receptor activating peptide were similar between HM3 and HVAD (all > .05). Likewise, agonist-inducible platelet aggregation by LTA and MEA did not differ between HM3 and HVAD (all > .05). VWF:Ag levels and FVIII:C were similar between both systems (both > .05), but patients with HVAD had significantly lower VWF:Ac ( = .011) and reduced large VWF multimers ( = .013). Finally, sP-selectin levels were similar in patients with HVAD and HM3 ( = .845). In conclusion, on-treatment platelet activation and aggregation are similar in HM3 and HVAD patients. Potential clinical implications of observed differences in VWF profiles between both LVAD systems need to be addressed in future clinical trials.
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http://dx.doi.org/10.1080/09537104.2021.1881950DOI Listing
March 2021

Growth differentiation factor-15 predicts major adverse cardiac events and all-cause mortality in patients with atrial fibrillation.

Eur J Intern Med 2021 06 9;88:35-42. Epub 2021 Mar 9.

Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: Growth-differentiation factor-15 (GDF-15) has recently been described as a potential biomarker for predicting risk of mortality and cardiovascular events in patients with atrial fibrillation (AF) but requires validation in clinical practice.

Methods: The study population consisted of 362 patients (mean age: 71 years, 37% women) with non-valvular AF included in a prospective cohort study. Relationship of GDF-15 with all-cause mortality and major adverse cardiac events (MACE) was analyzed using Cox regression. Survival analysis stratified by GDF-15 was based on national death records, while MACE was recorded at personal follow-up. Further, we evaluated the recently developed GDF-15 based prognostic score towards prediction of all-cause mortality (ABC-death score).

Results: Over a median observation period of 4.3 years, 81 (23.3%) patients died, and over a median personal follow-up of 316 days 47 MACE occurred. GDF-15 was independently associated with all-cause mortality (adjusted HR per double increase 2.33, 95%CI 1.74-3.13) and MACE (adjusted HR per double increase 2.33, 95%CI 1.60-3.39). GDF-15 levels, measured at follow-up, were similarly associated with mortality, and longitudinal measurements of GDF-15 did not significantly differ. Six-year survival probability of patients above vs. below the median GDF-15 level was 44% (95%CI 34-57) and 84% (95%CI 76-93), respectively. The ABC-death score revealed a C-statistic of 0.80.

Conclusion: GDF-15 predicts risk of all-cause mortality and MACE in patients with non-valvular AF. Further, the ABC-death score showed good predictive accuracy in a "real-world" cohort. Therefore, introduction of GDF-15 into clinical practice would enhance risk prediction of morbidity and mortality in AF patients.
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http://dx.doi.org/10.1016/j.ejim.2021.02.011DOI Listing
June 2021

Pain management in hemophilia: expert recommendations.

Wien Klin Wochenschr 2021 Oct 4;133(19-20):1042-1056. Epub 2021 Mar 4.

Department of Pediatrics, Medical University of Innsbruck, Innrain 52, 6020, Innsbruck, Austria.

Introduction: As a typical consequence of bleeding into muscles and joints, patients with severe hemophilia suffer from acute and chronic pain. In spite of its high prevalence, pain in this patient group is not always sufficiently considered or treated in an effective manner.

Aim: The recommendations presented in this paper address possible improvements in pain management in hemophilia patients and particularities that have to be taken into account in this patient group.

Method: The manifold aspects of pain management in hemophilia patients were discussed within the framework of an expert meeting. Based on the available literature and the experts' clinical experience, the participants developed a set of recommendations presented in this paper.

Results: Pain management in patients with hemophilia is often insufficient, a fact that not only influences the patients' quality of life but also implies the risk of difficult to manage chronic pain. Both the prevalent polypharmacy (due to comorbidities) as well as the underlying disease itself present special challenges to pain therapy in this patient group. The present review and recommendations are intended to support medical professionals in recognising the risks of pain chronicity, applying basic principles of multimodal pain therapy, including the options of psychological intervention and modalities of physical medicine in therapy concepts, and reaching a comprehensive understanding of the range of analgesic options available.
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http://dx.doi.org/10.1007/s00508-020-01798-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500904PMC
October 2021

Bleeding Risk Assessment in Patients with Venous Thromboembolism.

Hamostaseologie 2021 Aug 24;41(4):267-274. Epub 2021 Feb 24.

Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

The recommended treatment for patients with venous thromboembolism (VTE) is anticoagulation for at least 3 months. However, anticoagulant treatment increases the risk of bleeding, and patients at high risk for major bleeding might benefit from treatment discontinuation. In this review, we discuss strategies for assessing bleeding risk and compare different bleeding risk tools. Bleeding risk assessment is best viewed as a continuous approach with varying challenges throughout the acute and chronic phase. At diagnosis, bleeding risk factors must be identified and reversible risk factors treated or modified. After initial treatment, repeated bleeding risk assessment is crucial for the decision on extended/long-term anticoagulation. Current clinical prediction models (e.g., HAS-BLED, RIETE, or VTE-BLEED scores) are externally validated tools with relevant differences in specificity and sensitivity, which can aid in clinical decision-making. Unfortunately, none of the current bleeding risk assessment tools has been investigated in clinical trials and provides evidence to withhold anticoagulation treatment based on the score. Nevertheless, the HAS-BLED or RIETE score can be used to identify patients at high risk for major bleeding during the initial treatment phase, while the VTE-BLEED score might be used to identify patients at low risk for bleeding and, therefore, to safely administer extended/long-term anticoagulation for secondary thromboprophylaxis. As clinical prediction scores still lack predictive value, future research should focus on developing biomarker-based risk assessment models.
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http://dx.doi.org/10.1055/a-1339-9987DOI Listing
August 2021

American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer.

Blood Adv 2021 02;5(4):927-974

Cochrane Iberoamérica, Biomedical Research Institute Sant Pau-CIBERESP, Barcelona, Spain.

Background: Venous thromboembolism (VTE) is a common complication among patients with cancer. Patients with cancer and VTE are at a markedly increased risk for morbidity and mortality.

Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about the prevention and treatment of VTE in patients with cancer.

Methods: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The guideline development process was supported by updated or new systematic evidence reviews. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess evidence and make recommendations.

Results: Recommendations address mechanical and pharmacological prophylaxis in hospitalized medical patients with cancer, those undergoing a surgical procedure, and ambulatory patients receiving cancer chemotherapy. The recommendations also address the use of anticoagulation for the initial, short-term, and long-term treatment of VTE in patients with cancer.

Conclusions: Strong recommendations include not using thromboprophylaxis in ambulatory patients receiving cancer chemotherapy at low risk of VTE and to use low-molecular-weight heparin (LMWH) for initial treatment of VTE in patients with cancer. Conditional recommendations include using thromboprophylaxis in hospitalized medical patients with cancer, LMWH or fondaparinux for surgical patients with cancer, LMWH or direct oral anticoagulants (DOAC) in ambulatory patients with cancer receiving systemic therapy at high risk of VTE and LMWH or DOAC for initial treatment of VTE, DOAC for the short-term treatment of VTE, and LMWH or DOAC for the long-term treatment of VTE in patients with cancer.
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http://dx.doi.org/10.1182/bloodadvances.2020003442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903232PMC
February 2021

Natural IgM antibodies inhibit microvesicle-driven coagulation and thrombosis.

Blood 2021 03;137(10):1406-1415

Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.

Thrombosis and its associated complications are a major cause of morbidity and mortality worldwide. Microvesicles (MVs), a class of extracellular vesicles, are increasingly recognized as mediators of coagulation and biomarkers of thrombotic risk. Thus, identifying factors targeting MV-driven coagulation may help in the development of novel antithrombotic treatments. We have previously identified a subset of circulating MVs that is characterized by the presence of oxidation-specific epitopes and bound by natural immunoglobulin M (IgM) antibodies targeting these structures. This study investigated whether natural IgM antibodies, which are known to have important anti-inflammatory housekeeping functions, inhibit the procoagulatory properties of MVs. We found that the extent of plasma coagulation is inversely associated with the levels of both free and MV-bound endogenous IgM. Moreover, the oxidation epitope-specific natural IgM antibody LR04, which recognizes malondialdehyde adducts, reduced MV-dependent plasmatic coagulation and whole blood clotting without affecting thrombocyte aggregation. Intravenous injection of LR04 protected mice from MV-induced pulmonary thrombosis. Of note, LR04 competed the binding of coagulation factor X/Xa to MVs, providing a mechanistic explanation for its anticoagulatory effect. Thus, our data identify natural IgM antibodies as hitherto unknown modulators of MV-induced coagulation in vitro and in vivo and their prognostic and therapeutic potential in the management of thrombosis.
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http://dx.doi.org/10.1182/blood.2020007155DOI Listing
March 2021

Plasminogen activator inhibitor 1 and venous thrombosis in pancreatic cancer.

Blood Adv 2021 01;5(2):487-495

Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

Pancreatic cancer patients have a high risk of venous thromboembolism (VTE). Plasminogen activator inhibitor 1 (PAI-1) inhibits plasminogen activators and increases the risk of thrombosis. PAI-1 is expressed by pancreatic tumors and human pancreatic cell lines. However, to date, there are no studies analyzing the association of active PAI-1 and VTE in pancreatic cancer patients. We investigated the association of active PAI-1 in plasma and VTE in pancreatic cancer patients. In addition, we determined if the presence of human pancreatic tumors expressing PAI-1 impairs venous thrombus resolution in mice. Plasma levels of active PAI-1 in patients with pancreatic cancer and mice bearing human tumors were determined by enzyme-linked immunosorbent assay. We measured PAI-1 expression in 5 different human pancreatic cancer cell lines and found that PANC-1 cells expressed the highest level. PANC-1 tumors were grown in nude mice. Venous thrombosis was induced by complete ligation of the inferior vena cava (IVC). Levels of active PAI-1 were independently associated with increased risk of VTE in patients with pancreatic cancer (subdistribution hazard ratio per doubling of levels: 1.39 [95% confidence interval, 1.09-1.78], P = .007). Mice bearing PANC-1 tumors had increased levels of both active human and active mouse PAI-1 and decreased levels of plasmin activity. Importantly, mice bearing PANC-1 tumors exhibited impaired venous thrombus resolution 8 days after IVC stasis compared with nontumor controls. Our results suggest that PAI-1 contributes to VTE in pancreatic cancer.
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http://dx.doi.org/10.1182/bloodadvances.2020003149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839372PMC
January 2021

Elevated levels of tissue factor pathway inhibitor in patients with mild to moderate bleeding tendency.

Blood Adv 2021 01;5(2):391-398

Clinical Division of Hematology and Hemostaseology, Department of Medicine I.

High levels of tissue factor pathway inhibitor (TFPI), caused by a longer TFPIα half-life after binding to a factor V splice variant and variants in the F5 gene, were recently identified in 2 families with an as-yet-unexplained bleeding tendency. This study aimed to investigate free TFPIα in a well-characterized cohort of 620 patients with mild to moderate bleeding tendencies and its association to genetic alterations in the F5 gene. TFPIα levels were higher in patients with bleeding compared with healthy controls (median [interquartile range], 8.2 [5.5-11.7] vs 7.8 [4.3-11.1]; P = .026). A higher proportion of patients had free TFPIα levels more than or equal to the 95th percentile compared with healthy controls (odds ratio [OR] [95% confidence interval (CI)], 2.82 [0.98-8.13]). This was pronounced in the subgroup of patients in whom no bleeding disorder could be identified (bleeding of unknown cause [BUC; n = 420]; OR [95% CI], 3.03 [1.02-8.98]) and in platelet function defects (PFDs) (n = 121; OR [95% CI], 3.47 [1.09-11.08]). An increase in free TFPIα was associated with a mild delay in thrombin generation (prolonged lag time and time to peak), but not with alterations in routinely used global clotting tests. We could neither identify new or known genetic variations in the F5 gene that are associated with free TFPIα levels, nor an influence of the single-nucleotide variant rs10800453 on free TFPIα levels in our patient cohort. An imbalance of natural coagulation inhibitors such as TFPIα could be an underlying cause or contributor for unexplained bleeding, which is most probably multifactorial in a majority of patients.
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http://dx.doi.org/10.1182/bloodadvances.2020003464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839354PMC
January 2021
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