Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants.

Anticoagulation for cancer-associated venous thromboembolism (VTE) can be challenging due to complications-including bleeding and potential drug-drug interactions with chemotherapy-associated with vitamin K antagonists and inconvenience of low-molecular-weight heparin (LMWH). Direct oral anticoagulants (DOACs) could partially overcome these issues, but until recently there were no large clinical trials assessing their efficacy and safety in cancer patients. This review summarizes clinical treatment guidelines, prior clinical and real-world evidence for anticoagulant choice, recent clinical trials assessing DOACs for cancer-associated VTE (i.e. Hokusai-VTE Cancer, SELECT-D, CARAVAGGIO, and ADAM VTE), and special considerations for DOAC use. Based on established data, clinical guidelines recommend patients with cancer-associated VTE receive LMWH treatment of at least 3-6 months. Nevertheless, LMWH is underused and associated with poor compliance and persistence in these patients relative to oral anticoagulants. Clinical data supporting DOAC use in cancer patients are becoming available. In Hokusai-VTE Cancer, edoxaban was noninferior to dalteparin for the composite of recurrent VTE and major bleeding (12.8% versus 13.5%), with numerically lower recurrent VTE (7.9% versus 11.3%) and significantly higher major bleeding (6.9% versus 4.0%); only patients with gastrointestinal cancer had significantly higher risk of bleeding with edoxaban. In SELECT-D, rivaroxaban had numerically lower VTE recurrence (4% versus 11%), comparable major bleeding (6% versus 4%), and numerically higher clinically relevant nonmajor bleeding (13% versus 4%) versus dalteparin. Most bleeding events were gastrointestinal or urologic; patients with esophageal/gastroesophageal cancer had higher rates of major bleeding with rivaroxaban (36% versus 11%). For comparison of apixaban versus dalteparin, CARAVAGGIO is ongoing, and preliminary results from ADAM VTE are favorable. This review concludes that DOACs appear to be reasonable alternatives to LMWH for treatment of cancer-associated VTE. In patients with gastrointestinal cancer, DOAC use should be considered on a case-by-case basis with consideration of the relative risks and benefits.

Combination of isocitrate dehydrogenase 1 (IDH1) mutation and podoplanin expression in brain tumors identifies patients at high or low risk of venous thromboembolism.

Essentials Risk stratification for venous thromboembolism (VTE) in patients with brain tumors is challenging. Patients with IDH1 wildtype and high podoplanin expression have a 6-month VTE risk of 18.2%. Patients with IDH1 mutation and no podoplanin expression have a 6-month VTE risk of 0%. IDH1 mutation and podoplanin overexpression in primary brain tumors appear to be exclusive. SUMMARY: Background Venous thromboembolism (VTE) is a frequent complication in primary brain tumor patients. Independent studies revealed that podoplanin expression in brain tumors is associated with increased VTE risk, whereas the isocitrate dehydrogenase 1 (IDH1) mutation is associated with very low VTE risk. Objectives To investigate the interrelation between intratumoral podoplanin expression and IDH1 mutation, and their mutual impact on VTE development. Patients/Methods In a prospective cohort study, intratumoral IDH1 R132H mutation and podoplanin were determined in brain tumor specimens (mainly glioma) by immunohistochemistry. The primary endpoint of the study was symptomatic VTE during a 2-year follow-up. Results All brain tumors that expressed podoplanin to a medium-high extent showed also an IDH1 wild-type status. A score based on IDH1 status and podoplanin expression levels allowed prediction of the risk of VTE. Patients with wild-type IDH1 brain tumors and high podoplanin expression had a significantly increased VTE risk compared with those with mutant IDH1 tumors and no podoplanin expression (6-month risk 18.2% vs. 0%). Conclusions IDH1 mutation and podoplanin overexpression seem to be exclusive. Although brain tumor patients with IDH1 mutation are at very low risk of VTE, the risk of VTE in patients with IDH1 wild-type tumors is strongly linked to podoplanin expression levels.

High proportion of patients with bleeding of unknown cause in persons with a mild-to-moderate bleeding tendency: Results from the Vienna Bleeding Biobank (VIBB).

INTRODUCTION: Data on clinical characteristics and the prevalence of underlying coagulopathies in patients with mild-to-moderate bleeding disorders (MBDs) are scarce. AIM: We established the Vienna Bleeding Biobank (VIBB) to characterize and thoroughly investigate Austrian patients with MBDs. RESULTS: Four hundred eighteen patients (female = 345, 82.5%) were included. A platelet function defect (PFD) was diagnosed in 26 (6.2%) and a possible PFD in 30 (7.2%) patients. Eight patients (1.9%) were diagnosed with von Willebrand disease (VWD) (type 1 n = 6; type 2 n = 2), and 29 patients had low VWF (30-50 IU/dL). Deficiencies in factor VIII, IX, XI or XIII were found in 11 (2.6%), 3 (0.7%), 3 (0.7%) and 1 patient(s), 2 patients had dysfibrinogenaemia, and further 2 had possible PFD and FXI deficiency. Probable causal mutations were detected in 8 of 11 patients with FVIII deficiency, 2 of 3 patients with FIX deficiency and 2 of 8 patients with VWD. Three hundred three patients (72.5%) had normal results in the coagulation assays and were categorized as patients with bleeding of unknown cause (BUC). The bleeding score did not differ between patients with and without established diagnosis. A diagnosis of a bleeding disorder was more frequently made in men than in women (49.3% vs 22.9%). Male sex (OR 3.55, 95% CI: 2.02-6.22; P < .001) and blood group 0 (OR 1.86, 95% CI: 1.17-2.94; P = .008) were independently associated with diagnosis of a bleeding disorder. CONCLUSION: The high rate of patients with BUC despite in-depth haemostatic assessment underlines the incompleteness of available routine laboratory tests. Males with MBDs were more likely to be diagnosed with an established bleeding disorder than females.

Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients.

Essentials Neutrophil extracellular traps (NETs) might play a role in cancer-related coagulopathy. We determined NET biomarkers and followed cancer patients for venous thromboembolism (VTE). We found a constant association with VTE for citrullinated histone H3. Biomarkers of NET formation could reflect a novel pathomechanism of cancer-related VTE. SUMMARY: Background Neutrophil extracellular traps (NETs) are decondensed chromatin fibers that might play a role in the prothrombotic state of cancer patients. Objectives To investigate whether the levels of citrullinated histone H3 (H3Cit), a biomarker for NET formation, cell-free DNA (cfDNA) and nucleosomes predict venous thromboembolism (VTE) in cancer patients. Patients/Methods Nine-hundred and forty-six patients with newly diagnosed cancer or progression after remission were enrolled in this prospective observational cohort study. H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients were followed for 2 years. VTE occurred in 89 patients; the cumulative 3-month, 6-month, 12-month and 24-month incidence rates of VTE were 3.7%, 6.0%, 8.1%, and 10.0%, respectively. Results Patients with elevated H3Cit levels (> 75th percentile of its distribution, n = 236) experienced a higher cumulative incidence of VTE (2-year risk of 14.5%) than patients with levels below this cut-off (2-year risk of 8.5%, n = 710). In a competing-risk regression analysis, a 100 ng mL-1 increase in H3Cit level was associated with a 13% relative increase in VTE risk (subdistribution hazard ratio [SHR] 1.13, 95% confidence interval [CI] 1.04-1.22). This association remained after adjustment for high VTE risk and very high VTE risk tumor sites, D-dimer level, and soluble P-selectin level (SHR 1.13, 95% CI 1.04-1.22). The association of elevated nucleosome and cfDNA levels with VTE risk was time-dependent, with associations with a higher risk of VTE only during the first 3-6 months. Conclusion These data suggest that biomarkers of NET formation are associated with the occurrence of VTE in cancer patients, indicating a role of NETs in the pathogenesis of cancer-associated thrombosis.

Co-morbidities and bleeding in elderly patients with haemophilia-A survey of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH).

BACKGROUND: Nowadays patients with haemophilia survive longer due to improvements in haemophilia care. It has been hypothesized that the bleeding type and frequency may vary with age and are influenced by co-morbidities and co-medication in elderly patients. OBJECTIVES: To investigate a large group of patients older than 60 years of age with haemophilia concerning haemophilia treatment, bleeding pattern changes, co-morbidities, co-medication, bleeding sites and patient mortality. METHODS: A retrospective multi-centre data collection study was initiated on behalf of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH). Parameters of interest were investigated over the 5 years prior to study entry. RESULTS: A total of 185 haemophilia patients (mean age, 69.0±7.0 years, 29% with severe haemophilia) were included in the study. Regular prophylaxis was performed in 30% of the patients with severe haemophilia. In total, the annual bleeding rate was 2.49 and in patients with severe haemophilia 5.61, mostly caused by joint bleeds. Hypertension was the most common co-morbidity, but it occurred significantly less frequently than in an age-matched general population older than 70 years; 12% of the patients suffered from ischaemic heart disease, and 13% of the patients received anticoagulant or antiplatelet therapy. Within the observation period, 17% of the patients with severe haemophilia developed a higher frequency of bleeding symptoms, which was significantly associated with the use of antiplatelet or anticoagulant drugs. CONCLUSIONS: The most common co-morbidity of the patient population was hypertension, a considerable part had ischemic heart disease and antiplatelet or anticoagulant drugs.

Haemophilia patients' unmet needs and their expectations of the new extended half-life factor concentrates.

INTRODUCTION: National Member Organisations (NMO) of persons with haemophilia (PWH) from the DACH Region (D = Germany, A = Austria, CH = Switzerland) were interested to better understand PWH's expectations and concerns of extended half-life (EHL) factor concentrates (FC) before availability in these countries. METHODS: Based on an expert meeting and focus groups conducted across Germany a survey for haemophilia patients and their parents was developed and was sent out to 2,644 PWH. RESULTS: One thousand and seven questionnaires were sent back (38.1%); 743 adults and 262 parents. Most patients had haemophilia A (84.5%), were severely affected (73.7%), received prophylaxis (57%) and used recombinant FC (60.2%). One-quarter did not know the correct half-life of their FC [HA/FVIII: 26%, HB/FIX: 31.1%]. Four percent were unsatisfied with their current FC, mainly with short half-life of FC and difficult manageability. They expected from new EHL products less frequent injections (55.2%), better efficacy (32.1%) and safety/no side effects (15.7%); 59.5% would be willing to switch to new products if they have a prolonged half-life and the same safety of the current FC. They wish more information about half-life (84.4%), possible side-effects (81.3%) and efficacy (77%) and wanted to receive information about new products from their haemophilia treater (76.3%) and the newsletter of their NMO (74.3%). Significant differences across countries were found. CONCLUSIONS: The representative survey could show that although PWH were generally satisfied with their current FC, the majority would be willing to switch to EHL products assuming half-life is prolonged and has the same safety of the current FC.

Natural history and clinical characteristics of inhibitors in previously treated haemophilia A patients: a case series.

BACKGROUND: Development of inhibitors is the most serious complication in haemophilia A treatment. The assessment of risk for inhibitor formation in new or modified factor concentrates is traditionally performed in previously treated patients (PTPs). However, evidence on risk factors for and natural history of inhibitors has been generated mostly in previously untreated patients (PUPs). The purpose of this study was to examine cases of de novo inhibitors in PTPs reported in the scientific literature and to the EUropean HAemophilia Safety Surveillance (EUHASS) programme, and explore determinants and course of inhibitor development. METHODS: We used a case series study design and developed a case report form to collect patient level data; including detection, inhibitor course, treatment, factor VIII products used and events that may trigger inhibitor development (surgery, vaccination, immune disorders, malignancy, product switch). RESULTS: We identified 19 publications that reported 38 inhibitor cases and 45 cases from 31 EUHASS centres. Individual patient data were collected for 55/83 (66%) inhibitor cases out of 12 330 patients. The median (range) peak inhibitor titre was 4.4 (0.5-135.0), the proportion of transient inhibitors was 33% and only two cases of 12 undergoing immune tolerance induction failed this treatment. In the two months before inhibitor development, surgery was reported in nine (22%) cases, and high intensity treatment periods reported in seven (17%) cases. CONCLUSIONS: By studying the largest cohort of inhibitor development in PTPs assembled to date, we showed that inhibitor development in PTPs, is on average, a milder event than in PUPs.

Safety, efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial.

Essentials rVIII-SingleChain is a novel recombinant factor VIII with covalently bonded heavy and light chains. Efficacy, safety and pharmacokinetics were studied in pediatric patients with severe hemophilia A. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00. rVIII-SingleChain showed excellent hemostatic efficacy and a favorable safety profile. SUMMARY: Background rVIII-SingleChain is a novel B-domain truncated recombinant factor VIII (rFVIII) comprised of covalently bonded FVIII heavy and light chains, demonstrating a high binding affinity to von Willebrand factor. Objectives This phase III study investigated the safety, efficacy and pharmacokinetics of rVIII-SingleChain in previously treated pediatric patients < 12 years of age with severe hemophilia A. Patients/Methods Patients could be assigned to prophylaxis or on-demand therapy by the investigator. For patients assigned to prophylaxis, the treatment regimen and dose were based on the bleeding phenotype. For patients receiving on-demand therapy, dosing was guided by World Federation of Hemophilia recommendations. The primary endpoint was treatment success, defined as a rating of 'excellent' or 'good' on the investigator's clinical assessment of hemostatic efficacy for all treated bleeding events. Results The study enrolled 84 patients (0 to < 6 years, n = 35; ≥ 6 to < 12 years, n = 49); 81 were assigned to prophylaxis and three to an on-demand regimen. Patients accumulated a total of 5239 exposure days (EDs), with 65 participants reaching > 50 EDs. In the 347 bleeds treated and evaluated by the investigator, hemostatic efficacy was rated as excellent or good in 96.3%. The median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.00, 2.20), and the median annualized bleeding rate was 3.69 (Q1, Q3: 0.00, 7.20) across all prophylaxis regimens. No participant developed an inhibitor. Conclusions rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy and a favorable safety profile in a clinical study in children < 12 years of age with severe hemophilia A.

Ristocetin-induced platelet aggregation for monitoring of bleeding tendency in CLL treated with ibrutinib.

Bleeding because of impaired platelet function is a major side effect of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. We quantitatively assessed ristocetin-induced platelet aggregation (RIPA) in 64 patients with chronic lymphocytic leukemia (CLL) under ibrutinib at 287 time points. Eighty-seven bleeding episodes in 39 patients were registered (85 Common Toxicity Criteria (CTC) grade 1 or 2, 2 CTC grade 3) during a median observation period of 10.9 months. At times of bleeding, RIPA values were significantly lower (14 vs 28 U; P<0.0001). RIPA was impaired in patients receiving concomitant antiplatelet therapy or anticoagulation (14 vs 25 U, P=0.005). A gradual decline of median RIPA values was observed with increasing bleeding severity. Importantly, no CTC grade 2 or 3 bleeding were observed with RIPA values of >36 U. Sequential monitoring indicated a decrease of RIPA values from a median of 17 to 9 U within 2 weeks after initiation of treatment as well as an increase above the critical threshold of 36 U within 7 days when ibrutinib was paused. Low RIPA values were similar during treatment with another BTK inhibitor, CC292. Quantitative assessment of platelet function is a practical tool to monitor bleeding tendency under BTK-inhibitor therapy.

Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII.

Essentials Recombinant factor VIII BAY 94-9027 conjugates in a site-specific manner with polyethylene glycol. BAY 94-9027 was given to patients with severe hemophilia A as prophylaxis and to treat bleeds. BAY 94-9027 prevented bleeds at dose intervals up to every 7 days and effectively treated bleeds. BAY 94-9027 treatment was mainly well tolerated and no patient developed factor VIII inhibitors. Click to hear Dr Tiede's perspective on half-life extended factor VIII for the treatment of hemophilia A SUMMARY: Background BAY 94-9027 is a B-domain-deleted prolonged-half-life recombinant factor VIII (FVIII) that conjugates in a site-specific manner with polyethylene glycol. Objective Assess efficacy and safety of BAY 94-9027 for prophylaxis and treatment of bleeds in patients with severe hemophilia A. Patients/methods In this multinational, phase 2/3, partially randomized, open-label trial, men aged 12-65 years with FVIII < 1% and ≥ 150 exposure days to FVIII received BAY 94-9027 for 36 weeks on demand or prophylactically at intervals determined following a 10-week run-in period on 25 IU kg-1 body weight two times per week. Patients with > 1 bleed during the run-in subsequently received 30-40 IU kg-1 two times per week; patients with ≤ 1 bleed were eligible for randomization to every-5-days (45-60 IU kg-1 ) or every-7-days (60 IU kg-1 ) prophylaxis (1 : 1) for 26 additional weeks until randomization arms were filled. Patients who were eligible but not randomized continued twice-weekly prophylaxis. The primary efficacy outcome was annualized bleeding rate (ABR). Results The intent-to-treat population included 132 patients (prophylaxis, n = 112; on demand, n = 20). Median ABR (quartile [Q1; Q3]) for patients treated two times per week who were not eligible for randomization (n = 13) improved after dose increase (17.4 [14.3; 26.0] to 4.1 [2.0; 10.6]). Median ABR for patients randomized to every-5-days treatment (n = 43) was 1.9 (0; 4.2), similar to patients eligible for randomization but who continued treatment two times per week (n = 11). Median ABR for 32/43 patients (74%) who continued every-7-days prophylaxis until study end was 0.96 (0.0; 4.3). Six hundred and thirty-six of 702 bleeds (90.6%) were controlled with ≤ 2 infusions. No patient developed a FVIII inhibitor. Conclusions BAY 94-9027 prevented bleeding across three individually tailored dose regimens and was effective for treatment of bleeds.

Comparative pharmacokinetics of rVIII-SingleChain and octocog alfa (Advate(®) ) in patients with severe haemophilia A.

BACKGROUND: rVIII-SingleChain, a novel recombinant factor VIII (rFVIII), has been designed as a B-domain truncated construct with covalently bonded heavy and light chains, aiming to increase binding affinity to von Willebrand factor (VWF). Preclinical studies confirmed greater affinity for VWF, giving improved pharmacokinetic and pharmacodynamic properties compared with full-length rFVIII. AIM: To investigate the pharmacokinetics of rVIII-SingleChain and compare them against those of full-length rFVIII. METHODS: This study enrolled 27 patients with severe haemophilia A in the AFFINITY clinical trial programme. After a 4-day washout period, all patients received a single infusion of 50 IU kg(-1) octocog alfa (Advate(®) ); after a ≥4-day postinfusion washout period, they received a single infusion of 50 IU kg(-1) rVIII-SingleChain. Blood samples for pharmacokinetic assessments of each product were collected before infusion (predose) and at 0.5, 1, 4, 8, 10, 24, 32, 48 and 72 h postinfusion for both products. RESULTS: rVIII-SingleChain had a longer mean half-life (t1/2 ) (14.5 vs. 13.3 h), lower mean clearance (CL) (2.64 vs. 3.68 mL h(-1) kg(-1) ), higher mean residence time (20.4 vs. 17.1 h) and larger mean AUCinf (2090 vs. 1550 IU?h dL(-1) ) than octocog alfa, respectively. The mean AUCinf after rVIII-SingleChain infusion was ~35% larger than after octocog alfa. A similar pattern was observed for AUC0-last . No serious adverse events or inhibitors were reported. CONCLUSIONS: rVIII-SingleChain has a favourable pharmacokinetic profile compared with octocog alfa and was well tolerated. The prolonged t1/2 , larger AUC and reduced CL of rVIII-SingleChain may permit longer dosing intervals, thereby improving patient adherence to prophylactic treatment.

Efficacy and safety of long-acting recombinant fusion protein linking factor IX with albumin in haemophilia B patients undergoing surgery.

INTRODUCTION: Recombinant factor IX fusion protein (rIX-FP) has been developed to improve the pharmacokinetic (PK) profile of factor IX (FIX), allowing maintenance of desired FIX activity between injections at extended intervals, ultimately optimizing haemophilia B treatment. AIM: To determine the efficacy and safety of rIX-FP in the perioperative setting. METHODS: Subjects were adult and paediatric patients with severe to moderately severe haemophilia B (FIX ≤ 2%) participating in three Phase III clinical trials and undergoing a surgical procedure. PK profiles were established prior to surgery for each patient. Haemostatic efficacy was assessed by the investigator for up to 72 h after surgery. Safety measurements during the study included adverse events and inhibitors to FIX. FIX activity was monitored during and after surgery to determine if repeat dosing was required. RESULTS: Twenty-one, both major and minor, surgeries were performed in 19 patients. Haemostatic efficacy was rated as excellent (n = 17) or good (n = 4) in all surgeries. A single preoperative dose maintained intraoperative haemostasis in 20 of 21 surgeries. Nine major orthopaedic surgeries were conducted in eight patients with a mean of 7 (range: 6-12) rIX-FP injections during surgery and the 14-day postoperative period. Median rIX-FP consumption for orthopaedic surgeries was 87 IU kg(-1) preoperatively and 375 IU kg(-1) overall. No subject developed inhibitors to FIX or antibodies to rIX-FP. CONCLUSION: Recombinant factor IX fusion protein was well tolerated and effectively maintained haemostasis during and after surgery. Stable FIX activity was achieved with a prolonged dosing interval and reduced consumption compared to conventional or currently available long-acting recombinant FIX.

OC-16 - Neutrophil extracellular traps and tissue factor-bearing microvesicles: a liaison dangereuse causing overt DIC in cancer patients?

INTRODUCTION: Overt disseminated intravascular coagulation (DIC) is a systemic process characterized by excessive coagulation activation and fibrinolysis that may occur in cancer patients. The underlying pathomechanisms are still poorly understood. Recent experimental studies found an important role for the interaction between procoagulant neutrophil extracellular traps (NETs) and tissue factor (TF) in the pathogenesis of thrombosis. AIM: To investigate whether NETs and TF-bearing microvesicles (MVs) play a central role in cancer-related overt DIC. MATERIALS AND METHODS: Twenty-eight cancer patients with overt DIC (ISTH score ≥5, 14 females, median age: 62 years [range: 21-80], 13 with solid tumors, 15 with acute leukemia) and 28 matched healthy controls were included. NET formation parameters (plasma DNA and nucleosomes), MVassociated TF activity, and routine coagulation parameters were determined at study inclusion. In 11 patients with acute myeloid leukemia (AML), follow-up measurements were also performed. RESULTS: Plasma DNA, nucleosomes, and MV-TF activity were highly elevated in patients with cancer-related DIC compared to healthy individuals (all p-values<0.001). Strong correlations were found between plasma DNA and nucleosomes (Spearman correlation-coefficient: r=0.68), nucleosomes and MV-TF activity (r=0.62), and DNA and MV-TF activity (r=0.57). In multivariate regression, altered routine coagulation parameters were highly associated with NET parameters and MV-TF activity. In detail, a doubling in plasma DNA was associated with a 7.6% decrease in fibrinogen (p=0.012), a 15.3% decrease in platelet count (p=0.002), a 3.9% decrease in prothrombin time (p=0.014), and a 41.0% increase in D-dimer (p<0.001). A 10% increase in nucleosomes was associated with a 3.1% decrease in fibrinogen (p<0.001), a 5.0% decrease in platelet count (p<0.001), a 1.0% decrease in prothrombin time (p<0.009), and a 112.7% increase in D-dimer (p<0.001). A 10% increase in MV-TF activity was associated with a 4.9% decrease in fibrinogen (p<0.001), a 7.1% decrease in platelet count (p<0.001), a 1.3% decrease in prothrombin time (p<0.001), and a 15.5% increase in D-dimer (p<0.001). After initiation of chemotherapy in AML patients, NET parameters and MV-TF activity decreased significantly (nucleosomes: 3.3-fold decrease and normalization after 1 week; DNA: 1.2-fold decrease after 1 week and 1.5-fold decrease after 1 month; MV-TF activity: 10-fold decease after 1 week and normalization after 1 month) (Figure 1), and routine coagulation parameters improved. CONCLUSIONS: Our results add to experimental studies that have investigated the interaction between NETs and TF. Taken together, evidence indicates the presence of a liaison dangereuse between NETs and TF-bearing MVs, which could be the underlying cause of cancer-related overt DIC.

PO-01 - Congestive heart failure is an independent risk factor for venous thromboembolism and mortality in cancer patients.

INTRODUCTION: Prediction of venous thromboembolism (VTE) occurrence in cancer patients using individual risk factors may contribute to preventing the burden of disease associated with VTE. Congestive heart failure in patients with cancer may increase the risk of VTE and worsen the prognosis. AIM: We sought to investigate the association of congestive heart failure and occurrence of VTE in cancer patients, specifically with consideration for the poor prognosis in patients with heart failure and cancer. MATERIALS AND METHODS: Hospitalized and ambulatory cancer patients were included in the prospective Vienna Cancer and Thrombosis Study (CATS) in search of risk factors for occurrence of VTE. Cancer entities and comorbidities were recorded at baseline and verified using medical documentation including a diagnosis of congestive heart failure. The occurrence of VTE events was compiled via mail and telephone follow-ups for two years. Risk of VTE occurrence was calculated in the competing risk regression model, considering death as a competing event during follow-up. RESULTS: In the current analysis 1,433 patients (632 women, 44.1%) with a median age of 61 years (25th-75th percentile: 52-75) were included. During the observation period, 108 (7.5%) VTE events and 522 (36.4%) deaths occurred. The median observation time was 729 days (233-731), and 34 patients (2.3%) had diagnosed congestive heart failure at the time of study inclusion, 12 of which had NYHA II-IV and 22 unspecified congestive heart failure. In the group of heart failure patients, 6 had VTE events and 23 died. In univariate competing risk analysis, the risk of VTE occurrence was increased 2.6-fold in patients with heart failure compared to those without a diagnosis of heart failure (SHR 2.58, 95% CI 1.13-5.92, p=0.025). After multivariable adjustment for age, BMI, gender, diabetes, history of myocardial infarction or stroke, use of antiplatelet drugs, cancer site, hypertension, D-Dimer level and peripheral arterial disease, the risk of VTE in heart failure patients was 3-times the risk of patients without heart failure (HR 3.07, 95% CI 1.15-8.19, p=0.025). Further, congestive heart failure was a strong predictor of mortality (HR 1.70, 95% CI 1.10-2.65, p=0.018). CONCLUSIONS: Congestive heart failure is not only a risk factor for mortality in cancer patients, but also an independent predictor of VTE occurrence. In order to prevent VTE and the associated burden, patients with cancer and congestive heart failure may benefit from thromboprophylaxis.

PO-63 - Exhausted platelets in cancer patients with high risk of venous thromboembolism and poor prognosis.

INTRODUCTION: Platelets play a crucial role in cancer development, progression and metastatic spread of malignancy. In vitro data show that cancer cells have the ability to activate platelets, and clinical studies found increased levels of platelet activation markers in cancer patients. Moreover, platelets are thought to be involved in the development of venous thromboembolism (VTE) in cancer patients, a frequent complication of malignant disease associated with high morbidity and mortality. AIM: In this study, we aimed to examine the activation status of platelets in cancer patients and investigate the association with risk of future venous thromboembolism (VTE) and mortality. MATERIALS AND METHODS: In a prospective observational cohort study of cancer patients we measured pre-chemotherapy platelet P-selectin and glycoprotein (GP) IIb/IIIa expression and monocyte-platelet aggregates (MPA) in vivo and in response to ex vivo stimulation of the platelet activation receptors protease-activated receptor (PAR) -1, -4, and GPVI by whole blood flow cytometry. Primary and secondary endpoints of the study were occurrence of objectively confirmed VTE and death during 2-year follow-up, respectively. RESULTS: Out of 62 patients (median age [interquartile range, IQR]: 63 [54-70] years, 48% female) with cancers of the pancreas (n=19), lung (n=18), brain (n=14), colon (n=8) and stomach (n=3), 9 (14.5%) developed VTE and 32 (51.6%) died. P-selectin, activated GPIIb/IIIa expression and MPA formation did not significantly differ between tumor sites (Kruskal Wallis test). Reduced platelet responsiveness to PAR-1 and GPVI stimulation was associated with a higher risk of VTE (hazard ratio [HR] per decile increase in %P-selectin positive platelets: 0.73 [95% confidence interval: 0.56-0.92, p=0.007] and 0.77 [0.59-0.98, p=0.034], respectively; Table 1). Further, lower platelet P-selectin and activated GPIIb/IIIa expression in vivo and in response to PAR-1, -4 and GPVI stimulation, but not MPA formation, were associated with a higher risk of death (Table 1). CONCLUSIONS: Cancer patients with a poor prognosis had degranulated platelets, presumably as a consequence of previous activation. Our data suggest that platelets' continuous activation and thus exhaustion is involved in cancer-associated VTE and cancer mortality.

International Society on Thrombosis and Haemostasis core curriculum project: core competencies in clinical thrombosis and hemostasis.

UNLABELLED: Essentials The priority of ISTH was to establish a global core curriculum in thrombosis and hemostasis. International survey to determine competencies required for clinical specialists was carried out in the field. Competency framework provides a reference point for mapping and developing regional curricula. Core curriculum informs and links to a variety of ISTH educational materials. SUMMARY: Background The International Society on Thrombosis and Haemostasis (ISTH) identified the need for an international core curriculum on thrombosis and hemostasis for its society members and the larger thrombosis and hemostasis community. Aims The current research sought consensus on the core competencies required by medical doctors who are ready to practise as independent clinical specialists in thrombosis and hemostasis with the aim of developing a core clinical curriculum for specialists in the field. Method A draft list of competencies was developed by the Working Group and formed the basis of an online survey. ISTH members and the larger thrombosis and hemostasis community were asked to rate the importance of each competency, on a Likert scale, for clinical specialists in thrombosis and hemostasis. Results There were a total of 644 responses to the online survey with broad geographical representation. There was general agreement on what level of competency would be required for clinical specialists in thrombosis and hemostasis at the specified level of training. Conclusions Using the survey to gain consensus on the level of competency required by clinical specialists in the field of thrombosis and hemostasis enabled the development of a core clinical curriculum that has been endorsed by the ISTH Council. The curriculum will offer a framework and international reference that will be used by the society, by national and regional organizations, and for further research.

Longitudinal analysis of hemostasis biomarkers in cancer patients during antitumor treatment.

UNLABELLED: ESSENTIALS: Hemostasis biomarkers impact thrombosis occurrence and survival in cancer patients. We performed a longitudinal analysis of hemostatic parameters in 112 cancer patients. Hemostatic parameters are associated with disease state, patients' prognosis, and the risk of VTE. The procoagulant state exists not only at diagnosis, but also during the course of disease. BACKGROUND: Hemostasis biomarkers are known to have an impact on venous thromboembolism (VTE) occurrence and survival in cancer patients. OBJECTIVES: As there are almost no data on longitudinal changes, we aimed to evaluate those in the present prospective observational study during chemotherapy and the course of disease. PATIENTS/METHODS: Patients with cancer of the brain (n = 39), lung (n = 41), colon (n = 15) or pancreas (n = 17) were included before initiation of antitumor therapy. Blood samples for determination of factor VIII, thrombin peak height, D-dimer, F1 + 2 , fibrinogen and soluble P-selectin (sP-selectin) were drawn on a monthly basis. The study endpoints were death, VTE occurrence, or completion of the study period. RESULTS: Overall, 546 blood samples of 112 patients were analyzed. D-dimer and sP-selectin levels were significantly higher in patients with distant metastasis than in those without. Patients with complete remission had significantly lower levels of F1 + 2 , D-dimer and fibrinogen. Peak height thrombin levels showed a decrease over time in all tumor types. Levels of biomarkers behaved differently in the various tumor types. Patients who developed VTE (n = 14) showed increasing levels of FVIII, sP-selectin, and D-dimer. At the last blood sampling time-point before VTE occurrence, in 13 patients the D-dimer level was above the median, and in seven of these patients it was even above the 75th percentile; however, the individual course was highly variable. Regarding survival, steadily increased FVIII, sP-selectin and D-dimer levels were associated with higher mortality. CONCLUSIONS: Hemostatic parameters show an association with disease state, prognosis, and the risk of VTE, not only at diagnosis, but also during the course of antineoplastic treatment.

Decrease in microvesicle-associated tissue factor activity in morbidly obese patients after bariatric surgery.

BACKGROUND: Tissue factor (TF) is the main in vivo initiator of the blood coagulation cascade. Active circulating TF was detected on small, negatively charged membrane vesicles, the so-called microvesicles (MVs), which are released upon cell activation and apoptosis from a variety of cells. Increased coagulation activation was found in morbidly obese patients, and elevated levels of TF-bearing MVs may contribute to the prothrombotic state in these patients. AIM: To determine MV-associated TF activity levels in morbidly obese patients before and after weight loss due to bariatric surgery. METHODS: MV-TF activity was measured with a factor Xa generation assay in morbidly obese patients before and 2 years after bariatric surgery. In addition, clinical parameters were determined. RESULTS: Seventy-four morbidly obese patients (mean age: 42 (±11) years; 61 females) were included in this study. After bariatric surgery, the body mass index decreased from (median, 25-75th percentile) 45.5 (42.3-50.2) to 30.5 (28.0-34.4 kg m(-2); P<0.001), and a significant improvement in metabolic parameters was observed. Preoperative MV-TF activity correlated with C-reactive protein levels (r=0.3; P=0.02). Postoperatively, the mean MV-TF activity decreased significantly from 0.20 pg ml(-1) (0.18-0.47) to 0.02 (0.00-0.28; P<0.01). CONCLUSION: We could demonstrate a significant decrease in MV-TF activity after weight loss in morbidly obese patients. Decreased MV-TF activity might contribute to an improved coagulation profile in these patients after weight loss.

Novel, human cell line-derived recombinant factor VIII (human-cl rhFVIII; Nuwiq® ) in adults with severe haemophilia A: efficacy and safety.

INTRODUCTION: Nuwiq® [human cell line-derived recombinant factor VIII (human-cl rhFVIII)] is a new generation rFVIII protein, without chemical modification or fusion to any other protein, produced in a human cell line. AIM/METHODS: This prospective, open-label, multinational phase III study assessed the efficacy and safety of human-cl rhFVIII in 32 adult previously treated patients (PTPs) with severe haemophilia A during standard prophylaxis for ≥6 months and ≥50 exposure days. Efficacy in treating bleeds and during surgical prophylaxis was also assessed. RESULTS: Prophylactic efficacy, based on mean monthly bleeding rate, was rated as 'excellent' or 'good' in 97% of patients for all bleeds and in 100% of patients for spontaneous bleeds. Mean (SD) annualized bleeding rate was 2.28 (3.73) [median = 0.9] for all bleeds, 1.16 (2.57) [median = 0] for spontaneous bleeds and 1.00 (1.79) [median = 0] for traumatic bleeds. There were no bleeds in 50% of patients and there were no major, life-threatening bleeds. Efficacy was 'excellent' or 'good' in treating 28 (100%) of 28 bleeds. Overall efficacy was rated as 'excellent' during four surgical procedures (three major, one minor) and 'moderate' during one major surgery. Incremental in vivo recovery (IVR) data were comparable with the one-stage and chromogenic assays. IVR was >2.0% per IU kg-1 for all measurements and stable over 6 months. No patients developed FVIII inhibitors and there were no treatment-related serious or severe adverse events. CONCLUSION: These results in adult PTPs indicate that human-cl rhFVIII is effective for the prevention and treatment of bleeds in adults with severe haemophilia A.