ALBERT

Description: A family cohort study was performed to assess the absolute risk of thromboembolism associated with inherited protein S (PS) deficiency type I and type III. Probands were consecutive patients with thromboembolism and either type I or type III deficiency. Of living first degree relatives (age〉15 years), 156 (90%) from type I deficient probands (cohort 1) and 268 (88%) from type III deficient probands (cohort 2) were analyzed. Annual incidences of venous thromboembolism were 1.47 and 0.17 in deficient and non-deficient relatives in cohort 1 (RR 8.9; 95% CI 2.6–30.0), and 0.27 versus 0.24 in cohort 2 (RR 0.9; 95% CI 0.4–2.2). The cut off level of free PS to identify subjects at risk was 30%. Lower levels were found in 40% and 1% of relatives in cohort 1 and 2, respectively. We demonstrated that the cut-off level of free PS is considerably lower than the lower limit of its normal range in healthy volunteers, that is commonly used (in our study 30% in stead of 65%). If we had used only a total PS assay, 8 (2%) relatives at risk would have been missed, but 67% (346/517) of relatives would not be tested. Only testing for free PS deficiency (free PS levels

Description: Hyperhomocysteinemia is demonstrated as a risk factor for venous and arterial thrombosis. Experimental evidence suggests that its thrombogenic propensity results from endothelial dysfunction and injury followed by platelet and fibrin formation. However, lowering homocysteine concentrations with vitamin B6, B12 or folic acid has not resulted in a reduced risk of recurrent venous and arterial thrombosis in large prospective clinical trials. This suggests that hyperhomocysteinemia is a surrogate for another thrombophilic related specimen. As high factor VIII:C levels are associated with an increased risk of both venous and arterial thrombosis, and with endothelial injury, we hypothesize that hyperhomocysteinemia and factor VIII:C levels are closely related to each other. Therefore, we performed a study to assess the absolute risk of thrombosis in hyperhomocysteinemia and the effects of elevated factor VIII:C levels on this risk in a large cohort of families with hereditary (index) deficiencies of protein S, protein C or antithrombin. Hyperhomocysteinemia was defined as a fasting plasma homocysteine level above 18.5 μmol/l and factor VIII:C levels were elevated when higher than 150%. A total of 405 relatives were included. Median factor VIII:C levels in hyperhomocysteinemic relatives (n=26, 6%) were 169%, compared to 136% in normohomocysteinemic relatives (P=0.004) (Figure) and were more often elevated (65 vs. 38%, P=0.006). Other thrombophilic defects, including the index deficiencies, factor V Leiden and the prothrombin mutation were equally divided. Hyperhomocysteinemia was associated with an increased risk of venous and arterial thrombosis (relative risk’s 2.6 [1.3–4.8] and 3.7 [1.5–8.4)], respectively). Relatives with elevated factor VIII:C levels were also at risk; relative risk 2.3 (1.4–4.0) for venous thrombosis and 2.3 (1.0–5.1) for arterial thrombosis. After excluding all relatives with elevated factor VIII:C levels, relative risk for venous thrombosis and hyperhomocysteinemia dropped to 1.3 (0.2–9.8) and nil relatives had arterial thrombosis. These results suggest that hyperhomocysteinemia indeed is an epiphenomenon for elevated factor VIII:C levels and therefore homocysteine measurements can be omitted in risk assessment for venous and arterial thrombosis when factor VIII:C measurements are incorporated in thrombophilia screening. Figure Figure

Description: Introduction: Microalbuminuria (albuminuria 30–300 mg/24h) is a well known risk marker for arterial thromboembolism (ATE). It has been postulated that microalbuminuria is a reflection of generalized endothelial dysfunction that is associated with, among others, increased levels of several coagulation factors. The impact of coagulation disorders is more evident in the pathogenesis of venous thromboembolism (VTE), than in the pathogenesis of ATE. Therefore, we hypothesized that microalbuminuria might be an independent risk factor for VTE. Methods: In 1997, all inhabitants of the city of Groningen, aged between 28 and 75 years (n=85,421) were sent a postal questionnaire collecting information about risk factors for cardiovascular disease and a vial to collect a first morning urine sample for measurement of urinary albumin concentration (UAC). Of responded subjects (40,856), a cohort (8,592 subjects) enriched for higher levels of UAC was formed that completed screening at an outpatient clinic. Screening data were collected on albuminuria (assessed in two 24-h urine collections), and risk factors for atherosclerosis and renal disease. To identify subjects with VTE, we used the databases of the regional anticoagulation clinic, the national registry of hospital discharge diagnoses and the national registry of death certificates. Of identified subjects patient charts were drawn. Only symptomatic and objectively verified venous thromboembolic events were considered established. We evaluated the association between albuminuria and the incidence of VTE, using Cox-regression models. Results: Of 8592 subjects, 18 subjects were excluded because of missing data on albuminuria. Of the remaining 8574 subjects (mean age±SD, 49±13 years; 50% male), 129 subjects experienced VTE during a follow-up period of 8.6±1.8 years. In univariate analyses albuminuria, age, hypertension, smoking, body mass index (BMI), eGFR, triglycerides, C-reactive protein, tissue plasminogen activator, tissue plasminogen activator inhibitor 1 and cancer were associated with VTE (P300 mg/24h (n=134) conferred hazard ratios of 1.35 (95% CI, 0.83–2.19, P=0.23), 1.90 (1.02–3.53, P=0.04), 2.49 (1.56–3.99, P

Description: Abstract 2642 Introduction With the aging of the population clinicians are increasingly confronted with elderly, often frail, patients with a DLBCL. While the very elderly patients, defined by the age of ≥75 year, are often excluded from clinical trials, only few prospective data in the rituximab-era are available on the outcome in this patient cohort. To asses efficacy, tolerability and safety of standard intensive rituximab-containing therapy in those patients, a descriptive population-based, cohort study was performed. Detailed information on treatment, toxicity and outcome in all patients aged ≥75 year, diagnosed with DLBCL in the Dutch province Friesland was prospectively gathered and analyzed. Methods Since 2005 all patients diagnosed with a haematological malignancy in Friesland, a province with 600.000 inhabitants, are prospectively registered and followed in a population-based registry, the HemobaseR. For this analysis data of all patients aged ≥ 75 years with a newly diagnosed DLBCL over a period of six years were retrieved from the HemobaseR. Data of clinical characteristics, treatment and its adaptations, treatment-related toxicity and outcome were obtained. Treatment modality was divided in four groups: R-CHOP chemotherapy, other rituximab-containing therapy, palliative radiotherapy and only supportive care. Follow-up was completed until 31 December 2011. Cox Proportional hazards model was used for identifying significant prognostic risk factors. Kaplan-Meier curves for each group were evaluated by a logrank test. Results From 2005 until the end of 2011 103 patients aged ≥ 75 years were diagnosed with a DLBCL. The median age was 81 years (range 75 – 96) with a slight female predominance (57%). The median observation period was 13 months (range 1 – 78) and 31 months for those still alive at time of evaluation.19 patients (19%) had stage 1 disease; in 74 patients (71%) advanced disease (stage 2–4) was reported and in 10 patients (10%) staging was incomplete. In 84 patients (81%) an age adjusted International Prognostic Index was calculated, 43% of them had an aaIPI of 2 or 3. Of the patients with stage 1 disease, 13 (68%) received three courses of R-CHOP and radiotherapy with a curative intent. Eight (62%) of them did complete this therapy. Of the other 84 patients 57 (68%) received R-CHOP chemotherapy with a curative intent. 31 (54%) of them completed at least six cycles. Ultimately 39 patients (56%), who did start with a standard therapy regimen, completed their treatment. A complete remission was achieved in 30 patients (77%). In the remaining group 10 patients (10%) received alternative, suboptimal, rituximab-based chemotherapy, 9 (9%) of patients was treated with radiotherapy. In 12 patients (11%) only supportive care was given. Severe toxicity (grade 3–4), occurred in 66% of all patients treated with rituximab-containing chemotherapy. Toxicity grade 3–4 was the main reason for receiving less then six cycles of chemotherapy (44%). Ten toxicity-related deaths (13%) were observed in patients treated with R-CHOP, with eight deaths due to infectious complications. The two-year survival was 67% for the elderly who completed chemotherapy, 25% for those treated with incomplete or inferior chemotherapy regimens and 20% for those receiving palliative radiotherapy or supportive care. In a multivariate analysis completing therapy and not age was significantly associated with a better survival (p

Description: Easy bruising is frequently found in healthy women. This mild bleeding tendency may be enhanced by treatment with vitamin K antagonists. This may result in more intense monitoring of the level of anticoagulation (INR) to improve the individual time within target range (ITTR) and consequently to reduce the risk of major bleeding. We performed a retrospective study in 6758 consecutive patients receiving vitamin K antagonists for primary or secondary prophylaxis of venous or arterial thrombosis (mean age 67, 51% male and 189762 INRs in 6681 person-years) to evaluate differences in gender on the occurrence of minor and major bleeding, as well as the ITTR. The incidence rates (IR, per 100 person-years) of minor and major bleeding were assessed and survival analysis performed to obtain adjusted hazard ratios (HR, 95%CI) for major bleeding in men versus women with or without prior minor bleeding, controlling for significant patient characteristics. Minor bleeding occurred more frequently in women than men (IR=33.2 versus 21.1, respectively; HR=1.5, 95%CI 1.4–1.7, p

Description: Hyperhomocysteinemia is a risk factor for venous and arterial thrombosis. Different diagnostic strategies are used to identify subjects at risk of thrombosis, related to hyperhomocysteinemia. Measurements of fasting and methionine-loading levels are usually recommended. Alternatively, random homocysteine measurements may simplify the procedure. Random levels 〈 10 and 〉 20 μmol/l are considered to indicate normohomocysteinemia and hyperhomocysteinemia, respectively, while consecutive fasting and methionine-loading tests are required at levels 10–20 μmol/l. We performed a study to assess the most suitable strategy in a large cohort of families with hereditary (index) deficiencies of protein S, protein C or antithrombin. Random, fasting and methionine-loading homocysteine samples were measured in 713 relatives. According to predefined cut-off levels hyperhomocysteinemic and normohomocysteinemic relatives were identified and their absolute risks of thrombosis were compared. Relatives with random homocysteine levels 〉 20 μmol/l were not at risk of venous or arterial thrombosis compared to relatives with levels 〈 10 μmol/l (relative risks 0.9 [95% CI, 0.4–2.3] and 1.7 [0.5–5.7], respectively). Fasting hyperhomocysteinemia (homocysteine levels 〉 18.5 μmol/l) was associated with an increased risk of venous and arterial thrombosis (relative risks 2.6 [1.3–4.8] and 3.7 [1.5–8.4)], respectively) (Table). Relatives with normal fasting homocysteine levels, but methionine-loading hyperhomocysteinemia (homocysteine levels 〉 58.8 μmol/l) were not at risk; relative risk 0.8 (0.2–1.9) for venous thrombosis and 1.1 (0.2–3.9) for arterial thrombosis. Exclusion of relatives with an index deficiency did not alter the risk estimates, while annual incidences of normohomocysteinemic relatives decreased to 0.19% per year (0.12–0.29), which is comparable with the annual incidence in the normal population. As only fasting homocysteine identified subjects at risk of thrombosis, random homocysteine and methionine-loading tests can be omitted in clinical practice. Venous Thrombosis Observation Relatives Incidence/year (%) Relative Risk years with event (95% CI) (95% CI) * Methionine-loading performed in relatives with no fasting hyperhomocysteinemia Fasting Homocysteine No hyperhomocysteinemia 10408 55 0.53 (0.40–0.69) Reference Hyperhomocysteinemia 804 11 1.37 (0.68–2.45) 2.6(1.3–4.8) Methionine-loading test* No hyperhomocysteinemia 9341 50 0.54 (0.40–0.71) Reference Hyperhomocysteinemia 986 4 0.41 (0.11–1.04) 0.8(0.2–1.9) Arterial Thrombosis Fasting Homocysteine No hyperhomocysteinemia 11096 21 0.19 (0.12–0.29) Reference Hyperhomocysteinemia 1004 7 0.70 (0.28–1.44) 3.7(1.5–8.4) Methionine-loading test* No hyperhomocysteinemia10008 10008 19 0.19 (0.11–0.30) Reference Hyperhomocysteinemia 1000 2 0.20 (0.02–0.72) 1.1(0.2–3.9)

Description: TAFI (Thrombin-activatable fibrinolysis inhibitor) is a suppressor of fibrinolysis and high plasma levels of TAFI are assumed to induce venous thromboembolism (VTE). A few studies published on this subject identified TAFI as a mild risk factor for VTE. The risk may be increased if high TAFI levels are combined with other trombophilic defects. We performed a retrospective study to asses the absolute risk of VTE associated with elevated levels of TAFI and the contribution of concomitant thrombophilic defects. Subjects were recruited from a previous large family cohort study, which was designed to estimate the risk of VTE in first degree relatives of probands with documented VTE and a hereditary deficiency of antithrombin, protein C or protein S. Probands were excluded from analysis. Blood samples of relatives were tested on deficiencies of antithrombin, protein C and protein S, prothrombin G20210A, factor FV Leiden, hyperhomocysteinemia and increased levels of factor VIII:C, IX:C and XI:C. TAFI activity was additional measured by chromogenic assay on plasma samples stored at minus 80 degrees Celsius. We analysed 350 of 457 relatives, who were tested on TAFI. TAFI levels observed in women were lower than in men (median 97 versus 106 U/dL) and increased with age (median from 95 U/dL at age 15–30 yr to 107 U/dL at age〉60 yr). Relatives with TAFI levels above the 90th percentile (〉128 U/dL) had the same absolute risk of VTE as relatives with TAFI levels below the 90th percentile. Annual incidences (AI) were 0.74 versus 0.72 % per year: relative risk (RR) 1.0; 95% CI.0.51–2.10 (Table). Concomitant thrombophilic defects were demonstrated in 82% of the relatives. These defects were equally distributed among relatives with TAFI levels of 〉90th versus 90th percentile 9 1209 0.74 (0.3–1.4) 1.0 (0.51–2.10) Concomitance 9 1147 0.78 (0.4–14.9) 0.83 (0.41–1.68) No concomitance 0 62 0 TAFI 〈 90th percentile 53 7364 0.72 (0.5–0.9) Ref Concomitance 53 5724 0.93 (0.7–1.2) Ref No concomitance 0 1426 0

Description: Venous thromboembolism (VTE)during pregnancy is still an important cause of maternal morbidity and mortality in the Western world. The risk VTE in pregnant women is five times higher than in non-pregnant women of the same age. This risk is increased by thrombophilic defects. In a family cohort study we assessed the risk of VTE during pregnancy/puerperium and the contribution of concomitant thrombophilic defects in women with hereditary antithrombin, protein C or protein S deficiencies. Women were recruited from a previous large family cohort study, which was designed to estimate the risk of VTE in first degree relatives from probands with documented VTE and a deficiency of antithrombin, protein C or protein S. Probands were excluded from analysis. Blood samples of female relatives were tested on the index deficiencies and prothrombin G20210A, factor V Leiden, hyperhomocysteinemia and increased levels of VIII:C, IX:C and XI:C. Observation time was defined as the fertile period (from age 15–45 years), or until the first VTE, or until end of study period. The cohort contained 222 female relatives, of whom 101 women were deficient and 121 non-deficient. The absolute risk of venous thromboembolism in deficient women was 1.76 per 100 person-years versus 0.19 per 100 person-years in non-deficient women (Relative Risk (RR) 9.2; 95% CI 3.8–26.7). Concomitance of none, one and more than one thrombophilic defect increased the risk in deficient (1.55, 2.14 and 2.92 per 100 person-years, respectively) and non-deficient women (0.16, 0.09 and 0.54 per 100 person -years, respectively). Annual incidences (AI) were lower in ever pregnant than never pregnant deficient women, 1.37 per 100 person-years versus 2.96 per 100 person-years (RR 0.5; 95% CI 0.2–0.99)(Table). These were 0.09 per 100 person-years versus 0.70 per 100 person-years in non-deficient women (RR 0.1; 95% CI 0.02–0.9). In ever pregnant deficient women 71% of VTE episodes were pregnancy related. A majority (75%) of never pregnant deficient women revealed VTE associated with oral contraceptives. Women with hereditary antithrombin, protein C or protein S deficiencies are at high risk of VTE. Concomitance of other thrombophilic defects increased this risk. In fertile women most episodes of VTE are associated with either pregnancy or oral contraceptives. Deficient Non-deficient Ever pregnant (n=54) Never Pregnant (n=47) Ever pregnant (n=79) Never pregnant (n=42) Women with VTE, n 17 12 2 3 Observation period, yr 1241 405 2169 430 AI, % (95% CI) 1.37 (0.80–2.19) 2.96 (1.53–5.18) 0.09 (0.01–0.33) 0.70 (0.14–2.04) RR (95% CI) 0.5 (0.2–0.99) P=0.05 0.1 (0.02–0.9) P=0.04 Pregnancy related VTE, n (%) 12 (71) 0 1 (50) 0 Oral contraceptive related VTE, n (%) 2 (12) 9 (75) 0 3 (100)

Description: Introduction Clinical trials have shown improved response rates, progression-free survival and overall survival (OS) in patients with multiple myeloma (MM) when using the novel agents thalidomide, lenalidomide and bortezomib. However, outcome data provided by population-based registries, reflecting real-life, report predominantly improved OS in younger MM patients and only minimal improvement in OS in unselected MM patients older than 65 years. Population-based studies in unselected MM patients in the era of novel agents are relatively limited. Explanations for the marked variation in prognosis across patients may in part be explained by the heterogeneity in the initial clinical presentation, the pre-existing comorbidities, disease biology and response to the therapy. Specific end-organ damage caused by the disease, such as hypercalcemia, renal failure, anemia and bone lesions known as the CRAB symptoms may be associated with worse prognosis in the elderly MM patients. This descriptive prospective population-based cohort study was designed to determine the OS in patients with MM in Friesland, The Netherlands in the era of novel agents, and to analyze the influence of the CRAB symptoms and comorbidities at initial presentation on survival. Methods Since 2005 all patients diagnosed with hematological malignancies in Friesland, a province of the Netherlands, are prospectively registered and followed by their clinicians in a population-based registry, the HemoBase. For this analysis, data on clinical characteristics, comorbidities, treatment and outcome of all patients with newly diagnosed MM in Friesland during the period of January 2005 to January 2013 with a follow-up until January 2014 were retrieved from HemoBase. Supplementary information was obtained from the individual patient hospital records. Both symptomatic and asymptomatic patients were included in the study with subgroup analysis on the symptomatic patients. According to the guidelines from IMWG, each CRAB symptom was divided into two categories (11 mg/dL 〈 serum calcium ≤ 11 mg/dL; 2 mg 〈 creatinine ≤ 2 mg/dL; 10.2 g/d ≤ hemoglobin 〈 10.2 g/dL and the presence or absence of bone lesions). The patients were divided by age groups (100 months respectively. Divided into age categories 〈 65, 65 – 75 and ≥75 years old, the 50% OS is respectively 92, 40 and 29 months (figure 1). For all patients, implementing novel therapies improved OS compared to other therapies (43.5 vs. 21.1 months, hazard ratio (HR) = 1.8, P = 0.017. Patients with a CCI score of 0 have a higher median OS than patients with a score ≥ 2 (HR = 0.6, P = 0.036). Patients with two or more CRAB symptoms have a lower median OS than patients without any CRAB symptoms (HRadjusted = 2.2, P = 0.028). In multivariate analysis, differences in median OS were significant better for patients without hypercalcemia compared to patients with hypercalcemia (HRadj. = 0.6, P = 0.011) and for patients with a serum creatinine ≤ 2 mg/dL vs. ≥ 2 mg/dL (HRadj. = 0.4, P 〈 0.0001). Conclusion In this population-based study of a complete Dutch cohort of unselected MM patients over the last decade a median OS of 49.5 months was observed. Despite extensive introduction of novel agents increasing age remains an adverse prognostic factor. High comorbidity scores (CCI ≥ 2) and CRAB symptoms, such as hypercalcemia and impaired renal function at initial presentation were significantly correlated with worse median OS. Disclosures Hovenga: Jansen Cilag: Research Funding. Woolthuis:Jansen Cilag: Research Funding. Hoogendoorn:Jansen Cilag: Research Funding.

Description: Abstract 3656 Introduction Diffuse large B-cell lymphoma (DLBCL) is predominantly diagnosed in the elderly and its incidence is therefore rapidly increasing. Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is the standard treatment for patients with newly diagnosed DLBCL. This is mainly based on data from carefully controlled randomised trials with strict eligibility criteria. Therefore data reflecting the “real world” in the rituximab era are sparse. We conducted an observational prospective cohort study to identify whether comorbidity is an independent risk factor for overall survival (OS) in patients with newly diagnosed DLBCL treated with R-CHOP with curative intent. Methods All patients with newly diagnosed DLBCL in Friesland, a Dutch province, are prospectively registered by their clinicians in a population-based registry (HemoBase®) since January 2005. Patients ≥18 years, CD20 positive, Ann Arbor stage II-IV were included if they received ≥ one cycle of R-CHOP. Clinical variables registered were age, gender, performance status (PS), Ann Arbor stage, presence of B-symptoms, lactate dehydrogenase, bulky disease, number of extranodal sites involved. Comorbidity was scored using the Charlson Comorbidity Index (CCI) [Charlson et. al.; J Chron Dis, 1987]. The score is a summation of the number of comorbidities existing at the time of diagnosis. The group was divided in low CCI (0–1) and high CCI (≥2). The primary endpoint was OS, defined as start of diagnose of DLBCL until death by any cause. Cox Proportional hazards model was used to identify significant risk factors. Variables used to calculate International Prognostic Index (IPI) and CCI were entered into the model. Kaplan-Meier curves were evaluated by log-rank test. Results Over a period of 7 years 302 patients were newly diagnosed with DLBCL after the start of the HemoBase® registry. Of those patients, 76 received no R-CHOP therapy, 9 had unknown Ann Arbor stage and 61 had Ann Arbor stage I. Therefore data from 156 patients could be retrieved from the population-based registry for further analysis. The median age was 69 years (range 23 – 93). The median observation period for the total population was 24 months (range 0 – 83) and for patients still alive 33 months (range 2 – 83). Twenty-five percent of patients had a PS≥2, 39% had IPI≥3. The percentage of patients with 8, 7, 6, 5, 4, 3, 2, or 1 R-CHOP cycle(s) given were 49, 3, 32, 1, 3, 4, 2, 6 respectively. R-CHOP21 was given to 74% and R-CHOP14 to 26%. Dose reduction of 20% or more in doxorubicin, cyclophosphamide or vincristine occurred in 26, 19, and 36% of the patients respectively. In 54% of the patients dose reduction occurred in one or more antineoplastic drugs. Twenty-five patients had a CCI≥2. Most frequently observed comorbidities in the CCI≥2 group were diabetes (36%), peripheral vascular disease (32%), chronic pulmonary disease or second tumor (28%), myocardial infarction (24%), congestive heart failure or cerebrovascular disease (16%). The percentage of patients with a CCI score of 2, 3, 4 or 5 were 64, 28, 4 and 4% respectively. In the CCI≥2 group only 16% of the patients had also a PS≥2. Three year OS in the total study population was 68%: in patients with CCI