Introduction: The increased risk of venous thrombosis in women taking oral contraceptives (OCs) has been recognized since the early 1960s. Coexistence of hereditary risk factors appears to have an additive effect. Women under OCs that carry the factor V Leiden mutation have a 35-fold increased risk of thromboembolic events compared to women without the mutation who are not on OCs. Evaluation of family and personal history is the mainstay of prophylaxis prior to OC administration, but often family thrombophilia or thromboembolic (TE) events are not reported prior to OCs prescription. Patients-Methods: Fifty-seven women with a median age of 28 (21–48) years, which suffered OC-associated TE, were studied. The median period of OC therapy prior to TE event was 2 months (0.5–60). Fifty-five of them experienced VTE while 2 suffered stroke. Leg thrombosis was the most common clinical finding [37/55 (67,2%) patients] Apart from personal and family history, Thrombophilia investigation included measurement of : serum Homocysteine, Antithrombin, Protein C and S, Lipoprotein (a), Activated Protein C (APC) resistance, antiphospholipid antibodies and lupus anticoagulant. In addition the presence of FV Leiden, FII 20210 GA mutations and MTHFR 677 CT polymorphism were determined. Results: A high prevalence of the factor V Leiden mutation was detected in the study group; 50% had APC-resistance test positive, 26 (45%) patients were found to be heterozygous and 3 (5,2%) homozygous for the FV Leiden mutation. Lp(a) elevation was observed in 19,3% and Homocysteine elevation in 15,8% of patients. In 9 women (15,8%) both family history and thrombophilic profile were negative. Serious VTE events (2 abdominal and 6 CNS thromboses) were observed only in the Leiden subgroup. During the follow up period ranging from months to 18 years, 3 women (6,25%) experienced a miscarriage and 14 suffered additional VTE events (25%) and they are currently on permanent anticoagulation. Conclusions : Universal thrombophilia screening of women prior to prescription of OCs is not advisable as it does not appear to be cost effective. However, screening certain subgroups, such as women with a known personal or family history, may be of great value. If a full thrombophilic profile can’t be performed, a mere activated protein C resistance test, that reflects the presence of the factor V Leiden mutation, may provide an easy and cheap way of identifying and consulting properly women at higher risk for VTE prior to OC use. Women with OC-associated VTE and thrombophilia carry a substantial recurrence risk that persists for years.
1221 INTRODUCTION: Protein Z (PZ) is a vitamin K-dependent coagulation factor; it is a glycoprotein that inhibits activated factor Xa, acting as a co-factor to PZ-dependent protease inhibitor, enhancing its action approximately by 1000 times. PZ levels in normal individuals vary greatly, as a result of PZ gene polymorphisms. PZ deficiency has been involved in the pathogenesis of ischemic strokes and pregnancy complications. Gris et al [Blood 2002;99(7):2606–08] first described a possible role of PZ deficiency (PZ <= 1mg/L) in women with fetal loss between the beginning of the 10th and the end of the 15th week of gestation. In a recent meta-analysis [Sofi et al, Thrombosis and Haemostasis 2010;103(4):749–56] PZ deficiency was associated with increased risk of pre-eclampsia and fetal loss, as well as with increased risk of arterial and venous thrombotic events. MATERIALS-METHODS: We studied a total of 314 women, 70 women with three or more consecutive spontaneous abortions (group A), 145 women with less than 3 early spontaneous abortions (group B) and 99 control women with at least one normal pregnancy and negative history of a thrombotic complication (group C). All women were tested for congenital and acquired thrombophilia such as antithrombin, protein C and S levels, homocysteine levels, lupus anticoagulant (PTTLa), factor V Leiden mutation, prothrombin G20210A gene polymorphism and PZ levels. We also investigated protein Z polymorphism F79A in a subgroup of our patients. Measurements were made at least 3 months apart from a thrombotic event. Differences between groups were assessed with ANOVA and chi-squared tests for continuous and categorical variables respectively. RESULTS: Statistically significant difference was found in PZ levels between the three groups. Mean PZ level was 1.23mg/dL, 1.31mg/dL και 1.61mg/dL (p<0.00001) in groups A, B, C respectively. Post-hoc Bonferroni analysis revealed a significant difference between groups A and C (p=0.0003) and between groups B and C (p=0.001). The percentage of PZ deficiency (95% condidence interval) was 40% (28%–52%), 38% (30%–46%) and 18% (11%–26%) respectively (p=0.001). Both group A (OddsRatio[OR]=3) and group B (OR=2.75) have a statistically greater PZ deficiency than control group C. The other parameters did not differ significantly between the three groups. DISCUSSION/CONCLUSIONS: Spontaneous abortions are common in women especially in first trimester. Thrombophilia has a major role in pregnancy complications. In these women that one cannot find some of the well established thrombophilic factors, searching for other possible deficiencies is necessary. The role of PZ deficiency has been investigated thoroughly in the last decade with sometimes conflicting results. To the best of our knowledge, this is the first Greek study investigating the possible role of protein Z deficiency in women with early pregnancy losses. From our study it is evident that PZ deficiency is an independent risk factor for early pregnancy losses. From our study it seems that the other thrombophic factors may play a minor role. A plausible pathophysiologic explanation is the occurrence of microthrombi due to atherosclerotic lesions soon after the development of materno-placental circulation. The role of PZ gene polymorphisms in PZ levels and in thrombotic complications remains to be investigated further. According to preliminary results from a sub-group of our patients (Topalidou et al, Thrombosis Research 2009;124:24–27), the presence of the intron F79A polymorphism was associated with significantly lower PZ levels, but was unrelated to unexplained early pregnancy losses. Disclosures: No relevant conflicts of interest to declare.
2914 Background: AZA, a DNA hypomethylating agent, provides 50–60% responses in higher-risk MDS after administration of 6 courses of treatment. Recent laboratory data suggests that demethylation with AZA upregulates EPO-receptor mRNA (Wallach, 2009). AZA might also affect several genes involved in cell cycle, metabolism and signal transduction which are down-regulated in bone marrow erythroid cells in MDS patients non-responsive to rEPO. There is currently insufficient data to combine AZA and rEPO in MDS patients. Patients-Methods: We explored the safety and the efficacy of the AZA-rEPO combination in a cohort of 10 (M/F: 5/5) patients (pts) with a median age of 75(67-83) years. Diagnosis (WHO classification) was: RAEB-2: 5, CMML: 2 and RAEB-t: 3; IPSS was: int-2 in 8/10 and high in 2/10 pts. Median time from diagnosis was 6(1-31) months. 9/10 pts were transfusion dependent, 8/10 were refractory to previous rEPO administration while 2/10 pts were not treated with rEPO but their diagnostic serum EPO levels were >200 U/L. Patients were given AZA at FDA/EMEA-approved schedule (75 mg/m2/d x7d/4-weekly) initially for 5 courses and continued if response was obtained. rEPO (40,000IU/week) was given until achievement of steady Hb level >10.5 g/dL or until AZA discontinuation. Results: Median follow-up was 6.5(1-14) months. Patients received a median of 5 cycles (range 2–13) of AZA; 9/10 pts were treated with ≥5 courses of AZA. The median time of rEPO administration was 82(76-142) days. Best response (IWG 2006 criteria) was CR in 1/10 pts (RAEB-2: 1), marrow CR in 1/10 pts (RAEB-t: 1), and stable disease with hematological improvement (HI) in 4/10 pts (RAEB-t: 1, RAEB-2: 2, CMML: 1) leading to an overall response rate of 60%. As soon as 2 courses of AZA-rEPO were given, 5/6 responders experienced HI-erythroid response, 3/6 obtained HI-platelet response and 2/6 achieved HI-neutrophil response. Adverse events included 2 episodes of febrile neutropenia, nausea (2/10 pts), reversible renal impairment (2/10 pts) and hemorrhagic complications (3/10 patients). Currently, 9/10 patients remain alive, 1 patient experienced progression to AML and the estimated probability of 1 year-Progression Free Survival is 75%. Conclusions: This study provides clinical evidence that the AZA-rEPO combination is safe and rapidly effective in higher risk MDS pts. Our results emphasize the necessity for randomized trials in order to further evaluate the AZA-rEPO combination in MDS. Disclosures: No relevant conflicts of interest to declare.
3011 Background: CD81 is a tetraspanin cell surface protein that regulates CD19 expression in B lymphocytes and enables hepatitis C virus infection of human cells. Immunohistochemistry and FC have showed that CD81 expression is downregulated in multiple myeloma and PC lines (Luo, 2010). It appears also that normal PCs are CD81+ at a high percentage (Rawstron, 2008). However, information about CD81 utility in phenotypic diagnosis of PC disorders is scanty. We assessed the frequency and the diagnostic value of the FC detection of CD81 surface expression in multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS) and non-hematological malignancy subjects. Patients-Methods: A total of 84 bone marrow aspirates were analyzed in this study. These included 52 diagnosis/disease progression MM samples, 8 samples from MGUS patients and 24 samples from reactive plasmacytosis and ITP patients. A 4-color FC technique was used for PC analysis. Based on the European Myeloma Network guidelines (Rawstron, 2008), we evaluated expression of CD19, CD27, CD56 and CD81 on PCs identified by the CD38/CD45/CD138 combination. At least 100,000 events/tube were acquired, leading to a sensitivity limit of 0.1%. FC positivity threshold for studied antigens was set at 20%. Any deviation from the normal PC phenotype (CD19+CD27+CD56-) was considered as abnormal. Diagnostic tests also included FBC, biochemistry, beta-2 microglobulin, IgA, IgG, IgM, kappa and lambda light chain serum levels, serum protein electrophoresis and immunofixation, bone marrow aspirate and skeletal survey where required. Results: Median PC percentage was significantly higher in the bone marrow aspirate when compared to FC as expected [15.5(3-96)% vs. 2(0.11-53)%, p<0.001]. CD81 positivity was identified in 19% (10/52) of MM samples and 50% of MGUS (4/8) and normal PC samples (12/24). CD81 plasma cell expression was significantly different between normal and MM samples (median: 16.8(1.9-52.4)% vs. 2.5(0-90.4)%, p<0.001) and between MGUS and MM patients (median: 14.4(1.5-53)% vs. 2.5(0-90.4)%, p=0.001). Mean fluorescence intensity of CD81 was similar in the 3 groups. A positive correlation was found between CD81 and CD19 expression (rho=+0.596, p<0.0001) and between CD81 and CD27 (rho=+0.358, p=0.001) while CD56 expression was negatively correlated with CD81 (rho=-0.291, p=0.007). Flow cytometry provided correct diagnosis in 87% (73/84) of cases; 8 samples were identified as false positive and 3 as false negative. Subsequently, a Receiver Operating Characteristic (ROC) curve analysis was performed in order to assess CD19, CD27, CD56 and CD81 antigens' sensitivity and specificity in discriminating normal from malignant PCs (Figure); although CD81 shared similar sensitivity and specificity with CD27, CD19 was shown to have the highest sensitivity and specificity in detecting correctly PC identity. Conclusions: This study provides laboratory evidence that CD81 expression in PCs is strongly correlated with CD19, CD27 and CD56 expression. CD81 surface detection seems to characterize normal PCs in reactive plasmacytosis, ITP and MGUS. However, it has an inferior sensitivity and specificity, in discriminating normal from malignant PCs, when compared to CD19. Disclosures: No relevant conflicts of interest to declare.
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