Heit, John A.

Abstract Abstract 2976 Poster Board II-955 Background: AT deficiency is classified as type 1 (quantitative), or type 2 (qualitative), based on plasma AT activity and antigen levels. However, such levels can sometimes be only mildly and equivocally reduced. Type 2 deficiency can be subdivided into type 2a (reactive center loop [RCL]), type 2b (heparin binding domain), and type 2c (pleiotropic), usually by molecular analysis, but the role of AT molecular analysis in patient diagnosis and management is uncertain. Objectives: 1) to estimate the frequency of mutation detection in possible hereditary AT deficiency, and 2) to correlate clinical manifestations with AT deficiency type as determined by plasma AT, and by AT genotype. Methods: Mayo Clinic patients (n=16) were categorized as type 1 or 2 by plasma AT, or by molecular analysis for previously reported type 2a-c mutations. Patient characteristics were abstracted from medical records. The SERPINC1 putative promoter region, all exons (n=7) and splice junctions, and the 3'UTR were PCR amplified from leukocyte genomic DNA, and sequenced with both forward and reverse primers. Results: The mean patient age at diagnosis was 32 years (range 18-65); 11 (69%) were women. 12 (75%) patients were type 1 by plasma AT, while 4 were type 2 by molecular analysis (Table). The mean plasma AT (range) activity/antigen for types I and 2 patients were 52% (39-71%)/53% (39-68%) and 58% (43-67%)/85% (60-103%), respectively [normal range=80-130%]. 13 (82%) patients had VTE (8 [61%] idiopathic; 10 [77%] recurrent); 5 (32%) had stroke/TIA, 4 at a young age. Thrombosis “penetrance” appeared greater among type 1 families. Only 2 pregnancy losses occurred in 14 pregnancies among 6 type 1 women, and no losses occurred in 5 pregnancies among 2 type 2b women. Among the 14 (88%) patients with mutations identified, all were heterozygous and 8 patients had 6 novel mutations; 2 patients had no mutation detected. Plasma AT activity/antigen did not always correlate with genotype; 1 patient each with type 2b and 2c by molecular analysis had concordant decreases in plasma AT activity and antigen (i.e., a type 1 plasma phenotype), while amino acid changes (T85K and F239L) predicting reduced plasma AT activity only had a type 1 plasma phenotype. One type 2b (Q118P) patient had extensive recurrent VTE. Conclusion: 88% of patients had a detrimental mutation, suggesting that molecular analysis can be helpful for diagnosis. While our findings should be interpreted with caution, type 1 patients may have a higher prevalence of stroke/TIA at a young age and a higher family thrombosis penetrance compared to type 2. Plasma AT activity and antigen frequently did not correlate with genotype. However, whether molecular analysis is useful for clinical management remains uncertain. Finally, 50% of patients had a novel mutation, suggesting that reported mutations causing AT deficiency have not reached gene saturation. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2984 Poster Board II-960 In previous studies of venous thromboembolism (VTE) among all residents of Olmsted County, MN, the odds of VTE associated with surgery, medical hospitalization, or active cancer were extremely high (Univariate odds ratio [OR] =14.6; 4.6, and 8.4 respectively). We also showed that nursing home (NH) residency was an independent risk factor for VTE (OR =5.6). From a clinical practice perspective, it is important to identify which NH residents are at risk of VTE. While it might be assumed that, similar to estimates for the population generally, surgery, medical hospitalization, and cancer are associated with increased risk of VTE within the NH population, the answer remains unclear. We took advantage of the previous identification of all Olmsted County, MN residents who met research criteria for incident VTE 1998-2005 (N=1168). We then determined which individuals were resident of a local NH at time of symptom onset, regardless of location of symptom onset (i.e., for purposes of this study, individuals whose VTE occurred in-hospital having been admitted from a NH were considered NH residents). For each such NH VTE case (N=96), we identified 2 same sex Olmsted County residents of similar age and duration-of-medical-history who were resident of a local NH at the time of the case's VTE event (i.e., index date) (N=192). The detailed provider-linked medical records of NH VTE cases and NH non-VTE controls were reviewed for 3 months before index for surgery or medical hospitalization and for 6 months surrounding index for active cancer. Using conditional logistic regression, we tested and estimated the odds ratio associated with each of these potential risk factors. The proportions of NH VTE cases and NH non-VTE controls with surgery (33%, 28%), medical hospitalization (44%, 46%), and active cancer (12%, 9%) were similar. Univariate odds ratios (95% confidence intervals) and p values for surgery, medical hospitalization, and active cancer were 1.5 (0.7-3.1), p=0.30; 1.1 (0.6-2.1), p=0.74; and 1.4 (0.6-3.2), p=0.46 respectively. Compared to the entire Olmsted County population, the odds of VTE associated with surgery, hospitalization, and cancer are surprisingly much lower for NH residents. Additional investigation is needed to characterize the subset of NH residents at increased risk of VTE. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Venous stasis syndrome (VSS) is a relatively common long-term sequelae of deep vein thrombosis (DVT), although it frequently is noted in individuals with no prior history of DVT. Objective: To evaluate whether: (1) venous stasis syndrome (VSS) is associated with a prior history of DVT; (2a) venous outflow obstruction (VOO) and/or (2b) venous valvular incompetence (VVI) are associated with DVT; and (3) VSS is associated with VVI and/or VOO. Design: Case-control study nested within a population-based inception cohort study. Population: 230 residents of Olmstead County, MN (OCM) with a first lifetime VTE over the 25-year period, 1966 – 1990 (cases), and 135 age, gender and year of incident VTE-matched OCM residents without prior history of VTE (controls). Measurements: Physical examination and patient questionnaire for symptoms or signs of VSS, and strain gauge outflow plethysmography, continuous wave venous Doppler ultrasound, and passive venous drainage and refill testing for VOO and VVI performed between 1996 – 1998. Results: Of the 365 study participants, 43 (12%) had VOO, 136 (37%) had VVI, and 265 (73%) had VSS. In multivariate logistic regression analyses: (1) age at the follow-up visit [OR Δper 10 years: 1.70 (1.41, 2.04)], prior DVT in the affected limb [OR: 4.03 (2.32, 7.01)], and presence of prior varicose veins [OR: 4.36 (1.84, 10.31)] were significantly associated with VSS; (2a) age at the follow-up visit [OR Δper 10 years (95% CI): 1.84 (1.39, 2.44)] and prior DVT in the affected limb [OR: 5.01 (2.61, 9.63)] were significantly associated with VOO; (2b) prior DVT in the affected limb (OR: 3.91 (2.56, 5.97)], presence of prior varicose veins [OR: 2.19 (1.32, 3.63)] and symptoms of VSS prior to incident DVT [OR: 3.42 (1.46, 8.00)] significantly increased the odds for VVI; and (3) VOO (p=0.004) and VVI (p<0.0001) were highly associated with VSS. Having a DVT in the left leg was associated with a greater odds of developing VOO, VVI or VSS in that leg when compared to their association with right leg DVT (OR: 6.69 vs. 3.65; 4.82 vs. 3.09; 4.71 vs. 3.97, respectively). Interestingly, prior DVT in the opposite leg was associated with an increased odds of subsequent VVI [OR: 2.00 (1.28, 3.10) and VSS [OR: 2.20 (1.31, 3.70)], but not VOO, in the test leg. Conclusions: Prior DVT imparts an increased risk for subsequent VSS, likely due to VOO and/or VVI. The odds of VOO or VSS increases with age. Presence of varicose veins increases the odds for VVI and VSS. We speculate that the increased odds of left sided VOO, VVI and VSS in patients with prior DVT may be secondary to May-Thurner syndrome. The increased odds of VVI and VSS in the limb opposite to the one affected by prior DVT could reflect occult DVT in the test limb, inferior vena cava thrombosis, or other mechanisms leading for VVI and VSS.

Abstract Background: Recent trends in the incidence of venous thromboembolism (VTE), including idiopathic vs. non-idiopathic VTE, have not been well described. Objective: To estimate the incidence of deep vein thrombosis (DVT) and pulmonary embolism with or without DVT (PE), and describe trends in incidence. Methods: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with an incident DVT and PE over the 35-year period, 1966–2000 (n=3342). For all cases, the complete medical records in the community were reviewed for demographic and baseline characteristics previously identified as risk factors for VTE. Generalized linear models assuming a Poisson error structure, and using a log link function, and a log (population) offset will be used to assess the relationship of crude incidence rates to gender, year of diagnosis and age at diagnosis. Results: The overall average age- and sex-adjusted annual VTE incidence was 122 per 100,000 person-years (DVT, 56 per 100,000; PE, 66 per 100,000), with higher age-adjusted rates among men than women (134 versus 115 per 100,000, respectively). VTE incidence rates increased exponentially with age for both genders, ranging from 4 to 1110 per 100,000 for age groups 0–19 to 90–110 years. Compared to the 5-year period, 1981–85 (when non-invasive diagnostic testing became routinely available), the overall VTE incidence through 2000 remains unchanged. However, the DVT incidence and the PE incidence significantly increased and decreased, respectively, adjusting for age and gender (p<0.001 for both). The overall age- and sex-adjusted annual incidence of idiopathic VTE was 11.7 per 100,000 person-years (DVT, 6.6 per 100,000; PE, 5.1 per 100,000), with age-adjusted rates also higher among men than women (15.1 vs. 9.1 per 100,000). Interestingly, again compared to 1981–85, idiopathic VTE incidence decreased for 1991–95 (p=0.001) and 1996–2000 (p=0.32), adjusting for age and gender. Idiopathic DVT incidence decreased for 1991–95 (p=0.09), and idiopathic PE incidence decreased for both 1991–95 (p=0.004) and 1996–2000 (p=0.03). The overall age- and sex-adjusted annual incidence of non-idiopathic VTE was 109.4 per 100,000 (DVT, 48.4 per 100,000; PE, 60.7 per 100,000), again, with age-adjusted rates higher in men than women (115.1 vs. 106.8 per 100,000). Non-idiopathic DVT incidence increased steadily since 1981–85 (p=0.006, p<0.001, and p<0.001 for increasing DVT incidence for 1986–1990–1991–1995–1996–2000, respectively, adjusting for age and gender). Non-idiopathic PE incidence, however, remained unchanged for 1986–2000. Conclusions: VTE remains a major national health problem, especially among the elderly. Despite improved VTE prophylaxis efficacy and utilization, the overall incidence of VTE remains unchanged. However, the decreasing incidence of idiopathic DVT, and particularly idiopathic PE (with its associated poor survival) raises the possibility that the total number of VTE(PE)-related deaths may also be decreasing, albeit slightly. This hypothesis requires formal testing. The increasing or steady incidence of non-idiopathic DVT and PE, respectively, suggests the need for more widespread, effective VTE prophylaxis.

Introduction: Menorrhagia is a common health problem affecting ∼5-10% of women. The optimal management of menorrhagia among women with abnormal laboratory hemostasis is uncertain. The goal of this study was to determine the effect of intranasal desmopressin (IN-DDAVP) vs. oral tranexamic acid (TA) on menstrual blood loss (MBL) and quality of life (QOL). Methods: In a cross-over study design, 117 consenting women 18–50 years of age with menorrhagia (defined as subjective report of heavy bleeding and a pictorial blood assessment chart [PBAC] score > 100) with a negative gynecological evaluation and abnormal laboratory hemostasis (62% platelet dysfunction, 15% von Willebrand disease, 23% other coagulation defect or combined) were randomly assigned to initial IN-DDAVP or TA therapy each for two menstrual cycles, followed by cross-over to the second study drug for an additional two cycles. MBL by PBAC was measured at baseline and after each menstrual cycle while QOL was assessed by four validated instruments: Health Related Quality of Life (HRQOL), SF-36®, Center for Epidemiologic Studies Depression Scale (CES-D) and the Ruta menorrhagia questionnaire. Results: There was a statistically significant decrease in the PBAC for both treatments. On average, the estimated decrease in the PBAC from baseline for IN-DDAVP was −66.0 (CI = (−89.5, −42.6)) and for TA, −107.8 (CI = (−131.5, −84.1)). The decrease in the PBAC score was larger for TA with a difference of 41.8 (p-value = 0.0002, CI = (20.4, 63.2)) between the two treatments. In the multivariable analysis, the test for treatment-cycle number interaction was not significant, suggesting no carry-over effect. The test for a treatment type effect was significant (p<0.0001) suggesting a greater reduction in PBAC score with TA compared to IN-DDAVP. Both IN-DDAVP and TA generally improved QOL as assessed by each of the four instruments. Over-all, the Ruta Menorrhagia Questionnaire and the Center for Epidemiologic Studies Depression Scale measurements showed the most statistically significant improvements. Conclusion: Both TA and IN-DDDAVP reduce MBL and improve QOL in females with menorrhagia and abnormal laboratory hemostasis.The significance of these findings are underscored by the fact that prior studies of menorrhagia treatment in these patients have not included validated QOL instruments. The marked improvement in MBL and QOL noted with TA and IN-DDAVP appears to justify hemostasis screening in women presenting with menorrhagia for whom no gynecological cause can be found.

Abstract Background Congenital/hereditary qualitative platelet disorders (CQPD) can be classified by platelet count (eg, normal or decreased) and platelet size as well as by functional defect. Based on mean platelet volume (MPV), congenital thrombocytopenias (CT) are classified as macro-thrombocytopenias (eg, Bernard-Soulier syndrome [BSS], MYH-9 [myosin heavy chain 9, non-muscle]-associated thrombocytopenias, gray platelet syndrome [GPS], etc.); microthrombocytopenias (eg, Wiskott-Aldrich syndrome and variants); and those with normal platelet size. CQPDs with normal platelet count include Glanzmann thrombasthenia (GT), dense granule storage pool disorders (DG-SPD) including Hermansky-Pudlak syndrome (HPS), platelet secretion disorders and many others. Diagnosis has relied on platelet counting and sizing, blood smear light microscopy, platelet aggregation (agg) and platelet function analyzer (PFA-100) studies. Platelet transmission electron microscopy (PTEM) and flow cytometry can provide supplementary information and molecular analysis is also evolving. The objective of this study was to determine the roles of platelet transmission electron microscopy (PTEM) and flow cytometry in the diagnosis of CQPD and CT. Methods In this retrospective cohort study, after IRB approval, the electronic medical record system was queried for patients (pt) with a confirmed CQPD or CT seen at Mayo Clinic between 2000 and 2015. A detailed chart review was undertaken. Results 54 pt (64% female) met our study criteria; median age was 32 years (range 1 day to 81 years). 18/54 (33%) pt had macrothrombocytopenia: BSS 4 (7%); MYH-9 10 (19%); gray platelet syndrome 4 (7%). 36/54 (66%) had normal MPV: Glanzmann thrombasthenia 6 (11%); storage pool disorders including DG-SPD 10 (19%) and HPS 2 (3%), mild alpha granule deficiency 3 (6%) and York platelet syndrome 4 (7%); platelet secretion disorders 4 (7%); ANKRD26 mutation 3 (6%); congenital amegakaryocytic thrombocytopenia 1 (2%); GATA-1 mutation 1 (2%); RUNX-1 mutation 1 (2%); and Jacobsen syndrome 1 (2%). 44 pt (81%) had a positive bleeding history: epistaxis 52%, cutaneous bleeding 57%, gastrointestinal bleeding 21% and menorrhagia 54%; 10 pt (19%) had a negative bleeding history. Results of standard and esoteric platelet testing are summarized in Table 1. Diagnosis in the 10 pt with glycoprotein deficiency (BSS or GT) was established by agg; flow cytometry was confirmatory but not necessary. Of the 23 pt with SPD, 5 had a negative bleeding history; 4 pt had normal agg and PFA-100 and were diagnosed exclusively by PTEM. In this group, the abnormalities on platelet aggregation and PFA were variable and PTEM allowed for a better definition of the specific abnormalities. For MYH-9 patients, PTEM confirmed leukocyte inclusions that had already been identified on light microscopy. PTEM was the only diagnostic modality able to identify the abnormality in York platelet syndrome. In 5/54 (9%) genetic testing was necessary for diagnosis (GATA-1, ANKRD26 and RUNX-1) Conclusion In this cohort, standard platelet assays established the diagnosis in the large majority of CQPD and CT. PTEM was essential for confirmation in DG-SPD, mild alpha granule deficiency and York platelet syndrome and useful in combination with molecular testing to establish a diagnosis in selected cases. Guidance on selection of patients for such specialized testing requires further study. Table 1. Results of standard and esoteric platelet testing for 54 patients with congenital qualitative platelet disorders and/or thrombocytopenia Disorder n (%) Platelet aggregation PFA PTEM Flow cytometry Confirmation by genetics Done Abnormal Done Abnormal Done Abnormal Done Abnormal Glanzmann thrombasthenia 6 (11) 6 6 5 5 1 0 3 3 0 Bernard-Soulier syndrome & variants 4 (7) 4 4 4 4 3 0 4 4 0 MYH-9 related disorders 10 (19) 7 2 8 3 5 5 4 2 5 Dense granule deficiency and HPS 12 (22) 12 8 12 8 12 12 4 0 0 Alpha granule deficiency* 7 (13) 7 4 7 6 7 7 4 4 1 York platelet syndrome 4 (7) 1 0 1 1 4 4 1 1 0 TXA2 or PG synthesis/receptor defect 4 (7) 4 4 4 3 3 0 3 0 0 CATM 1 (2) 0 - 0 - 0 - 0 - 1 ANKRD26 3 (6) 3 3 3 2 3 3 3 3 3 GATA-1 1 (2) 0 - 1 1 1 1 1 1 1 RUNX-1 1 (2) 1 0 1 1 0 - 0 - 1 Jacobsen syndrome 1 (2) 1 0 1 1 1 1 1 0 1 MYH-9: myosin heavy chain 9, non-muscle (MHY-9) associated thrombocytopenia, HPS: Hermansky-Pudlak Syndrome, TXA2: thromboxane A2, PG: prostaglandin CATM: congenital amegakaryocytic thrombocytopenia. * Includes gray platelet syndrome Disclosures Pardanani: Stemline: Research Funding.

Abstract Abstract 1148 Background: Factor V Leiden (F5rs6025) has been suggested as a disease-susceptibility SNP for deep vein thrombosis (DVT) but not PE. Given the significantly reduced survival after PE, identifying individuals at risk for PE is important for targeting prophylaxis and improving survival. Objectives: To identify PE disease-susceptibility genes. Methods: We performed in silicoGWAS analyses of VTE cases using genotype data imputed to ∼2.5 million SNPs from adults with objectively-diagnosed PE ± DVT (n=745), and DVT only (n=758). We tested these SNPs for an association with PE ± DVT after adjusting for age, sex, stroke and/or myocardial infarction, and USA state of residence using unconditional logistic regression. Results: Of all SNPs, three were most strongly associated with PE ± DVT: one at BDH1 on chromosome (chr) 3q29 (rs1309873, OR=1.56, p=4.02E-07) and two at SLC39A10 on chr 2q32.3 (rs7578216, OR=2.55, p=4.57E-07; and rs4589778, OR=2.49, p=7.52E-07). Individually adjusting for F5 rs6025 (chr 1), F2 rs1799963 (prothrombin G20210A; chr 11) and ABO rs8176719 (ABO blood type O allele; chr 9) did not materially affect these associations. None of these three SNPs associated with PE were intragenic. BDH1 encodes for 3-hydroxybutyrate dehydrogenase 1, a key mitochondrial enzyme in fatty acid catabolism, and SLC39A10encodes for solute carrier family 39, member 10, an important protein for zinc transport. Conclusions: Chromosomes 3q29 (BDH1) and 2q32.2 (SLC39A10) may harbor PE disease-susceptibility gene regions (genes). These findings require independent confirmation. If confirmed, additional studies addressing the biologic mechanisms through which these genes and/or gene regions operate to increase PE risk also will be required. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: While Factor V Leiden is associated with an increased risk of thrombosis, the magnitude of that risk among homozygous carriers is uncertain. Methods: In a cross-sectional study of Mayo Clinic patients referred to the Special Coagulation Laboratory for a thrombophilia profile (n=379) over the 18-year period, 1996-2013, the prevalence of venous and arterial thrombosis was estimated for patients found to be Factor V Leiden carriers based on leukocyte genomic DNA genotyping. T tests and chi-square tests were used for continuous and categorical variables, respectively. Results: Among homozygous (n=111) and heterozygous (n=268) carriers, the mean age at testing (50.3 and 50.5 years, respectively; p=0.9) and the proportion of females (50% and 54%, respectively; p=0.5) did not differ significantly. Of 29 asymptomatic carriers at the time of testing, 14 were homozygotes. Of the remaining 350 carriers, the mean age at first venous or arterial thrombosis (42 vs 43.8 years; p=0.5) among homozygous and heterozygous carriers, respectively, did not differ significantly. Thirty-five (33%) and 83 (31%) homozygous and heterozygous carriers, respectively, had at least one recurrent venous or arterial thrombosis (p=0.72). The prevalence of deep venous thrombosis (DVT) was 61% and 46% in homozygous and heterozygous carriers, respectively (p=0.008); the prevalence of pulmonary embolism was 18% and 20%, respectively (p=0.69). The prevalence of arterial thrombosis (mainly stroke and/or TIA) was higher in heterozygous (23%) compared to homozygous carriers (8%). Conclusion: In the largest sample of homozygous Factor V Leiden carriers reported to date, thrombosis penetrance and phenotype did not appear to differ among homozygous vs. heterozygous carriers with the exception of a higher prevalence of DVT among homozygous carriers. These data should be interpreted with caution due to the potential for referral bias. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 2256 Background: The incidence of venous thromboembolism (VTE) may be increasing due to the obesity epidemic. Objective: To estimate the incidence of VTE and describe trends in incidence adjusted for the population's increase in BMI. Methods: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with an incident deep vein thrombosis (DVT) or pulmonary embolism (PE) over the 13-year period, 1988–2000 (n=1,400). Age and BMI at VTE diagnosis and gender were collected for all cases. Age was categorized into 10 year intervals. Using a model for the population distribution of BMI derived from several (n=6) non-VTE Olmsted County cohorts (n=8,011 individuals), we calculated the probability of falling into each of five BMI categories (<18.5, 18.5–24, 25–29, 30–34, 35+) for each age, gender and calendar year. In Olmsted County in the median age group, the prevalence of BMI >30 kg/m2increased from approximately 15% in 1980 to 36% in 2000. We applied these probabilities to the decennial census data for 1980, 1990, 2000 using linearly interpolated census values for intra-census years to obtain Olmsted County age/sex/calendar year/BMI category denominators. Generalized linear modeling assuming a Poisson error structure, and using a log link function, and a log (population) offset was used to assess the relationship of crude incidence rates to gender, year of diagnosis, age and BMI. Results: The overall average age- and sex-adjusted annual VTE incidence was 120 per 100,000 person-years (DVT: 66 per 100,000; PE: 54 per 100,000), with higher age-adjusted rates among men than women (129 versus 113 per 100,000, respectively). VTE incidence rates increased exponentially with age for both genders, ranging from 3 to 1,079 per 100,000 for age groups 0–19 to 90–110 years. Age and sex-adjusted VTE incidence increased by increasing BMI category (88, 112, 106, 150, and 195 per 100,000 person-years, respectively, by increasing BMI category). Unadjusted for BMI, VTE incidence was unchanged from 1988 through 2000 (p=0.70). After adjusting for age, gender and calendar year, VTE incidence increased with increasing BMI (p<0.0001). The calendar year incidence slope estimate decreased numerically from 3% per decade to minus 4% per decade after adjusting for increasing BMI, remaining nonsignificant (p=0.57). Conclusions: VTE remains a major national health problem, especially among the obese. Despite the dramatically increasing population BMI, and the significant association of BMI category with VTE incidence, the overall incidence of VTE remained unchanged over the timeframe, 1988–2000. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 150 Background: While bivariate interactions between Factor V Leiden, prothrombin G20201A and hereditary deficiency of antithrombin, protein C and protein S compound VTE risk, whether other gene-gene interactions are associated with VTE is largely unknown. Objective: To test gene-gene interactions for an association with VTE. Methods: Cases (n=1004) were Mayo Clinic European-American patients of non-Hispanic ancestry with objectively-diagnosed VTE in the absence of active cancer, venous catheter or antiphospholipid antibodies. Controls (n=1066) were Mayo Clinic outpatients without VTE who were frequency-matched on case age, gender, race, MI/stroke status and state of residence. We selected candidate genes relevant to the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways, focusing on platelet, monocyte, neutrophil and endothelial cell agonists, receptors, ligands, signal transduction and adhesion molecules, granule contents and effectors; plasma proteases and inhibitors; matrix metalloproteases; inflammatory cytokines and receptors; estrogen, progesterone and androgen receptors; co-regulators and enzymes related to estrogen metabolism; important enzymes for catechol, homocysteine, thromboxane A2 and prostacyclin biosynthesis and metabolism; and HMG CoA reductase. For these genes (n=780), we selected all non-synonymous coding single nucleotide polymorphisms (SNPs) with minor allele frequency ≥0.5%; the remaining SNPs were selected using an LD tagging algorithm (Carlson et al. AJHG 2004); 558 ancestry-informative markers were also included (total n=13,237 SNPs). Leukocyte genomic DNA was genotyped using a custom Illumina Infinium iSelect chemistry and platform, including appropriate controls. For these analyses, all pairwise SNP-SNP interactions for 12,313 SNPs were tested using logistic regression. In addition, we tested all Factor V Leiden -, prothrombin G20210A - and ABO non-O blood group - SNP interactions. Results: The mean ± SD case and control ages were 55.3 ± 16.4 and 56.5 ± 15.9 years, respectively, and 51% were female. Analysis of ancestry-informative markers gave no evidence of population stratification. Among almost 76 million pairwise interactions tested, 504, 44 and 8 SNP-SNP interactions reached p-values ≤ 1E-5, 1E-6, and 1E-7 respectively; none reached the Bonferroni statistical significance threshold (≤ 6.6E-10). The gene-gene pairwise interactions with p-values ≤ 1E-7 included: Leptin receptor - Estrogen receptor 1, α1 Antichymotrypsin - β2 glycoprotein 1, CRADD(caspace) - B1 Bradykinin receptor, ILF10 - Prolactin receptor and GFRA2(TGFβ neurotrophic factor receptor) - Bactericidal permeability-increasing protein. Gene-gene pairwise interactions with the lowest p-value for Factor V Leiden -, prothrombin G20210A - and ABO non-group O - were Protein kinase C beta (2.1E-5), von Willebrand Factor (7.6E-4) and Phospholipase C gamma-2 (6.7E-4), respectively. Conclusion: Pairwise gene-gene interaction analyses suggest potential associations between VTE and novel genes and gene pathways. These potential associations require confirmation in future replication studies. Disclosures: No relevant conflicts of interest to declare.