Factor VIIc Research Articles

Peri-operative thrombophilia in patients undergoing liver resection for colorectal metastases

BackgroundRoutine chemical venous thromboembolism (VTE) prophylaxis for liver surgery remains controversial, and often delayed post-operatively due to perceived bleeding risk. This study asked whether patients undergoing hepatectomy for colorectal metastases (CRM) were at risk from VTE pre-operatively, and the impact of hepatectomy on that risk. MethodsSingle-centre prospective observational cohort study of patients undergoing open hepatectomy for CRM, comparing pre-, peri- and post-operative haemostatic variables. ResultsOf 336 hepatectomies performed October 2017–December 2019, 60 resections in 57 patients were recruited. There were 28 (46.7%) major resections, with median (interquartile range [IQR]) blood loss 150.0 (76.3–263.7) mls, no blood transfusions, post-operative VTE events or deaths. Patients were prothrombotic pre-operatively (high median factor VIIIC and increased thrombin generation velocity index), an effect exacerbated post-hepatectomy. Major hepatectomies had a significantly greater median drop in Protein C, rise in Factor VIIIC and von Willebrand Factor, versus minor resections (p = 0.001, 0.005, 0.001 respectively). Patients with parenchymal transection times greater than median (40 min), had significantly increased median (IQR) PMBC-TFmRNA expression [1.65(0.93–2.70)2ddCt], versus quicker transections [0.99(0.69–1.28)2ddCt, p = 0.020]. ConclusionsPatients with CRM are prothrombotic pre-operatively, an effect exacerbated by hepatectomy, particularly longer, complex resections, suggesting chemical thromboprophylaxis be considered early in the patient pathway.

Hemostatic and thrombotic parameters in acure leukemia- A comparison of pre and post remission induction phase

This study was aimed to compare hemostatic, fibrinolytic and thrombotic parameters in pre and post induction chemotherapy in acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). A total of 110 diagnosed acute leukemia patients and 40 normal individuals were enrolled in the study. Questionnaire were filled and patients’ blood specimens were collected before the commencement and post induction chemotherapy. Prothrombin time (PT), activated partial thromboplastin time (aPTT), von Willebrand factor antigen (vWF Ag), fibrinogen level, factor VIIIc (FVIIIc), D-Dimers, fibrinogen degradation products (FDPs), anti-thrombin III (AT), lupus anticoagulant (LA), protein C (PC), protein S and diluted russel viper venom test (DRVVT) were conducted in all the participants. A significant rise was identified in post-induction levels of PT, aPTT, vWF Ag, fibrinogen and factor VIII in acute leukemia patients. Analysis of fibrinolytic markers indicated increased D-Dimers and plasminogen levels while the levels of alpha 2 anti-plasmin were reduced in pretreated patients. Thrombotic markers’ assessment showed increased levels of AT and LA while decreased level of PC in pretreated acute leukemia patients. It was concluded that remission induction chemotherapy, in acute leukemia patients, significantly affects the coagulation, fibrinolytic and thrombotic parameters.

Peri-Operative Thrombophilia in Patients Undergoing Liver Resection for Colorectal Metastases

Introduction: Routine peri-operative chemical venous thromboembolism (VTE) prophylaxis for liver surgery remains controversial, and is often delayed post-operatively until conventional coagulation parameters have normalised, due to perceived risks of bleeding. This study asked whether patients undergoing liver resection for colorectal metastases (CRM) were at risk from VTE pre-operatively, and the impact of liver resection on that risk. Method: A single-centre prospective observational cohort study of patients undergoing open liver resections for CRM, comparing pre-, peri- and post-operative haemostasis variables. Patients with cirrhosis, previous VTE or anticoagulated were excluded. Coagulation assays were measured pre-operatively, peri-operatively (after transection) and first post-operative day. Tissue Factor messenger ribonucleic acid (TFmRNA) activation was measured from peripheral blood mononuclear cells (PBMCs) pre- and post-operatively. Chemical thromboprophylaxis commenced on the first post-operative day after venesection. Results: Of 336 hepatectomies performed October 2017-December 2019, 60 resections in 57 patients were prospectively recruited (Table 1). Patients had raised Factor VIIIC and thrombin generation velocity index pre-operatively, which significantly increased post-operatively. Post-operative Factor VIIIC and von Willebrand Factor (vWF) were higher and Protein C lower following major resections. Longer transections exhibited greater PMBC-TFmRNA expression. Conclusions: These data show the risk of major haemorrhage in elective liver resection in a high-volume unit is low, and administration of chemical thromboprophylaxis within 13-20 hours of surgery is safe and effective. Furthermore, patients with CRM are prothrombotic pre-operatively, an effect exacerbated by liver resection, particularly in patients with longer, more complex resections, suggesting chemical thromboprophylaxis should be considered earlier in the patient pathway.

O-L04 Peri-operative thrombophilia in patients undergoing liver resection for colorectal metastases

Abstract Background The risk of major haemorrhage during liver surgery has decreased considerably in the modern era. However, there remains reluctance amongst liver surgeons to give routine peri-operative chemical thromboprophylaxis, either because of the perceived risk of bleeding, or transient post-operative abnormalities in conventional coagulation studies. The aim of this study was to ask whether a defined, homogeneous population of patients undergoing liver resection for colorectal metastases (CRM) were at risk from venous thromboembolism (VTE) prior to surgery, and what the impact of liver resection was on that risk. Methods A single-centre prospective observational cohort study comparing pre-, peri- and post-operative haemostasis variables in patients undergoing liver resection for CRM. Patients with cirrhosis, history of VTE or anticoagulated were excluded, as were patients undergoing small wedge, or laparoscopic liver resections. Blood samples for coagulation assays were collected pre-operatively, peri-operatively (after transection) and first post-operative day (13–20 hours post-operatively). Pre- and post-operative Tissue Factor messenger ribonucleic acid (TFmRNA) activation was measured from peripheral blood mononuclear cells (PBMCs) using semi-quantitative polymerase chain reaction (PCR). Patients received peri-operative mechanical thromboprophylaxis until mobile, plus chemical thromboprophylaxis on the first post-operative day, after venesection. Results Of 336 hepatectomies performed October 2017-December 2019, 60 resections in 57 patients were recruited. This included 46.7% major resections, with median (interquartile range [IQR]) blood loss 150.0mls (76.3-263.7), no blood transfusions, post-operative VTE events or deaths. Patients were prothrombotic pre-operatively (high factor VIIIC and thrombin generation velocity index), an effect exacerbated post-hepatectomy. Major hepatectomies had a significantly greater drop in Protein C, rise in Factor VIIIC and von Willebrand Factor, versus minor resections (p = 0.001,0.005,0.001 respectively). Patients with transection times greater than median (40minutes), had significantly increased median (IQR) PMBC-TFmRNA expression [1.65 (0.93-2.70)2ddCt], versus quicker transections [0.99 (0.69-1.28)2ddCt, p = 0.020]. Conclusions These data show the risk of major haemorrhage in elective liver resection in a high volume unit is low and administration of chemical thromboprophylaxis within 13-20 hours of surgery is safe and effective. The study demonstrates that patients with CRM are prothrombotic pre-operatively. Furthermore, this thrombophilia is exacerbated by liver resection, and most marked in patients with longer, more complex operations. These data suggest that chemical thromboprophylaxis should be considered earlier in the patient pathway, and has resulted in a change in practice for the authors.

Activation of inflammatory/coagulation system following electrical cardioversion of patient with recent onset atrial fibrillation: an explorative study of the relation to white matter hyperintensities

Abstract Background White matter hyperintensities (WMH), assessed using Fazekas scale, are more prevalent in patients with atrial fibrillation (AF), although its pathophysiologic mechanism(s) is unclear. Purpose The study objective was to explore the association between cardiac, inflammatory and coagulation biomarkers and white matter hyperintensities in anticoagulant-naïve patients following electrical cardioversion (CV) of recent onset AF. Methods Patients with AF duration <48 hours were prospectively included. Brain magnetic resonance imaging (MRI), C-reactive protein (CRP), high-sensitivity troponin T (hs-TNT), NT-proBNP, Interleukin 6, P-selectin, D-dimer, prothrombin fragment 1+2, von Willebrand factor Ag, coagulation factor VIII C and fibrinogen, were obtained sequentially prior, after (2–4 hours) and 7–10 days following CV. Repeated measure analysis of variance was performed. Results Forty-three patients (84% males), aged 55±9.6 years, (mean±SD) with median CHA2DS2-VASc score 1 (interquartile range 0–1) were included. Sequential MRI showed no new brain lesions after CV, while WMH were present at baseline in 21/43 (49%) patients. Repeated measure analysis of variance revealed a statistically significant overall change for hs-TNT: F(2,84)=6.056, p=0.03, NT-proBNP: F(2,84)=106.02, p<0.001, P-selectin: F(2,84)=8.69, p<0.001 and vWF:Ag: F(2,84)=4.078, p=0.02. CRP, IL-6, coagulation factor VIII-C and fibrinogen showed the same pattern, however none reached statistical significance. Patients with WMH had persistent higher values for CRP, hs-TNT, D-dimer, prothrombin fragment 1+2 and fibrinogen prior and after CV, as values at 7–10 days coincided; however, statistical interaction was not significant. Conclusion Transient activation of inflammatory and coagulation systems during atrial fibrillation subsides within 7–10 days after electric cardioversion of recent onset atrial fibrillation. A tendency of higher degree of activation during atrial fibrillation was observed in patients with white matter hyperintensities. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Swedish Heart-Lung Foundation, Swedish Research Council, Correvio International Sárl (Geneva Switzerland), Selanders Stiftelse

The Type and Amount of Dietary Fat Affect Plasma Factor VIIc, Fibrinogen, and PAI-1 in Healthy Individuals and Individuals at High Cardiovascular Disease Risk: 2 Randomized Controlled Trials

Factor VIIc, fibrinogen, and plasminogen activator inhibitor 1 (PAI-1) are cardiovascular disease (CVD) risk factors and are modulated, in part, by fat type and amount. We evaluated fat type and amount on the primary outcomes: factor VIIc, fibrinogen, and PAI-1. In the Dietary Effects on Lipoproteins and Thrombogenic Activity (DELTA) Trial, 2 controlled crossover feeding studies evaluated substituting carbohydrate or MUFAs for SFAs. Study 1: healthy participants (n=103) were provided with (8 wk) an average American diet [AAD; designed to provide 37% of energy (%E) as fat, 16% SFA], a Step 1 diet (30%E fat, 9% SFA), and a diet low in SFA (Low-Sat; 26%E fat, 5% SFA). Study 2: participants (n=85) at risk for CVD and metabolic syndrome (MetSyn) were provided with (7 wk) an AAD, a step 1 diet, and a high-MUFA diet (designed to provide 37%E fat, 8% SFA, 22% MUFA). Study 1: compared with AAD, the Step 1 and Low-Sat diets decreased mean factor VIIc by 1.8% and 2.6% (overall P=0.0001), increased mean fibrinogen by 1.2% and 2.8% (P=0.0141), and increased mean square root PAI-1 by 0.0% and 6.0% (P=0.0037), respectively. Study 2: compared with AAD, the Step 1 and high-MUFA diets decreased mean factor VIIc by 4.1% and 3.2% (overall P<0.0001), increased mean fibrinogen by 3.9% and 1.5% (P=0.0083), and increased mean square-root PAI-1 by 2.0% and 5.8% (P=0.1319), respectively. Replacing SFA with carbohydrate decreased factorVIIc and increased fibrinogen in healthy and metabolically unhealthy individuals and also increased PAI-1 in healthy subjects. Replacing SFA with MUFA decreased factorVIIc and increased fibrinogen but less than carbohydrate. Our results indicate an uncertain effect of replacing SFA with carbohydrate or MUFA on cardiometabolic risk because of small changes in hemostatic factors and directionally different responses to decreasing SFA. This trial was registered at https://clinicaltrials.gov/ct2/show/NCT00000538?term=NCT00000538&rank=1 as NCT00000538.

Von Willebrand factor (vWF): marker of endothelial damage and thrombotic risk in COVID-19?

COVID-19 infection is characterised, among other features, by a prothrombotic state with high rate of venous thromboembolism (VTE), D-dimer, and fibrinogen levels. Clinical observations have also highlighted that these patients have elevated von Willebrand factor (vWF) and factor VIIIc. 24 consecutive COVID-19 positive patients were selected from the intensive care unit (ICU) or the high acuity ward of Brighton and Sussex University Hospitals NHS Trust. The rate of VTE was 25% and mortality rate was 16.7%. Fibrinogen and D-Dimers were elevated, 7.9 (1.6) g/L and 2.4 (2.02) ug/ml respectively. Factor VIIIc and von vWF antigen levels were both extremely elevated at 279 (148) u/dL and 350 (131) % respectively, which are comparable to levels seen in ICU patients with severe sepsis. vWF levels were significantly higher in patients that died (p=0.017) and showed a positive correlation with age. There was a statistically significant association between COVID-19 disease and non-O blood group (p=0.02); 80% (4/5) of COVID-19 patients with VTE were blood group A. Very high levels of vWF and factor VIIIc are common in COVID-19 patients, comparable to levels in severely septic non-COVID ICU patients. This could contribute to the hypercoagulable state and increased VTE rate in COVID-19. Further studies are needed to evaluate the use of vWF for stratifying thrombotic risk in COVID-19 and to determine if elevated vWF is contributing to disease pathogenesis.

Platelet activation and clotting cascade activation by dialyzers designed for high volume online hemodiafiltration.

Hemodialysis patients are pro-thrombotic. Higher volume online postdilutional hemodiafiltration (OL-HDF), with increasing hematocrit increases the risk of clotting in the extracorporeal circuit (ECC). We wished to determine whether OL-HDF increased platelet activation and ECC clotting. Coagulation parameters, platelet, white cell, and endothelial activation markers were measured at the start and end of dialysis sessions in 10 patients and also pre- and post-dialyzer after 15 minutes using two different dialyzers designed for high volume OL-HDF; cellulose triacetate (TAGP) and polysulphone (PS), and polyvinylpyrrolidone (PVP). Patients were anticoagulated with a heparin bolus. At the start of OL-HDF, D dimers, thrombin antithrombin complexes (TATs), and soluble adhesions molecules (sICAM-1 and sVCAM-1) were increased. Post-treatment soluble P selectin (PS/PVP 26.7 ± 7.1 versus 36.6 ± 9.9; TAGP 28.7 ± 7.2 versus 43.5 ± 8.4 ng/ml, P < 0.001), and soluble CD40 ligand (PS/PVP 297 ± 228 versus 552 ± 272, TAGP 245 ± 187 versus 390 ± 205 ng/ml, P < 0.05) increased. Post-dialyzer concentrations increased versus pre-dialyzer for tissue factor (PS/PVP 117 ± 12 versus 136 ± 16, TAGP 100 ± 25 versus 128 ± 40 ng/ml, P < 0.05), factor VIIIc (PS/PVP 174 ± 54 versus 237 ± 83, TAGP 163 ± 60 versus 247 ± 102 IU/ml, P < 0.01), sVCAM-1 (PS/PVP 782 ± 64 versus 918 ± 140, TAGP 722 ± 121 versus 889 ± 168 ng/ml, P < 0.01), and D-dimers (PS/PVP 292 ± 132 versus 355 ± 167, TAGP 300 ± 129 versus 391 ± 171 ng/ml, P < 0.001). There was no macroscopic thrombus noted in the ECC, and no increase in microparticles, platelet factor-4, or TATs. Despite being pro-thrombotic, with activation of platelets, and lymphocytes during passage through ECC, no macroscopic clotting, or increased TATs were noted during OL-HDF, and no major differences between cellulosic and polysulphone dialyzers.

Estimating the associations of apparent temperature and inflammatory, hemostatic, and lipid markers in a cohort of midlife women

Associations between temperature and cardiovascular (CVD) mortality have been reported, but the underlying biological mechanisms remain uncertain. We explored the association between apparent temperature and serum biomarkers for CVD. Using linear mixed effects models, we examined the relationships between residence-proximate apparent temperature (same day and 1, 7, and 30 days prior) and several inflammatory, hemostatic, and lipid biomarkers for midlife women from 1999 through 2004. Our study population consisted of 2,306 women with mean age of 51 years (± 3 years) enrolled in Study of Women's Health Across the Nation (SWAN) in Chicago, Illinois; Detroit, Michigan; Los Angeles and Oakland, California; Newark, New Jersey; and Pittsburgh, Pennsylvania. Mean daily apparent temperature was calculated using temperature and relative humidity data provided by the National Climatic Data Center and the US Environmental Protection Agency, while daily data for fine particles, ozone, carbon monoxide, and nitrogen dioxide from the US Environmental Protection Agency Air Quality Data Mart were considered as confounders. All analyses were stratified by warm and cold seasons.More significant (p < 0.10) negative associations were found during the warm season for various lag times, including hs-CRP, fibrinogen, tissue plasminogen activator antigen (tPA-ag), tissue plasminogen activator antigen (PAI-1), Factor VIIc, high-density lipoprotein (HDL), and total cholesterol. During the cold season, significant negative associations for fibrinogen and HDL, but significant positive associations for tPA-ag, PAI-1, and triglycerides were observed for various lag times. With the exception of ozone, pollutants did not confound these associations. Apparent temperature was associated with several serum biomarkers of CVD risk in midlife women, shedding light on potential mechanisms.

Impact of carbon monoxide and nitrogen dioxide on cardiovascular biomarkers in the Study of Women's Health Across the Nation

Introduction: Impacts from ambient carbon monoxide (CO) and nitrogen dioxide (NO2) on cardiovascular disease (CVD) has been reported, but the biologic mechanisms connecting them remain uncertain. This study examined whether elevated ambient CO and NO2 levels related to levels of CVD markers in midlife women. Methods: Annual repeated measurements of ten CVD markers, including high-sensitivity C-reactive protein (hs-CRP), fibrinogen, Factor VIIc, tissue-type plasminogen activator antigen (tPA-ag), plasminogen activator inhibitor Type 1 (PAI-1), and lipoprotein markers, were obtained from 2,207 women from five racial/ethnic groups enrolled in 6 US cities for the longitudinal Study of Women’s Health Across the Nation (average 3.8 visits/woman, mean age: 51±3 years). CO and NO2 data were obtained from the USEPA and assigned to each woman based on proximity to her home address. Prior year, 6-month, 30-day, 7-day, and one-day exposures were calculated, and their associations with CVD markers were examined using longitudinal mixed-effects models. Results: Adjusting for site, race/ethnicity, education, menopause status, body mass index, smoking, and recent alcohol use, CO and NO2 exposures were positively associated with fibrinogen, PAI-1, and tPA-ag levels. For an interquartile increase of the 1-year average gas concentration, 0.68 ppm for CO and 13 ppb for NO2, PAI-1 level increased 35% (95% CI: 29%, 42%) and 71% (57%, 86%), respectively. The same increases in the 30-day average CO and NO2 concentration corresponded to 4.5% (2.6%, 6.5%) and 4.5% (2.0%, 7.0%) increases in fibrinogen level. Adjusting for long-term PM2.5 exposure, the impact of 1-year CO exposure on PAI-1 was reduced to 18% (12%, 25%), and the association between CO and tPA-ag was null, indicating that PM2.5 also contributed to variations in these CVD markers. Conclusions: CO and NO2 exposures may increase coagulation and thrombotic potential, and thus may increase risks of CVD in midlife women.

Effects of Factor XIII Deficiency on Thromboelastography. Thromboelastography with Calcium and Streptokinase Addition is more Sensitive than Solubility Tests.

BackgroundHomozygous or double heterozygous factor XIII (FXIII) deficiency is characterized by soft tissue hematomas, intracranial and delayed spontaneous bleeding. Alterations of thromboelastography (TEG) parameters in these patients have been reported. The aim of the study was to show results of TEG, TEG Lysis (Lys 60) induced by subthreshold concentrations of streptokinase (SK), and to compare them to the clot solubility studies results in samples of a 1-year-old girl with homozygous or double heterozygous FXIII deficiency.CaseA year one girl with a history of bleeding from the umbilical cord. During her first year of life, several hematomas appeared in soft upper limb tissue after punctures for vaccination and a gluteal hematoma. One additional sample of a heterozygous patient and three samples of acquired FXIII deficiency were also evaluated.Materials and MethodsClotting tests, von Willebrand factor (vWF) antigen and activity, plasma FXIII-A subunit (pFXIII-A) were measured by an immunoturbidimetric assay in a photo-optical coagulometer. Solubility tests were performed with Ca2+-5 M urea and thrombin-2% acetic acid. Basal and post-FXIII concentrate infusion samples were studied. TEG was performed with CaCl2 or CaCl2 + SK (3.2 U/mL) in a Thromboelastograph.ResultsProthrombin time (PT), activated partial thromboplastin time (APTT), thrombin time, fibrinogen, factor VIIIc, vWF, and platelet aggregation were normal. Antigenic pFXIII-A subunit was < 2%. TEG, evaluated at diagnosis and post FXIII concentrate infusion (pFXIII-A= 37%), presented a normal reaction time (R), 8 min, prolonged k (14 and 11min respectively), a low Maximum-Amplitude (MA) ( 39 and 52 mm respectively), and Clot Lysis (Lys60) slightly increased (23 and 30% respectively). In the sample at diagnosis, clot solubility was abnormal, 50 and 45 min with Ca-Urea and thrombin-acetic acid, respectively, but normal (>16 hours) 1-day post-FXIII infusion. Analysis of FXIII deficient and normal plasma mixtures (< 2–102% of pFXIII-A), showed that Ca-urea solubility was abnormal at pFXIII-A < 9%, thrombin-acetic acid at pFXIII-A<18%, but TEG MA and elasticity at 23% and Lys60 with SK at pFXIII-A< 40%.ConclusionsTEG parameters MA and elasticity, and Lys 60 in TEG either with Ca2+ or Ca2+ and SK are more sensitive to low levels of pFXIII than solubility tests. The increased Lys60 induced by a subthreshold concentration of SK could probably reflect the clot characteristics “in vivo” in many patients with pFXIII levels between 5–40% and could be potentially considered as screening test.

Inflammatory/hemostatic biomarkers and coronary artery calcification in midlife women of African-American and White race/ethnicity: the Study of Women's Health Across the Nation (SWAN) heart study.

Inflammatory/hemostatic biomarkers are associated with coronary heart disease events, but relationships in asymptomatic midlife women are uncertain. We evaluated separately whether high-sensitivity C-reactive protein (hsCRP), fibrinogen, plasminogen-activator inhibitor 1, tissue plasminogen activator antigen, and circulating factor VII (factor VIIc) were associated with coronary artery calcification (CAC) in healthy midlife women. A cross-sectional study was performed of participants from the Study of Women's Health Across the Nation. Logistic and Tobit regression was used to assess associations between log-transformed biomarkers, and CAC presence (CAC > 0) and extent. Effect modification by race/ethnicity was evaluated. The study included 372 women (mean age 51.3 y; 35.2% African-American). All biomarkers were positively associated with CAC presence and extent (P < 0.001 for all), adjusting for Framingham risk score, site, race/ethnicity, menopause status, income, and education. Additional adjustment for body mass index explained all associations except for factor VIIc, which remained associated with CAC extent only (P = 0.02). Final adjustment for insulin resistance, family history of cardiovascular disease, and cardiovascular medication use produced similar results. Associations between hsCRP, and CAC presence and extent were modified by race/ethnicity (P < 0.05). Log(hsCRP) was positively associated with CAC presence (odds ratio 3.25; 95% CI, 1.53-6.90; P = 0.002; per 1 log unit increase) and CAC extent (β = 19.66; SE = 7.67; P = 0.01; per 1 log unit increase) in African-Americans only. Inflammatory/hemostatic biomarkers were associated with CAC through obesity, except for factor VIIc. Among African-American women only, hsCRP was independently associated with CAC, suggesting that hsCRP may have a role in coronary heart disease prevention in African-American midlife women.

PO-24 - Determinants of thrombin generation in gynaecological malignancies

Increased thrombin production is associated with malignancy and is a marker for venous thromboembolism (VTE). Our group has shown that thrombin generation is increased in gynaecological malignancies. Although tumour derived Tissue Factor (TF) has been implicated, the precise mechanism by which thrombin production is increased is not fully understood. Our group has shown that gynaecological cancers can alter tumour expression of cogulation proteases. These changes may be implicated in the increased thrombin generation observed. Previous studies in normal control patients by other groups have shown that multiple coagulation factors are implicated in thrombin generation and that the effects depend on assay conditions however free Tissue Factor Pathway Inhibitor (TFPI), Factors V, VIIIc and protein S, were significant determinants of thrombin generation. The aim of this study was to determine the effect of factor V factor, VIIIc, TFPI and free protein S on the thrombin generation in patients with endometrial and ovarian cancer compared with benign controls. Patients with a gynaecological malignancy (n=43) (ovarian or endometrial) were matched with patients with a benign tumour (n=43) gave full and informed consent. Venous blood samples were obtained prior to surgery and chemotherapy. Thrombin generation was was measured using a fluorogenic assay. Lag time, peak thrombin and area under the thrombin generation curve (ETP) was determined and reported for each sample. Free protein S, free TFPI and factor V were determined using ELISA. Factor VIIIc was determined using a hromogenic assay. Factor V and factor VIIIc were significantly increased in the malignant group compared with the benign group (P<0.03; P<0.006). Increased free TFPI levels were also observed in the malignant group but this did not reach significance (P<0.06). There was no difference in free Protein S levels between the groups. Highest levels of peak thrombin generation were observed in the high grade serous and clear cell ovarian cancer patients. Changes were less marked in the endometrial patients. Free TFPI, factor V and factor VIIIc were important determinants of thrombin generation in the malignant group. Coagulation factors V and VIIIc and free TFPI are altered in patients with gynaecological malignancies and contribute to the increased thrombin generation found in these cancer patients. We have previously found increased expression of factor V in tumours from patients with ovarian cancer in addition to increased TF expression. These changes may explain the high rate of venous thromboembolism found in these patients.

Childhood Socioeconomic Circumstances, Inflammation, and Hemostasis Among Midlife Women: Study of Women's Health Across the Nation.

Childhood socioeconomic status (SES) is related to risk for cardiovascular disease in adulthood, perhaps, in part, due to associations with inflammatory and hemostasis processes. We tested the hypotheses that childhood SES is related to C-reactive protein (CRP), fibrinogen, factor VIIc, and plasminogen activator inhibitor-1 (PAI-1) in midlife women and that the associations are mediated by adult SES and/or adult body mass index (BMI). Using data from the prospective Study of Women's Health Across the Nation, we classified 1067 black and white women into 3 multidimensional childhood SES groups based on latent class analysis. Biological measures were assessed across 7 years along with covariates and mediators and analyzed by mixed regression models, followed by tests for mediation. Compared with women raised in high SES families, those from the lowest SES families had higher levels of CRP (b [standard error] = 0.37 [0.11]), PAI-1 (b = 0.23 [0.07]) factor VIIc (b = 0.05 [0.02]), and fibrinogen (b = 11.06 [4.89]), after adjustment for ethnicity, site, age, ratings of health between ages 11 and 18 years, visit, smoking status, menopausal status, stroke or heart attack, medications, and hormone use. Introduction of adult SES and BMI into the models reduced the childhood SES associations to nonsignificance for all four measures. Indirect mediation was apparent for adult education and BMI for CRP, and BMI for PAI-1. Women raised in lower SES families had elevated markers of inflammation and hemostasis, in part, due to elevated BMI and education in adulthood.

Hemostatic Factors, APOL1 Risk Variants, and the Risk of ESRD in the Atherosclerosis Risk in Communities Study.

Hemostatic factors have been associated with kidney function decline, and evidence suggests stronger effects among African Americans. The presence of APOL1 renal risk variants, common in African Americans, might partly underlie this risk difference. A total of 13,337 participants in the Atherosclerosis Risk in Communities study were followed from 1987-1989 until 2010. Participants were categorized into three groups by ancestry and APOL1 risk status: European Americans (n=10,206), African Americans with zero or one APOL1 risk allele (n=2,733), and African Americans with two APOL1 risk alleles (n=398). ESRD events were ascertained through linkage to the US Renal Data System. Cox regression was used to estimate the risk for ESRD associated with hemostatic factors (factor VIIc, factor VIIIc, fibrinogen, von Willebrand factor, protein C, and antithrombin III). There were 232 cases of ESRD over 21.5 years (European Americans, 119; African Americans with zero or one APOL1 risk allele, 94; African Americans with two APOL1 risk alleles, 19). In unadjusted and adjusted analysis of the overall population, higher levels of all hemostatic factors, except antithrombin III, were significantly associated with ESRD (all P<0.05). Factor VIIc had the strongest association (per one interquartile range; adjusted hazard ratio, 1.46; 95% confidence interval, 1.21 to 1.76). With the exception of fibrinogen, the risk associated with each hemostatic factor was stronger in African Americans with two APOL1 risk alleles compared with the other two groups. Statistically significant interactions were seen for factor VIIIc and protein C (interaction between those with two APOL1 risk allele and the other two groups: P<0.02 for factor VIIIc and <0.04 for protein C). Higher levels of factor VIIc, VIIIc, fibrinogen, von Willebrand factor, and protein C were associated with ESRD risk, with a significantly stronger association of factor VIIIc and protein C in African Americans with two APOL1 risk alleles.

G331(P) Haemophilia: a lot to learn from a near miss event

Introduction A two year old girl presented with prolonged bleeding following a fall. A strong family history of haemophilia was ignored during visits to health professionals due to the misconception that female carriers are unaffected! She was extensively investigated and was found to have Factor VIII deficiency which did not respond to Tranexamic acid and Desmopressin. This was discovered three weeks prior to her preoperative assessment for an adenotonsillectomy. Routine pre op checks, which do not always involve clotting and the above misconception, could have affected her severely perioperatively. This case highlights the importance of detailed history taking including family history and remembering that Haemophilia can, and does affect females. Case report AG was born without complication, at term by forceps delivery. Mother had heavy postpartum bleeding. She developed obstructive sleep apnoea, and adeno-tonsillectomy was planned. Three weeks before her pre-operative assessment she fell, tearing her frenulum. Persistent bleeding led to a paediatric assessment. Initial investigation revealed her haemoglobin was 88, APTT 1.5 and APTT ratio 45 and rest normal. Further investigation revealed low Factor VIIIc levels (36), 72% of expected. Other factors were normal. Detailed history taking revealed a family history of Factor VIII deficiency (maternal grandmother: carrier, maternal aunt: affected). AG received Tranexamic Acid and a Desmopressin infusion, followed by a Factor VIII infusion at the Haematology unit due to persistent bleeding. Communications between ENT a haematology is ongoing to carry out a safe surgery. Conclusion This was a near miss event which will require ongoing care from a consultant haematologist. Clinicians need to be aware that Haemophilia can, and does, affect females. 28% of female carriers of Haemophilia A are known to have Factor VIII levels consistent with mild Haemophilia. This case should raise our awareness about thorough history taking, and updating our knowledge about Haemophilia, to avoid future catastrophes. There are also important implications for her mother. We recommend checking Factor VIII activity levels in all haemophilia carriers before haemostatic challenge, such as pregnancy.

Intra and Post Circumcision Bleeding in Nigerian Neonates: Correlation with Hemostatic Parameters

Circumcision is one of the oldest operations known. In Nigeria there is dearth of knowledge about the incidence of post-circumcision bleeding. Only one out of every seven males in the world is circumcised, however circumcision is the rule rather than the exception within all Nigerian ethnic groups and religions. This study investigated the relationship between some hemostatic parameters, family history and bleeding associated with circumcision of male infants in Ibadan, South West Nigeria. Materials and methods: The study design involved a population of 244 male infants drawn from University College Hospital and Oluyoro Catholic Hospital, in Ibadan, Nigeria. Pre-circumcision PT and aPTT, factor VIIIc level, Platelet Count, incidence of Intra and post-operative bleeding were determined. Results: None of the infants had a family history of bleeding disorder or thrombocytopenia. Six of the full term neonates (2.5%) had prolonged PT while only 2 of the subjects (0.8%) had prolonged aPTT. The factor VIIIc level was between 31-49% in 16.1%, while 1.6% of the neonates had levels between 20-26%. Intra-operatively, 28.9% (manual method, Gomco Clamp) and 4.9% (plastibell) had moderately severe bleeding while excessive postcircumcision bleeding was found in 2.8% and 6.8% for manual methods and plastibell respectively. Conclusion: There was a positive correlation between pre-circumcision aPTT and the degree of post circumcision bleeding. A relationship would have been expected to exist between post-circumcision bleeding and factor VIIIc but this was not found to be significant in this study. Activated Partial Thromboplastin Time would probably be sufficient as a screening hemostatic test for the detection of neonates that may be at risk of bleeding post-operatively.

Estimating the Effects of Long-Term Exposure to Air Pollution on Inflammatory/Hemostatic Markers. Findings from the SWAN Study

Estimating the Effects of Long-Term Exposure to Air Pollution on Inflammatory/Hemostatic Markers. Findings from the SWAN StudyAbstract Number:2038 Rochelle Green*, Rachel Broadwin, Brian Malig, Rupa Basu, Ellen Gold, Lihong Qi, Joyce Bromberger, Gail Greendale, Howard Kravitz, Kristin Tomey, Karen Matthews, Carol Derby, Elizabeth Jackson, Robin Green, and Bart Ostro Rochelle Green* Office of Environmental Health Hazard Assessment, United States, E-mail Address: [email protected] Search for more papers by this author , Rachel Broadwin Office of Environmental Health Hazard Assessment, United States, E-mail Address: [email protected] Search for more papers by this author , Brian Malig Office of Environmental Health Hazard Assessment, United States, E-mail Address: [email protected] Search for more papers by this author , Rupa Basu Office of Environmental Health Hazard Assessment, United States, E-mail Address: [email protected] Search for more papers by this author , Ellen Gold Department of Public Health Sciences, University of California Davis School of Medicine, United States, E-mail Address: [email protected] Search for more papers by this author , Lihong Qi Department of Public Health Sciences, University of California Davis School of Medicine, United States, E-mail Address: [email protected] Search for more papers by this author , Joyce Bromberger Department of Psychiatry, University of Pittsburgh School of Medicine, United States, E-mail Address: [email protected] Search for more papers by this author , Gail Greendale Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, United States, E-mail Address: [email protected] Search for more papers by this author , Howard Kravitz Rush University Medical Center, United States, E-mail Address: [email protected] Search for more papers by this author , Kristin Tomey School of Public Health, University of Michigan, United States, E-mail Address: [email protected] Search for more papers by this author , Karen Matthews Department of Psychiatry, University of Pittsburgh School of Medicine, United States, E-mail Address: [email protected] Search for more papers by this author , Carol Derby Albert Einstein College of Medicine, United States, E-mail Address: [email protected] Search for more papers by this author , Elizabeth Jackson Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Hospital and Health Systems, United States, E-mail Address: [email protected] Search for more papers by this author , Robin Green Albert Einstein College of Medicine, United States, E-mail Address: [email protected] Search for more papers by this author , and Bart Ostro Office of Environmental Health Hazard Assessment, United States, E-mail Address: [email protected] Search for more papers by this author AbstractBackground: Several studies have reported associations between long-term air pollution exposures and cardiovascular mortality. The biological mechanisms connecting them remain uncertain.Objectives: Examine effects of fine particles (PM2.5) and ozone on serum markers of cardiovascular disease (CVD) risk in a cohort of midlife women.Methods: We obtained information from women enrolled at six sites in the multi-ethnic, longitudinal Study of Women’s Health Across the Nation, including repeated measurements of high-sensitivity C-reactive protein (hs-CRP), fibrinogen, tissue-type plasminogen activator antigen (tPA-ag), plasminogen activator inhibitor Type 1 (PAI-1), and Factor VIIc. We obtained residence-proximate PM2.5 and ozone monitoring data for a maximum five annual visits, calculating prior year, six-month, one-month, and one-day exposures and their relations to serum markers using longitudinal mixed models.Results: For the 2,086 women studied, after adjusting for age, race/ethnicity, site, body mass index, smoking and recent alcohol use, PM2.5 exposures were significantly associated with all blood markers except Factor VIIc. Adjusted associations were of the highest magnitude for year-prior exposures for hs-CRP (20.88% increase per 10 µg/m3 PM2.5, 95% CI: 6.59, 37.10), tPA-ag (8.61%, 95% CI: 1.82, 15.86), and PAI-1 (34.64%, 95% CI: 18.70, 52.72). Findings did not change significantly after further adjustment for health and other lifestyle characteristics. A significant association was also observed between year prior ozone exposure and Factor V11C (5.67% increase per 10 ppb ozone, 95% CI: 2.90 , 8.53).Conclusions: Our findings suggest that prior year exposures to PM2.5 and ozone adversely affect inflammatory and hemostatic pathways for cardiovascular outcomes in midlife women.

C0292: The Role of Breast Cancer Cell Microparticles in Thrombogenicity, Angiogenesis and Apoptosis Following Chemotherapy

Background: There is a lack of information regarding thromboembolism, thrombophilia and clinical management in different specific clinical settings such as vascular obstetric complication in women in the clinical practice. In this context, we are conducting a national registry of women in those situations, the so-called TEAM Project: a multicenter observational cohort study (see website: www.SETH.es). Methods: From 2009 since now, almost 60 Centers from Spain and also now, Uruguay have been including patients. The inclusion criteria are women with hormonal therapy or pregnancy-related thrombosis disease, vascular placental complications (VPC) or ischemic placental disease or ART and women with thrombophilia, that will undergo or not thromboprophylaxis during pregnancy or ART The study has been approved by the Ethical Committee of each Center. Among the primary outcomes, the investigation will focus on the incidence, prophylaxis and treatment of TD, hormonal or antineoplasic therapies or ART, as well as the management of vascular placental complications or thrombosis in those situations. Results: We have already recruited 329 patients from 20 Centers. 10% were women with thrombosis during pregnancy, 14% were women with VPC, 36% were included for thrombosis prophylaxis during pregnancy, 26% for prophylaxis of VPC during pregnancy and 2% had recurrent implantation failure. The thrombophilia test revealed that the most common risks factor were homozygous for F12 46C/T polymorphism, Factor V Leiden and high levels of Factor VIIIc. In general, 70% women received heparin for prophylaxis, some of them 30.6% received aspirin alone or in combination, of treatments during pregnancy. Heparin was used as treatment (11%) and prevention (89%), being tinzaparin 45% and enoxaparin (30%) the most indicated, along with bemiparin (20.5%) or dalteparin (4.5%). Clinical outcomes, in terms of relapse of thrombosis or VPC, showed only 1 case of thrombosis and 9 of CVG. Conclusions: The preliminary results from the Team Project reflects the clinical practice, and the differences among investigators in thromboprophylaxis, indication of thrombophilia testing and treatment in the clinical setting. Also new risk biological factors in women’s issues such as FVIIIc or homozygous for F12 46C/T polymorphism. The information of this ongoing registry will allow us to make the translation from clinical practice to clinical and biological investigation. Acknowledgement: The TEAM Project is partially sponsored by an unrestricted grant from LeopharmaTM. C0292 THE ROLE OF BREAST CANCER CELL MICROPARTICLES IN THROMBOGENICITY, ANGIOGENESIS AND APOPTOSIS FOLLOWING CHEMOTHERAPY

Impact of stearic acid and oleic acid on hemostatic factors in the context of controlled diets consumed by healthy men

The effects of stearic acid (STA) on cardiovascular disease risk beyond lipid and lipoprotein risk factors, including hemostasis, are unclear, particularly when compared with unsaturated fatty acids. The aim of the present study is to compare the effects of STA with those of oleic acid (OL) on markers of hemostasis. In a randomized crossover study, 50 men consumed six controlled diets for 5 weeks each (39% energy from fat, 15% energy from protein, 46% energy from carbohydrate (CHO)). Fat (8% energy) was replaced across diets by: STA, OL, CHO (control), trans fatty acids (TFAs), TFA/STA and 12:0–16:0 saturated fatty acids. Factor VIIc, plasminogen activator inhibitor-1 (PAI-1) and plasmin alpha-2-antiplasmin complex concentrations were not different between OL and STA (P>0.05). Compared with control, OL increased factor VIIc and PAI-1 (P⩽0.05), whereas there were no differences with STA (P>0.05). STA and OL similarly affect markers of hemostasis in healthy men, within the context of a highly controlled diet.