Hypercoagulable Thromboelastography Research Articles

Hypercoagulability and Thrombosis Risk in Prostate Cancer: The Role of Thromboelastography.

Thrombosis is one of the leading causes of death in cancer. Cancer-induced hypercoagulable state contributes to thrombosis and is often overlooked. Prostate cancer may not be of high thrombogenic potential compared with other cancers, but its high prevalence brings it into focus. Pathological evidence for venous thromboembolisms (VTEs) in prostate cancer exists. Factors such as age, comorbidities, and therapies increase the VTE risk further. There is a need to systematically identify the risk of VTE in regard to patient-, cancer-, and treatment-related factors to risk stratify patients for better-targeted and individualized strategies to prevent VTE. Sensitive tests to enable such risk assessment are urgently required. There is sufficient evidence for the utility of thromboelastography (TEG) in cancer, but it is not yet part of the clinic and there is only limited data on the use of TEG in prostate cancer. One study revealed that compared with age-matched controls, 68.8% of prostate cancer patients demonstrated hypercoagulable TEG parameters. The absence of clinical guidelines is a limiting factor in TEG use in the cancer population. Cancer heterogeneity and the unique cancer-specific microenvironment in each patient, as well as determining the hypercoagulable state in each patient, are added limitations. The way forward is to combine efforts to design large multicenter studies to investigate the utility and clinical effectiveness of TEG in cancer and establish longitudinal studies to understand the link between hypercoagulable state and development of thrombosis. There is also a need to study low thrombogenic cancers as well as high thrombogenic ones. Awareness among clinicians and understanding of test applicability and interpretation are needed. Finally, expert discussion is critical to identify the investigation priorities.

Hypercoagulability in Septic Shock Patients With Thrombocytopenia.

Despite thrombocytopenia, patients with sepsis often experience hypercoagulability. However, limited information is available on the prevalence and effect of hypercoagulability in patients with sepsis-induced thrombocytopenia. Hence, we evaluated the prevalence of hypercoagulability and the association between hypercoagulability and clinical outcomes in septic shock patients with thrombocytopenia. Thromboelastography (TEG) was performed prospectively in 1294 patients with septic shock at the emergency department (ED) between January 2016 and December 2019. After excluding 405 patients who did not require resuscitation, refused enrollment, or developed septic shock after ED presentation, 889 patients were included. We defined thrombocytopenia as an admission platelet count lower than 150,000/µl according to SOFA score. We defined hypocoagulability and hypercoagulability as coagulation index (CI)< -3 and >3 on TEG, respectively. Of the 889 septic shock patients (mean age 65.6 ± 12.7 years, 58.6% male), 473 (53.2%) had thrombocytopenia. Eighty-five (18.0%) patients showed hypercoagulable TEG and73 (15.4%) patients showed hypocoagulable TEG. The hypercoagulable TEG group had a significantly higher fibrinogen level and a lower 28-day mortality rate than the normal and hypocoagulable TEG groups (518 vs. 347 and 315 mg/dL; 7.1% vs. 21.1% and 36.8%, P < 0.01, respectively). In multivariate analysis, hypercoagulable TEG was associated with a decreased mortality rate (odds ratio: 0.395; 95% confidence interval, 0.162-0.965). In septic shock patients with thrombocytopenia, hypercoagulability was not uncommon. TEG can quickly distinguish the hypercoagulability and hypocoagulability states and serve as a valuable tool for evaluating the degree and risk in septic shock patients with thrombocytopenia.

Global coagulation assays in healthy controls: are there compensatory mechanisms within the coagulation system?

Global coagulation assays (GCAs) may provide a more comprehensive individual hemostatic profiling. We aim to evaluate GCAs (thromboelastography, thrombin generation) in healthy controls, and correlate results with age, gender, lipid status, tissue factor pathway inhibitor (TFPI) and P-selectin. Blood samples were collected from healthy controls (> 18years of age) not taking anticoagulation or antiplatelet agents and without known cardiovascular disease. Thromboelastography (TEG) was performed on citrated whole blood while calibrated automated thrombogram (CAT), P-selectin (endothelial marker) and TFPI (principle inhibitor of tissue factor-initiated coagulation) were performed on platelet-poor plasma. 153 healthy controls (mean age 42years, 98 females (64%)) were recruited. Female controls demonstrated more hypercoagulable TEG and CAT parameters while those over 50years of age demonstrated more hypercoagulable TEG parameters despite comparable thrombin generation. Paradoxically, individuals with "flattened" thrombin curves (lower velocity index (rate of thrombin generation) despite preserved endogenous thrombin potential (amount of thrombin)) were more likely to be male (49% vs 20%, p = 0.003) with increased low-density lipoprotein cholesterol (3.3 vs 2.6mmol/L, p = 0.003), P-selectin (54.2 vs 47.3ng/mL, p = 0.038) and TFPI (18.7 vs 8.6ng/ml, p = 0.001). In addition to reduced velocity index and thrombin peak, controls in the highest TFPI tertile also demonstrated a poorer lipid profile. GCAs can detect subtle changes of the hemostatic profile. Interestingly, reduced thrombin generation was paradoxically associated with increased cardiovascular risk factors, possibly attributable to increased TFPI. This finding may suggest compensation by the coagulation system in response to endothelial activation and represent a biomarker for early cardiovascular disease. A larger prospective study evaluating these assays in the cardiovascular disease population is ongoing.

Routine Venous Thromboembolism Prophylaxis May Be Inadequate in the Hypercoagulable State of Severe Coronavirus Disease 2019.

Objectives:The aim of this study was to determine the frequency of venous thromboembolism in critically ill coronavirus disease 2019 patients and associate a degree of inflammatory marker elevation to venous thromboembolism development.Design:An observational study that identified patients with severe coronavirus disease 2019 between March 12, 2020, and March 31, 2020. Data reported are those available through May 6, 2020.Setting:A multicenter study including three Indianapolis area academic hospitals.Patients:Two-hundred forty consecutive patients with confirmed severe acute respiratory syndrome coronavirus 2 infection were admitted to one of three hospitals. One-hundred nine critically ill coronavirus disease 2019 patients admitted to the ICU were included in the analysis.Interventions:All patients received routine subcutaneous chemical venous thromboembolism prophylaxis.Measurements and Main Results:The primary outcome of this study was to determine the frequency of venous thromboembolism and the degree of inflammatory and coagulation marker elevation associated with venous thromboembolism development.Descriptive statistics outlined the frequency of venous thromboembolism at any time during severe coronavirus disease 2019. Clinical course and laboratory metrics were compared between patients that developed venous thromboembolism and patients that did not develop venous thromboembolism. Hypercoagulable thromboelastography was defined as two or more hypercoagulable parameters.Main Results:One-hundred nine patients developed severe coronavirus disease 2019 requiring ICU care. The mean (± sd) age was 61 ± 16 years and 57% were male. Seventy-five patients (69%) were discharged home, 7 patients (6%) remain in the hospital, and 27 patients (25%) died. Venous thromboembolism was diagnosed in 31 patients (28%) 8 ± 7 days after hospital admission, including two patients diagnosed with venous thromboembolism at presentation to the hospital. Elevated admission d-dimer and peak d-dimer were associated with venous thromboembolism development (p < 0.05). d-dimer greater than 2,600 ng/mL predicted venous thromboembolism with an area under the receiver operating characteristic curve of 0.760 (95% CI, 0.661–0.858; p < 0.0001), sensitivity of 89.7%, and specificity of 59.5%. Twelve patients (11%) had thromboelastography performed and 58% of these patients had a hypercoagulable study. The calculated coagulation index was hypercoagulable in 50% of patients with thromboelastography.Conclusions:These data show that coronavirus disease 2019 results in a hypercoagulable state. Routine chemical venous thromboembolism prophylaxis may be inadequate in preventing venous thromboembolism in severe coronavirus disease 2019.

P106 PREOPERATIVE HYPERCOAGULABLE THROMBOELASTOGRAPHY PROFILES ARE ASSOCIATED WITH POST-OPERATIVE VENOUS THROMBOEMBOLISM IN INFLAMMATORY BOWEL DISEASE PATIENTS

Abstract Background We previously reported our pilot experience using thromboelastography (TEG) to assess hypercoagulability in 19 inflammatory bowel disease (IBD) surgical patients. We now report our expanded experience in 55 patients. Our hypothesis is that a hypercoagulable TEG (HyperTEG) profile is associated with post-operative venous thromboembolism (VTE) after surgery for IBD. Methods This was a single institution IRB-approved study from June 2018 - July 2019. Preoperative TEGs were obtained as part of routine preoperative labs in consecutive adult patients with either Crohn’s disease (CD) or ulcerative colitis (UC) who underwent major abdominopelvic surgery. Patients were stratified into two groups based on their TEG profiles: Normal vs. HyperTEG. HyperTEG was defined as at least 2 of the 3 abnormal for clotting TEG parameters: 1) low R-value, 2) high degree angle, 3) high maximum amplitude (MA). Clinical data was collected by chart review. Short-term (30-day) surgical outcomes including length of stay (LOS), readmission, reoperations, and major complications were collected. The primary endpoint was VTE. Potential differences between groups were assessed with nonparametric univariate analysis. Results A total of 55 IBD patients were included, and 37% (n=20) patients had a HyperTEG profile. The median age at the time of surgery was 40 (21 – 84); 57% (n=31) were women and most patients had CD 67% (n=37). Overall 47% (n=26) patients were receiving oral steroids and 51% had received a biologic within 90 days (15 patients were receiving both), while 12 (22%) of patients were hospitalized pre-operatively. There were no statistically significant differences between baseline or perioperative characteristics between the Normal and HyperTEG patients (Table 1). Post-operatively a total of 3 (5.5%) VTE’s occurred, and the VTE rate was 0 in the Normal group and 15% in the HyperTEG group (p=0.04). Of the VTEs, 1 was a superior mesenteric vein thrombus after subtotal colectomy for UC that was diagnosed pre-discharge, 1 was a deep venous thrombosis in a CD diagnosed pre-discharge, and 1 was a pulmonary embolism in a UC patients diagnosed 1 day post discharge; all patient were on prophylactic enoxaparin at the time.Table 2 shows the TEG parameters in non-VTE and VTE patients. All 3 (100%) VTE patients had a high degree angle (p=0.02) and high coagulation index (p=0.01) while 2 (67%) patients had a low R-value (p=0.13) and high MA (p=0.13). In this series, a preoperative HyperTEG, compared to a preoperative Normal TEG, was associated with the occurrence of post-operative VTE (p=0.04). Conclusion We observed that over one third of IBD patients have a hypercoagulable profile preoperatively, with an observed 15% VTE rate, despite prophylaxis with enoxaparin. In this series, an abnormal TEG profile was associated with VTE occurrence after surgery for IBD; our findings suggests that more effective prophylaxis is indicated in these high-risk patients.

P085 Hypercoagulability in patients undergoing abdominopelvic surgery for inflammatory bowel disease: insights from thromboelastography

BACKGROUND: Hypercoagulability in patients with inflammatory bowel disease (IBD) is a hematological extra-intestinal manifestation thought to be driven by the gut inflammatory response. However, mechanisms driving the coagulation abnormalities are poorly understood. The aim of this study is to characterize coagulation profiles in IBD surgical patients using thromboelastography (TEG). METHODS: A single center, single surgeon retrospective study was performed after IRB approval. Consecutive patients with Crohn's disease (CD) or ulcerative colitis (UC) who underwent bowel surgery from June to September 2018 were included. All patients (100%) received perioperative VTE chemoprophylaxis. Clinical data was collected by retrospective chart review. Hypercoagulability profile based on TEG results was defined by any combination of: (1) low R-value, (2) high degree angle, (3) high maximum amplitude (MA), (4) elevated coagulation index. Short-term (30-day) surgical outcomes including length of stay (LOS), readmission, reoperations, and major (Clavien-Dindo grade 3/4) complications were reported. Figures represent frequency (proportion) or median (range). RESULTS: A total of 19 IBD patients had a TEG prior to surgery. The age was 33 (23–70), more were women (63%, n = 12) and most patients had CD (78%, n = 15). Overall 11 (58%) of patients were receiving steroids and 10 (53%) had were receiving biologics, while 6 (32%) of patients were hospitalized pre-operatively. Surgery was laparoscopic in 11 (58%) with 1 conversion to laparotomy. All patients (100%) received VTE chemoprophylaxis peri-operatively. Overall, 14 (74%) patients had a hypercoagulable TEG profile with 7 of these patients (50%, or 37% overall) having more than one hypercoagulable TEG parameter. A high MA (platelet hyperfunction) in 7 (37%) patients, and 8 (42%) patients had high degree angle (increased fibrinogen concentration/function), and 8 (42%) patient had low R-value (hyperfunctioning coagulation cascade). The coagulation index, indicating hypercoagulability, was abnormally high in 2 (10%) patients. The overall median LOS was 7 days (1, 42). Clavien-Dindo grade 3 complications occurred in 3 (16%) patients; there were no unplanned reoperations, while 3 (16%) of patients were re-admitted. A total of 16 of 18 eligible patients (88%) received extended post-discharge VTE chemoprophylaxis; one patient (5.5%) with unexplained tachycardia was diagnosed with a groin VTE 14 days post-operatively prior to discharge and required anticoagulation (TEG parameters: low R-value, high degree angle, and high coagulation index. Another patient had superficial thrombophlebitis related to a midline but did not require anticoagulation; this patient had a low R-value. Thus any VTE occurred in 2 (14%) of those with hypercoagulable TEG profiles and in zero of those with normal TEG profiles. CONCLUSION(S): We observed that the majority of surgical IBD patients have a hypercoagulable TEG profile, and patients with evidence of hypercoagulability on thromboelastography may be at increased risk of post-operative VTE. Our data suggests, given the mutlifactorial nature of hypercoaguability in these patients, novel VTE chemoprophylaxis approaches are needed.

The influence of inflammation and hematocrit on clot strength in canine thromboelastographic hypercoagulability.

To investigate parameters causing canine thromboelastographic hypercoagulability and to investigate whether thromboelastography (TEG) with Cytochalasin D (Cyt D) added is related to parameters of platelet activity. Prospective observational study on hemostatic and inflammatory parameters. Data were collected between November 2012 and July 2013. University teaching hospital. Twenty-eight dogs suffering from diseases predisposing to thrombosis and 19 clinically healthy dogs. Diseased dogs were enrolled if they fulfilled inclusion criteria regarding age, size, informed client consent, and obtained a diagnosis of a disease that has been associated with thrombosis or hypercoagulability. None. Parameters of coagulation and anticoagulation, fibrinolysis, and antifibrinolysis, platelet activity, inflammation, platelet count, and hematocrit were measured using CBC, TEG, platelet aggregation on multiplate, platelet activity on flow cytometry, and hemostatic and inflammatory markers on plasma and serum analyses. ANOVA and multilinear regression analyses indicated that especially hematocrit and the inflammatory parameters C-reactive protein and interleukin-8 showed best association with overall clot strength in diseased dogs with hypercoagulable TEG tracings. Ratios presumed to reflect platelet contribution to the TEG tracing obtained in TEG analyses with Cyt D were related especially with hematocrit and P-selectin expression of platelets measured after γ-Thrombin activation on flow cytometry. Overall clot strength in TEG analyses of the hypercoagulable dogs included in the present study appears to be primarily associated with inflammation as well as hematocrit. Furthermore, the ratio between standard TEG analyses and TEG analyses with Cyt D may reflect some degree of platelet activity.

Evaluation of thromboelastography in bitches with pyometra.

We investigated the effect of pyometra on kaolin-activated thromboelastography (TEG). Eighteen client-owned dogs with pyometra and 8 healthy spayed dogs were recruited. TEG parameters and packed cell volume were determined. Results from spayed females and from intact females with pyometra were compared using a Student t-test and Wilcoxon rank sum test. Bitches with pyometra were hypercoagulable compared to spayed bitches as evidenced by elevated maximum amplitude, G, and alpha angle. There were no significant group differences in R time, K time, or clot lysis at 30 or 60 min. Dogs with pyometra should be anticipated to have hypercoagulable TEG variables, and this should be addressed when planning surgical and medical therapy.

The rate of deep vein thrombosis doubles in trauma patients with hypercoagulable thromboelastography

Venous thromboembolism (VTE) in trauma can occur in patients at low risk. Conventional coagulation tests do not predict VTE. Studies investigating thromboelastography (TEG) for VTE risk are conflicting and have not included routine surveillance to detect deep vein thrombosis (DVT). We undertook a prospective study of TEG to evaluate its utility in predicting VTE. We conducted a prospective cohort study on all adult trauma patients admitted to our Level I trauma center from 2013 to 2015. TEG was performed immediately on arrival to the trauma bay. Hypercoagulable TEG was defined as reaction time (R) below, angle (α) above, or maximum amplitude (MA) above reference ranges. All patients received mechanical and/or pharmacologic prophylaxis and were followed up for DVT with our ultrasound surveillance protocol. The primary outcome was lower-extremity DVT. After bivariate analysis of variables related to DVT, those with p values of 0.100 or less were included for multivariate logistic regression. A total of 983 patients were evaluated with TEG on admission; of these, 684 (69.6%) received at least one surveillance ultrasound during the index admission. Lower-extremity DVT was diagnosed in 99 (14.5%) patients. Hypercoagulability based on admission TEG occurred in 582 (85.1%) patients. The lower-extremity DVT rate was higher in patients with hypercoagulable TEG than in those without hypercoagulable TEG (15.6% vs. 8%; p = 0.039). Multivariate analysis showed hypercoagulable TEG remained associated with DVT after adjustment for relevant covariates available at admission, with an odds ratio of 2.41 (95% confidence interval, 1.11-5.24; p = 0.026). Most trauma patients were hypercoagulable at admission and remained at risk of developing DVT. The rate of DVT doubled in patients with hypercoagulable TEG indices despite prophylaxis. Beyond its current clinical roles, TEG is useful for assessing DVT risk, particularly in patients otherwise perceived to be at low risk. Prognostic study, level II.

Hypercoagulability progresses to hypocoagulability during evolution of acetaminophen-induced acute liver injury in pigs

Increases in prothrombin time (PT) and international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF), yet a wide heterogeneity in clotting abnormalities exists. This study defines evolution of coagulopathy in 10 pigs with acetaminophen (APAP)-induced ALI compared to 3 Controls. APAP administration began at 0 h and continued to ‘ALF’, defined as INR >3. In APAP pigs, INR was 1.05 ± 0.02 at 0 h, 2.15 ± 0.43 at 16 h and > 3 at 18 ± 1 h. At 12 h thromboelastography (TEG) demonstrated increased clot formation rate, associated with portal vein platelet aggregates and reductions in protein C, protein S, antithrombin and A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats–13 (ADAMTS-13) to 60%, 24%, 47% and 32% normal respectively. At 18 ± 1 h, INR > 3 was associated with: hypocoagulable TEG profile with heparin-like effect; falls in thrombin generation, Factor V and Factor VIII to 52%, 19% and 17% normal respectively; further decline in anticoagulants; thrombocytopenia; neutrophilia and endotoxemia. Multivariate analysis, found that ADAMTS-13 was an independent predictor of a hypercoagulable TEG profile and platelet count, endotoxin, Protein C and fibrinogen were independent predictors of a hypocoagulable TEG profile. INR remained normal in Controls. Dynamic changes in coagulation occur with progression of ALI: a pro-thrombotic state progresses to hypocoagulability.

Effects of androgen-deprivation therapy on hypercoagulability in prostate cancer patients: A prospective, longitudinal study.

Androgen-deprivation therapy (ADT) is the mainstay of systemic therapy for advanced prostate cancer (PCa), but has significant adverse effects, including increasing concern for cardiovascular (CV) and thromboembolic (TE) complications. This study carefully investigates any relationship between ADT use and hypercoagulability as a possible mechanism of these adverse effects. We performed a prospective, longitudinal study in a cohort of patients with advanced PCa initiating ADT (n=18). Controls included men with biochemical failure after local therapy on watchful waiting (n=10), as well as healthy controls (n=8). Global hemostasis was evaluated using the sensitive global hemostasis assay, thromboelastography (TEG). Patients were evaluated at baseline and every three months for a minimum of 12 months. The results of the TEG studies demonstrated 14/18 (78%) of advanced PCa patients had evidence of a hypercoagulable state before initiating therapy. Significant baseline hypercoagulability was documented in this cohort compared to the two control groups. ADT did not appear to exacerbate hypercoagulability over time as a whole: only 10/18 (56%) patients had TEG findings consistent with hypercoagulability at the end of study. However, 3/18 (17%) PCa patients initiating ADT had significantly new hypercoagulable TEG changes on treatment compared to baseline. This prospective pilot study demonstrates a complex interaction between ADT and hypercoagulable state in men with advanced PCa. TEG abnormalities were mostly associated with volume of cancer as compared to ADT use; however, it is possible that ADT may lead to hypercoagulability in a subset of men, suggesting that sensitive monitoring of coagulation of men on ADT could help identify those at risk of developing CV/TE complications. Study limitations include the relatively small cohort of men followed after initiating ADT and these results require confirmation in a larger trial to rule out subtle effects on hypercoagulability.

Inflammation-induced haemostatic response in layer chickens infected with Streptococcus equi subsp. zooepidemicus as evaluated by fibrinogen, prothrombin time and thromboelastography

Streptococcus zooepidemicus has recently been shown to be a severe pathogen in layer chickens, where it is able to cause serious lesions in the vascular system. To evaluate the haemostatic response, 10 layer chickens were inoculated intravenously with S. zooepidemicus. Four hypotheses were tested: that the infection-induced inflammation would increase the plasma fibrinogen (Fbg) concentration, would prolong the prothrombin time (PT) and would prompt hypercoagulability or hypocoagulability as assessed by whole-blood thromboelastography (TEG), and that a possible correlation would exist between one of the TEG values and Fbg/PT. Each parameter was measured at days 1, 3 and 6 post inoculation (p.i.), and compared with the values at day 0 from each individual bird and with values obtained from non-infected control chickens (n = 10). In the infected chickens, the mean (± standard error) of Fbg was higher at day 3 p.i. (9.4 ± 1.4 g/l) and day 6 p.i. (8.0 ± 0.7 g/l) and the PT was prolonged at day 6 p.i. (168.1 ± 21.0 sec) compared with the day 0 standards (2.6 ± 0.2 g/l and 104.6 ± 2.0 sec, respectively) (P < 0.05). The majority of infected chickens demonstrated a hypercoagulable TEG result with increased mean values of the clot formation rate (α-angle) and maximal amplitude (MA) of TEG tracing at day 3 p.i. (83.1 ± 0.7°, 83.8 ± 1.4 mm) and day 6 p.i. (84.0 ± 0.4°, 89.8 ± 1.0 mm) compared with the day 0 values (75.8 ± 2.2° and 66.9 ± 1.4 mm, respectively) (P < 0.05). In control birds, the means of Fbg (1.5 ± 0.1 g/l), PT (79.4 ± 6.4 sec), TEG-α (76.7 ± 1.5°) and TEG-MA (64.0 ± 2.3 mm) were lower at day 6 compared with values observed for the infected chickens (P < 0.05). A negative correlation coefficient (−0.71) was found between the clot formation time (TEG-K) and Fbg at day 1 in the control group (P = 0.02). In conclusion, infection with S. zooepidemicus following intravenous injection in layer chickens induced haemostatic alterations including hyperfibrinogenaemia, prolonged PT, and hypercoagulability as measured by increased TEG-α and TEG-MA.

Thromboelastography Identifies Hypercoagulablilty and Predicts Thromboembolic Complications in Patients with Prostate Cancer

Cancer patients are at higher risk for thromboembolism compared to the normal population. This may be related to tumour burden and/or enhanced by systemic therapy. While there is ample evidence regarding venous thromboembolism, systematic studies investigating arterial thrombotic events are scarce. Conventional coagulation tests have limited capacity in evaluating the coagulability or the need for anticoagulant prophylaxis. In this pilot study, we investigated whether assessment of global haemostasis using thromboelastography (TEG) and quantification of plasma pro-coagulant microparticles can help determine the risk of adverse thrombotic events in patients with prostate cancer (PCa). Thirty two patients were recruited a priori into three groups: 11 men on 'watchful waiting' following recurrent disease after definitive treatment (Group A); 10 patients with metastatic disease on Androgen deprivation therapy (ADT) (Group B); and 11 with castration resistant cancer (Group C) and followed up over a period of 12months. These patients were compared to a control group composed of 8 men with negative prostate biopsy. Whole blood TEG and plasma tissue factor-carrying microparticles (TF-MPs) in addition to basic coagulation testing, plasma fibrinogen and d-dimer were performed. 22/32 (68.8%) of the patients demonstrated hypercoagulable TEG traces. Hypercoagulability was marked in group B compared to the control. Plasma MPs were significantly elevated in patients compared to the controls with significant increase in group B. All other coagulation tests were normal. Seven of the 22 hypercoagulable patients (31.8%) developed one or more thromboembolic events over 12months follow up period. The data in this pilot study show that PCa patients are hypercoagulable, particularly those with advanced disease on ADT and that this hypercoagulability can be identified by TEG. While this needs to be verified in a larger study, the data indicate TEG may aid in thrombosis risk stratification and determining the subsequent need for anticoagulant prophylaxis in PCa patients.

Effects of hematocrit and red blood cell–independent viscosity on canine thromboelastographic tracings

It is well established that hematocrit (Hct) influences whole blood thromboelastography (TEG) tracings. Previous studies showed hypercoagulable TEG tracings in anemic patients despite clinical expectations that anemia often prolongs bleeding. TEG is a viscoelastic assessment of clot kinetics, and Hct is the main determinant of whole blood viscosity. TEG changes in anemia may be an in vitro artifact due to Hct effect on blood viscosity rather than true in vivo changes in hemostasis. The effect of changes in whole blood viscosity on TEG independent of Hct is not well understood. Twenty-one blood samples from seven dogs were manipulated to produce one of three Hct conditions (45, 20, and 10%). Each was tested in two situations: viscosity adjusted to normal by adding alginate (ALG) or dilution with equal volume of saline (SAL). Both samples were analyzed with TEG simultaneously. Twenty percent Hct plus ALG and 10% Hct plus ALG were significantly more viscous than their SAL counterparts (p=0.0156). Ten percent Hct plus SAL, 20% Hct plus SAL, and 45% Hct plus SAL all had different viscosities (p=0.006). Twenty percent Hct plus SAL and 10% Hct plus SAL had significantly shorter K and higher angle, MA, and G compared to their ALG counterparts as well as 45% Hct plus SAL (p<0.05). ALG samples with low Hct, normal viscosity showed hypocoagulable tracings, whereas SAL samples with low Hct, low viscosity showed hypercoagulable tracings. TEG variables are influenced by whole blood viscosity altered with ALG, independently of Hct.

Disseminated Intravascular Coagulation in a Novel Porcine Model of Severe Staphylococcus aureus Sepsis Fulfills Human Clinical Criteria

Sepsis is a common and often fatal complication in human patients in intensive care units. Relevant and well characterized animal models of sepsis may provide valuable information on pathophysiological mechanisms and be a mean of testing new therapeutic strategies. Large animal models of Staphylococcus aureus sepsis are rare, even though S. aureus increasingly affects human patients. Sepsis changes the haemostatic balance and leads to endothelial cell (EC) activation, coagulopathy and, in severe cases, disseminated intravascular coagulation (DIC). The aim of this study was to characterize the haemostatic and vascular alterations in a novel porcine model of severe S. aureus sepsis, investigating whether the changes fulfill the human clinical criteria for DIC. Five pigs were inoculated intravenously with S. aureus and two control animals were sham-inoculated. Blood samples were collected for thromboelastography (TEG) and assessment of plasma-based haemostatic parameters. Tissue was collected for histopathology and reverse transcriptase quantitative real-time polymerase chain reaction for measurement of mRNA encoding EC markers. All infected animals developed DIC; including procoagulant activation represented by hypercoagulable TEG profiles and prolonged clotting time. Histologically, numerous pulmonary thrombi were present in one pig. Inhibitor consumption was represented by decreasing antithrombin levels in infected pigs. Hyaline globules were found in three infected pigs, confirming fibrinolytic activation. EC activation was identified by expression of von Willebrand factor in small vessels together with elevated mRNA encoding activated EC markers. Severe haemostatic and vascular changes fulfilling the human criteria for DIC were therefore seen in all infected pigs. A tendency towards uncompensated DIC was seen in two animals.

Insertion of central venous catheters induces a hypercoagulable state

Central venous catheters (CVCs) increase the risk of venous thromboembolism. We have previously demonstrated that pulmonary artery catheters are associated with a hypercoagulable state in an animal model and in patients. The purpose of this study is to determine whether the insertion of a CVC is associated with a similar response. 7F femoral artery catheters were placed in healthy anesthetized swine (N = 16). Serial arterial blood samples were drawn immediately before and after an 8.5F jugular vein CVC and then for 3 hours after CVC removal. Samples were analyzed using kaolin-activated thromboelastography (TEG) at precisely 2 minutes. Human: An institutional review board-approved prospective observational trial was conducted, with informed consent, in patients with critical illness (N = 8) at a Level I trauma center. Blood was drawn from indwelling arterial catheters immediately before and 60 minutes after CVC insertion. Samples were stored in sodium citrate for 15 minutes before TEG. Routine and special coagulation tests were performed on stored samples in the hospital pathology laboratory. Insertion of a CVC decreased TEG clotting time (R) by 55% in swine and by 29% in humans (p < 0.001 and 0.019, respectively). Initial clot formation time (K) was reduced by 41% in swine and by 36% in humans (p = 0.003 and 0.019). Fibrin cross-linking (α) was accelerated by 28% in swine and by 17% in humans (p = 0.007 and 0.896), but overall clot strength (maximum amplitude) was not affected. There was no change in routine or special coagulation factors, including von Willebrand factor, antithrombin III, prothrombin time, international normalized ratio, or activated partial thromboplastin time. In animals, the hypercoagulable TEG response was persistent for 3 hours after CVC removal and was prevented by pretreatment with enoxaparin (n = 4) but not heparin (n = 2). In healthy swine and patients with critical illness, a systemic hypercoagulable state occurred after CVC insertion, and this may partially account for an increased risk of venous thromboembolism. However, because the sample size was small and not powered to detect changes in coagulation proteins, no inferences can be made about the mechanism for the hypercoagulable response.

Prothrombotic Markers As Predictors of Thrombosis in Newly Diagnosed Cancer Patients

Abstract 2298The prevalence of prothrombotic markers and their association with thrombosis in pediatric solid tumor patients is not well defined. This study was aimed to discern the value of the following laboratory measures in assessment of thrombotic risk in pediatric patients with solid tumor: Prothrombin and activated partial thromboplastin times (PT and aPTT), D-dimer level, fibrinogen level, inherited and acquired hypercoagulability risk factors and soluble pro-inflammatory cytokines.Forty pediatric patients with newly-diagnosed malignancy and same number of age and sex-matched normal healthy controls were enrolled in the study. The median age was 7.5 and 8 years, respectively. Exclusion criteria included: history of autoimmune, hematologic, or chronic disease; history of chemotherapy administration; anticoagulant or anti-platelet therapy within 2 weeks of enrollment. Control subjects were selected from children undergoing elective surgery who had no known coagulation disorder and had not received anticoagulant or anti-platelet therapy within the previous 7 days.The following laboratory parameters were measured at the time of initial diagnosis: thromboelastography (TEG), thrombin generation assay (TGA), PT and aPTT, D-dimer level, fibrinogen level, lupus anticoagulant (LA) and anticardiolipin antibodies (ACA), interleukin (IL)-1b, IL-6, IL-8, and tumor necrosis factor (TNF)-α. Two years after completion of the laboratory component of the study, the patient cohort was retrospectively reviewed for the occurrence of thrombosis. Comparisons were made between patients vs. controls and patients with thrombosis vs. patients without thrombosis.As compared to controls, pediatric patients with newly diagnosed solid tumors demonstrated significantly higher prothrombotic markers, including TEG parameters, proinflammatory cytokines, and endogenous thrombin potentials assessed by TGA (Table 1).Among the 40 cancer patients, 4 (10%) experienced following thrombotic complications: cerebral sigmoid sinus thrombosis; right subclavian vein thrombosis; left internal jugular vein thrombosis; inferior vena cava thrombosis. All 4 patients had a hypercoagulable TEG profile as shown by increased maximum amplitude and elevated fibrinogen level at initial presentation.PT, fibrinogen level, and maximum amplitude of TEG were further predictive of thrombosis development in cancer patients (Table 2). Further studies are needed to support recommendations for prophylaxis of thrombosis in this vulnerable patient population.Table 1:Statistically significant parameters in cancer patients compared to controlsParameterN=40 Patients Median (range)N=40 Controls Median (range)P ValueFibrinogen (mg/dL)342 (202–734)266 (183–456)0.00D-dimer (μg/mL)1.4 (0.2–13.7)0.2 ((0.0–3.9)0.00Factor VIII (%)145 (59–361)100 (50–173)0.00ACA IgM (MPL)1.5 (0.0–7.4)1.2 (0.0–3.8)0.03Maximum amplitude (mm)66.9 (52.0–82.0)61.4 (55.0–68.0)0.00Coagulation index2.1 (−1.0–4.0)1.3 (0.0–3.0)0.00G (k d/sec)10.2 (5.4–23.1)8.0 (6.1–10.7)0.00AUC/ETP5300 (1970–6501)4864 (2300–5832)0.03IL-1β0.8 (0.1–6.5)0.5 (0.1–1.1)0.01IL-60.8 (0.1–18.8)0.2 (0.1–0.6)0.00TNF-α0.1 (0.0–2.3)0.1 (0.1–0.3)0.02Table 2:Statistically significant parameters in cancer patients with thrombosis compared to those without thrombosisParameterN=4 Thrombosis (+) Median (range)N=36 Thrombosis (−) Median (range)P ValuePT (sec)15.8 (15.6–18.2)13.9 (12.3–16.7)0.00Fibrinogen (mg/dL)579 (430–724)333 (202–734)0.00Maximum amplitude (mm)72.2 (67.3–74.8)66.4 (46.4–56.3)0.03G (k d/sec)13.3 (4.3–23.1)9.1 (10.3–14.8)0.03ACA IgM (MPL)4 (1–5)0 (0–16)0.04 Disclosures:No relevant conflicts of interest to declare.

Poor outcome following revascularization predicted by thromboelastography

Abstract Background Infrainguinal revascularization procedures are associated with a high risk of graft failure, amputation and early death. Hypercoagulability predicts a poor overall outcome but conventional tests are expensive and results are not immediately available. A cheap, rapid method for identifying hypercoagulability would allow screening before revascularization. Thromboelastography (TEG) is a rapid, reliable, bedside method of assessing whole blood clotting. Normally used to assess hypocoagulability, this study determined the role of TEG in identifying patients with a poor prognosis following revascularization. Methods Between November 1998 and January 2000, 106 patients with critical leg ischaemia were admitted for radiological or surgical revascularization (mean age 71 (range 33–90) years). All underwent TEG analysis, standard thrombophilia screening (STS), and fasting homocysteine and fibrinogen assays. All patients were followed for 6 months after revascularization by means of clinical examination, ankle: brachial pressure index (ABPI) and duplex imaging. Results At the 6-month follow-up of 106 patients, 29 (27 per cent) had arterial or graft occlusion, five (5 per cent) had died and four (4 per cent) had undergone a major amputation. Analysis of risk factors revealed that a hypercoagulable TEG (P = 0·0009), STS and/or raised fibrinogen level (P = 0·01), and rest pain (P = 0·006) were associated with poor outcome. Other factors such as age, sex, diabetes, current or previous smoking, coronary artery or cerebrovascular disease, hypertension, previous intervention, aspirin or lipid-lowering therapy were not significantly different. In addition, hyperlipidaemia, hyperhomocysteinaemia, raised level of C-reactive protein, eyrthrocyte sedimentation rate, lipoprotein a level, haemocrit, STS or fibrinogen alone were not useful as predictors of poor outcome. Conclusion TEG, a rapid inexpensive test of hypercoagulability, is associated with poor outcome following infrainguinal revascularization.