Algorithm for Rapid Exclusion of Clinically Relevant Plasma Levels of Direct Oral Anticoagulants in Patients Using the DOAC Dipstick: An Expert Consensus Paper.

BACKGROUND: With the widespread use of direct oral anticoagulants (DOACs), there is an urgent need for a rapid assay to exclude clinically relevant plasma levels. Accurate and rapid determination of DOAC levels would guide medical decision-making to (1) determine the potential contribution of the DOAC to spontaneous or trauma-induced hemorrhage; (2) identify appropriate candidates for reversal, or (3) optimize the timing of urgent surgery or intervention. METHODS AND RESULTS: The DOAC Dipstick test uses a disposable strip to identify factor Xa- or thrombin inhibitors in a urine sample. Based on the results of a systematic literature search followed by an analysis of a simple pooling of five retrieved clinical studies, the test strip has a high sensitivity and an acceptably high negative predictive value when compared with levels measured with liquid chromatography tandem mass spectrometry or calibrated chromogenic assays to reliably exclude plasma DOAC concentrations ≥30 ng/mL. CONCLUSION: Based on these data, a simple algorithm is proposed to enhance medical decision-making in acute care indications useful primarily in hospitals not having readily available quantitative tests and 24/7. This algorithm not only determines DOAC exposure but also differentiates between factor Xa and thrombin inhibitors to better guide clinical management.

Association of Angiopoetin-2 and TNF-α With Bleeding During Left Ventricular Assist Device Support: Analysis From the PREVENT Biorepository.

The purpose of this study was to describe the changes in plasma levels of angiogenic and inflammatory biomarkers, specifically Ang-2 and TNF-α, in patients receiving HeartMate II (HMII) left ventricular assist device (LVAD) and correlate them with nonsurgical bleeding. It has been shown that angiopoietin-2 (Ang-2) and tissue necrosis factor-α (TNF-α) may be linked to bleeding in LVAD patients. This study utilized biobanked samples prospectively collected from the PREVENT study, a prospective, multicenter, single-arm, nonrandomized study of patients implanted with HMII. Paired serum samples were obtained in 140 patients before implantation and at 90 days postimplantation. Baseline demographics were as follows: age 57 ± 13 years, 41% had ischemic etiology, 82% male, and 75% destination therapy indication. In the 17 patients with baseline elevation of both TNF-α and Ang-2, 10 (60%) experienced a significant bleeding event within 180 days postimplant compared with 37 of 98 (38%) patients with Ang-2 and TNF-α below the mean ( p = 0.02). The hazard ratio for a bleeding event was 2.3 (95% CI: 1.2-4.6) in patients with elevated levels of both TNF-α and Ang-2. In the PREVENT multicenter study, patients with elevations in serum Angiopoietin-2 and TNF-α at baseline before LVAD implantation demonstrated increased bleeding events after LVAD implantation.

Glycemic Control and Plasma Levels of Pro-Inflammatory and Pro-Thrombotic Biomarkers in Diabetic Patients Presenting with Acute Pulmonary Embolism.

Type I and type II diabetes are closely associated with a pro-inflammatory state and to a pro-thrombotic state. The role of glycemic control in pulmonary embolism (PE) is poorly understood and requires additional investigation. The aim of this study is to investigate the relationship between glycemic control and thrombo-inflammatory biomarkers in a PE patient cohort compared to normal samples. Demographic and clinical information for 86 diabetic patients and 106 non-diabetic patients presenting with acute PE was collected via retrospective chart review. Plasma levels of pro-inflammatory (C-reactive protein [CRP], tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6]) and pro-thrombotic (d-dimer, plasminogen activator inhibitor-1 [PAI-1], tissue plasminogen activator [tPA], thrombin activatable fibrinolysis inhibitor [TAFI], von-Willebrand factor [vWF], endogenous glycosaminoglycans [GAGs]) biomarkers were drawn within 24 hours of diagnosis of acute PE. Data was also obtained for a population of healthy adult controls. All the pro-inflammatory and pro-thrombotic biomarkers were elevated in diabetic PE patients in comparison to healthy controls. None of the biomarkers were elevated in diabetic PE patients when compared to non-diabetic PE patients. There was no difference in the levels of the pro-inflammatory biomarkers according to glycemic control. The plasma level of TAFI was elevated in diabetic patients with poor glycemic control. Diabetic patients were more likely to have a more severe PE. These studies demonstrate that thrombo-inflammatory biomarkers are elevated in diabetic PE patients with associated comorbidities in comparison to normal individuals. However, there is no difference between the PE cohort alone in comparison to PE with diabetes. The role of TAFI within the continuum of diabetic vascular disease warrants additional investigation.

Inflammatory cytokines in robot-assisted thoracic surgery versus video-assisted thoracic surgery.

Background: Cytokines play a crucial role in the inflammatory response and are essential modulators of injury repair mechanisms. While minimally invasive operations have been shown to induce lower levels of cytokines compared to open thoracotomy, the inflammatory cytokine profile difference between video-assisted (VATS) and robotic-assisted thoracic surgery (RATS) techniques has yet to be elucidated. Methods: In this prospective observational study of 45 patients undergoing RATS (n=30) or VATS (n=15) lung resection for malignancy, plasma levels of interleukin (IL)-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), interferon (IFN)-γ, tumor necrosis factor (TNF)-α, monocyte chemo-attractant protein (MCP)-1, and endothelial growth factor (EGF) were measured before and after surgery via immunoassay. Results: Levels of IL-6 and MCP-1 were significantly higher in patients undergoing VATS than in patients undergoing RATS (P<0.001 and P=0.005, respectively) 2 hours following surgery. MCP-1 levels were also found to be significantly higher in the VATS group (P<0.001) 24 hours following surgery. IL-1α, IL-1ß, IL-2, IL-4, IL-8, IL-10, IFN-γ, TNF-α, and EGF levels were not significantly different at any time-point comparing VATS to RATS. Conclusions: The VATS approach is associated with a more robust pro-inflammatory cytokine response through the upregulation of MCP-1 and IL-6 when compared to the RATS approach in patients undergoing anatomic lung resection. Further studies are necessary to validate the clinical significance of this finding.

Multiplex genome editing of mammalian cells for producing recombinant heparin.

Heparin is an essential anticoagulant used for treating and preventing thrombosis. However, the complexity of heparin has hindered the development of a recombinant source, making its supply dependent on a vulnerable animal population. In nature, heparin is produced exclusively in mast cells, which are not suitable for commercial production, but mastocytoma cells are readily grown in culture and make heparan sulfate, a closely related glycosaminoglycan that lacks anticoagulant activity. Using gene expression profiling of mast cells as a guide, a multiplex genome engineering strategy was devised to produce heparan sulfate with high anticoagulant potency and to eliminate contaminating chondroitin sulfate from mastocytoma cells. The heparan sulfate purified from engineered cells grown in chemically defined medium has anticoagulant potency that exceeds porcine-derived heparin and confers anticoagulant activity to the blood of healthy mice. This work demonstrates the feasibility of producing recombinant heparin from mammalian cell culture as an alternative to animal sources.

Medical management of stable peripheral artery disease: the COMPASS trial. Perspectives from a vascular standpoint.

The late-breaking presentation of the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial at the European Society of Cardiology Congress in 2017 with a simultaneous publication in The New England Journal of Medicine described important information on the relative risk/benefit of combining anticoagulation with antiplatelet therapy in both coronary artery disease and/or peripheral artery disease (PAD) patients. In this special article, a review of the literature addressing the effects of antiplatelets and anticoagulants in symptomatic PAD patients focusing on the two most relevant clinical endpoints: major adverse cardiovascular events and major adverse limb events is addressed. In addition, a critical review of the COMPASS trial results, with emphasis on the PAD population is performed from a vascular surgery standpoint. It is concluded that this important study validated the combined anticoagulation/antiplatelet strategies in the management of vascular disorders including stable atherosclerotic patients. However, challenges in implementing this strategy in clinical practice are expected, with bleeding complications still remaining as major concern, particularly for vascular surgeons. Further studies with different combinations of different anticoagulants/antiplatelets, eventually on top of new strategies such as PCSK9 inhibition are warranted to address the significant unmet medical need in this population of symptomatic atherosclerotic patients.

Production of Anti-platelet Factor 4/Heparin Complex Antibodies After Cardiovascular Surgery.

To study the production of anti-platelet factor 4 (anti-PF4)/heparin complex antibodies of Ig (immunoglobulin) G/IgA/IgM using enzyme-linked immunosorbent assay (ELISA; heparin-induced thrombocytopenia [HIT] antibodies) in 79 patients undergoing cardiovascular surgery, we employed Δoptical density (OD) as a marker of HIT-antibody production. The ΔODs were calculated from the differences in the ODs using ELISA. Patient were classified into 3 ΔOD ranges: ΔOD ≥ 1.0, ΔOD ≥ 0.4 to <1.0, and ΔOD < 0.4. The underlying disease, time course of the postoperative platelet count, D-dimer level, postoperative brain magnetic resonance imaging (MRI), use of cardiopulmonary bypass and postoperative thrombocytosis were not considered for the 3 ΔOD classifications. None of the 6 patients with ΔOD ≥ 1 .0 and a positive functional assay was diagnosed with HIT due to the absence of HIT-derived thrombocytopenia. In conclusion, HIT-antibody production increased until day 7 after heparin cessation and reached a trace level on day 14. It was demonstrated that HIT-antibody production is in remission unless there is any evidence of a further increase during the second week postsurgery.

Sustained release of tissue factor following thrombosis of lower limb trauma.

This study was undertaken to provide evidence for the mechanism of venous thromboembolism (VTE) in healthy patients with minor lower limb injury (fracture; Achilles tendon rupture) that was medically managed with plaster cast/brace immobilization. The Plaster Cast clinical trial provided a unique opportunity to identify the natural history of VTE using placebo-controlled patients (n = 183) with validation of the mechanism using the low-molecular-weight heparin (LMWH; reviparin)-treated patients (n = 182). Confirmed VTE in this population was associated with a burst of tissue factor release (and a minor fibrinolytic deficit) leading to thrombin generation that was sustained at least 5 weeks, greater with fractures than with soft-tissue injuries and greater with surgery than with conservative treatment. The root cause likely involves platelet/leukocyte activation (inflammation) rather than endothelial cell injury. Thromboprophylaxis with a low dose of LMWH reduced thrombin generation, with patients undergoing surgery benefitting the most.

Evolution of heparin anticoagulants to ultra-low-molecular-weight heparins: a review of pharmacologic and clinical differences and applications in patients with cancer.

The burden of venous thromboembolism (VTE) is high in patients with cancer, particularly those with metastatic disease and those receiving chemotherapy. The use of heparin and heparin derivatives should be considered for primary prevention of VTE in hospitalized patients with cancer and in patients undergoing cancer surgery. Preliminary evidence also suggests that heparins may have direct anticancer benefits owing to effects on tumor growth, angiogenesis, and metastasis. Despite the potential benefits of heparin-derived anticoagulants, many at-risk patients do not receive adequate thromboprophylaxis. The evolution of unfractionated heparin to low-molecular-weight and ultra-low-molecular-weight heparins has provided practitioners with alternatives for VTE prevention in cancer, although these alternatives present challenges related to clinically relevant pharmacologic differences between agents. In this review, we present results from our review of the medical literature focusing on the use of the heparin-derived anticoagulants in prospective interventional studies of primary thromboprophylaxis in patients with cancer in surgical, hospitalized, and ambulatory settings.

Left ventricular assist device-induced coagulation and platelet activation and effect of the current anticoagulant therapy regimen.

Left ventricular assist devices (LVADs) are mechanical pumps that enhance cardiac function in patients with heart failure. In all, 7 patients with an LVADs (1.8 international normalized ratio warfarin, 81 mg aspirin) were evaluated monthly for 3 months for platelet and coagulation activation (controls: 5 healthy adults and 5 patients having warfarin). Platelet works revealed greater inhibition of collagen (31.8% vs 7.9%; P = .004), arachidonate- (30.9% vs 8.2%; P = .001), and adenosine diphosphate- (10.9% vs 6.1%; P = .004)-induced platelet aggregation for LVADs. Thrombelastography (recalcified whole blood) showed inhibition of clot initiation time (R; 8.81 vs 6.02 min; P = .001) and stronger clot formation (maximum amplitude; 69.1 vs 64.9 mm; P = .016). Platelet function determined by plateletMapping and flow cytometry was within the normal range. The LVADs had increased ratio of von Willebrand Factor (vWF) antigen and vWF propeptide, indicating increased degradation of vWF (2.04 vs 1.44; P = .144). Coagulation and platelet activation caused by LVAD is suppressed by pharmacotherapy, yielding a profile similar to that of patients on warfarin alone.

Low molecular weight heparins differ substantially: impact on developing biosimilar drugs.

Generic drugs are an important component for meaningful health-care reform currently being debated in the United States. Aside from defining the period of drug exclusivity, however, there is a critical need to ensure that generics of biologic medicines (biosimilars) are safe and effective. For low molecular weight heparins (LMWHs), the standard of care for management of venous thromboembolism, their complex structure and polypharmacological actions make producing a generic LMWH more challenging than a generic small molecule medicine. Because biosimilar LMWHs will be used interchangeably with their branded product, inherent variability between products could lead to important differences in potency, safety, or effectiveness, including unanticipated immune responses. Awareness of the specific problems associated with biosimilar LMWH development led to new recommendations from several expert bodies. This article discusses the implications of these differences for the production of biosimilar LMWHs and provides recommendations to address the limitations in the pending U.S. Congress legislation, a well-intentioned undertaking but one that must preserve the health and welfare of citizens who require these critical care medications.

Safety and efficacy of thrombin-JMI: a multidisciplinary expert group consensus.

BACKGROUND: The use of bovine thrombin has been an effective approach to aiding hemostasis during surgery for over 60 years. Its use has a reported association with the development of antibodies to coagulation factors with limited evidence to the clinical significance. METHODS: The Collaborative Delphi survey methodology was used to develop a consensus on specified topic areas from a panel of 12 surgeons/scientists who have had experience with topical thrombins; it consisted of 2 rounds of a Web-based survey and a final live discussion. RESULTS: Some key issues that reached consensus included: bovine, human plasma-derived and recombinant human thrombin are equally effective hemostatic agents with similar adverse event rates, and immunogenicity to a topical protein rarely translate into adverse events. CONCLUSIONS: Although a risk of immunogenicity is associated with all topical thrombins, no conclusive clinical evidence is available that these antibodies have any significant effect on short- and long-term clinical consequences.

Pharmacology of argatroban.

Argatroban is a synthetic, small-molecule direct thrombin inhibitor that is approved in the USA, the EU and Japan for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT), and for anticoagulation of HIT patients undergoing PCI. Argatroban binds reversibly to, and inhibits both soluble and clot-bound thrombin. Argatroban does not generate antibodies, is not susceptible to degradation by proteases and is cleared hepatically. It has a predictable anticoagulant effect and there is a good correlation between dose, plasma concentration and pharmacodynamic effect. Initial clinical studies suggest that further investigations to establish the use of argatroban in ischemic stroke, acute coronary syndrome, hemodialysis, blood oxygenation, off-pump cardiac surgery and other clinical indications are warranted.

Low anticoagulant heparin targets multiple sites of inflammation, suppresses heparin-induced thrombocytopenia, and inhibits interaction of RAGE with its ligands.

While heparin has been used almost exclusively as a blood anticoagulant, important literature demonstrates that it also has broad anti-inflammatory activity. Herein, using low anti-coagulant 2-O,3-O-desulfated heparin (ODSH), we demonstrate that most of the anti-inflammatory pharmacology of heparin is unrelated to anticoagulant activity. ODSH has low affinity for anti-thrombin III, low anti-Xa, and anti-IIa anticoagulant activities and does not activate Hageman factor (factor XII). Unlike heparin, ODSH does not interact with heparin-platelet factor-4 antibodies present in patients with heparin-induced thrombocytopenia and even suppresses platelet activation in the presence of activating concentrations of heparin. Like heparin, ODSH inhibits complement activation, binding to the leukocyte adhesion molecule P-selectin, and the leukocyte cationic granular proteins azurocidin, human leukocyte elastase, and cathepsin G. In addition, ODSH and heparin disrupt Mac-1 (CD11b/CD18)-mediated leukocyte adhesion to the receptor for advanced glycation end products (RAGE) and inhibit ligation of RAGE by its many proinflammatory ligands, including the advanced glycation end-product carboxymethyl lysine-bovine serum albumin, the nuclear protein high mobility group box protein-1 (HMGB-1), and S100 calgranulins. In mice, ODSH is more effective than heparin in reducing selectin-mediated lung metastasis from melanoma and inhibits RAGE-mediated airway inflammation from intratracheal HMGB-1. In humans, 50% inhibitory concentrations of ODSH for these anti-inflammatory activities can be achieved in the blood without anticoagulation. These results demonstrate that the anticoagulant activity of heparin is distinct from its anti-inflammatory actions and indicate that 2-O and 3-O sulfate groups can be removed to reduce anticoagulant activity of heparin without impairing its anti-inflammatory pharmacology.

Profiling of heparin-induced thrombocytopenia antibody levels in patients with and without diabetes.

Heparin/platelet factor 4 (H:PF4) antibodies are the causative agent in heparin-induced thrombocytopenia (HIT). The antibodies are frequently formed after exposure to heparin, most commonly without any signs of clinical HIT. Heparin-induced thrombocytopenia antibodies have been detected by enzyme-linked immunosorbent assay (ELISA) in individuals who have not been exposed to heparin. It is possible that the antibodies could be elicited by PF4 associated with endogenous, heparin-like glycosaminoglycans (GAGs). This risk would be higher in individuals with endothelial dysfunction and chronic platelet activation. In the setting of an outpatient endocrinology clinic, both diabetic and nondiabetic patients were studied and compared with healthy volunteers. Heparin/platelet factor 4 antibody titers were measured by ELISA and analyzed to determine the frequency of clinically seropositive responses, and median and interquartile ranges of baseline antibody titers. The study found no increase in frequency of ELISA-positive patients among diabetic patients. Moreover, the diabetic population had lower overall level of H:PF4 antibody titer, especially the subgroups treated with thiazolidinedione drugs or angiotensin receptor blockers. Further studies are needed to determine whether subthreshold titers of HIT antibody may be reflective of the physiological state of platelet/endothelial balance.

Heparin-induced thrombocytopenia: a serious complication of heparin therapy for acute stroke.

BACKGROUND: Despite the lack of supporting evidence, unfractionated heparin (UFH) is frequently given to acute ischemic stroke patients. This study was designed to determine the incidence of heparin-induced thrombocytopenia (HIT) during acute stroke and to elucidate the clinical features of stroke patients with HIT. METHODS: Of 1,078 consecutive patients with acute ischemic stroke, 392 were given intravenous UFH. Ten of these developed prominent thrombocytopenia without any other underlying etiology; they were suspected of having HIT. These 10 patients were studied retrospectively. The clinical diagnosis of HIT was made according to two published scoring systems. Antiplatelet factor 4/heparin antibodies in the plasma were detected by the enzyme-linked immunosorbent assay (ELISA) and were confirmed by the 14C-serotonin release assay. RESULTS: Eight patients met the criteria for clinical HIT according to both scoring systems. Of these, serological tests were positive in 2 patients only on ELISA and in 2 patients on both assays. The amount of UFH given was greater in the 4 patients with positive serological findings than in the others (p = 0.043). Three patients developed further thromboembolic events, including 1 patient who developed possible cancer-associated thrombosis. Two patients were dead and the remaining 6 patients were dependent at the time of hospital discharge. The clinical severity and outcome of these patients were relatively unfavorable compared to other acute patients. CONCLUSIONS: The prevalence of HIT was 0.5% based on both the clinical scoring systems and serological assays. Monitoring for HIT should be included in the medical management of stroke to avoid further complications.

Differentiating low-molecular-weight heparins based on chemical, biological, and pharmacologic properties: implications for the development of generic versions of low-molecular-weight heparins.

Low-molecular-weight heparins (LMWHs) are polypharmacologic drugs used to treat thrombotic and cardiovascular disorders. These drugs are manufactured using different chemical and enzymatic methods, resulting in products with distinct chemical and pharmacologic profiles. Generic LMWHs have been introduced in Asia and South America, and several generic suppliers are seeking regulatory approval in the United States and the European Union. For simple small-molecule drugs, generic drugs have the same chemical structure, potency, and bioavailability as the innovator drug. Applying this definition to complex biological products such as the LMWHs has proved difficult. One major issue is defining appropriate criteria to demonstrate bioequivalence; pharmacopoeial specifications alone appear to be inadequate. Whereas available generic versions of LMWHs exhibit similar molecular and pharmacopoeial profiles, marked differences in their biological and pharmacologic behavior have been noted. Preliminary studies have demonstrated differences in terms of anti-Xa activity and tissue factor pathway inhibitor release after subcutaneous administration, as well as antiplatelet and profibrinolytic effects. The current data emphasize the need to consider multiple functional parameters when defining bioequivalence of biologic drugs with complex structures and activities and also underscore the importance of further pharmacologic studies involving animal models and human clinical trials. The U.S. Food and Drug Administration and the European Medicine Evaluation Agency are currently developing guidelines for the acceptance of biosimilar agents including LMWHs. Until such guidelines are complete, generic interchange may not be feasible.

The future of anticoagulation.

The conventional management of thrombotic disorders is based on the use of heparin, oral anticoagulants, and aspirin. The development of low molecular weight heparins and the synthesis of heparinomimetics such as the chemically synthesized pentasaccharide represent a refined use of heparin. Aspirin still remains the lead drug in the management of thrombotic and cardiovascular disorders. The newer antiplatelet drugs such as the adenosine diphosphate receptor inhibitors, glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors and other specific inhibitors have limited effects and have been tested in patients who have already been treated with aspirin. The oral anticoagulants such as warfarin provide a convenient and affordable approach in the long-term outpatient management of thrombotic disorders. The optimized use of these drugs still remains the approach of choice to manage thrombotic disorders. The new anticoagulant drugs target specific sites in the hemostatic network. There is a major thrust on the development of orally bioavailable anticoagulant drugs to replace oral anticoagulants. Heparin and low molecular weight heparins have been considered with various chemical enhancers for absorption. Both the factor Xa and antithrombin agents have been developed for oral use and some of these agents are in clinical development. Besides the limited bioavailability, the therapeutic indices of some of these drugs have been rather disappointing. Factor Xa inhibitors such as the pentasaccharides have undergone aggressive clinical development. The newer antiplatelet drugs have added a new dimension in the management of thrombotic disorders. The newer drugs are attractive for several reasons; however, none of these are expected to completely replace the conventional drugs in polytherapeutic approaches. It is conceivable that some of the newer drugs in combined modalities may mimic the broad therapeutic spectrum of heparins and warfarin. However, clinical validation is required for the therapeutic interchange for specific indications.

The relationship between the antiphospholipid syndrome and heparin-induced thrombocytopenia.

Antiphospholipid syndrome (APS) and heparin-induced thrombocytopenia (HIT) are immune-mediated thrombotic conditions caused by antibodies targeted to a protein-antigen complex. Although each disorder is attributed to two distinct antibodies, these autoimmune disorders are characterized by a similar pathogenesis that includes a hypercoagulable state, platelet activation, damage to the vascular endothelium, and inflammation. APS and HIT share similarities in the clinical presentation because each is associated with thrombocytopenia, a high risk of thrombosis in all venous and arterial sites, and catastrophic thrombotic outcomes occur if untreated. Understanding the disease process for one disorder could potentially aid in understanding the other disorder.

Inflammatory and hemostatic activation in patients undergoing off-pump coronary artery bypass grafting.

To characterize hemostatic differences imposed by 2 common cardiac surgeries, the authors studied patients undergoing coronary artery revascularization by off-pump (n = 13) or cardiopulmonary bypass on-pump (n = 26) technique. Blood samples collected to 4 days post-surgery were evaluated by flow cytometry and enzyme-linked immunosorbent assay. A significant inflammatory response occurred in both the groups after surgery shown by increased interleukin cytokines and C-reactive protein; however, levels peaked lower and hours later in the off-pump group. Platelets (P-selectin; platelet-leukocyte complexes) and leukocytes (CD11b) were activated only in on-pump patients. Thrombin generation was enhanced in both groups after surgery. Only in the on-pump patients, the thrombin-antithrombin complex, pro-thrombin fragment 1.2, and thrombomodulin (vascular integrity) decreased intraoperatively. Tissue plasminogen activator and plasminogen activator inhibitor-1 were greater in the on-pump patients. Off-pump surgery may place patients at higher risk of postoperative hypercoagulability because of normal platelet function, intraoperative thrombin generation, less fibrinolytic activity, and lack of vascular protection.