Antithrombotic Intervention Research Articles

Evaluation of viscoelastic coagulation monitoring parameters and fibrinogen concentrations in healthy dogs undergoing stifle arthroscopy and tibial plateau leveling osteotomy.

Evaluation of viscoelastic parameters along with Hct percentages, platelet numbers, and fibrinogen concentrations in healthy dogs undergoing elective stifle arthroscopy and tibial plateau leveling osteotomy (TPLO). These results determine if dogs are in a normal, hypocoagulable, or hypercoagulable state at 4 different time points. Prospective study of 37 client-owned dogs enrolled between February 2, 2022, and November 10, 2022. All dogs received a standardized anesthetic protocol. Patients enrolled in the study underwent stifle arthroscopy using a 3-portal technique with a TPLO performed by board-certified surgeons. Viscoelastic testing, Hct percentage, fibrinogen concentration, and platelet numbers were measured preoperatively, immediately postoperatively, 24 hours postoperatively, and 14 days postoperatively. Stifle arthroscopy and TPLO surgery was not associated with significant effects on viscoelastic coagulation monitoring and fibrinogen concentrations in healthy dogs when comparing the time points. Humans have a high risk of thrombotic events when undergoing elective orthopedic surgery and are often placed on prophylactic antithrombotic medication prior to surgery. Viscoelastic coagulation monitoring in dogs undergoing similar orthopedic procedures has been evaluated in veterinary medicine, but the effects on platelets and fibrinogen concentrations from similar orthopedic procedures and uniform anesthesia protocols have not been documented. Cranial cruciate ligament insufficiency is the most common orthopedic injury in dogs. Treatment requires elective surgical correction for the best results and improved long-term prognosis. The findings of this study suggest that similar preoperative prophylactic antithrombotic intervention is not needed for canine patients.

Glioblastoma cell populations with distinct oncogenic programs release podoplanin as procoagulant extracellular vesicles

Vascular anomalies, including local and peripheral thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of deregulation of the cancer cell genome and epigenome. Although the molecular effectors of these changes are poorly understood, the upregulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk for venous thromboembolism (VTE) in GBM patients. Therefore, regulation of this platelet-activating protein by transforming events in cancer cells is of considerable interest. We used single-cell and bulk transcriptome data mining, as well as cellular and xenograft models in mice, to analyze the nature of cells expressing PDPN, as well as their impact on the activation of the coagulation system and platelets. We report that PDPN is expressed by distinct (mesenchymal) GBM cell subpopulations and downregulated by oncogenic mutations of EGFR and IDH1 genes, along with changes in chromatin modifications (enhancer of zeste homolog 2) and DNA methylation. Glioma cells exteriorize their PDPN and/or tissue factor (TF) as cargo of exosome-like extracellular vesicles (EVs) shed from cells in vitro and in vivo. Injection of glioma-derived podoplanin carrying extracelluar vesicles (PDPN-EVs) activates platelets, whereas tissue factor carrying extracellular vesicles (TF-EVs) activate the clotting cascade. Similarly, an increase in platelet activation (platelet factor 4) or coagulation (D-dimer) markers occurs in mice harboring the corresponding glioma xenografts expressing PDPN or TF, respectively. Coexpression of PDPN and TF by GBM cells cooperatively affects tumor microthrombosis. Thus, in GBM, distinct cellular subsets drive multiple facets of cancer-associated thrombosis and may represent targets for phenotype- and cell type–based diagnosis and antithrombotic intervention.

Safety of antithrombotic therapy in East Asian patients.

Antithrombotic agents are widely used on the globe for prevention of thrombotic events such as atherothrombotic events and thromboembolic stroke in atrial fibrillation or for prevention and treatment of venous thromboembolism. However, the net clinical benefit of antithrombotic intervention may differ substantially in various sub-population of patients. Here, the authors attempt to address the risk of serious bleeding in East Asian as compared to the other regions of the world. The community-based epidemiological data suggest numerically higher risk of hemorrhage stroke in East Asian as compared to the globe. Importantly, the life-time risk of ischemic stroke in East Asia is higher than that of the globe. Regarding the serious bleeding risk in East Asians with the use of antithrombotic agents, various clinical trials and international registries provided conflicting information. It is hard to draw generalized conclusion, but there are some specific sub-population in East Asian with higher risk of specific serious bleeding events with the use of specific antithrombotic agents such as the risk of intra-cranial bleeding (ICH) with Vitamin K antagonists. Specific characteristics in East Asian such as higher prevalence of lacunar stroke may contribute higher risk of ICH in East Asian, but the detailed mechanism is still to be elucidated. In conclusion, further investigations are necessary to clarify the specific conditions where the risk of serious bleeding events in East Asian patients differ substantially compared to the global. In addition, further understanding of the mechanisms causing the different bleeding response in specific conditions in East Asian is awaited.

Passive ankle motion and calf massage without anticoagulation therapy after total hip arthroplasty: A retrospective study

BackgroundIt has been previously reported that manual calf massage and passive ankle motion after total hip arthroplasty could reduce the incidence of venous thromboembolism. However, a combination of chemical and mechanical prophylaxes was employed. In this study, we aimed to examine the effect of mechanical prevention without pharmacological antithrombotic intervention. MethodsOf the 313 patients who underwent unilateral primary total hip arthroplasty and received passive ankle motion and calf massage postoperatively at our hospital between January 2015 and December 2019, 261 (58 men, 203 women; mean age 62.1 years) were included in this retrospective study. Pharmacological anticoagulation therapy was administered in 176 patients (combination group); 137 patients only underwent calf massage and passive ankle motion without anticoagulation therapy (single group). The study outcomes were operation time, the incidence of deep vein thrombosis, pulmonary thromboembolism, intraoperative bleeding, estimated actual blood loss, blood transfusion, and major bleeding. ResultsNo significant differences were found in sex, age, side, platelet counts, activated partial thromboplastin time, prothrombin time, prothrombin time - International Normalized Ratio, intraoperative blood loss, estimated blood loss, and operation time. Moreover, the incidence of deep vein thrombosis, pulmonary thromboembolism, and intraoperative bleeding was not significantly different between the groups (deep vein thrombosis 4.0% vs. 6.3%, p = 0.244; pulmonary thromboembolism 0.7% vs. 0%, p = 0.548; and intraoperative bleeding 394 ± 173.6 ml vs. 365.4 ± 168.5 ml, p = 0.550). However, estimated actual blood loss and postoperative bleeding differed between the groups (eABL 996.6 ± 348.3 ml vs. 858.5 ± 269.6 ml, p = 0.003; postoperative bleeding 601.8 ± 330.0 ml vs. 492.1 ± 277.1 ml, p = 0.016), and both increased in the combination group. No major bleeding was noted in the two groups. ConclusionPostoperative anticoagulant therapy does not have to be routinely used if mechanical prophylaxis is performed in patients without deep vein thrombosis before total hip arthroplasty.

Blood clots in COVID-19 patients: Simplifying the curious mystery

The universal phenomenon of blood clotting is well known to be protective in external cellular/ tissue injury. However, the emergence of unusual thrombotic presentations in COVID-19 patients is the real concern. Interaction of the spike glycoprotein with ACE2 receptor present in the host cell surface mediates the entry of SARS-CoV-2 causing COVID-19 infection. New clinical findings of SARS-CoV-2 pathogenesis are coming out every day, and one such mystery is the formation of mysterious blood clots in the various tissues and organs of COVID-19 patients, which needs critical attention. To address this issue, we hypothesis that, high ACE2 expression in the endothelium of blood vessels facilitates the high-affinity binding of SARS-CoV-2 using spike protein, causing infection and internal injury inside the vascular wall of blood vessels. This viral associated injury may directly/indirectly initiate activation of coagulation and clotting cascades forming internal blood clots. However, the presence of these clots is undesirable as they are responsible for thrombosis and need to be treated with anti-thrombotic intervention.

Development of New Antithrombotic Regimens for Patients with Acute CoronarySyndrome.

Patients with acute coronary syndrome (ACS) require long-term antithrombotic intervention to reduce the risk of further ischemic events; dual antiplatelet therapy with a P2Y12 inhibitor and acetylsalicylic acid (ASA) is the current standard of care. However, pivotal clinical trials report that patients receiving this treatment have a residual risk of approximately 10% for further ischemic events. The development of non-vitamin K antagonist oral anticoagulants (NOACs) has renewed interest in a ‘dual pathway’ strategy, targeting both the coagulation cascade and platelet component of thrombus formation. In the phase III ATLAS ACS 2 TIMI 51 trial, a ‘triple therapy’ approach (NOAC plus dual antiplatelet therapy) showed reduced ischemic events with rivaroxaban 2.5 mg twice daily, albeit at an increased risk of bleeding. Two studies have investigated the role of NOACs in combination with a P2Y12 inhibitor, with or without ASA, in reducing bleeding risk in patients with atrial fibrillation undergoing percutaneous coronary intervention; two further studies are underway. Although these trials will help to inform optimal treatment protocols for secondary prevention of ACS, an individualized approach to treatment will be needed, taking account of the high frequency of co-morbid conditions found in this patient population.

P047: Antithrombotic intervention for pregnancy complications: comparisons of various approaches

P047: Antithrombotic intervention for pregnancy complications: comparisons of various approaches

Precision Medicine in Assisted Conception: A Multicenter Observational Treatment Cohort Study of the Annexin A5 M2 Haplotype as a Biomarker for Antithrombotic Treatment to Improve Pregnancy Outcome

(Abstracted from EBioMedicine 2016;10:298–304) More than 25% of pregnancies are affected by pregnancy failure and placenta-mediated pregnancy complications (PMPCs). Although there is biological plausibility for coagulation activation being an underlying mechanism for a proportion of PMPC events, several trials of antithrombotic intervention in women at risk of PMPC have found it to be ineffective.

Microthrombotic Renal Vascular Lesions Are Associated to Increased Renal Inflammatory Infiltration in Murine Lupus Nephritis.

Background: Vascular microthrombotic lesions in lupus nephritis with or without antiphospholipid antibodies may relate to worse renal outcomes. Whether microthrombotic lesions are a consequence of renal inflammation or independently contribute to renal damage is unclear. Our aim was to investigate the relationship between microthrombotic renal vascular lesions and nephritis progression in MRL/lpr mice.Methods: MRL/lpr mice were analyzed for the presence of renal microvascular, glomerular and tubulointerstitial lesions and the effect of anti-aggregation (aspirin or clopidogrel) and dexamethasone on renal clinical and pathological manifestations was evaluated. Intravascular platelet aggregates (CD41), peri- (F4/80), and intraglomerular (Mac-2) macrophage infiltration, and C3 deposition were quantified by immunohistochemistry. Renal function was assessed by measuring proteinuria, and serum levels of creatinine and albumin. Anti-dsDNA and anti-cardiolipin antibodies, and thromboxane B2 levels were quantified by ELISA.Results: Frequency of microthrombotic renal lesions in MRL/lpr mice was high and was associated with immune-mediated renal damage. Proteinuria positively correlated with glomerular macrophage infiltration and was higher in mice with proliferative glomerular lesions. All mice had detectable anti-dsDNA and anti-cardiolipin IgG, regardless the presence of microthrombosis. Proteinuria and glomerular macrophage infiltration were significantly reduced in all treatment groups. Dexamethasone and platelet anti-aggregation similarly reduced glomerular damage and inflammation, but only platelet anti-aggregation significantly reduced anti-cardiolipin antibodies, renal complement deposition and thromboxane B2 levels.Conclusions: Platelet anti-aggregation reduced renal inflammatory damage, renal complement deposition, anti-cardiolipin antibodies, and thromboxane B2 levels and in MRL/lpr mice, suggesting that platelet activation has a pathogenic effect on immune-mediated nephritis. Our results point to MRL/lpr mice with lupus nephritis as an appropriate model to analyze the potential impact of anti-thrombotic intervention on renal inflammation.

Humanized Von Willebrand Factor-Glycoprotein Ibα Interaction in Mouse Models of Hemostasis and Thrombosis

Introduction: The interaction between von Willebrand Factor (VWF) and platelet glycoprotein (GP) Ibα is key for initiating the response to vascular injury that leads to hemostasis or, in pathological conditions, may be a cause of thrombosis. VWF binding to GPIbα occurs through the A1 domain (VWFA1) and its role in platelet adhesion and aggregation becomes progressively more important with increasing shear rates, i.e., in arterioles or pathologically stenosed arteries. Owing to the key role in platelet adhesion/aggregation under arterial flow conditions, VWFA1 has been considered an obvious target for antithrombotic intervention. However, efforts to develop this concept have been complicated by the lack of suitable animal models due to species-specificity in VWFA1-GPIb binding. To obviate the problem, we have generated new mouse strains with humanized VWF-GPIb interaction and characterized the resulting phenotypes in experimental ex vivo and in vivo models of hemostasis and thrombosis.Methods: In the human VWF gene, and in the mouse Vwf ortholog, exon 28 encodes domains A1 and A2, including the VWFA1 GPIb-binding site. We generated a knock-in mouse by targeted insertion of human VWF exon 28 (VWFh28) into the mouse Vwf exon28 locus such that mouse platelet GPIbα (M1) interacted with mouse VWF containing human A1 domain (HA); the strain was designated M1HA (Table). These mice were cross-bred with the previously described transgenic strain (mGPIbαnull;hIbαTg) in which human GPIbα is expressed on the platelet surface in the context of the mouse GPIb-IX-V complex (strain designation: H1MA). The resulting strain was thus designated H1HA, with humanized GPIb-VWF interaction. The unmodified wild type mouse strain used for reference was designated M1MA (Table). All mouse strains were in C57BL/6 genetic background. VWF plasma concentration was measured by ELISA and function ex vivo was evaluated by ristocetin-induced platelet aggregation. In vivo, we measured the tail bleeding time to gauge hemostatic efficiency as well as the propensity to support pathological thrombosis in the carotid artery injured by exposure to ferric chloride.Results: Plasma of VWFh28 mice expressing mouse or human platelet GPIbα had VWF levels (M1HA: 876.4 ± 209.5 mU/ml, n = 16; H1HA: 848.9 ± 121.0 mU/ml, n = 15) not significantly different from wild type mice (M1MA: 1022 ± 267.4 mU/ml, n = 23). Addition of 1.5 mg/ml ristocetin into platelet-rich plasma (PRP) from M1MA, M1HA and H1MA mice elicited no response; only in PRP of H1HA mice did ristocetin cause platelet aggregation that, as in human PRP, was inhibited by the anti-human VWFA1 monoclonal antibody, NMC-4. The tail bleeding time was abnormally prolonged in the M1HA strain expressing human VWFA1/mouse GPIbα, but normal in the H1HA strain expressing human VWFA1/human GPIbα (6.0 ± 3.8 min vs. 1.5 ± 0.9 min; n = 12); the latter was similar to the bleeding time in the M1MA strain (1.0 ± 0.1 min, n = 10). Thrombus formation (time to occlusion) following a carotid artery injury with 9% FeCl3·6H2O was greatly delayed in the M1HA strain (1760.0 ± 538.5 s, n = 6) but similar to WT M1MA in the H1HA strain (485.2 ± 63.7 s vs. 598.3 ± 84.0 s, n = 6, respectively).Conclusions: Knock-in of human VWF exon 28 into the mouse Vwf locus led to successful biosynthesis of chimeric mouse-human VWF protein in vivo under endogenous promoter control, maintaining normal physiologic expression in endothelial cells and megakaryocytes/platelets. Tail bleeding time and in vivo thrombosis assays confirmed the normal functional interaction of mouse VWF containing human A1 domain with hGPIbα. Moreover, the normal response to ristocetin with platelet aggregation, and inhibition of the latter by the specific NMC4 antibody, indicates that the "humanized" H1HA mouse strain could be a powerful tool to select and develop new interventions for the diagnosis and treatment of hemostatic and thrombotic disorders. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Precision Medicine in Assisted Conception: A Multicenter Observational Treatment Cohort Study of the Annexin A5 M2 Haplotype as a Biomarker for Antithrombotic Treatment to Improve Pregnancy Outcome

BackgroundPregnancy failure and placenta mediated pregnancy complications affect >25% of pregnancies. Although there is biological plausibility for a procoagulant mechanism underlying some of these events, antithrombotic intervention trials demonstrate limited benefit, possibly through lack of stratification in heterogeneous patient groups. The ANXA5 M2 haplotype is a possible procoagulant biomarker and was tested pragmatically to determine whether this screening and LMWH treatment normalized the outcome for ANXA5 M2 positive couples.This was a pragmatic study that aimed to measure the effectiveness of a testing (for the M2 haplotype) and treatment (LMWH) pathway in routine clinical practice where there is variation between patients. Such a study in couples with fertility problems can inform choices between treatments; it is then the management protocol which is the subject of the investigation, not the individual treatments. MethodsCouples (N=77) with one or both partners ANXA5 M2 positive demonstrated association of this haplotype with adverse IVF outcome. A pragmatic, multicenter, prospective cohort study of ANXA5 M2 haplotype screening, and LWMH treatment following embryo transfer (ET) in 103 IVF couples positive for ANXA5 M2 was performed. They were compared with a group of 1000 contemporaneous randomly selected unscreened and untreated couples undergoing assisted conception, from which 103 matched control couples were derived. The primary outcome measure was live birth incidence. Secondary outcomes were results following embryo transfer (ET) and live birth outcome by gender and M2 carriage, and allelic dose influence. FindingsThe tested and treated cohort of ANXA5 M2 carriers achieved a similar live birth rate (37.9%) per ET cycle compared to both the more fertile comparison group (38.5%), and to the 103 matched controls (33.0%). Significantly more treated male carrier only couples had a live birth versus female M2 only (47.7% vs. 25.0% p=0.045). InterpretationPragmatic ANXA5 M5 screening and treatment with LMWH in couples undergoing IVF is associated with similar outcome to couples with more favorable prognostic factors. The difference in live birth outcome for treated male only carrier couples may be consistent with an additional maternal thrombophilic factor that may adversely affect pregnancy, although other mechanisms are possible. This study suggests that LMWH treatment should be started prior to clinical pregnancy.

Su1498 The Revised Japanese Guideline for Gastroenterological Endoscopy Alters the Management of Antithrombotic Drugs and Colonoscopic Intervention

Su1498 The Revised Japanese Guideline for Gastroenterological Endoscopy Alters the Management of Antithrombotic Drugs and Colonoscopic Intervention

Distinct Mechanism of Anti-Hemophilic FVIII Activation By Nascent FXa in the Tissue Factor-FVIIa Coagulation Initiation Complex Resistant to FXa-Directed Inhibition

Hemorrhagic complications may occur during anticoagulant therapy, but clinical studies indicate that FXa-directed anticoagulants are not inferior to vitamin K antagonists in preventing thrombosis while decreasing the incidence of intracranial bleeding. Anti-hemophilic FVIII has a central role in hemostasis, thus we hypothesized that elucidating effects of FXa-directed anticoagulants on FVIII function could advance understanding of mechanisms differentiating hemostasis and thrombosis. Currently, FVIII is thought to be activated by limited amounts of thrombin (FIIa) initially produced by FXa generated by the tissue factor (TF)-FVIIa complex. Activated FVIII (FVIIIa) then amplifies FXa generation through intrinsic tenase (FVIIIa-FIXa) complex, leading to more FIIa production. We now propose an alternative mechanism of FVIII activation resistant to the TF pathway inhibitor (TFPI) and direct anti-FXa anticoagulants. In this process, nascent FXa generated by the TF-FVIIa complex generates FVIIIa independently of FIIa feedback activation. We first verified whether TF-dependent FVIII activation by FXa can promote FIIa generation by FIXa-FVIIIa in human platelet-rich plasma (PRP). Addition of relipidated TF (0.15 pM) into PRP synergistically enhanced FIIa production by FIXa (20 pM) in a process requiring both FVIIa and FVIII. Synergistic FIIa generation was blocked by an anti-TF monoclonal antibody (MoAb) and the blockade was reversed by FVIIIa, supporting the concept that FVIII activation is a key TF-dependent function in the process. We further tested the hypothesis in vivo using a ferric chloride-induced mouse thrombosis model. Concurrent administration of anti-FXI and anti-TF MoAbs at individually ineffective doses markedly reduced fibrin deposition onto the lesion, suggesting that TF and contact phase (CP)-initiated pathways cooperate in generating coagulation proteases leading to thrombosis. Infusion of FVIIIa, but not FVIII, by-passed the inhibitory effect of the anti-TF MoAb, but full FXI inhibition still prevented thrombosis, in agreement with the concept FVIII activation in vivo is a TF-dependent function. We next evaluated whether the TF pathway can generate FVIIIa in reactions with purified components including FVIII, FX, FV and FII in which relipidated TF (50 pM) provided a limiting phospholipid surface. Addition of FIXa (10 nM) with FVIIa (200 pM) synergistically increased FXa generation even when the thrombin inhibitor dansylarginine N-(3-ethyl-1,5-pentanediyl)amide (DAPA) was added or wild-type FII was replaced by the catalytically inactive FII S195A mutant. TF-FVIIa-induced FVIII activation was reduced, but not abolished, by DAPA. Thus, TF-FVIIa-mediated FVIII activation by FXa is sufficient for productive FVIIIa-FIXa complex assembly even without FIIa feedback activation. TFPI/protein S and antithrombin/pentasaccharide did not prevent FIIa-independent but inhibited FIIa-dependent FVIIIa generation, indicating that the newly discovered FIIa-independent functional link between TF and intrinsic pathways escapes control by physiologic inhibitors. To verify that FVIII activation is a distinct function of FXa possibly still assembled within the TF-FVIIa complex, we showed that the nematode anticoagulant protein (NAP) c2-stabilized complex of FXa, TF and catalytically inactive FVIIa (S195A) - in which FXa is the only active protease - but not free FXa with NAPc2, generated FVIIIa even in the presence of physiologic TFPI inhibition. At therapeutic concentrations, the FXa-directed anticoagulants, rivaroxaban and apixaban, moderately inhibited FVIII activation by nascent FXa, while both blocked FVIII activation by free and RussellÕs viper venom-activated FXa, indicating resistance of nascent FXa-mediated FVIIIa generation also to pharmacologic FXa inhibition. Inefficient inhibition of FVIII activation by FXa anticoagulants allowed FVIIIa/FIXa-dependent thrombin production even under TFPI control. In conclusion, persistent FVIII activation preserving hemostasis could explain why the antithrombotic efficacy of FXa inhibitors is associated with a relatively low risk of bleeding complications. Our findings provide new perspectives for designing antithrombotic intervention with lesser anti-hemostatic effects as well as for personalized evaluation of bleeding risk during anticoagulant therapy. DisclosuresGale:University of California, San Diego: University of California, San Diego Patents & Royalties. Gruber:Aronora, Inc: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Petersen:NovoNordisk A/S: Employment.

Abstract 17480: Safety and Efficacy of Continuous Anticoagulant and Antiplatelet Combination Therapy during Implantation of Cardiac Rhythm Devices

Introduction: Previous studies showed that continuous anticoagulation during implantation of cardiac rhythm device (CRD) was safe. However, the safety and efficacy of continuous anticoagulant and antiplatelet combination therapy in patients undergoing CRD interventions has not been clearly defined. Hypothesis: We sought to evaluate the safety and efficacy of this therapy during implantation of CRD. Methods: A total of consecutive 300 patients (mean 68.7 years old, 171 males) underwent CRD implantation were enrolled from April 2012 to December 2012. We divided patients into Non-drug (patients without antithrombotic therapy), Single-drug (patients with anticoagulant or antiplatelet therapy), and Combination-drug (patients with anticoagulant and antiplatelet therapy) group, and evaluated the clinical outcome among 3 groups. Clinically significant hematoma was defined as device-pocket hematoma that needed prolonged hospitalization, interruption of antithrombotic therapy, surgical intervention, or blood products transfusion. Results: The number of Non-drug, Single-drug, and Combination-drug groups was 129, 139, and 32, respectively. Clinical outcome was shown in Table. Hematoma occurred significantly more in Combination-drug than Non-drug group, but occurrence of clinically significant hematoma was not different among 3 groups. Cardiac tamponade was none and thrombo-embolic event was rare. Conclusions: Continuous anticoagulant and antiplatelet combination therapy was safe and effective during implantation of CRD.

Risk factors analysis of pulmonary embolism among 182 patients and comparison of the effect of different therapy

Objective To study the risk factors of pulmonary embolism and comparison of the effect of different therapy.Methods Risk factors of 182 patients with pulmonary embolism were analyzed retrospectively.The patients were randomly divided into simple drug group and drug joint intervention group.Simple drug group was given heparin and warfarin,or jiont urokinase fibrinolytic therapy.The drug joint intervention group was given the same drug therapy joint vena cava filter implantation and/or catheter broken bolt therapy.After different treatment,the clinical prognosis was compared between the two groups.Results Of 182 patients with pulmonary embolism,the elderly and smoking prevalence rate increased significantly,deep vein thrombosis,cardiovascular disease,cancer,blood system diseases,trauma and surgery,chronic lung disease,fracture and orthopaedic surgery were the main risk factors.The effective rate and mortality between the pure drug therapy group and drug joint intervention group had no significant differences(x2 =0.145,P ＞ 0.05).Conclusion The incidence of pulmonary embolism is closely related to the risk factors.Cancer is one of the important diseases caused by pulmonary embolism.In a timely manner to give the antithrombotic drug treatment has great significance to the prognosis of pulmonary thromboembolism,there was no significant difference compared with the antithrombotic joint intervention. Key words: Pulmonary thromboembolism; Risk factors

Mechanical antithrombotic intervention by LAA occlusion in atrial fibrillation

Stroke in patients with atrial fibrillation (AF) is often associated with substantial morbidity and mortality. Oral anticoagulation remains the first-line approach to stroke prevention in such individuals; however, for a considerable proportion of patients, traditional treatment using warfarin is limited by a number of factors, such as the inconvenience of frequent therapeutic monitoring and the risk of haemorrhage. The development of new oral anticoagulants with improved efficacy and safety profiles has provided viable options for oral anticoagulation therapy in patients with nonvalvular (nonrheumatic AF). Nonetheless, in patients who have an increased risk of major haemorrhage, a nonpharmacological approach to antithrombotic therapy remains an attractive alternative. The left atrial appendage (LAA) has been found to be the source of >90% of thrombi in patients with nonvalvular AF; thus, prevention of thrombus formation via transcatheter mechanical LAA occlusion is a novel therapeutic target for stroke prevention in this patient population. In this Review, we present the rationale for LAA occlusion in patients with AF, the available occlusion devices and their clinical evidence to date. We also discuss the roles of various imaging techniques in device implantation and the management strategy for associated procedural complications.

Extracranial-Intracranial Bypass Surgery for Stroke Prevention in Hemodynamic Cerebral Ischemia

Context Patients with symptomatic atherosclerotic internal carotid artery occlusion (AICAO) and hemodynamic cerebral ischemia are at high risk for subsequent stroke when treated medically. Objective To test the hypothesis that extracranial-intracranial (EC-IC) bypass surgery, added to best medical therapy, reduces subsequent ipsilateral ischemic stroke in patients with recently symptomatic AICAO and hemodynamic cerebral ischemia. Design Parallel-group, randomized, open-label, blinded-adjudication clinical treatment trial conducted from 2002 to 2010. Setting Forty-nine clinical centers and 18 positron emission tomography (PET) centers in the United States and Canada. The majority were academic medical centers. Participants Patients with arteriographically confirmed AICAO causing hemispheric symptoms within 120 days and hemodynamic cerebral ischemia identified by ipsilateral increased oxygen extraction fraction measured by PET. Of 195 patients who were randomized, 97 were randomized to receive surgery and 98 to no surgery. Follow-up for the primary end point until occurrence, 2 years, or termination of trial was 99% complete. No participant withdrew because of adverse events. Interventions Anastomosis of superficial temporal artery branch to a middle cerebral artery cortical branch for the surgical group. Antithrombotic therapy and risk factor intervention were recommended for all participants. Main Outcome Measure For all participants who were assigned to surgery and received surgery, the combination of (1) all stroke and death from surgery through 30 days after surgery and (2) ipsilateral ischemic stroke within 2 years of randomization. For the nonsurgical group and participants assigned to surgery who did not receive surgery, the combination of (1) all stroke and death from randomization to randomization plus 30 days and (2) ipsilateral ischemic stroke within 2 years of randomization. Results The trial was terminated early for futility. Two-year rates for the primary end point were 21.0% (95% CI, 12.8% to 29.2%; 20 events) for the surgical group and 22.7% (95% CI, 13.9% to 31.6%; 20 events) for the nonsurgical group (P = .78, Z test), a difference of 1.7% (95% CI, −10.4% to 13.8%). Thirty-day rates for ipsilateral ischemic stroke were 14.4% (14/97) in the surgical group and 2.0% (2/98) in the nonsurgical group, a difference of 12.4% (95% CI, 4.9% to 19.9%). Conclusion Among participants with recently symptomatic AICAO and hemodynamic cerebral ischemia, EC-IC bypass surgery plus medical therapy compared with medical therapy alone did not reduce the risk of recurrent ipsilateral ischemic stroke at 2 years. Trial Registration clinicaltrials.gov Identifier: NCT00029146

Direct thrombin inhibitors and factor Xa inhibitors in patients with cerebrovascular disease

Stroke is a leading cause of cardiovascular morbidity and mortality worldwide. Approximately, 795,000 strokes occur in the USA each year, 610,000 of which are first events, and 185,000 of which are recurrent events. Of all strokes, 87% are ischemic strokes. Novel anticoagulants serve as an alternative antithrombotic intervention in patients with ischemic cerebrovascular disease. This paper reviews the role of the novel anticoagulants, dabigatran, rivaroxaban and apixaban, in stroke prevention among patients with nonvalvular atrial fibrillation.

Anti-inflammatory and anti-thrombotic intervention strategies using atorvastatin, clopidogrel and knock-down of CD40L do not modify radiation-induced atherosclerosis in ApoE null mice

Background and purposeWe previously showed that irradiating the carotid arteries of ApoE−/− mice accelerated the development of macrophage-rich, inflammatory and thrombotic atherosclerotic lesions. In this study we investigated the potential of anti-inflammatory (atorvastatin, CD40L knockout) and anti-thrombotic (clopidogrel) intervention strategies to inhibit radiation-induced atherosclerosis. Material and methodsApoE−/− mice were given 0 or 14Gy to the neck and the carotid arteries were harvested at 4 or 28weeks after irradiation. Atorvastatin (15mg/kg/day) or clopidogrel (20mg/kg/day) was given in the chow; control groups received regular chow. Clopidogrel inhibited platelet aggregation by 50%. CD40L−/−/ApoE−/− and ApoE−/− littermates were also given 0 or 14Gy to the neck and the carotid arteries were harvested after 30weeks. ResultsClopidogrel decreased MCP-1 expression in the carotid artery at 4weeks after irradiation. Expression of VCAM-1, ICAM-1, thrombomodulin, tissue factor and eNOS was unchanged in atorvastatin and clopidogrel-treated mice. Neither drug inhibited either age-related or radiation-induced atherosclerosis. Furthermore, loss of the inflammatory mediator CD40L did not influence the development of age-related and radiation-induced atherosclerosis. ConclusionsThe effects of radiation-induced atherosclerosis could not be circumvented by these specific anti-inflammatory and anti-coagulant therapies. This suggests that more effective drug combinations may be required to overcome the radiation stimulus, or that other underlying mechanistic pathways are involved compared to age-related atherosclerosis.

Antithrombotic treatment for recurrent pregnancy loss?

Recurrent pregnancy loss (RPL) is a major issue for women's health. Acquired and heritable thrombophilias are associated with RPL, this association could reflect a general prothrombotic phenotype rather than a specific thrombophilia. Antithrombotic intervention has therefore been assessed for RPL. Two large randomised trials with untreated control groups showed no benefit from antithrombotic treatment with LMWH and low dose aspirin in women with RPL. These trials had insufficient power to exclude an effect in women with underlying thrombophilia, ≥ 3 losses, or late losses. Antithrombotic intervention should not be recommended for unexplained RPL in general. There may be specific groups such as those with an heritable thrombophilia, or with three or more losses, or second trimester losses that might benefit and where further trials are required. Further there is a need to consider the benefits of LMWH on implantation such as in women undergoing assisted conception therapy.