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[Is the assessment of prothrombin fragment F1+2 for monitoring of heparin therapy in patients with deep vein thrombosis useful?].

Prothrombin fragments (F1+2) can be used to monitor oral anticoagulation; their generation is also suppressed by heparin. We studied the course of F1+2, aPTT, heparin doses administered and heparin concentrations, as well as prothrombin time, during the first 7 days of heparin therapy (target aPTT 70 s) and overlapping oral anticoagulation (target INR 2-3) in 26 patients routinely treated for deep venous thrombosis (deep venous thrombosis +/- pulmonary embolism, 23 patients) or pulmonary embolism with a history of recurring deep venous thrombosis (3 patients). Although we found significant suppression of F1+2 between all pre- and post-treatment values, a transient, significant increase was seen on days 2-4. The amount of heparin given was stable from day 1-5; the fact of a transient increase in F1+2 might thus indicate that heparin doses routinely used are too low for the treatment of hypercoagulability in deep venous thrombosis in patients. We also found a decrease in heparin concentration on day 2, which may be explicable by changed pharmacokinetics of heparin in individuals with deep venous thrombosis. In conclusion, F1+2 may be useful for monitoring heparin treatment and oral anticoagulation in deep venous thrombosis patients from a laboratory point of view. However, larger studies are necessary to confirm these results. It remains to be clarified whether monitoring of anticoagulation by molecular markers might improve therapy of deep venous thrombosis. Such studies are in progress.

Heparin↗

Comparison of thrombin active site and exosite inhibitors and heparin in experimental models of arterial and venous thrombosis and bleeding.

Different pharmacological approaches to thrombin inhibition were compared for their effects on thrombosis and bleeding time in anesthetized rats. Thrombosis was induced in the carotid artery by transmural vessel injury and in the vena cava by partial blood flow stasis combined with mild endothelial disruption. Small mesenteric arteries were punctured with a hypodermic needle to measure the bleeding time. Dose-response relationships were determined with a thrombin active site inhibitor, N-methyl (GYKI 14,766); a thrombin exosite inhibitor, succinyl-Phe-Glu-Pro-Ile-Pro-Glu-Glu-Tyr-cyclohexylalanine-Gln (BMS 180,742); and heparin. BMS 180,742 interferes with fibrinogen binding to the thrombin exosite but, unlike GYKI 14,766, it does not block thrombin's catalytic site. The effects on thrombosis and bleeding time were correlated with ex vivo clotting times using the activated partial thromboplastin time for heparin and the thrombin time for GYKI 14,766 and BMS 180,742. Venous thrombosis was inhibited more than 90% by all three inhibitors at doses that either produced threshold increases or had no effect on bleeding and clotting times. Arterial thrombosis was inhibited 82% by GYKI 14,766 and 63% by heparin but it was not inhibited by BMS 180,742. These antithrombotic activities were accompanied by a maximal activated partial thromboplastin time increase and doubling of the bleeding time with heparin and a maximal thrombin time prolongation and 35% increase in bleeding time with GYKI 14,766. These results suggest that thrombin inhibitors, which act at the active site or exosite or through antithrombin III, are equally efficacious against venous thrombosis but active site inhibitors are the most effective against arterial thrombosis.

Amino Acid Sequence↗

Thrombosis and thrombocytopenia in antiphospholipid syndrome (idiopathic and secondary to SLE): first report from the Italian Registry. Italian Registry of Antiphospholipid Antibodies (IR-APA).

BACKGROUND: Since 1989 we have been promoting an Italian Registry of patients with APA (IR-APA), and we report here the analysis on 319 cases (80 males and 239 females, aged from 2 to 76 years, median 31 years) from 22 institutions. METHODS: A two-page questionnaire was prepared, divided into 4 parts: 1. personal data, 2. associated conditions, 3. biology (for the diagnosis of APA), 4. history of thromboembolism, haemorrhage and pregnancy. Every information was entered into a computerized registry. RESULTS: The IR-APA included 207 cases of idiopathic APA and 112 cases of APA secondary to SLE. Seventy-one out 207 (34.3%) and 47 out of 112 (42%) cases experienced arterial and/or venous thrombosis, respectively (not significant). Among patients with a thrombotic history, venous thrombosis were experienced by 60.5% vs 57.4%, arterial thrombosis by 26.7% vs 31.9%. Venous thrombosis of the legs and arterial thrombosis of the cerebral vessels were the most common types of thrombosis in both groups. Thrombocytopenia was present in 27.7% of idiopathic APA vs 22.4% of secondary APA (not significant). Four patients experienced major haemorrhagic events. CONCLUSIONS: This retrospective study shows that the prevalence of thrombosis and thrombocytopenia in patients with idiopathic APA is similar to that observed in patients with APA secondary to SLE.

Adolescent↗

The roles of von Willebrand factor and factor VIII in arterial thrombosis: studies in canine von Willebrand disease and hemophilia A.

We have studied the roles of von Willebrand factor (vWF) and factor VIII in arterial thrombosis in four canine phenotypes: normal (n = 6), hemophilia A (n = 11), von Willebrand disease (vWD) (n = 9), and hemophilia A/vWD (n = 1). vWF activity was determined by botrocetin-induced agglutination of fixed human platelets and vWF antigen (vWF:Ag) by Laurell electroimmunoassay and crossed immunoelectrophoresis. Plasma from normal dogs and those with hemophilia A had vWF activity, vWF:Ag, and a full range of vWF:Ag multimers on gel electrophoresis equivalent to normal canine plasma pool. Platelet cytosol contents were isolated by freezing and thawing, triton X-100 solubilization, or sonication of washed platelets with and without protease inhibitors and inhibitors of platelet activation. Washed platelets were also stimulated with calcium ionophore and MgCl2. There was no measurable vWF activity or vWF:Ag in platelet lysates or releasates in any dog regardless of phenotype. All dogs were studied using a standard arterial stenosis and injury procedure to induce arterial thrombosis. Thromboses were detected by cyclic reductions in Doppler blood flow velocity. Vessels were examined by light and scanning electron microscopy. Thrombosis developed in the arteries of normal (9 of 10) and hemophilia A dogs (16 of 16) but in none of the vWD dogs (0 of 10). Infusion of canine vWF cryoprecipitate into vWD dogs markedly shortened bleeding time but did not support thrombosis as seen in dogs with vWF in the plasma and subendothelium. Thrombosis, then, fails to occur when vWF is absent from the plasma and subendothelial compartments or present only in the plasma compartment. These data are consistent with the hypothesis that vWF in the plasma and subendothelium supports thrombosis. Neither plasma FVIII nor platelet vWF is essential for thrombosis in this model.

Animals↗

Vascular graft thrombosis after pancreatic transplantation: univariate and multivariate operative and nonoperative risk factor analysis.

BACKGROUND: Vascular thrombosis is still the leading cause of nonimmunologic, technical pancreatic transplant graft failures. The paucity of published data--coupled with our large institutional experience with pancreatic transplantation in all recipient and transplant categories, using a wide spectrum of surgical techniques--provided the impetus for a retrospective study of graft thrombosis risk factors. STUDY DESIGN: Four hundred thirty-eight patients with pancreatic transplants (45 percent simultaneous pancreas-kidney [SPK], 23 percent pancreas-after-kidney [PAK], and 32 percent pancreatic transplants alone [PTA] and with Type I insulin-dependent diabetes mellitus were studied retrospectively. Of 438 pancreatic transplants, 90 percent were bladder-drained and 10 percent were enteric-drained. Ninety-three percent were from cadaver donors, 90 percent were whole-organ grafts, and 20 percent were retransplantations. Quadruple immunosuppression was given. For bladder-drained, whole-organ transplantations (n=378), we performed Cox regression analyses to study the impact on pancreatic graft thrombosis of donor, recipient, mode of preservation, and surgical variables. RESULTS: The overall thrombosis rate was 12 percent (5 percent arterial, 7 percent venous). For cadaver, bladder-drained, whole-organ pancreatic transplants, the thrombosis incidence was highest in PAK recipients (20 percent). The PAK category was also found to be an independent risk factor for thrombosis by stepwise Cox regression analysis. In separate stepwise Cox regression analyses for each category, other identified risk factors for thrombosis included the following: donor age (PAK, PTA); cardiocerebrovascular cause of donor death (SPK, PAK); the use of an aortic Carrel patch (SPK); arterial pancreatic graft reconstruction using a splenic artery to superior mesenteric artery anastomosis (SPK, PTA) or an interposition graft between the splenic artery and the superior mesenteric artery (PTA); portal vein extension graft (PAK); left-sided implantation into the recipient (PAK); and graft pancreatitis (defined as hyperamylasemia exceeding five days post-transplant [PAK, PTA]). CONCLUSIONS: Older donors or those who died of cardiocerebrovascular disease should not be considered for any recipient category. Preservation time needs to be minimized and strategies need to be developed to decrease graft pancreatitis. Surgically, left-sided implantation and arterial reconstructions other than the Y-graft also increase risk, as do portal vein extensions. Renal transplants alone in prospective PAK recipients with Type I diabetes mellitus should, therefore, always be implanted left-sided to allow for right-sided pancreatic graft placement.

Adult↗

Sagittal sinus thrombosis in adult minimal change nephrotic syndrome.

Nephrotic syndrome causes a hypercoagulable state, leading to both venous and arterial thrombosis. The mechanisms are as yet unclear, but numerous alterations in coagulant and anti-coagulant factors have been reported [Llach et al. 1985, Harris and Ismail 1994]. The most common clinical features in adults are renal vein thrombosis, femoral vein thrombosis and pulmonary embolism, although thrombosis in numerous other arterial and venous sites has been described [Cameron 1984, Llach et al. 1985]. Intracranial thrombosis is rare, although in adult nephrotic syndrome arterial thrombosis is well recognized [Fuh et al. 1991]. We report a patient with minimal change nephrotic syndrome who developed venous sinus thrombosis detected by magnetic resonance (MR) scanning.

Adult↗

Factor V Leiden, antiphospholipid antibodies and thrombosis in systemic lupus erythematosus.

Thromboembolic complications are frequently observed in patients with systemic lupus erythematosus (SLE). Significant associations have been reported between these complications and the presence of antiphospholipid antibodies, notably the lupus anticoagulant and anticardiolipin antibodies. Factor V Leiden is a genetic disorder associated with an increased risk of venous thrombosis. We studied these factors in 173 patients with SLE in relation to both arterial and venous thrombosis. The frequency of factor V Leiden in SLE patients in comparable to that in the Dutch population (5%) and a risk factor for venous thrombosis (odds ratio 4.9; CI 1.2-19.6), but not for arterial thrombosis. The lupus anticoagulant is a risk factor for both arterial thrombosis (odds ratio 7.1: CI 2.9-17.4) and venous thrombosis (odds ratio 6.4; CI 2.7-15.4). From multivariate analysis, both the lupus anticoagulant and factor V Leiden appeared independent risk factors for venous thrombosis.

Adolescent↗

Ovarian vein thrombosis during cesarean section. A report of two cases.

BACKGROUND: Puerperal ovarian vein thrombosis occurs in 0.2-0.5% of deliveries. It is usually thought to result from infection, but it has been hypothesized that thrombosis may occur as a primary event, and radiologic studies raise the possibility that ovarian vein thrombosis may occur quite frequently. CASES: Case 1 had right ovarian vein thrombosis diagnosed at the time of nonemergency cesarean section for placenta previa. This was treated with ligation of the infundibulopelvic ligament above the level of the clot. Subsequent magnetic resonance imaging showed contralateral ovarian vein thrombosis, and therefore anticoagulant therapy was begun. The patient was asymptomatic. Case 2 had right ovarian vein thrombosis extending to the inferior vena cava diagnosed at elective repeat cesarean section. She was heparinized in the recovery room; subsequent ventilation/perfusion scan showed a probable pulmonary embolism. Both patients recovered uneventfully. CONCLUSION: These two cases demonstrate that ovarian vein thrombosis may occur as a primary event, in the absence of infection, and result in pulmonary embolism. Individualized management based on operative findings is recommended.

Adult↗

Superficial thrombophlebitis and deep vein thrombosis. A controversial association.

BACKGROUND: Superficial thrombophlebitis is a common and benign disease. However, an association with deep vein thrombosis, a more severe condition that requires anticoagulant treatment, has been reported repeatedly with frequencies ranging from 12% to 44%. METHODS: All consecutive records of patients with lower limb superficial thrombophlebitis were retrieved from the laboratory database over a 6-year period (1989-1994), and association with deep vein thrombosis was sought. Also, to detect late events, consultations were registered over a 3-month period after the initial examination. Patients with the association of superficial thrombophlebitis and deep vein thrombosis were also compared with a randomly selected sample of subjects with superficial thrombophlebitis only. RESULTS: Objectively confirmed deep vein thrombosis was detected in 31 patients (5.6%; 95% confidence interval, 3.8%-7.9%). Additional late thromboembolic events were detected in 1.7% of the patients during the 3-month follow-up period. Previous immobilization was more common among patients with deep vein thrombosis associated with superficial phlebitis (11/31, 36%) than among a randomly selected subset of patients with superficial thrombophlebitis only (13/93, 14%), the difference being statistically significant (P < .02). CONCLUSIONS: When large populations of patients with superficial thrombophlebitis are studied, the association with deep vein thrombosis appears rather small. Thus, systematic screening for deep vein thrombosis may not be warranted in the presence of superficial thrombophlebitis unless additional risk factors (eg, immobilization) are present.

Adult↗

IL-10 regulates thrombus-induced vein wall inflammation and thrombosis.

Vein wall inflammation associated with venous thrombosis is mediated by an imbalance in proinflammatory as compared with antiinflammatory molecules. We hypothesize that IL-10 is an important antiinflammatory cytokine that influences vein wall inflammation and thrombus propagation during venous thrombosis. To test this hypothesis a model of inferior vena caval thrombosis was used. Studies were performed at sacrifice 2 days after thrombus induction and included leukocyte morphometrics, myeloperoxidase activity, vein wall permeability, thrombus weight, and IL-10 ELISA analysis from the vein wall. IL-10 was elevated in the vein wall during venous thrombosis. Neutralization of IL-10 increased inflammation, while supplementation with rIL-10 demonstrated a dose- and time-dependent decrease in inflammation. Interestingly, a low 2.5-microg rIL-10 dose given at time of initiation of thrombosis most significantly decreased inflammation. Thrombus weight was importantly diminished by reconstitution of IL-10. These studies support an important role for IL-10 in the regulation of thrombus-associated inflammation and thrombosis and suggest that IL-10 could be used as a therapeutic agent in the treatment of venous thrombosis.

Animals↗

Hemostatic effects of oral contraceptives in women who developed deep-vein thrombosis while using oral contraceptives.

OBJECTIVE: Comparison of the effect of oral contraceptives on hemostatic variables in venous thrombosis patients (thrombosis while using oral contraceptives) with the effect in healthy control subjects. Our aim was to assess whether some of these effects were more pronounced in women who had suffered thrombosis, i.e., whether these were "hemostatic hyperresponders". STUDY DESIGN: A population-based case-control study, the Leiden Thrombophilia Study. MATERIALS AND METHODS: We investigated 99 pre-menopausal women, age 15-49 years, who had used oral contraceptives at the time of a first, objectively confirmed episode of deep-vein thrombosis. They were not pregnant, nor in puerperium, nor had had a recent miscarriage, and were not using injectable progestogens, nor suffering from inherited coagulation defects. The median time between occurrence of deep-vein thrombosis and venepuncture was 18 months, and 30 of the 99 women were still using oral contraceptives, while 69 had discontinued oral contraceptive use. In addition, a group of 153 control women (54 of them were oral contraceptive users and 99 were non-users) were studied. The following hemostatic variables were measured: APTT, factor VII, factor VIII, factor XII, fibrinogen, prothrombin, total antithrombin, normalised activated protein C sensitivity ratio (n-APC-sr), protein C, protein S and free protein S. RESULTS: We found marked and significant effects of oral contraceptive use on the levels of several clotting factors, with an increase in factor VII, factor XII, protein C and a decrease in antithrombin, n-APC-sr and protein S. Less marked effects that were non-significant or only significant in either patients or controls, were an increase in factor VIII, fibrinogen and prothrombin and a decrease in the APTT and free protein S. In the former thrombosis patients several of these effects of oral contraceptives were more pronounced than in healthy women: specifically on factor VII, antithrombin, n-APC-sr and protein C. CONCLUSIONS: Our results of the effects of oral contraceptives generally confirm previous reports in healthy volunteers. Our data also show that in former deep-vein thrombosis patients these effects are more pronounced. Apparently some women become "high hemostatic responders" when exposed to oral contraceptives, and they may be the women most vulnerable to its thrombogenic effects.

Abortion, Spontaneous↗

Refractory ascites due to portal vein thrombosis in liver cirrhosis--report of two cases.

Portal vein thrombosis as a complication of liver cirrhosis has been reported to be extremely rare in Japan, as compared with European countries. There are few reports discussing the correlation of portal vein thrombosis with refractory ascites. Between January 1994 and December 1995, 20 cases (91%) of 22 patients with liver cirrhosis with ascites admitted to our hospital responded well within 2 months to a combination therapy of diuretics and albumin infusion, and the other two cases (9%) with refractory ascites were associated with portal vein thrombosis. The ascites in the first patient continued for 1 year, despite diuretics and albumin infusion therapy, and portal vein thrombosis was confirmed by autopsy. The ascites in the other patient continued for more than 4 months, and portal vein thrombosis was detected by ultrasound. Portal vein thrombosis was not found in the other 20 cirrhotic patients with ascites. These two cases suggest that portal vein thrombosis may be a contributing factor to refractory ascites in patients with decompensated liver cirrhosis.

Ascites↗

New experimental model of sinus and cortical vein thrombosis in pigs for MR imaging studies.

INTRODUCTION: Diagnosis of cerebral sinus vein thrombosis is still a challenge for imaging. MRI and MRA play a major role in sinus imaging. For further development of MR techniques, MR-compatible animal models are required. The aim of this study was to develop an animal model for sinus thrombosis and additional cortical vein thrombosis with a clot of human blood for MR imaging studies. METHODS: A combined surgical and interventional approach was carried out in 13 pigs. After minimal invasive surgical access to the anterior superior sagittal sinus and cortical vein, thrombosis with human blood was induced using an interventional catheter approach. MR imaging was performed prior to and after thrombus induction. RESULTS: Sinus thrombosis was induced in 12 of 13 animals. Three animals suffered acute subdural haemorrhage; one of these animals died during the intervention, and one died after thrombus induction. MR imaging of the thrombosed sinus could easily be performed without significant artefacts in 11 of 13 animals. CONCLUSION: This new model of sinus and cortical vein thrombosis with a clot of human blood allows artefact-free imaging studies on MR.

Animals↗

Thrombosis in end-stage renal disease.

Although renal failure has classically been associated with a bleeding tendency, thrombotic events are common among patients with end-stage renal disease (ESRD). A variety of thrombosis-favoring hematologic alterations have been demonstrated in these patients. In addition, "nontraditional" risk factors for thrombosis, such as hyperhomocysteinemia, endothelial dysfunction, inflammation, and malnutrition, are present in a significant proportion of chronic dialysis patients. Hemodialysis (HD) vascular access thrombosis, ischemic heart disease, and renal allograft thrombosis are well-recognized complications in these patients. Deep venous thrombosis and pulmonary embolism are viewed as rare in chronic dialysis patients, but recent studies suggest that this perception should be reconsidered. Several ESRD treatment factors such as recombinant erythropoietin (EPO) administration, dialyzer bioincompatibility, and calcineurin inhibitor administration may have prothrombotic effects. In this article we review the pathogenesis and clinical manifestations of thrombosis in ESRD and evaluate the evidence that chronic renal failure or its management predisposes to thrombotic events.

Acute Kidney Injury↗

Incidence and risk of venous thromboembolism in patients with verified arterial thrombosis: a population study based on 23,796 consecutive autopsies.

BACKGROUND: The relationship between atherothrombotic disease and venous thromboembolism (VTE) remains unclear. PATIENTS AND METHODS: In a cohort of 23,796 consecutive autopsies, performed using a standardized procedure and representing 84% of all in-hospital deaths between 1970 and 1982 in an urban Swedish population, we investigated the relationship between verified arterial thrombosis and VTE, with the hypothesis that patients with thrombosis in major artery segments have increased odds of VTE. RESULTS: We found an increased risk of VTE in patients with arterial thrombosis (Odds ratio; OR adjusted for gender and age 1.4, 95% confidence interval; CI 1.3-1.5) (P < 0.001). Patients with cervico-cranial and peripheral artery thrombosis had an excess risk even when controlling for age and major concomitant diseases. A negative association between coronary thrombosis and VTE in the univariate analysis (OR 0.7; 95% CI 0.6-0.8) (P < 0.001), was less pronounced in the multivariate analysis (OR 0.8; 95% CI 0.7-1.0) (P = 0.016). CONCLUSIONS: A positive association between atherothrombosis and VTE was confirmed, except in patients with coronary thrombosis, where IHD as competing death cause is a possible confounder. Our findings indicate a potential for directed prevention, but may also imply similarities in etiology.

Aged↗

Clinical picture of patients with cerebral venous thrombosis and patterns of dural sinus involvement.

BACKGROUND/OBJECTIVES: Cerebral venous thrombosis may cause focal brain lesions or an isolated intracranial hypertension without focal signs. We investigated whether these different clinical pictures correspond to different patterns of dural sinus thrombosis. METHODS: Forty-eight patients with cerebral venous thrombosis were classified in 2 groups based on the clinical and neuroradiological picture at admission: one group had clinical signs of intracranial hypertension, without focal neurological signs; the other group had focal neurological signs. The extension of thrombosis in dural sinuses was compared between the groups. RESULTS: The amount of thrombosed sinuses was significantly different in the two groups, the involvement of the dural sinuses being greater in patients with isolated intracranial hypertension. CONCLUSIONS: The clinical picture of cerebral venous thrombosis is related to the pattern of dural sinus involvement. The presence of isolated intracranial hypertension is more frequent in patients with a more extended thrombosis of the dural sinuses.

Angiography, Digital Subtraction↗

Venous thrombosis after elective hip replacement--the influence of preventive intermittent calf compression and of surgical technique.

The effect of preventive intermittent calf compression on the incidence, distribution and extent of venous thrombosis after elective hip replacement was examined by randomized trial in 90 patients who were screened for postoperative thrombosis with 125I-fibrinogen leg scanning and impedance plethysmography, followed by routine venography on the seventh postoperative day. Venography showed that leg compression reduced the incidence of calf vein thrombosis from 45 per cent (21/47) in untreated patients to 16 per cent (7/43) (P less than 0.005), but not that of proximal (i.e. popliteal or femoral) vein thrombosis, which occurred in 23 per cent of treated and 26 per cent of untreated patients. However, proximal vein thrombosis appeared to be less extensive in treated patients. Proximal vein thrombosis was found in 40 per cent of patients who had hip replacement by a modified Charnley technique (17/43 patients), and 9 per cent of patients in whom a posterior surgical approach was used (4/43 patients) (P less than 0.005), strongly suggesting that surgical technique may influence the proximal vein thrombosis rate after elective hip replacement.

Aged↗

Novel Antithrombotic Strategies for the Treatment of Coronary Artery Thrombosis: A Critical Appraisal.

Large-scale clinical trials have demonstrated that treatment of patients with acute myocardial infarction and unstable angina with antithrombotic agents significantly improves outcome. Despite the proven benefit of current therapies, there is a widespread perception that outcome could be enhanced further with novel antithrombotic agents. Enthusiasm for novel antithrombotic strategies has been stimulated by recent advances in the understanding of the mechanisms responsible for coronary artery thrombosis, which has led to the development of diverse inhibitors of platelet function and coagulation factors. In experimental models of coronary artery thrombosis, aspirin and heparin have been ineffective in preventing recurrent thrombosis after coronary thrombolysis and in preventing the progression of thrombosis in response to strong thrombogenic stimuli. In contrast, inhibitors of the platelet fibrinogen receptor, direct-acting thrombin inhibitors, and inhibitors of coagulation factors that promote elaboration of thrombin have been shown to be effective in attenuating arterial thrombosis in a variety of experimental preparations. Initial clinical trials with these agents have also documented efficacy in attenuating thrombotic events in patients treated with coronary thrombolysis and in those with unstable angina. However, optimal doses of novel antithrombotic agents, the degree to which combination antiplatelet and anticoagulant therapies are needed, and the risk/benefit ratio associated with specific novel antithrombotic drugs are still relatively undefined. With regard to the latter, it is possible that the large-scale clinical trials now in progress may show an increase in bleeding complications with novel anticoagulants compared with conventional therapy. Nonetheless, there are considerable data that suggest that treatment with aspirin and heparin is not completely effective in preventing the progression of thrombosis or its recurrence after interventions in high-risk subgroups of patients with coronary artery thrombosis and unstable coronary artery disease. Accordingly, continued investigation of a large variety of antithrombotic agents, both currently available and in development, should improve the treatment of high-risk patients with coronary disease if regimens with appropriate efficacy but without serious hemorrhagic effects can be designed.

Journal Article↗