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PubMed2003

Fibrinolytic function and atrial fibrillation.

Atrial fibrillation (AF) is the commonest sustained cardiac arrhythmia, which is associated with a substantial risk of stroke and thromboembolism. A prothrombotic or hypercoagulable state has been observed in these patients, although previous studies have mainly focused on various clotting factors, endothelial damage or dysfunction markers and platelet activation. However, fibrinolytic function has been less frequently studied, despite the fibrinolytic system playing an important role in preventing intravascular thrombosis. Indeed, increasing evidence suggests that an imbalance between the fibrinolytic function is of great importance in cardiovascular disease. This review will begin by providing a brief approach to fibrinolytic function and examine previous studies about fibrinolytic activity and atrial fibrillation.

Atrial Fibrillation↗
PubMed2003

Management of heparin-induced thrombocytopenia: a critical comparison of lepirudin and argatroban.

Heparin-induced thrombocytopenia (HIT) is a transient hypercoagulability state initiated, paradoxically, by the anticoagulant, heparin. It is characterized by antibody-induced activation of platelets, leading to thrombin generation. Many patients with HIT develop thrombosis; even when heparin is stopped because of "isolated HIT" detected during routine platelet count monitoring, 25-50% of patients subsequently develop symptomatic thrombosis. Thus, an alternative anticoagulant should be substituted for heparin when HIT is strongly suspected. Two direct thrombin inhibitors (DTIs), lepirudin and argatroban, have been studied for prevention and treatment of thrombosis in HIT patients. Lepirudin is a polypeptide that binds irreversibly to the fibrin-binding and catalytic sites on thrombin (bivalent inhibitor). In contrast, argatroban is a synthetic, small-molecule DTI that binds reversibly to the catalytic site alone (univalent inhibitor). Results of historically controlled clinical trials suggest both agents are effective for preventing and treating thrombosis in HIT. However, these agents have not been compared directly, and important differences in study design limit conclusions from indirect comparison. For example, lepirudin was given for 12-14 days (mean) in treatment studies of thrombosis complicating HIT, whereas argatroban was given only for 6-7 days, a difference that could explain apparent lower thrombosis rates (and greater bleeding) with lepirudin. Recently, the transition from DTI therapy to oral anticoagulation in patients with deep venous thrombosis (DVT) complicating HIT has been identified as a risk period for coumarin-induced venous limb gangrene. Thus, the DTI should be given alone during acute HIT, with oral anticoagulants deferred until substantial resolution of the thrombocytopenia has occurred.

Anticoagulants↗
PubMed2003

Increase in hepatic mRNA expression of coagulant factors in type 2 diabetic model mice.

AIM: The purpose of the study is to investigate whether hypercoagulation in diabetes is observed not only in increased plasma levels of the coagulative factors but also in increased hepatic mRNA levels. MATERIALS AND METHODS: The age-related changes of coagulation factors were determined using KK and KK-A(y) mice as a model for human type 2 diabetes mellitus. Expression of the alpha-, beta- and gamma-chains of fibrinogen-mRNA and prothrombin-mRNA from the mouse liver was examined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Hemoglobin A(1c) (HbA(1C)), plasma fibrinogen, triglyceride and insulin levels increased apparently, especially in KK-A(y) mouse at 4 months old. The mRNA levels of gamma-chain of fibrinogen significantly increased at 3 and 4 months of age in both mice. The mRNA levels of alpha- and beta-chains of fibrinogen and prothrombin were significantly increased in 4-month-old KK-A(y) mouse. CONCLUSIONS: These results suggest that the increase in hepatic mRNA expression of coagulant factors contributes to the hypercoagulable state in type 2 diabetic mice.

Animals↗
PubMed1998

Prothrombin fragment 1 + 2 measures treatment effect in patients with antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is characterized by recurrent thrombosis. The anticoagulant management of APS thrombosis remains controversial. Few reports on markers of in vivo activation of coagulation have been reported. To determine whether plasma levels of prothrombin fragment 1 + 2 (F1 +2) correlate with thrombotic risk and treatment effect in patients with APS, plasma F1 + 2 levels were followed in 57 patients with this syndrome for more than 2 years. Clinical findings were also observed in these patients. Plasma levels of F1 + 2 in patients with APS were significantly higher when compared with control subjects (p<.05). These results suggest patients with APS are in a hypercoagulable state. Plasma levels of F1 + 2 significantly decreased following treatment with either aspirin, or aspirin plus warfarin (p<.05 and p<.01, respectively). Recurrent thromboses or spontaneous abortions occurred in all eight patients whose plasma levels of F1 + 2 remained higher than 1 nmol/l after treatment with either aspirin alone or no anticoagulants. These patients were subsequently treated with warfarin as well as aspirin, and plasma levels of F1 + 2 decreased to less than 1 nmol/l, with no additional thrombotic events over the remainder of the 2-year follow-up. No fatal bleeding was observed in treated patients. Our results suggest plasma levels of F1 + 2 are useful indicators of successful treatment. It is also suggested that warfarin plus mini-dose aspirin therapy is effective for patients with APS to protect from recurrent thromboses without harmful side effects. Further, prospective cohort studies are needed to substantiate these associations.

Antiphospholipid Syndrome↗
PubMed1998

Thrombin generation and activation of the thrombomodulin protein C system in open heart surgery depend on the underlying cardiac disease.

The exposure of blood to foreign surfaces during extracorporeal circulation (ECC) leads to an activation of the coagulation system. In arteriosclerotic patients thrombin activation is increased and plasma fibrinogen is elevated, while protein C levels are reduced. In this study we investigated the influence of different cardiac diseases on ECC-induced thrombin generation and activation of the thrombomodulin-protein C system. Twenty-four patients undergoing either elective coronary artery bypass grafting (CABG) or elective aortic valve replacement (AVR) were included in the study. Blood samples were taken at different time intervals before, during and after ECC, and in the postoperative period. Plasma concentrations of thrombin-antithrombin III-complex (TAT), modified antithrombin (ATM), prothrombin fragment F1+2, free protein S, thrombomodulin, and protein C-antigen were determined by ELISA. Fibrinogen and antithrombin III levels were detected by nephelometry. Both groups were comparable with respect to biometric and ECC-related data. TAT concentrations were elevated in both groups after induction and increased during surgery (p<0.001). As a marker of thrombin generation levels of F1+2 were higher in the CABG group during cardiopulmonary bypass (p=0.003). In CABG patients ATM peaks were higher during ECC (p=0.0024). Significantly higher plasma thrombomodulin concentrations were found in CABG patients after induction (p<0.001), while protein S concentrations were higher in the AVR group (p=0.002). Protein C levels and antithrombin III concentrations did not differ between the groups. Patients undergoing CABG were found to have lower protein S levels and increased plasma thrombomodulin concentrations as markers of endothelial damage. In these patients contact activation and as a consequence thrombin generation takes place at a higher level, indicating a hypercoagulable state. Thromboembolic events in the perioperative period may be caused by different hemostatic changes in CABG patients.

Aged↗
PubMed1999

A specific inhibitor of factor Xa, DX-9065a, exerts effective protection against experimental tumor induced disseminated intravascular coagulation in rats.

(+)-2S-2-[4-[[(35S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-[7- amidino-2-napthyl]propanoic acid hydrochloride pentahydrate (DX-9065a) is an antithrombin III-independent, selective inhibitor of activated blood coagulation factor X (FXa). We investigated the protective effects of DX-9065a against tumor-bearing experimental disseminated intravascular coagulation (DIC) induced by the inoculation of AH-109A cells into rats. DX-9065a was subcutaneously administered at doses of 0.03 and 0.1 mg/kg/hour through an osmotic pump transplanted immediately after the inoculation of the tumor cells during the observation period. Platelet count decreased 12 days after the inoculation, concomitant with an increase in the thrombin-antithrombin III complex and fibrin and fibrinogen degradation products. Doses of 0.03 and 0.1 mg/kg/hour of DX-9065a significantly inhibited the decrease in plasma fibrinogen concentration and platelet count 13 days after the inoculation, respectively. These findings suggest that direct, selective inhibition of FXa by DX-9065a improves the hypercoagulable state induced by the progress of solid tumor.

Animals↗
PubMed2000

Markers of activated hemostasis and fibrinolysis in patients with pulmonary malignancies: comparison of plasma levels in central venous and pulmonary venous blood.

Malignancy frequently is accompanied by activated coagulation and fibrinolysis indicating a hypercoagulable state. The purpose of our study was to estimate the contribution of local tumor-induced mechanisms to the activation of hemostasis and fibrinolysis. In a prospective study, we compared the plasma levels of thrombin-antithrombin complexes, prothrombin fragment 1+2, and D-dimers in blood samples that simultaneously were drawn from the superior vena cava and the pulmonary vein of a tumor-bearing pulmonary lobe. Samples from the superior vena cava were drawn before operation and served as controls. After thoracotomy, a second group of samples was simultaneously taken from the pulmonary veins of the tumor-bearing lobe and the superior vena cava. Forty-five patients with pulmonary malignancies were included (25 adenocarcinomas and 20 squamous cell carcinomas). There were no significant differences of thrombin-antithrombin complexes, prothrombin fragment 1+2, and D-dimers levels in patients suffering from adenocarcinoma and from squamous cell carcinoma. Intraoperatively, prothrombin fragment 1+2 and D-dimers levels were markedly increased when compared with the preoperative values (p<0.0001). There was no increase of thrombin-antithrombin complexes levels due to the operative traumatization. Prothrombin fragment 1+2, thrombin-antithrombin complexes, and D-dimers plasma levels were significantly higher in the pulmonary venous blood than in the blood simultaneously drawn from the superior vena cava (p<0.0001). Our findings indicate that malignant lung tumors directly contribute to the activation of hemostasis and fibrinolysis in these clinical settings.

Aged↗
PubMed2006

Activation of coagulation system during air travel: a crossover study.

BACKGROUND: There is an increased risk of venous thrombosis after air travel, but the underlying mechanism is unclear. Our aim was to ascertain whether flying leads to a hypercoagulable state. METHODS: We did a crossover study in 71 healthy volunteers (15 men, 56 women), in whom we measured markers of activation of coagulation and fibrinolysis before, during, and after an 8-h flight. The same individuals participated in two control exposure situations (8-h movie marathon and daily life) to separate the effect of air travel on the coagulation system from those of immobilisation and circadian rhythm. To study the effect of risk factors for thrombosis, we included participants with the factor V Leiden mutation (n=11), those who took oral contraceptives (n=15), or both (n=15), as well as 30 individuals with no specific risk factors. FINDINGS: After the flight, median concentrations of thrombin-antithrombin (TAT) complex increased by 30.1% (95% CI 11.2-63.2), but decreased by 2.1% (-11.2 to 14) after the cinema and by 7.9% (-16.2 to -1.2) after the daily life situation. We recorded a high response in TAT levels in 17% (11 of 66) of individuals after air travel (3% [2 of 68] for movie marathon; 1% [1 of 70] in daily life). These findings were most evident in the group with the factor V Leiden mutation who used oral contraceptives. We noted a high response in all variables (prothrombin fragment 1 and 2, TAT, and D-dimer) in four of 63 (6.3%) volunteers after the flight, but in no-one after either of the control situations. INTERPRETATION: Activation of coagulation occurs in some individuals after an 8-h flight, indicating an additional mechanism to immobilisation underlying air travel related thrombosis.

Adult↗
PubMed1983

Hypertriglyceridaemia and hypercoagulability.

18 patients with severe hypertriglyceridaemia (mean fasting plasma triglyceride 5.7 mmol/l) had significantly higher concentrations of plasma fibrinogen and clotting factor Xc than did a normolipidaemic comparison group. Fibrinolytic activity was significantly lower in the hyperlipidaemic patients. Six months of treatment (diet or diet and clofibrate) lowered the patients mean plasma triglyceride to 3.1 mmol/l and caused a fall of clotting factors VIIc and Xc and a significant rise in fibrinolytic activity. None of these variables changed in the comparison group. Raised fibrinogen and factor VIIc concentrations are risk factors for cardiovascular mortality, and raised factor Xc and lowered fibrinolytic activity have both been found in groups at high risk of ischaemic heart-disease. Despite the fact that in population studies triglycerides do not consistently appear to be an independent risk factor for ischaemic heart disease, these data suggest that a pronounced increase in triglycerides warrants energetic therapy because it may be associated with a "hypercoagulable state".

Adult↗
PubMed1995

Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor.

Thromboembolic complications are common in patients with malignant disease. We studied the activation of coagulation in 106 patients with solid tumours and 72 healthy volunteers by measuring plasma levels of tissue factor, factor VIIa, factor XIIa, thrombin-antithrombin complex, and prothrombin fragments 1 + 2. Tissue factor was 67% higher in cancer patients (median 582 vs 349 pg/mL, p = 0.0006) and factor VIIa was 46% higher (100 vs 69 mU/mL, p = 0.0002), indicating extrinsic pathway activation. Modest activation of the intrinsic pathway (elevated factor XIIa) was seen only in patients with advanced disease or those receiving chemotherapy. Excess thrombin generation was manifested by elevations in thrombin-antithrombin complex and prothrombin fragments 1 + 2. Tissue factor pathway is clearly implicated in the hypercoagulable state of cancer.

Blood Coagulation↗
PubMed1979

Disorders of hemostasis in malignancy.

Disorders of hemostasis are frequent in malignant disease and their cause is often multifactorial and complex. Both primary (platelets and vessel walls) and secondary (coagulation factors) hemostasis are impaired, often concurrently. Therapy is most often directed toward the underlying disease; however, a knowledge of the complications and treatment of each malignancy will often prevent a number of the problems cited in this chapter. The hypercoagulable states are still poorly understood and need better definition, but their recognition, treatment and prevention may decrease morbidity significantly.

Blood Coagulation Disorders↗
PubMed1988

Visual symptoms associated with the presence of a lupus anticoagulant.

The lupus anticoagulant is an acquired serum immunoglobulin that prolongs several coagulation parameters, most notably the partial thromboplastin time (PTT). Most commonly, this condition is found in association with systemic lupus erythematosus (SLE) but may be seen with other collagen-vascular diseases and in otherwise healthy individuals. Despite the laboratory tests suggesting impaired coagulation, clinically the lupus anticoagulant has been associated with thrombosis. The authors present five patients with the lupus anticoagulant who came to medical attention because of branch retinal artery occlusion, ischemic optic neuropathy, transient visual loss, transient diplopia, or vertebrobasilar insufficiency. Eleven previously reported patients with the lupus anticoagulant and disturbed vision are also reviewed with additional findings of retinal venous occlusive disease and homonymous visual field loss. The relationship of these findings to retinopathy in SLE is discussed. Patients with the lupus anticoagulant (with or without SLE) may develop disturbances in vision due to thrombosis from a hypercoagulable state. We recommended obtaining a PTT, VDRL, and the more sensitive anticardiolipin antibody in patients with unexplained visual symptoms.

Adult↗
PubMed1997

Activation of the coagulation cascade in untreated primary open-angle glaucoma.

PURPOSE: The authors studied the coagulation cascade and fibrinolysis pathway in patients with untreated glaucoma (P = 0.00001 and P = 0.0003, respectively) and patients with normal pressure glaucoma ([NPG] P = 0.00001 and P = 0.03, respectively). METHODS: Forty-two untreated patients with NPG, 25 untreated patients with primary open-angle glaucoma (POAG), and 32 age-matched normal controls were recruited. Patients taking anticoagulant therapy beta blockers or calcium channel blockers were excluded. Venous blood was assessed for markers of the coagulation and fibrinolysis pathways using enzyme-linked immunosorbent assay techniques. RESULTS: Patients with POAG had elevated levels of prothrombin fragments 1 + 2 and D-dimer compared with both the NPG and controls (P = 0.00001 and P = 0.0003, respectively). Both glaucoma groups had more (P < 0.05) systemic vascular disease than the control group. The patients with POAG had higher (P < 0.05) systemic blood pressure (systolic and pulse pressure) than the control and NPG groups. Both glaucoma groups had greater levels of fibrinogen (which was of borderline statistical significance) than the control group. CONCLUSION: Elevated levels of prothrombin fragments 1 + 2 and D-dimer indicate activation of the coagulation cascade and fibrinolysis pathway, respectively, leading to a hypercoagulable state in untreated POAG. These findings may contribute to the reported increased prevalence of retinal venous thrombosis in glaucoma and also to the pathogenesis of optic nerve damage in glaucoma.

Aged↗
PubMed2004

Cerebral venous and dural sinus thrombosis in severe falciparum malaria.

Common causes of coma in falciparum malaria are cerebral malaria, hypoglycaemia and electrolyte disturbances. Focal deficits due to arterial infarcts may sometimes occur in children, but are rare in adults. Three adults with falciparum malaria who had fever, altered consciousness and focal neurological deficits (one of whom also had seizures) are being reported here. CT scan of the brain revealed haemorrhagic infarction of the cerebral cortex and subcortical white matter with surrounding oedema suggestive of venous infarction in all three patients. The diagnosis of cerebral venous thrombosis was missed in the first patient, and was detected only at autopsy. In the next two patients, superior sagittal sinus thrombosis was confirmed angiographically. Only one patient survived; the other two died of increased intracranial pressure. Two of the three patients also had Plasmodium vivax co-infection. A hypercoagulable state resulting from severe malaria may be responsible for this rare and potentially fatal complication. Cerebral malaria may be associated with raised intracranial pressure due to cerebral oedema. Cerebral venous thrombosis may worsen this and adversely affect outcome. This diagnosis should be suspected in patients with severe malaria who develop focal neurological deficits and confirmed by appropriate imaging; judicious use of local thrombolytic therapy may help improve outcome.

Adult↗
PubMed2000

Thromboangiitis obliterans: an old disease in need of a new look.

Almost a century after Buerger's original description of thromboangiitis obliterans, there is still no consensus about diagnostic criteria. The lack of a universally accepted method of diagnosis causes confusion, and mars research efforts. Some authors quote 'hematological disease' as one of the exclusion criteria. But in most recent reports, suspected Buerger patients did not undergo hematological tests to diagnose or rule out any primary or secondary hypercoagulable states. However, immunogenetic studies of Buerger's disease have led to a revived interest in the role of blood coagulation in the pathogenesis of thromboangiitis obliterans. Some association has been suggested between Buerger's disease and the antiphospholipid syndrome, as well as hyperhomocysteinemia. Other thrombophilic conditions have been described anecdotally in patients with Buerger's disease. In view of this developing line of investigation, there is a clear need to redefine the diagnostic algorithm and the criteria for diagnosing Buerger's disease.

Antiphospholipid Syndrome↗
PubMed2001

Effect of antihypertensive therapy using enalapril or losartan on haemostatic markers in essential hypertension: a pilot prospective randomised double-blind parallel group trial.

To test the hypothesis that the hypercoagulable state in hypertension is significantly altered by anti-hypertensive therapy, we conducted a pilot prospective randomised double-blind trial of 40 untreated hypertensive patients (30 males, mean age 59 years) who were treated with either enalapril (10-20 mg per day) or losartan (50-100 mg per day) for 8 weeks. Thrombogenicity was assessed by measurement of plasma fibrinogen, soluble P-selectin (an index of platelet activation), plasminogen activator inhibitor 1 (PAI-1, an index of fibrinolysis) and von Willebrand factor (an index of endothelial dysfunction). Baseline von Willebrand factor alone was significantly higher in untreated hypertensive patients compared to controls (P<0.001). Following 8 weeks treatment with enalapril (mean dose 17 mg/day) or losartan (mean dose 77 mg/day), there was a significant reduction in mean blood pressure from 169+/-11/94+/-8 mmHg (baseline) to 147+/-14/84+/-7 mmHg (post-treatment) (P<0.001). However, there were no statistically significant changes in the levels of haemostatic markers (von Willebrand factor, fibrinogen, s-Psel and PAI-1). Our pilot study confirms previous observations of endothelial dysfunction in hypertensives. However, plasma fibrinogen and indices of platelet activation, fibrinolysis or endothelial dysfunction were not significantly affected by antihypertensive treatment with enalapril or losartan, despite satisfactory blood pressure control.

Angiotensin Receptor Antagonists↗
PubMed2003

Decreased platelet activation and endothelial dysfunction after percutaneous mitral balloon valvuloplasty.

OBJECTIVE: This study was conducted to assess the changes in platelet activation and endothelial dysfunction in patients with mitral stenosis (MS) and sinus rhythm (SR) following percutaneous mitral balloon valvuloplasty (PMBV). BACKGROUND: Systemic thromboembolism is a serious complication in patients with valvular heart disease, and its incidence is highest in those with mitral stenosis. A hypercoagulable state has also been reported in patients with mitral stenosis and sinus rhythm. A recent study has shown that patients with previous PMBV had a lower incidence of thromboembolism. METHODS AND RESULTS: The study was conducted in 21 patients (two men, 19 women, mean age=34+/-6 years) with mitral stenosis and sinus rhythm (SR) who underwent percutaneous mitral balloon valvuloplasty and 17 healthy control subjects (two men, 15 women, mean age=33+/-6 years). Biochemical markers of platelet activity (beta thromboglobulin, BTG, and soluble P-selectin, sPsel) and endothelial dysfunction (von Willebrand Factor, vWF) were measured in both control subjects' and patients' serum samples taken immediately before PMBV and 24 h after PMBV procedure. All patients underwent successful PMBV. Significant improvement of mitral valve area, pulmonary artery pressure, mean mitral gradients, and left atrial diameter were achieved in all patients after PMBV. Compared with control subjects, patients with MS had higher plasma levels of BTG (66+/-26 ng/ml vs. 14+/-6 ng/ml, P<0.001), vWF (177+/-67 units/dl vs. 99+/-37 units/dl, P<0.0001), sPsel (226+/-74 ng/ml vs. 155+/-66 ng/ml, P<0.001). There was a significant reduction of plasma levels of BTG (66+/-26 ng/ml vs. 48+/-20 ng/ml, P=0.002), vWF (177+/-67 units/dl vs. 134+/-60 units/dl, P=0.001) and P-selectin (226+/-74 ng/ml vs. 173+/-71 ng/ml, P=0.008,) 24 h after PMBV. CONCLUSION: We have shown that patients with severe MS and SR have increased platelet activation and endothelial dysfunction compared with control subjects and PMBV results in decreased platelet activity and improvement of endothelial injury.

Adult↗