Primary Thrombosis Prevention Research Articles

Primary prevention of deep venous thrombosis and pulmonary embolism in acute spinal cord injured patients

Prospective clinical trial. To evaluate the efficacy of a specific protocol for prevention of thrombo-embolic disease occurring during the acute stage of spinal cord lesions, based on the simultaneous use of pharmacological plus mechanical procedures. Regional Spinal Unit of Florence, Italy. Deep venous thrombosis (DVT) is a dangerous pathology whose first clinical sign can be represented by unexpected pulmonary embolism (PE). Its incidence in acute spinal cord injured (SCI) patients is reported to range between 9% and 90%. Its prevention represents one of the major challenges for the clinicians involved in the care of such patients. Two hundred and seventy-five SCI patients consecutively admitted to our Centre were investigated by colour doppler ultrasonography of lower limbs and pelvis on admission, after 30-45 days and whenever clinically requested. Subcutaneous Nadroparine, a low molecular weight heparin (LMWH), plus early mobilisation, permanently dressed gradient elastic stockings (PGES), and external sequential pneumatic compression (ESPC) of the lower limbs, applied during the first 30 days after injury, were given to all of them. Colour doppler ultrasonography (CDUS) complete investigations of the lower limbs and pelvis were performed on admission, after 30-45 days and whenever clinically requested. The patients were divided into two groups according to their time interval from injury to the admission to our Centre. The incidence of detected DVT was 2% in those patients (99) admitted early to our centre (within 72 h from the trauma), who immediately received our prophylactic protocol. No PE was reported. The other group of patients (176), all admitted between 8 and 28 days (mean 12 days) developed DVT in 26% of cases. None of these patients received ESPC before being admitted to our Centre. No patient had been admitted between 3 and 8 days interval time post injury. Early application of pharmacological plus mechanical treatment for DVT prevention produces a marked reduction in such complications. It also reduces the risks of morbidity and mortality in our patients, and, not least, reduces the hospitalization costs during the early period of rehabilitation.

What is the standard treatment in essential thrombocythemia.

The treatment of patients with essential thrombocythemia (ET) should be based primarily on the expected risk of major thrombotic complications. Although the specific values chosen for separating different risk categories are in part arbitrary, the following recomendations can be made. Young asymptomatic subjects with platelet counts below 1,500x10(9)/L are at lower risk and can be followed untreated. However, it should be emphasized that thrombotic events can also occur in a small percentage of these lower-risk cases. Low-dose aspirin (100-300 mg/day) should be given to patients with symptoms of microvascular occlusion, such as erythromelalgia or transient neurological attacks, and avoided in those with bleeding manifestations. The risk/benefit of low-dose aspirin in the primary prevention of thrombosis in asymptomatic patients remains uncertain. For high-risk patients (age >60 years, or platelet count >1,500x10(9)/L, or previous thrombosis), hydroxyurea, plus aspirin in the case of thrombosis, is the treatment of choice because its efficacy in preventing thrombotic complications has been proven in a randomized clinical trial. However, the possible long-term leukemogenicity of this drug, as well as that of other effective cytoreductive agents such as busulphan and pipobroman, remains a major concern. Anagrelide and interferon could overcome this worry but their efficacy has been hitherto demonstrated only in lowering the platelet count. Controlled clinical studies showing a benefit in preventing thrombotic and hemorrhagic complications are urgently needed.

The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both.

Factor V Leiden and the G20210A mutation in the prothrombin gene are the most frequent abnormalities associated with venous thromboembolism. It is unknown whether the risks due to the presence of either mutation are of the same magnitude. We compared the prevalence and incidence rate of venous thromboembolism in relatives with either mutation or both. The finding of different rates might influence the strategies for primary prevention of thrombosis in carriers of these mutations. The study population included 1076 relatives of probands with the prothrombin gene mutation, factor V Leiden or both who underwent screening for inherited thrombophilia and were found to be carriers of single mutations or double mutations or who were non-carriers. The prevalence of venous thromboembolism was 5.7% in relatives with the prothrombin gene mutation, 7.8% in those with factor V Leiden, 17.1% in those with both mutations and 2.5% in non-carriers. Annual incidences of thrombosis were 0.13% [95% confidence interval (CI) 0.06-0.24], 0.19% (0.13-0.25), 0.42% (0.15-0.83) and 0.066% (0.03-0.11), respectively, and the relative risk of thrombosis was two times higher in carriers of the prothrombin gene mutation, three times higher in those with factor V Leiden and six times higher in double carriers than in non-carriers. The incidence of venous thromboembolism in carriers of the prothrombin gene mutation is slightly lower than that observed in carriers of factor V Leiden, whereas in carriers of both mutations it is two or three times higher. These findings suggest that lifelong primary anticoagulant prophylaxis of venous thromboembolism is not needed in asymptomatic carriers of single or double mutations. Anticoagulant prophylaxis seems to be indicated only when transient risk factors for thrombosis coexist with mutations.

The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both

Factor V Leiden and the G20210A mutation in the prothrombin gene are the most frequent abnormalities associated with venous thromboembolism. It is unknown whether the risks due to the presence of either mutation are of the same magnitude. We compared the prevalence and incidence rate of venous thromboembolism in relatives with either mutation or both. The finding of different rates might influence the strategies for primary prevention of thrombosis in carriers of these mutations. The study population included 1076 relatives of probands with the prothrombin gene mutation, factor V Leiden or both who underwent screening for inherited thrombophilia and were found to be carriers of single mutations or double mutations or who were non‐carriers. The prevalence of venous thromboembolism was 5·7% in relatives with the prothrombin gene mutation, 7·8% in those with factor V Leiden, 17·1% in those with both mutations and 2·5% in non‐carriers. Annual incidences of thrombosis were 0·13% [95% confidence interval (CI) 0·06–0·24], 0·19% (0·13–0·25), 0·42% (0·15–0·83) and 0·066% (0·03–0·11), respectively, and the relative risk of thrombosis was two times higher in carriers of the prothrombin gene mutation, three times higher in those with factor V Leiden and six times higher in double carriers than in non‐carriers. The incidence of venous thromboembolism in carriers of the prothrombin gene mutation is slightly lower than that observed in carriers of factor V Leiden, whereas in carriers of both mutations it is two or three times higher. These findings suggest that lifelong primary anticoagulant prophylaxis of venous thromboembolism is not needed in asymptomatic carriers of single or double mutations. Anticoagulant prophylaxis seems to be indicated only when transient risk factors for thrombosis coexist with mutations.

Lotrafiban: an oral platelet glycoprotein IIb/IIIa blocker

Platelets play a major role in thrombus formation, as well as in the pathogenesis of atherothrombosis. Inhibition of platelet function is now emphasised more than ever for prevention and treatment of almost all vascular diseases, since thrombosis is established as the key pathogenic event causing acute ischaemic coronary and cerebrovascular syndromes. Although acetylsalicylic acid (aspirin) has been shown to reduce the incidence of myocardial infarction and stroke, its effect is weak and more effective antithrombotic agents are required to manage patients at high-risk for recurrent vascular events. Platelet glycoprotein IIb/IIIa receptor (GPIIb/IIIa) blockade represents a significant advance in interventional cardiology and treatment of acute ischaemic syndromes. The past several years have seen the introduction of many platelet GPIIb/IIIa blockers into the clinical arena targeting the unique platelet GPIIb/IIIa receptor for the adhesive proteins, fibrinogen and von Willebrand Factor. Platelet GPIIb/IIIa blockers administered intravenously have proven efficacious in mitigating arterial thrombosis in acute coronary syndromes (unstable angina and non-ST-elevation myocardial infarction) and percutaneous coronary interventions (PCI) such as balloon dilatation and stent implantation. Currently, orally-active platelet GPIIb/IIIa blockers are being developed to provide additional benefits for primary and secondary prevention of thrombosis as chronic treatment, especially in high-risk patients. Lotrafiban (SmithKline Beecham) is a member of the latest generation of orally-active platelet GPIIb/IIIa blockers undergoing Phase III clinical trials to test the relative effectiveness versus other oral platelet inhibitors for ischaemic conditions including unstable angina, restenosis after PCI and stroke. Lotrafiban is converted from an esterified prodrug by plasma and liver esterases to a peptidomimetic of the arginine-glycine-aspartic acid amino acid sequence. This sequence itself mimics the binding site of fibrinogen and von Willebrand Factor to the platelet GPIIb/IIIa receptor. Preliminary results of the clinical trial APLAUD (antiplatelet useful dose) show that lotrafiban is clinically safe and well-tolerated in patients with recent myocardial infarction, unstable angina, transient ischaemic attack (TIA), or stroke when added to aspirin therapy. With lotrafiban, a worldwide large-scale Phase III clinical trial BRAVO (blockage of the GPIIb/IIIa receptor to avoid vascular occlusion) is currently underway. In general, GPIIb/IIIa blockade seems clinically very promising. A number of unresolved issues, however, remain to be elucidated.

Primary Prevention of Thrombosis in Subjects with Positive Antiphospholipid Antibodies

A major cause of stroke, as well as other arterial and venous thromboembolic disease has been identified—the presence of antiphospholipid antibodies (aPL). Now it is possible to identify individuals positive for aPL and still free of thrombosis. The tests to measure aPL have been standardized (aCL by ELISA and LA by coagulometric assays) and they are routinely performed in patients with SLE and other connective tissue diseases and women with recurrent pregnancy loss. However, very little is known about the risk of thrombosis in individuals positive for aPL but still free of thrombosis. Should these individuals receive any treatment? If so, which one?

Aspirine et syndrome des antiphospholipides

Antiphospholipid syndrome is the most frequent cause of acquired thrombophilia. Aspirin may have some indications. CURRENT KONWLEDGE AND KEY POINTS: The usefulness of low doses of aspirin is now well demonstrated in the prevention of obstetric complications associated with antiphospholipid antibodies (especially pregnancy loss). When heparin is combined with low-dose aspirin, the recurrent rate of fetal loss is lower than 30%. In patients with arterial or venous thrombosis, there is a high rate of recurrence during the two first years except if high-dose warfarin was used (i.e., INR > or = 3). The association warfarin-aspirin in secondary prevention of thrombosis may be evaluated in prospective studies. It is not so clear in the literature and in our experience that warfarin is superior to aspirin in stroke recurrence prevention in patients with antiphospholipid antibodies, except in Sneddon's syndrome. There are no guidelines in primary thrombosis prevention in patients with antiphospholipid antibodies. In lupus patients, aspirin may not be sufficient after many years of follow-up in preventing a first episode of thrombosis. Prospective studies may be undertaken. Atherosclerotic patients with antiphospholipid antibodies are particularly exposed to the risk of thrombosis after revascularisation or angioplasty and stent implantation. Aspirin may have a place in those patients but these must be evaluated. FUTUR PROSPECTS AND PROJECTS: Except in prevention of obstetric complications, the usefulness of aspirin in patients with antiphospholipid antibodies must be evaluated in prospective studies.

Aspirin in essential thrombocythemia: status quo and quo vadis.

Aspirin has a well established role in the prevention of arterial thrombosis. Discussion on the efficacy and safety of aspirin in the treatment and prophylaxis of thrombosis in essential thrombocythemia (ET) has become an important issue. The rationale for its use in ET comes from the observation that arterial thrombosis and platelet-mediated microcirculatory disturbances are the major causes of morbidity and mortality in ET. Experimental data have shown persistently elevated levels of thromboxane A2 (TXA2) in ET patients probably reflecting an enhanced in vivo platelet activation. Increased TXA2 biosynthesis and platelet activation in vivo in ET are selectively suppressed by repeated low doses of aspirin. ET-related symptoms such as erythromelalgia, transient neurologic and ocular disturbances are sensitive to aspirin. However, the benefit of low-dose aspirin is still uncertain in the primary prevention of thrombosis in ET. Furthermore, aspirin may unmask a latent bleeding diathesis frequently present in ET which may result in severe hemorrhagic complications. Thus, aspirin is contraindicated in ET patients with a bleeding history or a very high platelet count (> 1500 x 10(9)/L) leading to the acquisition of von Willebrand factor deficiency. If indicated, aspirin is presently used in the widely accepted low-dose regimen of 100 mg daily. However, an optimal effective dose has not yet been established. To further evaluate the efficacy and safety of aspirin in ET, prospective clinical trials are needed.

Cancer and venous thromboembolism

Neoplastic cells can activate the clotting system directly, thereby generating thrombin, or indirectly, by stimulating mononuclear cells to synthesize and express various procoagulants. Clinical manifestations of increased thrombin generation may be accentuated by down-regulation of endothelial cell counterregulatory mechanisms, such as decreased hepatic synthesis of antithrombin III and protein C. Cancer cells and chemotherapeutic agents can injure endothelial cells, thereby intensifying hypercoagulability. In addition, normal endothelial cell function may be disrupted by various defects in platelet function. Currently, primary prevention of venous thrombosis should be considered for cancer patients (1) during and immediately after chemotherapy, (2) when long-term indwelling central venous catheters are placed; or (3) when hospitalization for cancer is characterized by prolonged immobilization, trauma, or surgery. Secondary prevention of recurrent venous thrombosis usually necessitates anticoagulation. In some patients with cancer, the condition is resistant to warfarin, and long-term adjusted high-dose heparin is required. For patients unable to tolerate heparin or warfarin because of major bleeding problems, placement of an inferior vena caval filter should be considered. The diagnosis of venous thrombosis may help to uncover previously occult carcinoma by prompting a complete physical examination, chest roentgenography, and mammography. However, extensive cancer screening with total-body computed tomography or magnetic resonance imaging has not been shown to be cost effective for patients with venous thrombosis.

Primary Prevention of Coronary Arterial Thrombosis with the Factor Xa Inhibitor rTAP in a Canine Electrolytic Injury Model

The antithrombotic efficacies of the coagulation factor Xa inhibitor recombinant tick anticoagulant peptide (rTAP) and heparin were compared in a canine model of left circumflex (LCX) coronary artery electrolytic lesion. Intravenous infusions of saline (controls), rTAP (50 micrograms/kg/min continuous infusion) or heparin (200 U/kg bolus followed by 2 U/kg/min continuous infusion) were started 60 min prior to the initiation of LCX coronary artery electrolytic injury (150 microA continuous anodal current). All 6/6 saline-treated control animals developed occlusive thrombi at 49.8 +/- 13.6 min after the initiation of vessel injury, and possessed a residual thrombus mass of 20.7 +/- 3.3 mg. In the rTAP treatment group, 4/6 preparations developed occlusive thrombi, but with times to thrombosis delayed significantly compared to both the saline control as well as to the heparin treatment group (202.7 +/- 28.9 min; p < 0.01 to both saline and heparin groups). The remaining 2 rTAP-treated preparations remained patent despite the continued electrical stimulation of the coronary vessel for 5 h. Residual thrombus mass in the rTAP treatment group was reduced markedly compared to the saline control group (4.4 +/- 1.0 mg; p < 0.01). Heparin infusion resulted in a modest but statistically insignificant delay in occlusive LCX coronary artery thrombosis compared to saline controls, with all 6/6 heparin-treated preparations occluding at 79.7 +/- 16.5 min after the initiation of vessel injury. Residual thrombus mass in heparin-treated animals, however, was reduced compared to saline controls (9.4 +/- 1.4 mg; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Trials of Primary and Secondary Prevention of Thrombosis and Restenosis

In the primary prevention of arterial disease, there may be a role for anti-oxidant vitamins and for oestrogen replacement therapy in postmenopausal women. For the secondary prevention of thrombotic complications of atherosclerosis, aspirin has proven efficacious in reducing both mortality and morbidity. Patients with ischaemic heart disease and moderately elevated serum cholesterol benefit from simvastatin administration. Heparin and oral anticoagulants are the mainstay in the primary and secondary prevention of venous thrombosis. More potent antithrombotic compounds, the direct thrombin inhibitors and the glycoprotein IIb-IIIa antagonists, are mainly being evaluated in emergency coronary medicine. Preliminary results are encouraging but haemorrhagic problems need to be solved. The trend toward a decrease in late restenosis following coronary angioplasty using a IIb-IIIa antagonizing Fab fragment may prove to be a major therapeutic breakthrough.

Oral Anticoagulant Therapy Recommendations

Oral Anticoagulant Therapy Recommendations

Therapeutic target values in oral anticoagulation--justification of Dutch policy and a warning against the so-called moderate-intensity regimens.

Careful scrutiny of relevant thrombosis prevention studies in the light of recent knowledge on the responsiveness to the anticoagulant defect of the various prothrombin time assays used in these studies casts serious doubts on the adequacy of the so-called moderate-intensity warfarin regimens, currently recommended by British and North American experts, in the majority of clinical situations. As long as there is strict laboratory monitoring, more intensive anticoagulation provides satisfactory prevention of thromboembolic events. The Federation of Dutch Thrombosis Centers recommends a target of 3.0 International Normalized Ratio (INR) for the primary and secondary prevention of venous thrombosis and thromboembolism, 3.5 INR in case of recurrence under the former regimen and for patients at risk for a cardiogenic embolism from any source (including tissue heart valve replacement) and those with atherothrombotic disease, and 4.0 INR for patients with a mechanical heart valve prosthesis. The risk of hemorrhage at such levels of anticoagulation remains acceptable.

Utilization of antithrombotic medicines in primary prevention and risk assessment of deep vein thrombosis at a tertiary care teaching hospital

Background: Deep vein thrombosis (DVT) and pulmonary embolism (PE) are common preventable conditions often associated with high morbidity if not treated promptly. Evaluation of antithrombotic drugs is essential in considering the spectrum of use and the risks associated with their therapy in patients with DVT. Therefore, this study was undertaken to evaluate the usage pattern of antithrombotics and assessment of DVT risk in primary prevention of DVT at a tertiary care teaching hospital. Materials and Methods: It was an observational, prospective and single-center study carried out over a period of 18 months. Out of 26,687 hospitalized patients assessed for eligibility as per Wells' score. Only 186 patients met inclusion criteria, but 164 patients were analyzed for primary prevention and risk assessment of DVT. Results: Out of 164 patients of primary prevention of DVT, 54 (32.92%) patients were given thromboprophylaxis for DVT. Out of 54 patients, 23 patients were given warfarin either alone or in combination with other drugs, whereas aspirin was given as a single drug in two patients only. No modification in the treatment of either anticoagulant or antiplatelet drugs was observed in patients for primary prevention of DVT (n = 54). As per Wells' score, 87 patients were considered to be “high” risk of DVT, but only six patients developed DVT versus, whereas 31 patients were considered to be of “moderate” risk, only two patients developed DVT. Conclusion: Few patients of primary prevention of DVT received adequate antithrombotic thromboprophylaxis. Heparin and warfarin were mainly used for thromboprophylaxis of DVT. DVT prophylaxis is very important and thromboprophylaxis is the mainstay of treatment among patients of primary prevention of DVT.