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PubMed2002

Laboratory thrombophilias and venous thromboembolism.

Inherited abnormalities of coagulation are increasingly recognized in patients with venous thromboembolism. Common causes of hypercoagulability, also known as thrombophilia, include factor V Leiden, the prothrombin gene mutation, hyperhomocysteinemia, and antiphospholipid antibodies. Thrombophilia should be suspected in patients who develop idiopathic venous thromboembolism at a young age, recurrent thrombosis, thromboses at unusual sites, recurrent unexplained pregnancy loss, or if there is a family history of thrombotic disorders. The most cost-effective approach is to initially screen for factor V Leiden, the prothrombin gene mutation, hyperhomocysteinemia, and antiphospholipid antibodies because these are the most common defects causing thrombophilia. Long-term anticoagulation is controversial but should be considered if unprovoked venous thromboembolism recurs.

Humans↗
PubMed1998

Survival impact of adjuvant tamoxifen on competing causes of mortality in breast cancer survivors, with analysis of mortality from contralateral breast cancer, cardiovascular events, endometrial cancer, and thromboembolic episodes.

PURPOSE: This study provides estimates of the effect of tamoxifen treatment on mortality from four conditions known to be affected by tamoxifen in women who survive their breast cancer: contralateral breast cancer, cardiovascular events, endometrial cancer, and thromboembolic events. These estimates are in addition to tamoxifen's impact on primary breast cancer mortality. METHODS: The effects of tamoxifen were calculated by the use of the published relative risk (RR) rates of the four conditions as affected by adjuvant tamoxifen and their application to the respective Canadian age-specific mortality rates for the same conditions. The final mortality impact of tamoxifen was expressed as net mortality difference between users and nonusers of tamoxifen. RESULTS: At 10 years of follow-up, the sum of avoided deaths (contralateral breast cancer, cardiovascular events) and excess deaths (uterine cancer, thromboembolic episodes) resulted in an overall (net) mortality reduction because of tamoxifen use, with 3 to 41 avoided deaths per 1,000 tamoxifen-treated patients who were 50 to 80 years of age. With the follow-up projected until the age of 90 years, the numbers of avoided late deaths attributed to tamoxifen ranged from 38 to 56 per 1,000 patients. CONCLUSION: Our calculations that pertain to late breast cancer survivors indicate that there is a more substantial mortality reduction as a result of deaths avoided from contralateral breast cancer and cardiovascular events, despite the moderately increased mortality from endometrial cancer and thromboembolic episodes. The overall tamoxifen-associated mortality reduction occurs, in different magnitudes, in patients of all ages from 50 to 80 years at diagnosis of the primary breast cancer.

Aged↗
PubMed2003

Markers of coagulation and angiogenesis in cancer-associated venous thromboembolism.

PURPOSE: We sought to determine whether venous thromboembolism in cancer patients is associated with aberrant plasma levels of hemostatic and angiogenic factors. PATIENTS AND METHODS: Peripheral blood was collected before anticoagulant therapy from cancer patients with acute deep venous thrombosis (DVT; DVT + cancer group, n = 32), those without DVT (cancer control group, n = 36), and patients with acute DVT but no cancer (DVT control group, n = 58). Plasma assays of activation and inhibition of coagulation and fibrinolysis, as well as angiogenesis activation, were then performed. RESULTS: Median levels of thrombin-antithrombin complex, prothrombin fragments 1 + 2, and von Willebrand factor antigen were significantly greater in the DVT + cancer group than in the cancer control and DVT control groups (17.8 ng/mL v 4.6 ng/mL and 9.8 ng/mL, P =.0001 and P =.003, respectively; 3.65 nmol/L v 1.60 nmol/L and 2.71 nmol/L, P <.0001 and P =.011, respectively; and 4.04 U/mL v 2.26 U/mL and 2.06 U/mL, P <.0001, respectively). Median levels of tissue-type plasminogen activator were also significantly higher, while protein C activity was lower in the DVT + cancer group than in the DVT control group (14.6 ng/mL v 9.50 ng/mL, respectively, P =.0005; 0.89 U/mL v 1.11 U/mL, respectively, P =.0008). CONCLUSION: These data not only support prior observations of coagulation activation in patients with malignancy, but also provide new evidence for enhanced coagulation activation in the setting of acute venous thromboembolism in cancer. Future prospective studies are warranted to determine whether these and other potential markers of hypercoagulability may help to identify cancer patients at highest risk for venous thromboembolism.

Biomarkers↗
PubMed1993

Complications of therapy for venous thromboembolic disease in patients with brain tumors.

Venous thromboembolic disease is a frequent complication in patients with intracranial malignancies. Because these patients are often perceived to be at increased risk of intracranial hemorrhage with anticoagulation, inferior vena cava (IVC) filters are frequently used in their treatment. We reviewed the records of 49 patients with intracranial malignancies and venous thromboembolic disease to determine the effectiveness of, and the complications resulting from, treatment. Of the 42 patients receiving IVC filters, a strikingly high percentage (62%) developed complications. Twelve percent developed recurrent pulmonary embolism, while 57% developed either IVC or filter thrombosis, recurrent deep venous thrombosis, or post-phlebitic syndrome. These complications severely reduced the quality of life of the affected patients. Only 15 of our patients were treated with anticoagulation, and seven of these received it because of continued thromboembolic disease. None of these 15 patients had proven hemorrhagic complications. This study suggests that the complication rate of IVC filters in patients with brain tumors is higher than commonly perceived and may outweigh the risk of anticoagulation.

Anticoagulants↗
PubMed1994

High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events.

High-dose intravenous immunoglobulin (IVIg) can increase blood viscosity in vitro and has been associated with cardiovascular or cerebrovascular thromboembolism. Because thromboembolic events were observed in two (3%) of 65 patients we treated with IVIg, we measured serum viscosity serially in 13 patients (five with amyotrophic lateral sclerosis [ALS], eight with IgM paraproteinemic polyneuropathy) before and immediately after each of three consecutive monthly infusions of IVIg. We correlated changes in viscosity with serial determinations of the total serum IgG, IgM, and IgA before and after each infusion. Serum viscosity increased after IVIg in all the patients by 0.1 to 1.0 centipoise (cp) (mean, 0.55 cp). In three ALS patients and in all the patients with paraproteinemic polyneuropathy, serum viscosity exceeded the upper limit of normal (normal, 1.5 to 1.9 cp) and increased as high as 2.6 cp. The increase in viscosity occurred immediately after completion of the infusion, declined over 1 month, and appeared to correlate best with the serum IgG level, which after the infusions was as high as 6,160 mg/dl (normal, 545 to 1,560 mg/dl). I conclude that IVIg increases serum viscosity and in many patients can cross the symptomatic threshold level. Because increased serum viscosity can impair blood flow and trigger a cardiovascular or cerebrovascular thromboembolic event, IVIg should be used judiciously and with concurrent monitoring of serum viscosity in elderly patients and patients with cryoglobulinemia, monoclonal gammopathies, high lipoproteins, or preexisting vascular disease.

Adult↗
PubMed1982

Prophylaxis of thromboembolism in the neurosurgical patient: a review.

The incidence of postoperative thromboembolic complications in neurosurgical patients is 29 to 43%. However, anticoagulant treatment of these complications increases the inherent risk of hemorrhage into the operative site. We have reviewed the literature on the prophylaxis of deep vein thrombosis and pulmonary embolism; the incidence of thromboembolic complications, the mechanism of deep venous thrombosis, risk factors, and methods of prophylaxis for deep vein thrombosis are discussed in relation to possible prophylactic treatment of neurosurgical patients. We conclude from our review that low dose heparin therapy is indicated for patients undergoing elective neurosurgical procedures, especially for patients over the age of 40 and for patients under the age of 40 who are known to be at risk of developing thromboembolic complications.

Anticoagulants↗
PubMed2001

Recurrence of idiopathic thromboembolism during anticoagulant therapy.

Patients with acute pulmonary embolism and venous thromboembolism are usually treated with anticoagulant therapy for at least 3 months as the optimum duration. A patient with recurrent idiopathic venous thromboembolism at the eighth month during anticoagulation (warfarin to target international normalized ratio of 2.0-3.0) is described. The case suggests that patients with idiopathic venous thromboembolism have a high risk of recurrence, even if a strict anticoagulant regimen is followed.

Adult↗
PubMed2006

Effects of intra-arterial urokinase on a non-human primate thromboembolic stroke model.

One of the most important prognostic factors in the thrombolytic treatment of acute ischemic stroke is to re-canalize. The purpose of this study was to evaluate the effectiveness and safety of urokinase in a primate thromboembolic stroke model. Thromboembolic stroke was accomplished via occlusion of the middle cerebral artery (MCA) obtained by injecting an autologous blood clot into the left internal carotid artery in 21 male cynomolgus monkeys. Animals were randomly assigned to the following treatment groups: Group 1: vehicle (saline), Group 2: urokinase (40,000 IU), Group 3: urokinase (120,000 IU,) over 2 or 6 h via intra-internal carotid catheter starting 1 h after embolization, respectively. In the urokinase-treated groups, neurologic deficits were improved in consciousness and skeletal muscle coordination, but not sensory and motor systems. The infarction size in Group 2 (11.9 +/- 3.9% of the hemisphere) and 3 (7.6 +/- 2.5%) were significantly smaller than that (24.7 +/- 3.5%) in Group 1. However, 2 of 5 animals in Group 3 died. In conclusion, urokinase improved neurologic deficits and reduced cerebral infarction on thromboembolic stroke in the cynomolgus monkey.

Animals↗
PubMed2007

A prospective long-term study of 220 patients with a retrievable vena cava filter for secondary prevention of venous thromboembolism.

BACKGROUND: The immediate and long-term clinical events associated with the placement and removal of a retrievable filter (ALN filter; ALN Implants Chirurgicaux; Ghisonaccia, France) remain largely unknown. METHODS: This was a prospective cohort study with an 18-month follow-up. All consecutive patients scheduled for placement of an ALN filter between April 1999 and June 2005 in the Radiology Department of our hospital were included. RESULTS: During the study period, placement of an ALN filter was indicated in 220 patients (mean age, 70.8 years), who were followed up for a median duration of 338.5 days (range, 1 to 561 days); 148 patients (67.3%) completed the 18-month follow-up. No patients were unavailable for follow-up. All patients had an acute or past venous thromboembolism. Main indications were recurrent venous thromboembolism despite adequate anticoagulation therapy (10.9%), transient bleeding event (21.8%), definitive contraindication for anticoagulant therapy (26.8%), or obligation to stop anticoagulant therapy due to major surgery, major trauma, or invasive procedure (37.7%). Filter insertion was successful in 98.6% of patients and resulted in an immediate complication in 11.8%. The median duration of filter implantation was 166 days (first to third quartiles, 34 to 478 days). Meanwhile, 17.0% (37 of 217 patients) had at least one venous thromboembolic event. Filter retrieval was attempted in 25.3% of patients after a median of 51 days (range, 6 to 352 days); removal was successful at the first attempt in 92.7% of patients. CONCLUSIONS: The filter could be easily inserted and successfully removed up to 1 year after insertion. Its safety and efficacy in preventing pulmonary embolism should be properly assessed in a randomized study.

Adult↗
PubMed1992

Platelet imaging of thromboembolism. Natural history of postoperative deep venous thrombosis and pulmonary embolism illustrated using the 111In-labelled platelet-specific monoclonal antibody, P256.

BACKGROUND: Deep venous thrombosis (DVT) and pulmonary thromboembolic disease are difficult to diagnose, particularly following surgery. This report demonstrates the use of 111In-labelled platelet-specific monoclonal antibody, P256 Fab', for the diagnosis and study of the time course of thromboembolic disease in a patient following total hip replacement. METHOD: One hundred micrograms of pentetic acid (DTPA)-P256 Fab' was labelled with 8 to 10 MBq of 111In chloride by incubation at room temperature for 15 min. After dilution in physiologic saline, the tracer was injected intravenously on the third and sixth days postoperatively. Imaging of the chest, pelvis, and legs was carried out at 24, 48 and 72 h following each injection. RESULTS: The first image four days after surgery demonstrated activity in the right heart which moved to the right pulmonary artery on the following day. Activity was seen in both femoral veins; on the left, this increased over two days, followed by a reduction on the seventh day after surgery, at which time new activity was seen in the right heart. After a further two days, this activity moved to the left pulmonary artery. The DVT was confirmed by venography and the pulmonary embolism (PE) by ventilation perfusion scan. CONCLUSIONS: 111Indium-labelled platelet-specific monoclonal antibody, P256 Fab', provides a technique for studying the natural history of thromboembolic disease and its treatment.

Aged↗
PubMed1996

Thromboembolism following cardioversion of "common" atrial flutter. Risk factors and limitations of transesophageal echocardiography.

Based on multiple recent studies, anticoagulant therapy is recommended prior to elective cardioversion for patients with atrial fibrillation of more than 24 h duration. The value of anticoagulation in patients with atrial flutter, however, is less well established. Published recommendations for pericardioversion anticoagulation of atrial fibrillation often do not extend to patients with atrial flutter. We evaluated the risk of thromboembolism in our patient population undergoing cardioversion for atrial flutter. Over a period of 30 months, clinically indicated electrical cardioversions were performed in 41 patients with "common" atrial flutter. Sixteen of these patients underwent transesophageal echocardiograms immediately prior to cardioversion to exclude a left atrial thrombus. Three of the 41 patients with atrial flutter developed neurologic ischemic syndromes within 48 h of elective cardioversion. All three patients who developed ischemic neurologic complications had undergone transesophageal echocardiography immediately prior to cardioversion and did not have any evidence of left atrial clot. One patient had cardiomyopathy and the other two had left ventricular hypertrophy. Thus, electrical cardioversion without anticoagulation in patients with atrial flutter and associated heart disease is associated with a risk of thromboembolic events. A normal transesophageal echocardiogram is of doubtful value in prevention of thromboembolic complications.

Aged↗
PubMed2006

Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases.

Novel anticoagulants to replace unfractionated heparins, low molecular weight heparins and vitamin K antagonists, are needed urgently. Coagulation factor Xa is an attractive target for drug development because of its position at the convergence of the intrinsic and extrinsic clotting pathways. There are two differing strategies of inhibiting factor Xa that are being pursued: indirect inhibition by compounds such as fondaparinux and idraparinux, requiring antithrombin as a cofactor; and direct inhibition by compounds such as rivaroxaban (BAY 597939), DX-9065a, otamixaban, LY517717 and YM150. Of these compounds, fondaparinux is approved for the prevention and treatment of venous thromboembolism, and idraparinux is in Phase III for venous thromboembolism treatment and stroke prevention in patients with atrial fibrillation. Rivaroxaban has undergone extensive Phase II studies for venous thromboembolism prevention after orthopaedic surgery, and Phase III studies have begun. In this review, we will discuss the pharmacological effects of factor Xa inhibitors and the latest clinical developments.

Administration, Oral↗
PubMed2002

Review of enoxaparin and its clinical applications in venous and arterial thromboembolism.

Venous and arterial thromboembolic disorders are common medical conditions that are associated with considerable morbidity and mortality. Unfractionated heparin (UFH) and its derivatives, the low molecular weight heparins (LMWHs), are the anticoagulants of choice when a rapid anticoagulant effect is required. LMWHs have several advantages over UFH, including a longer plasma half-life and higher bioavailability; a predictable dose response, which enables once- or twice-daily dosing; and a more convenient route of administration (subcutaneous instead of intravenous), which enables patients to self-inject in an out-patient setting. Enoxaparin is a LMWH prepared by alkaline hydrolysis of the benzylin ester of UFH. The efficacy of enoxaparin in the management of venous and arterial thromboembolism has been shown in a wide range of patient groups using doses ranging from fixed doses of 20 - 60 mg o.d. and 0.75 - 1.5 mg/kg b.i.d. Other doses, such as 80 mg/day for pregnant women with combined thrombophilic defects, have also been studied. The use of subcutaneous enoxaparin as an effective and safe home treatment for patients with acute proximal deep vein thrombosis (DVT) has been demonstrated. The benefits of preventing venous thromboembolic events with enoxaparin include reducing the costs associated with investigating the symptoms of DVT, acute treatment and hospitalisation, and potentially the development of post-thrombotic syndrome, while improving quality of life and so making the treatment cost effective. In contrast to other LMWHs, enoxaparin has been shown to provide better outcomes than UFH in the treatment of unstable angina and non-ST-segment elevation myocardial infarction, without increasing major bleeding. Adverse events with enoxaparin are infrequent; the most common events are minor bleeding complications. It should be noted that different doses or indications are approved in each country.

Anticoagulants↗
PubMed2004

Research approaches for studying flow-induced thromboembolic complications in blood recirculating devices.

The advent of implantable blood recirculating devices has provided life-saving solutions to patients with severe cardiovascular diseases. Recently it has been reported that ventricular assist devices are superior to drug therapy. The implantable total artificial heart is showing promise as a potential solution to the chronic shortage of available heart transplants. Prosthetic heart valves are routinely used for replacing diseased heart valves. However, all of these devices share a common problem--significant complications such as hemolysis and thromboembolism often arise after their implantation. Elevated flow stresses that are present in the nonphysiologic geometries of blood recirculating devices, enhance their propensity to initiate thromboembolism by chronically activating the blood platelets. This, rather than hemolysis, appears to be the salient aspect of blood trauma in devices. Limitations in characterizing and controlling relevant aspects of the flow-induced mechanical stimuli and the platelet response, hampers our ability to achieve design optimization for these devices. The main objective of this article is to describe state-of-the-art numerical, experimental, and in vivo tools, that facilitate elucidation of flow-induced mechanisms leading to thromboembolism in prosthetic devices. Such techniques are giving rise to an accountable model for flow-induced thrombogenicity, and to a methodology that has the potential to transform current device design and testing practices. It might lead to substantial time and cost savings during the research and development phase, and has the potential to reduce the risks that patients implanted with these devices face, lower the ensuing healthcare costs, and offer viable long-term solutions for these patients.

Computer-Aided Design↗
PubMed2006

Pregnancy-associated venous thromboembolism in combined heterozygous factor V Leiden and prothrombin G20210A mutations.

CONTEXT: Pregnancy and puerperium raise the risk of thromboembolic events, and these risks are increased in women who are carriers of thrombophilia factors. Prothrombin (FII) G20210A and factor V Leiden heterozygous mutations are associated with moderate risk of thrombosis. The association of these thrombophilic conditions is very rare in pregnancy, and the real risk of thrombosis is unknown. CASE REPORT: We describe a case of a pregnant woman who was found to be carrier of heterozygous factor V Leiden and prothrombin (FII) G20210A mutations. Five years before pregnancy she had had an episode of extensive deep venous thrombosis in the ileofemoral region, while using hormonal contraceptives. Anticardiolipin antibody (ACA), lupus anticoagulant and deficiencies of protein C, protein S and antithrombin III were evaluated by means of enzyme-linked immunosorbent assay (ELISA), dilute Russell Viper Venom time (dRVVT), coagulometric and chromogenic methods. Deoxyribonucleic acid (DNA) was amplified using the polymerase chain reaction (PCR) to study the factor V Leiden and G20210A mutations in the prothrombin gene and C677T mutation in the methylene tetrahydrofolate reductase (MTHFR) gene. In the sixth week of her first pregnancy, she developed another episode of deep venous thrombosis in the femoropopliteal veins of the right leg. She was treated with low-molecular weight heparin (nadroparin) until parturition (0.3 ml or 2,850 UI/day). The pregnancy evolved without any significant obstetric morbidity. The patient delivered a healthy baby by cesarean section. During the puerperium, she used prophylactic doses of nadroparin for (0.3 ml or 2,850 UI/day) six weeks and had no complications. We suggest that women who have an association of thrombophilia factors and a prior episode of venous thromboembolism must have antepartum anticoagulation management using unfractioned or low-molecular weight heparin and postpartum management using low-molecular weight heparin or oral anticoagulants. Anticoagulation is recommended during pregnancy because the real magnitude of the risk of major and life-threatening thromboembolic events in these women is unknown.

Adult↗
PubMed1997

Prevention of thromboembolism with use of recombinant hirudin. Results of a double-blind, multicenter trial comparing the efficacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement.

Specific inhibition of thrombin is a new method for the prevention of postoperative deep-vein thrombosis. The objective of this multicenter, randomized, double-blind study was to compare the efficacy and safety of desirudin (Revasc, CGP 39393; fifteen milligrams two times a day) with that of unfractionated heparin (5000 international units three times a day) in patients having a primary elective total hip replacement. The medications were administered subcutaneously, starting preoperatively and continuing for eight to eleven days. The primary end point was a confirmed thromboembolic event during the treatment period. The presence of deep-vein thrombosis was evaluated with bilateral venograms, which were centrally assessed by two independent radiologists. A total of 445 eligible patients were randomized: 220, to management with heparin, and 225, to management with desirudin. A per-protocol analysis of efficacy was performed for the 351 patients (79 per cent) for whom an adequate bilateral venogram had been made within eight to eleven days after the operation or who had had a proved thromboembolic event. The prevalence of confirmed deep-vein thrombosis was thirteen (7 per cent) of 174 patients who had received desirudin and forty-one (23 per cent) of 177 patients who had received heparin, a significant difference (p < 0.0001). The prevalence of proximal deep-vein thrombosis was also significantly reduced (p < 0.0001), by 79 per cent, in the group that had received desirudin (six [3 per cent] of 174 patients) compared with in the group that had received heparin (twenty-nine [16 per cent] of 177). There were no confirmed pulmonary embolisms or deaths during the period of prophylaxis. During a six-week follow-up period, pulmonary embolism was confirmed in four patients, all of whom had received heparin. There was no significant difference between the treatment groups with respect to bleeding variables or bleeding complications. These data demonstrate that a fixed dose of fifteen milligrams of desirudin, started preoperatively and administered subcutaneously twice daily for at least eight days, provided effective, safe prevention of thromboembolic complications, with no specific requirements for laboratory monitoring, in patients who had a total hip replacement.

Aged↗
PubMed1997

Oral contraception and venous thromboembolism. A New Zealand perspective.

Several recent case control studies have shown an excess rate of venous thromboembolism in women using third generation progestogen-containing combined contraceptive pills compared to second generation combined contraceptive pills. This excess is about 1 in 10,000 women per year of use. It is likely that second and third generation pills have been preferentially prescribed to users who have varying susceptibility to venous thromboembolism and that this may account for at least part of the observed differences. In practice, it is essential that all women using combined oral contraceptive pills have a thorough history taken to exclude any contraindications or risk factors. Each client should be counselled about the risks and benefits of oral contraception. In New Zealand, the Ministry of Health has recommended that prescribers for women starting a contraceptive pill for the first time should consider a pill that does not contain a third generation progestogen. Women already receiving a third generation pill may elect to continue that pill after the differential rates of venous thromboembolism have been discussed.

Bias↗
PubMed1999

Preventing thromboembolic complications in older orthopaedic surgery patients: interventions and outcomes.

The aging of the population in developed countries has been associated with a growing burden of degenerative joint disease and hip fracture, and this has contributed to a progressive increase in the utilisation of major hip and knee arthroplasty. In the absence of effective thromboprophylaxis, patients undergoing major orthopaedic surgery are at high risk of deep vein thrombosis, which may in turn lead to life-threatening complications such as pulmonary embolism, as well as long term sequelae including the post-thrombotic syndrome. However, increasing age is also associated with an increased risk of venous thromboembolism, and older orthopaedic patients are, therefore, at particularly high risk. Randomised trials have demonstrated that the risk of venous thromboembolism in these patients, as demonstrated by venography, can be reduced by more than 50% with the use of effective thromboprophylaxis. However, antithrombotic agents such as low molecular weight heparin and warfarin, which are widely used for the prevention of venous thromboembolism, are also associated with an increased risk of bleeding complications, and selection of the most appropriate strategy should, therefore, involve consideration of the potential risks as well as benefits of the currently available interventions.

Aging↗