The risk of recurrent venous thromboembolism

Venous thromboembolism (VTE) is a chronic rather than acute disease. After withdrawal of secondary thromboprophylaxis, many patients will experience a subsequent episode of thrombosis. Of these patients, approximately 5% will die from pulmonary embolism. The risk of recurrent VTE depends on the number of risk factors and their severity. High-risk patients, i.e. those with a natural coagulation inhibitor deficiency, recurrent thrombosis, active cancer, the lupus anticoagulant or compound clotting defects most probably benefit from indefinite oral anticoagulation. In these patients the risk of bleeding due to anticoagulant treatment seems to be outweighed by the risk of VTE. Patients with hyperhomocysteinemia or high factor (F) VIII plasma levels are also at an increased risk of recurrence. The optimal duration of secondary thromboprophylaxis in these patients is currently under investigation. Patients with the heterozygous F V Leiden mutation or the G20210A mutation in the F II gene do not require extended anticoagulation since their risk of recurrence is similar as in patients without the aforementioned mutations. Patients with VTE secondary to surgery or trauma have a relatively low risk of recurrence. In these patients short-term secondary thromboprophylaxis (6 to 12 weeks) is justified whereas patients with a first episode of spontaneous VTE should be treated with oral anticoagulants for a longer period of time (3 to 6 months).     

ABO blood groups and age groups in surgical venous thromboembolism.

In a series of cases of surgical thromboembolism there were significant age differences in the ratio of cases of blood group A to those of blood group O, the ratio being highest in the youngest age groups.     

Managing venous thromboembolism with novel oral anticoagulants in the elderly and other high-risk patient groups

The novel oral anticoagulants represent a new era of anticoagulation for patients with deep vein thrombosis and pulmonary embolism. These agents may offer advantages to patients in whom the use of traditional anticoagulants is typically challenging, such as elderly patients, patients with renal impairment and those with low body weight. Currently, rivaroxaban and dabigatran are the only approved novel oral anticoagulants for the treatment and secondary prevention of venous thromboembolism. It is likely that additional agents will become available in the near future. This review summarises recent phase III data for these agents, focusing, where possible, on results obtained in frail patients.     

Prevention of venous thromboembolism in high-risk surgical and medical patients

Although pharmacologic prophylaxis against venous thromboembolism has become the standard of care following total hip and knee replacement, prophylaxis among patients undergoing surgery for hip fracture and other lower extremity trauma remains underutilized. Available experience consistently supports the view that low-molecular-weight heparins are more effective than unfractionated heparin for prevention of proximal deep vein thrombosis (DVT) with no additional hemorrhagic risk and more effective than oral anticoagulants for prevention of in-hospital (mostly distal) venous thrombosis at the price of a higher surgical site bleeding and wound hematoma. The choice between low-molecular-weight heparin and warfarin should be tailored to the individual patients based on the clinical assessment of postoperative thrombosis and bleeding risk as well as the prophylaxis-specific cost and convenience. Whether thromboprophylaxis should be continued for a few additional weeks after hospital discharge is controversial. The overall incidence of postoperative DVT in patients with cancer is about twice as high as that of patients free of malignancy. Accordingly, they require prophylactic measures comparable with those usually recommended for major orthopedic surgery. In this setting, dermatan sulfate shows promise. In contrast to surgical patients, prevention of venous thromboembolism is less well studied in hospitalized medical patients. In a recent controlled randomized trial, enoxaparin in high prophylactic doses was an effective and safe measure of thromboprophylaxis in ordinary bedridden patients.     

Gender and the risk of venous thromboembolism

The role of gender in the causation of first and recurrent venous thromboembolism (VTE) is uncertain. The use of hormonal therapy and pregnancy has been associated with VTE in women. Epidemiological studies have described a higher incidence of first VTE in women of childbearing age. Nevertheless, no consistent differences in the overall incidence of VTE between males and females have been found. Recent studies have shown that women exhibit a lower risk of recurrent VTE than men, although these data were not confirmed in other studies that evaluated only women with idiopathic VTE. This article reviews the role of gender as a risk factor for first and recurrent VTE.     

Epidemiology and risk factors of venous thromboembolism

Venous thromboembolism (VTE) is a common disorder that can affect apparently healthy as well as hospitalized patients. The actual incidence and prevalence of this disease are difficult to estimate because of its often silent nature. The clinical relevance of VTE is highlighted by the important rates of recurrence and mortality. The individual risk of VTE varies as a result of a complex interaction between congenital and transient or permanent acquired risk factors. Risk factors can be either intrinsic (e.g., age, obesity, history of VTE, or thrombophilia) or disease related (e.g., surgical procedures and medical disorders such as cancer, heart failure, or acute respiratory failure). The presence or absence of specific risk factors may play an important role in decisions about the type (and duration) of thromboprophylaxis/anticoagulation to be used.     

Genetic risk factors of venous thromboembolism

Up to date several hereditary disorders have been identified as prothrombic risk factors. The most common inherited thrombotic disorders include activated protein C resistance (factor V Leiden), prothrombin G20210A mutation, hyperhomocysteinemia, deficiencies of protein C, protein S, antithrombin III, and thrombomodulin. This article focuses on the clinical and the laboratory aspects of some of the inherited venous thrombotic disorders including the factor V Leiden, prothrombin G20210A mutation and protein S deficiency.     

The prevalence of risk factors for venous thromboembolism among hospital patients.

BACKGROUND--This study provides an estimate of the prevalence of risk factors for venous thromboembolism among hospital patients. METHODS--The presence of risk factors for venous thromboembolism was determined from a retrospective review of the medical records of 1,000 randomly selected patients in 16 acute care hospitals in central Massachusetts. RESULTS--The most common risk factors for venous thromboembolism were age 40 years (59%) or more, obesity (28%), and major surgery (23%). The average number of risk factors increased with increasing age. One or more risk factors for venous thromboembolism were present in 78% of hospital patients, two or more in 48%, three or more in 19%, four or more in 6%, and five or more in 1%. CONCLUSION--Risk factors for venous thromboembolism are common among hospital patients, suggesting that prophylaxis should be widely employed. The cost-effectiveness and risk benefit of prophylaxis is well established in patients undergoing major surgery. Further studies are needed to confirm the benefit of prophylaxis in patients with nonsurgical risk factors for venous thromboembolism.     

The risk of recurrent venous thromboembolism in heterozygous carriers of factor V Leiden and a first spontaneous venous thromboembolism

BACKGROUND: Factor V (FV) Leiden is a risk factor for venous thrombosis (VT). Data on its influence on the risk of recurrent venous thromboembolism (VTE) are controversial owing to different study designs and patient cohorts. METHODS: We reevaluated the risk of recurrence among heterozygous carriers and noncarriers of FV Leiden with a first spontaneous proximal VT of the leg and/or pulmonary embolism. Patients with secondary VTE, homozygous FV Leiden, natural inhibitor deficiencies, lupus anticoagulant, cancer, or long-term anticoagulation were excluded. The study end point was objectively documented, symptomatic, recurrent VTE. RESULTS: After discontinuation of oral anticoagulant therapy for a first VTE, we prospectively observed 287 patients, 83 (29%) of whom were heterozygous for FV Leiden. Recurrent VTE was seen in 17 (20%) of 83 patients with and 44 (21.6%) of 204 without FV Leiden. The probability of recurrence among heterozygotes was 12% (95% confidence interval [CI], 8%-16%), 27% (95% CI, 21%-33%), and 27% (95% CI, 21%-33%) after 2, 4, and 6 years, respectively, and was not higher than that among patients without the mutation (16%, 23%, and 34%, respectively). The relative risk of recurrence in heterozygotes was 0.9 (95% CI, 0.5-1.6; P =.60) after adjustment for confounding variables. The risk of recurrence among patients with and without FV Leiden was not different when sex distribution or duration of anticoagulation therapy was taken into account. CONCLUSIONS: The risk of recurrence is similar among carriers and noncarriers of FV Leiden. Heterozygous patients should receive secondary thromboprophylaxis for a similar length of time as patients without FV Leiden.     

Vascular placental pathology in high-risk groups: definition and synopsis

The vascular placental pathology (VPP) is associated with many etiologies. Some are the consequence of a maternal genetic or acquired predisposition. Others are associated with a chronic maternal disease (hypertension, lupus, obesity, diabetes, ...). Finally, some others are associated with placental implantation leading to fetal ischemia (multiple pregnancy, chorioangioma, primiparity, feto-placental hydrops) or to environmental (altitude) or nutritional factors (famine and specific alimentary depressions). We classify these factors into three categories according to the risk level (moderate, significant and elevated). While any of these factors can increase the risk of VPP, no one is sufficiently sensitive or specific in predict inevitable onset of VPP. In most cases VPP results from a combination of two (or more) risk factors. The risk factors of VPP classified as moderate include age (> or = 35 years), increased blood pressure during the second trimester of pregnancy, a new paternity, dietetic factors or environmental factors, smoking and controlled diabetes (class B, C), or inactive systemic diseases. Risk is significantly elevated among obese (BMI > or = 25), primiparous women, women with a past familial history (first degree) of preeclampsia or eclampsia, cocaine use or association of tobacco and caffeine use, increased placental mass (associated with twin pregnancy, fetal hydrops or molar pregnancy), uncontrolled diabetes, lupus, active scleroderma. Risk is considered to be high among patients with chronic hypertension, women with a past history of preeclampsia, diabetes (class D, F, R), patients with active systemic disease or with antiphospholipid antibodies or women with lupus or renal lesions and/or proteinuria as well as chronic kidney disease resulting in proteinuria, hypertension and renal insufficiency. Finally, the risk of VPP is considered to be increased in the presence of acquired thrombophilia. It remains moderate in the presence of isolated genetic thrombophilia, except in forms presenting with multiple genetic mutations or associated with an hyperhomocysteinemia. A "high-risk group" is defined among women with past history of deep venous thromboembolic events outside pregnancy, or with a past history of placental vascular pathology (intra-uterine death, placental abruptio, severe and precocious placental, intra-uterine growth retardation, early and repetitive fetal loss) and who, in addition, present with acquired thrombophilia (antiphospholipid antibodies, thrombocytemia), unique homozygous genetic thrombophilia, amultiple genetic thrombophilia or unique heterozygous genetic thrombophilia associated with hyperhomocysteinemia. Prophylactic treatment of acquired thrombophilia and of the multiple genetic forms or associated with hypercysteinemia is a logical rationale, particularly among women with a past history of placental vascular pathology, or with a past history of venous thromboembolic events. On the contrary, prophylaxis using low-molecular-weight heparin in the event of asymptomatic genetic thrombophilic mutations and for women without a past history of deep venous thromboembolism or vascular placental pathology remains controversial.     

Evaluation of venous thromboembolism risk following hospitalization

A better understanding of the relationship between outpatient venous thromboembolism (VTE) and prior hospitalization is needed including data regarding the utilization of inpatient pharmacologic VTE prophylaxis and its effect on outpatient venous thromboembolic risk. The primary objective was to assess the association between development of outpatient VTE and inpatient hospitalization within the previous 90 days. Additional outcome measures included describing patients who received pharmacologic anticoagulation during hospitalization and identification of factors independently associated with VTE. Case patients in this matched case–control study were diagnosed with an outpatient deep vein thrombosis or pulmonary embolus between January 2005 and December 2007 and were matched on age with up to five to patients who were seen for an outpatient health maintenance visit but had no VTE during the same time frame as their matched case. Information collected from electronic administrative databases and patient medical records included health services utilization, medication use, medical diagnoses, and patient demographic information. Of 2190 cases, 560 patients (25.6%) compared to 151 (1.4%) of 10,942 control patients were hospitalized in the previous 90 days (P < 0.001). Among hospitalized patients, 53.5% of cases and 47.0% of controls received an anticoagulant during hospitalization (P = 0.186). Factors associated with a VTE diagnosis included hospitalization for a surgical, medical, or orthopedic indication in the previous 90 days, younger age, longer hospitalization, cancer and an elevated Chronic Disease Score. Conclusions: A strong association exists between outpatient VTE diagnosis and hospitalization and gaps in pharmacologic prophylaxis utilization during hospitalization are evident.     

Cumulative flying time and risk of venous thromboembolism

The risk of venous thromboembolism (VTE) associated with cumulative flying time remains uncertain. In a case-control study in general practices throughout the UK, participants comprised 550 VTE cases identified from practice records and 1971 age- and gender-matched controls. Participants returned identical questionnaires asking for information including air travel details. Compared to not flying, cumulative flying time >12 h within the previous 4 weeks was associated with a threefold increase in the risk of VTE [odds ratio (OR) 2·75, 95% confidence interval (CI), 1·44-5·28]. Those who had flown >4 h in a single leg in the previous 4 weeks had twice the risk of VTE (OR 2·20, 95% CI, 1·29-3·73). These risks were no longer evident by 12 weeks and were similar to those of day-case or minor surgery (OR 5·35, 95% CI, 2·15-13·33). Equivalent risks for moderate and high-risk surgery were over 30-fold (OR 36·57, 95% CI, 13·05-102·52) and 140-fold (OR 141·71, 95% CI, 19·38-1036·01) respectively. The temporary nature of the association of cumulative and long-haul air travel with VTE suggests a causal relationship. The risks of VTE in those with a higher baseline risk due to surgery, previous VTE or obesity are further increased by air travel.     

Predicting the risk of venous thromboembolism recurrence

Venous thromboembolism (VTE) is a chronic disease with a 30% ten-year recurrence rate. The highest incidence of recurrence is in the first 6 months. Active cancer significantly increases the hazard of early recurrence, and the proportions of time on standard heparin with an APTT ≥ 0.2 anti-X(a) U/mL, and on warfarin with an INR ≥ 2.0, significantly reduce the hazard. The acute treatment duration does not affect recurrence risk after treatment is stopped. Independent predictors of late recurrence include increasing patient age and body mass index, leg paresis, active cancer and other persistent VTE risk factors, idiopathic VTE, antiphospholipid antibody syndrome, antithrombin, protein C or protein S deficiency, hyperhomocysteinemia and a persistently increased plasma fibrin D-dimer. A recommendation for secondary prophylaxis should be individualized based on the risk for recurrent VTE (especially fatal pulmonary embolism) and bleeding. The appropriateness of secondary prophylaxis should be continuously reevaluated, and the prophylaxis stopped if the benefit no longer exceeds the risk.     

Inflammatory plasma markers and risk for venous thromboembolism

Venous thromboembolism (VTE) and arterial thrombosis have been thought to result from two different mechanisms. Recent data indicate that the two diseases may share some common risk factors, such as the activity of inflammation on haemostasis. In this population-based study we explored whether raised levels of inflammation-sensitive plasma markers (ISPs) increase the risk for venous thromboembolism. Measurements of five ISPs (fibrinogen, haptoglobin, ceruloplasmin, α1-antitrypsin and orosomucoid) were performed in 6,068 subjects from “the Malmö Preventive Study”. These apparently healthy men from the city of Malmö in Sweden, were included in the study between 1974 and 1982 and followed up until 2008. We calculated the hazard ratio (HR) for VTE in relation to the number of raised ISPs as well as individual ISPs in the fourth quartile. Mean follow-up time was 26.2 years. Out of the cohort (n = 6,068), 398 (6.6 %) had a venous thromboembolism during the follow-up. The number of raised ISPs was significantly associated with age, BMI and smoking. Age, BMI and diabetes mellitus type 2 were also significant risk factors for developing a VTE (HR = 1.05 with p < 0.01 and 95 % CI 1.01–1.08, HR = 1.10 with p < 0.001 and 95 % CI 1.06–1.14 and HR = 1.78 with p < 0.05 and 95 % CI 1.13–2.81, respectively). Incidence of venous thromboembolism was not significantly related to number of raised inflammatory proteins (p for trend = 0.37) or any of the individual ISPs. Age and BMI is significantly associated with the risk for developing VTE. Incidence of VTE was not associated with any of the inflammatory proteins.