Incidence Of Symptomatic Thromboembolism Research Articles

Evaluation for inherited and acquired prothrombotic defects predisposing to symptomatic thromboembolism in children with acute lymphoblastic leukemia: a protocol for a prospective, observational, cohort study

BackgroundThromboembolism (TE) is a serious complication in children with acute lymphoblastic leukemia (ALL). The incidence of symptomatic thromboembolism is as high as 14% and case fatality rate of ~15%. Further, development of thromboembolism interferes with the scheduled chemotherapy with potential impact on cure rates. The exact pathogenesis of ALL-associated thromboembolism is unknown. Concomitant administration of asparaginase and steroids, two important anti-leukemic agents, is shown to increase the risk of ALL-associated TE. Dana-Farber Cancer Institute (DFCI) ALL studies reported ~10% incidence of thrombosis with significantly increased risk in older children (≥10 yrs.) and those with high-risk ALL. The majority (90%) of thromboembolic events occurred in the Consolidation phase of therapy with concomitant asparaginase and steroids when high-risk patients (including all older patients) receive higher dose steroids. Certain inherited and acquired prothrombotic defects are known to contribute to the development of TE. German investigators documented ~50% incidence of TE during therapy with concomitant asparaginase and steroids, in children with at least one prothrombotic defect. However, current evidence regarding the role of prothrombotic defects in the development of ALL-associated TE is contradictory. Although thromboprophylaxis can prevent thromboembolism, ALL and it’s therapy can increase the risk of bleeding. For judicious use of thromboprophylaxis, identifying a population at high risk for TE is important. The risk factors, including prothrombotic defects, predisposing to thrombosis in children with ALL have not been defined.MethodsThis prospective, observational cohort study aims to evaluate the prevalence of inherited prothrombotic defects in children with ALL treated on DFCI 05–01 protocol and the causal relationship of prothrombotic defects in combination with patient and disease-related factors to the development of TE. We hypothesize that the combination of prothrombotic defects and the intensive therapy with concomitant high dose steroids and asparaginase increases the risk of TE in older patients and patients with high-risk ALL.DiscussionThe results of the proposed study will help design studies of prophylactic anticoagulant therapy. Thromboprophylaxis given to a targeted population will likely reduce the incidence of TE in children with ALL and ultimately improve their quality of life and prospects for cure.

The incidence of symptomatic thromboembolism in patients receiving adjuvant anthracycline-based chemotherapy for early stage breast cancer

Thromboembolism is a well recognised complication of systemic chemotherapy and cancer. Its incidence is frequently not reported in clinical trials of adjuvant chemotherapy for early stage breast cancer. Our own experience suggested that thromboembolic complications were common and we undertook a retrospective review of consecutive patients receiving adjuvant chemotherapy to determine the incidence and morbidity/mortality of this complication. A total of 280 consecutive patients were identified who had received adjuvant ECMF chemotherapy between January 2001 and February 2007. Thromboembolic events occurred in 21 patients (7.5%). Events were distributed across chemotherapy cycles, but were more common during CMF chemotherapy (18 cases vs 3 cases). Patients over the age of 60 years appeared to be at particular risk of thromboembolism with an event rate of 27% (15/56 patients). Thromboembolic events were associated with dose delays and cessation of chemotherapy in some patients. With a median follow up of 28 months there is no significant difference in the incidence of breast cancer recurrence (16.7% vs 14.3%, p = 0.9) or overall survival (89.5% vs 89.9%, p = 0.8) between patients who experienced a thromboembolic event during adjuvant chemotherapy and those who did not. Based on the incidence of thromboembolism in our unselected patient population we believe that further prospective studies are indicated seeking to identify those patients at increased risk of this important complication who might benefit from thromboprophylaxis.

Impact of thrombophilia on incidence of symptomatic thromboembolism in first degree family members (FM) of pediatric index cases: a prospective cohort study in FM > 14 years of age

Impact of thrombophilia on incidence of symptomatic thromboembolism in first degree family members (FM) of pediatric index cases: a prospective cohort study in FM > 14 years of age

Impact of Thrombophilia and Incidence of Symptomatic Thromboembolism in First Degree Family Members (FM) of Pediatric Index Cases: a Prospective Cohort Study in FM > 14 Years of Age.

Abstract 2977Poster Board II-957 Background:Venous thrombosis is a multifactorial disease and inherited genetic traits (IT) constitute a major risk factor. The aim of the present prospective cohort study was to determine i) the relative and absolute risks of first symptomatic thromboembolism [TE] in previously healthy family members of children with venous thromboembolism, and ii) whether to screen family members in a high risk population. Methods:In 205 patients (neonate to 18 years) and 526 FM followed over a total person-time of 14157 years /1000 units [person-time] a comprehensive IT screening was performed along with recording of family histories of preexisting cardiovascular diseases. FM were followed until July 2009: study endpoint was cumulative time to first TE within FM. Survival analysis (Cox regression: hazard ratio (HR/95% Confidence intervals (CIs)] adjusted for age and gender and number of new cases divided by the total population at risk (incidence rate) were calculated (events (%) per 1000 person-years [CIs]). Results:The final study population included 526 FM with 462 subjects > 14 years. The cumulative TE –free survival in FM with IT was significantly lower compared to those without: HR/CI: 6.6/ 3.3-13.5. The overall rate of symptomatic TEs was 2.9%[2.07-3.9]. The hazard adjusted for age and gender in the group of antithrombin(AT)-/protein C[PC)-/protein S(PS)-deficient FM was 29.4%[13.3-62.5], and for carriers of factor (F) V G1691A, F II G202010A mutations or elevated lipoprotein (a) it was found to be 3.3%[1.3-8.3], 1.96% [0.4- 9.0] and 2.1%[1.04-3.8]. Corresponding annual incidence rates in FM > 14 years were 4.8% for AT-/PC- or PS-deficiency states, 0.72% in subjects carrying the FV mutation, 0.36 % in FII carriers, and 0.20% for subjects with elevated lipoprotein (a) compared with 0.19% in FM with no IT. Thus, compared to adult data from the view of adult index cases [Lijfering W et al. Blood 2009] i) the risk of TE in family members of pediatric index cases with TE depends on IT, ii) the age at TE in the index patient as well as in the family members has a strong effect on TE incidence, and iii) the first symptomatic TE in primary healthy family members > 14 years of age with respect to the IT investigated is comparable to or exceeds adult data. Conclusions:i) Adult family members of pediatric index patients with an early onset of symptomatic thrombosis should be considered for IT testing, ii) primary thromboprophylaxis in family members derived from pediatric index patients should be considered in risk situations in adult carriers of AT/PC/PS-deficiencies & FV mutation. In addition, iii) larger prospective studies are needed to investigate the effects of multiple ITs and its interactions to take into account whether events are provoked or not to investigate the effect of screening. Disclosures:Off Label Use: Enoxaparin (LMWH) is used off-label in children to prevent symptomatic thromboembolism.

Comparison of low‐molecular‐weight heparin and antithrombin versus antithrombin alone for the prevention of symptomatic venous thromboembolism in children with acute lymphoblastic leukemia

Children with acute lymphoblastic leukemia (ALL) have a substantial risk for thromboembolism (TE) that is related to L-asparaginase-induced antithrombin (AT) deficiency and placement of central venous lines. Recent in vitro studies showed that the anticoagulant effects of low-molecular-weight heparin were profoundly affected by endogenous AT levels in children undergoing ALL therapy. A total of 112 consecutively recruited children with newly diagnosed ALL treated according to BFM 95/2000 protocols were enrolled in this trial. This prospective cohort study was carried out to determine the influence of combined low molecular weight heparin-prophylaxis (enoxaparin 1 mg/kg/ per day) and AT supplementation versus AT alone (noncontemporaneous control group) on the incidence of symptomatic TE during a follow-up of 240 days. To maintain AT plasma levels above 50%, nearly 60% of all children needed at least one, most children two or three AT supplementations during induction therapy. 12.7% of the children that did receive only AT-prophylaxis (n = 71) (95% CI = 6.0-22.7) developed objectively confirmed symptomatic TE, as compared with no TE in children after combined prophylaxis (n = 41) (95% CI = 0.0-8.6, P < 0.05). Thromboses were located in the sinovenous system in the brain (n = 3), the lower deep veins (n = 3), the upper deep veins (n = 2) and in an upper deep vein combined with pulmonary embolism (n = 1). Prophylaxis with enoxaparin was safe and effective in preventing TE. Although our data are encouraging, the in vivo efficacy of combined enoxaparin and AT prophylaxis to prevent symptomatic venous TE in children with ALL should be evaluated in a prospective randomized clinical trial.

A prospective observational study of a cohort of outpatients with an acute medical event and reduced mobility: incidence of symptomatic thromboembolism and description of thromboprophylaxis practices

The study was performed to determine the incidence of symptomatic venous thromboembolism in outpatients with an acute medical event causing temporary reduced mobility. Risk factors for venous thromboembolism and thromboprophylaxis practices were also studied. This was a prospective, observational, multicentre, cohort study. General practitioners randomly selected from a registry of 25,000 active representative doctors in France including eligible outpatients. Outpatients aged at least 40 years anticipated to have reduced mobility for at least 48 h due to an acute medical event were eligible. None required. Symptomatic deep-vein thrombosis and pulmonary embolism at 3 weeks were the main study end-points. Overall, 16,532 evaluable patients of mean age 71 years were recruited between October 2002 and June 2003 by 2895 doctors. The main acute medical events leading to reduced mobility were infection, acute rheumatism and falls without fracture. The incidence rates (95% confidence interval) of symptomatic deep-vein thrombosis and pulmonary embolism were 1% (0.84-1.14) and 0.20% (0.13-0.27) respectively. Venous insufficiency in legs, cancer, and a personal or family history of venous thromboembolism were independent risk factors for venous thromboembolism. Pharmacological thromboprophylaxis was initiated in 35.0% (n=5782) of the patients. The principal driver of prescription was a personal history of venous thromboembolism. The risk of symptomatic venous thromboembolism in outpatients with reduced mobility for medical reasons is close to that reported in medical and surgical inpatients. This risk and the potential need for thromboprophylaxis should be taken into account by primary care doctors.

Traveler's thrombosis

It is pathophysiologically conceivable that prolonged sitting in a tight space (e.g., in airplane or other transport vehicle) may lead to leg vein thrombosis. The association between the incidence of venous thromboembolism and long travel has not been sufficiently documented but seems probable. However, this association is only weak and the incidence of symptomatic thromboembolism much lower than the impression given by the recent publicity. In a healthy person, the risk of suffering a clinically relevant leg vein thrombosis solely because of a flight is extreme low. In persons with risk factors for venous thromboembolism, the flight represents an additional, as yet not quantifiable risk. This risk increases with the duration of the travel. The most important cause of thrombosis during long journeys seems to be venostasis due to relative immobilization. It is not clear whether flight travel represents a higher risk of thrombosis compared to other transport vehicles with comparable duration and immobilization. Until more exact information becomes available, it seems reasonable to recommend simple isometric and isotonic leg exercises during long travel. More aggressive measures must be considered for persons with risk factors for thromboembolism, but these measures should be individualized.