Thrombophilia and risk of VTE recurrence according to the age at the time of first VTE manifestation.

BACKGROUND: Whether screening for thrombophilia is useful for patients after a first episode of venous thromboembolism (VTE) is a controversial issue. However, the impact of thrombophilia on the risk of recurrence may vary depending on the patient's age at the time of the first VTE. PATIENTS AND METHODS: Of 1221 VTE patients (42 % males) registered in the MAISTHRO (MAin-ISar-THROmbosis) registry, 261 experienced VTE recurrence during a 5-year follow-up after the discontinuation of anticoagulant therapy. RESULTS: Thrombophilia was more common among patients with VTE recurrence than those without (58.6 % vs. 50.3 %; p = 0.017). Stratifying patients by the age at the time of their initial VTE, Cox proportional hazards analyses adjusted for age, sex and the presence or absence of established risk factors revealed a heterozygous prothrombin (PT) G20210A mutation (hazard ratio (HR) 2.65; 95 %-confidence interval (CI) 1.71 - 4.12; p < 0.001), homozygosity/double heterozygosity for the factor V Leiden and/or PT mutation (HR 2.35; 95 %-CI 1.09 - 5.07, p = 0.030), and an antithrombin deficiency (HR 2.12; 95 %-CI 1.12 - 4.10; p = 0.021) to predict recurrent VTE in patients aged 40 years or older, whereas lupus anticoagulants (HR 3.05; 95%-CI 1.40 - 6.66; p = 0.005) increased the risk of recurrence in younger patients. Subgroup analyses revealed an increased risk of recurrence for a heterozygous factor V Leiden mutation only in young females without hormonal treatment whereas the predictive value of a heterozygous PT mutation was restricted to males over the age of 40 years. CONCLUSIONS: Our data do not support a preference of younger patients for thrombophilia testing after a first venous thromboembolic event.

Thrombosis of the inferior vena cava and malignant disease.

BACKGROUND: Inferior vena cava thrombosis (IVCT) is a rare event, and studies detailing its underlying aetiologies are scarce. METHODS: One hundred and forty-one IVCT patients (57% females, median age 47 years) were analysed with a focus on malignancy-related thrombosis and compared with 141 age- and sex-matched control patients with isolated lower-extremity deep vein thrombosis. RESULTS: Malignancies were more prevalent among IVCT patients compared with the control group (39% vs. 7.8%; P<0.001). Malignancy-related IVCT more frequently involved the suprarenal and hepatic segments of the IVC and extended more often to the right atrium than IVCT did in non-cancer patients. Among IVCT patients with malignancies, renal cell carcinoma (38%) and other malignancies of the genitourinary tract (25%) were the most common tumours. Analysis of the underlying pathological mechanisms of malignancy-related thrombosis identified external compression of the IVC by tumour masses in 9 cases (16%), and progression of malignancy into the IVC (so-called "tumour thrombosis") in 24 cases (44%). The remaining 22 cases (40%) were attributed to malignancy-related hypercoagulability and the presence of additional venous thromboembolism risk factors, such as previous surgery, immobilisation, or chemotherapy. CONCLUSIONS: Malignancies substantially contribute to the risk of thrombosis involving the IVC. Tumour invasion, especially in cases of renal cell cancer and malignancy-related hypercoagulability are major triggering factors for thrombogenesis.

Prevalence of established risk factors for venous thromboembolism according to age.

OBJECTIVE: To date, the factors that contribute to the rise in venous thromboembolism (VTE) risk observed with higher ages remain unknown. Therefore, the aim of the present analysis was to study the distribution of established VTE risk factors in categories of manifestation age in a large cohort of VTE patients. METHODS: Data were taken from the MAISTHRO (MAin-ISar-THROmbosis) registry, a cross-sectional study of patients with acute or documented history of VTE. The registry enrolled 1500 consecutive patients (869 females; median age, 43 years) with a first lower-extremity deep vein thrombosis or pulmonary embolism. RESULTS: VTE was attributed to established risk factors in 76.6% of cases. By classifying patients into categories of VTE manifestation age, we observed a steep rise in the prevalence of malignancies with advancing age (ie, 1.3% of cases of VTE occurred under the age of 30 and 34.0% of VTE cases manifested over the age of 70; P < .001). In contrast, VTE was more likely to be related to thrombophilia, a family history of VTE, oral contraceptives, and pregnancy in younger patients. Hereditary thrombophilia was detected in 50% of VTE patients younger than 20 and in 21.8% over the age of 70 (P < .001). With regard to other VTE risk factors, the results were insignificant. In addition, we were unable to demonstrate an accumulation of common VTE risk factors among patients at higher ages. CONCLUSIONS: The distribution of established VTE risk factors varies with the age of VTE manifestation. Future studies are needed to clarify the role of age-specific risk factors in the development of VTE and in the incidence gradient with aging.

Prevalence of thrombophilia according to age at the first manifestation of venous thromboembolism: results from the MAISTHRO registry.

Thrombophilia is a well-established risk factor for a venous thromboembolic event (VTE), and it has been proposed that hereditary thrombophilia may substantially contribute to the development of VTE in young patients. We aimed to analyse the prevalence of thrombophilia with special regard to the age of VTE manifestation. The study cohort consisted of 1490 patients (58% females) with a median age 43 years at the time of their first VTE. At least one thrombophilic disorder was identified in 50·1% of patients. The probability of detecting a hereditary thrombophilia declined significantly with advancing age (from 49·3% in patients aged 20 years and younger to 21·9% in patients over the age of 70 years; P < 0·001). This may be primarily attributed to the decreasing frequencies of the F5 R506Q (factor V Leiden) mutation and deficiencies of protein C or protein S with older age at the time of the initial VTE event. Moreover, thrombophilia was more prevalent in unprovoked compared with risk-associated VTE (57·7% vs. 47·7%; P = 0·001). The decline in the prevalence of hereditary thrombophilia with older ages supports the use of a selected thrombophilia screening strategy dependent on age and the presence or absence of additional VTE risk factors.

Patients with inferior vena cava thrombosis frequently present with lower back pain and bilateral lower-extremity deep vein thrombosis.

BACKGROUND: Inferior vena cava (IVC) thrombosis is rare, and data about the clinical presentation of patients are scarce. Therefore, we reviewed all cases of IVC thrombosis consecutively registered in the MAISTHRO (MAin-ISar-THROmbosis) database and described patients’ characteristics in terms of their clinical presentations in the acute setting of IVC thrombosis. PATIENTS AND METHODS: From the MAISTHRO registry, which enrolled 1470 consecutive patients with documented histories of venous thromboembolism, we identified 60 patients (0,4 %; females 60 %) with IVC thrombosis and 888 patients (60.4 %; females 55 %) with isolated lower-extremity deep vein thrombosis (LE-DVT). RESULTS: The median age at the time of IVC thrombosis manifestation was 36.5 years (9 to 83). IVC thrombosis was the initial VTE event in 47 patients (78 %). In the majority of cases, IVC thrombosis extended to the lower-extremity veins, and both lower extremities were affected in 17 cases (28 %). The initial clinical symptom of IVC thrombosis was lower back or abdominal pain which preceded typical symptoms of LE-DVT in 29 (48 %) patients. Symptomatic pulmonary embolism was more frequently observed in IVC thrombosis patients when compared to a sex- and age-matched subgroup of LE-DVT patients, although the difference was not significant (27 % vs. 12 %; p = 0.064). Malignant disease was the only established VTE risk factor with a higher prevalence among IVC thrombosis patients than patients with isolated LE-DVT (27 % vs. 9 %; p = 0.015). Congenital IVC anomalies were identified in another eight IVC thrombosis patients (13 %). CONCLUSIONS: IVC thrombosis should be considered a differential diagnosis for inexplicable lower back or abdominal pain especially in young patients. Malignant disease and congenital IVC anomalies seem to be predisposing factors for thrombosis involving the inferior vena cava.

Performance of five D-dimer assays for the exclusion of symptomatic distal leg vein thrombosis.

The diagnostic value of D-dimer (DD) in the exclusion of proximal deep-vein thrombosis (DVT) is well-established but is less well-known in the exclusion of distal (infrapopliteal) DVT. Therefore, we evaluated the diagnostic abilities of five DD assays (Vidas-DD, Liatest-DD, HemosIL-DD, HemosIL-DDHS, Innovance-DD) for excluding symptomatic proximal and distal leg DVT. A total of 243 outpatients whose symptoms were suggestive of DVT received complete compression ultrasonography (cCUS) of the symptomatic leg(s). The clinical probability of DVT (PTP) was assessed by Wells score. Thirty-eight proximal and 31 distal DVTs (17 tibial/fibular DVTs, 14 muscle DVTs) were diagnosed by cCUS. Although all assays showed high sensitivity for proximal DVT (range 97-100%), the sensitivity was poor for distal DVT (range 78-93%). None of the assays were individually able to rule out all DVTs as a stand-alone test (negative predictive value [NPV] 91-96%). However, a negative DD test result combined with a low PTP exhibited a NPV of 100% for all DVTs (including proximal, tibial/fibular, and muscle DVTs) with the HemosIL-DDHS and Innovance-DD. All proximal and tibial/fibular DVTs, but not all muscle DVTs, could be ruled out with this strategy using the Liatest-DD and Vidas-DD. The HemosIL-DD could not exclude distal leg DVT, even in combination with a low PTP. The combination of a negative DD with a low PTP showed a specificity of 32-35% for all DVTs. In conclusion, our study shows that when used in conjunction with a low PTP some DD assays are useful tools for the exclusion of distal leg DVT.

Variability of residual platelet function despite clopidogrel treatment in patients with peripheral arterial occlusive disease.

Residual platelet function despite treatment with clopidogrel may predict an unfavourable cardiovascular outcome. The majority of studies have investigated the effects of clopidogrel administration in conjunction with aspirin in patients undergoing percutaneous coronary intervention. The primary objective of the present study was to assess the platelet response to clopidogrel in the absence of aspirin in patients with peripheral arterial occlusive disease (PAOD) and to investigate whether non-responsiveness to clopidogrel is reproducible during long-term follow-up. Fifty-four clinically stable PAOD patients on a maintenance dose of 75 mg/d clopidogrel were enrolled in this study. Platelet function was assessed at baseline and after a median follow-up of 18 months using light transmittance aggregometry (LTA) with 2 microM ADP as an agonist. HPLC-coupled mass spectrometry was used to detect clopidogrel and clopidogrel carboxylic acid, the main metabolite of clopidogrel. Residual platelet function, as defined by late aggregation values within the reference range (i.e., >43%), was observed in 35.2% of patients at baseline and 17.6% during follow-up. During the observation period, 26.5% had switched from responder to non-responder status or vice versa. Among non-responders, either clopidogrel or its metabolite was detected in 89.5% and 83.3% of patients at baseline and at follow-up, respectively. We conclude that non-responsiveness to clopidogrel as determined by ADP-induced LTA is not stable over time. This phenomenon cannot be attributed to non-compliance alone.

Assessment of clopidogrel non-response by the PFA-100 system using the new test cartridge INNOVANCE PFA P2Y.

Until now, the PFA-100 system has been considered unsuitable for monitoring clopidogrel efficacy. The authors evaluated platelet function in peripheral arterial occlusive disease (PAOD) patients using a new PFA-100(R) test cartridge (product name: INNOVANCE PFA P2Y*) specifically designed for this purpose. Twenty-two stable PAOD patients on antithrombotic therapy with clopidogrel alone (n = 22) and 18 patients undergoing a peripheral catheter intervention, preliminarily treated with 100 mg/day of aspirin followed by co-administration of clopidogrel (loading dose 300 mg, maintenance dose 75 mg/day), were enrolled in this study. Defining non-responsiveness to clopidogrel as an aggregation response within the reference range (90% central interval), four (18.2%) non-responders using light transmittance aggregometry (LTA) induced by 5 microM adenosine diphosphate (ADP) and six (27.3%) non-responders using LTA induced by 2 microM ADP (LateAggr >72.1% and >42.9%, respectively) were identified. INNOVANCE PFA P2Y* determined six (27.3%) non-responders (CT < 87 s). Agreement between the two aggregometry assays and INNOVANCE PFA P2Y* on the definition of clopidogrel response and non-response exceeded 70%. Only three patients were uniformly identified as clopidogrel non-responders by all three assays. When clopidogrel was co-administered with aspirin, two (11.1%) non-responders to clopidogrel were detected with INNOVANCE PFA P2Y*, whereas ADP-induced LTA found all patients to be responsive. INNOVANCE PFA P2Y* appears to be suitable for monitoring the effect of clopidogrel on platelet function. Its sensitivity in detecting responsiveness or non-responsiveness to clopidogrel is comparable to ADP-induced LTA. Additional prospective studies are needed to clarify the clinical relevance of the test results and classification obtained with INNOVANCE PFA P2Y*.

Variability of non-response to aspirin in patients with peripheral arterial occlusive disease during long-term follow-up.

Non-responsiveness to aspirin as detected by laboratory tests may identify patients at high risk for future vascular events. The aim of this prospective study was to evaluate whether non-responsiveness to aspirin is stable over time. Ninety-eight patients with stable peripheral arterial occlusive disease (PAOD) treated with 100 mg/d aspirin were followed over a median timeframe of 17 months. Platelet function tests were performed initially and at follow-up using arachidonic acid-induced light transmittance aggregometry (LTA) in native platelet-rich plasma with the Behring Coagulation Timer and by measuring the collagen-epinephrine closure time (CT) on a Platelet Function Analyzer (PFA-100). When determining platelet function using LTA, four patients (4.1%) had residual platelet function (i.e., MaxAggr > or =78%) despite aspirin treatment, whereas, according to the PFA-100 results, 12 patients (12.2%) were identified as non-responders (i.e., CT <192 s). Fifty-seven patients who were still under treatment with 100 mg/d aspirin at the time of follow-up provided a second blood sample. Further platelet function tests with the PFA-100 system identified a persistent non-responsiveness to aspirin over time in three patients (5.3%) whereas four (7.0%) and 15 (26.3%) patients had changes in response status when platelet function was assessed by LTA and on the PFA-100(R), respectively. We conclude that true non-responsiveness to aspirin is a rare phenomenon in stable PAOD patients. Furthermore, we conclude that in a number of patients, aspirin non-responsiveness is not stable over time.

Hereditary and acquired thrombophilia in patients with upper extremity deep-vein thrombosis. Results from the MAISTHRO registry.

The prevalence of coagulation disorders in patients with upper extremity deep-vein thrombosis (UE-DVT) is unknown due to only a few observational studies of limited size reporting varying results. Therefore, we aimed to evaluate the prevalence of thrombophilia in patients with UE-DVT compared to patients with lower extremity deep vein thrombosis (LE-DVT). One hundred fifty consecutive patients (15 to 91 years of age) with UE-DVT were recruited from the MAISTHRO (MAin-ISar-THROmbosis) registry. Three hundred LE-DVT patients matched for gender and age served as controls. Thrombophilia screening included tests for the factor V Leiden mutation, the prothrombin G20210A mutation, antiphospholipid antibodies and factor VIII (FVIII), protein C, protein S and antithrombin activities. At least one thrombophilia was present in 34.2% of UE-DVT and 39.2% in UE-DVT that was unrelated to venous catheters relative to 55.3% in LE-DVT patients (p<0.001). In particular, a persistently elevated FVIII is less likely to be found in UE-DVT patients than in those with LE-DVT and is the only thrombophilia that is differentially expressed after controlling for established VTE risk factors [OR 0.46, (95% CI 0.25-0.83)]. Although less prevalent than in LE-DVT patients, thrombophilia is a common finding in patients with UE-DVT, especially in those with thrombosis that is unrelated to venous catheters.

Impact of sex and traditional cardiovascular risk factors on the risk of recurrent venous thromboembolism: results from the German MAISTHRO Registry.

As arterial and venous thrombosis share common risk factors, a link between arterial and venous thrombosis has been suggested recently. Therefore, we aimed to investigate the impact of established cardiovascular risk factors on the risk of recurrent venous thromboembolism (VTE). With a cross-sectional study design, we analyzed the data of 1006 patients (582 F, 424 M) consecutively treated in our outpatient department for VTE (i.e. lower extremity deep vein thrombosis and/or pulmonary embolism) and registered in the MAISTHRO (MAin-ISar-THROmbosis) database. Of the total cohort, 324 (32.2%) patients suffered a recurrent VTE. Compared with the patients with a single thromboembolic event, patients with recurrent VTE were more frequently male (39.4 vs. 27.0%, P < 0.001). In univariate analysis, the relative risk of recurrent VTE was 1.9 [95% confidence interval (CI) 1.53-2.39] for male sex and 1.6 (1.25-1.95) for age over 50 years (PAOD). After adjustments for age, sex, thrombophilia and other common VTE risk factors, male sex [hazard ratio (HR) = 1.7 (1.38-21.9)] and arterial hypertension [HR = 1.4 (1.05-1.78)] were independent risk factors of recurrent VTE. The higher risk in men than in women persisted even after the exclusion of women with transient hormonal risk factors [HR = 1.57 (1.19-2.07)]. In contrast, no association between the presence of diabetes, obesity, hypercholesterolemia or smoking and the risk of VTE recurrence was observed. Male sex and arterial hypertension are independently associated with an increased risk of recurrent VTE after termination of anticoagulant therapy for the first VTE event.

Determination of clopidogrel main metabolite in plasma: a useful tool for monitoring therapy?

This study was performed to determine whether analysis of clopidogrel and its main carboxylic acid metabolite in plasma provides additional information about the wide variability of platelet aggregation inhibition in clopidogrel-treated patients with peripheral arterial occlusive disease. Consecutive outpatients (n = 56) with stable peripheral arterial occlusive disease treated with 75 mg clopidogrel daily, without co-administration of aspirin, were investigated. With use of a standardized questionnaire, the time of drug intake was documented. Blood sampling was performed within 24 hours after the most recent drug intake. Platelet function was measured by optical aggregometry using adenosine diphosphate (ADP) (2 mumol/L) as the agonist. Plasma concentrations of clopidogrel and its main metabolite, clopidogrel carboxylic acid, were quantitated using high-performance liquid chromatography analysis coupled to mass spectrometry. In 95% (53/56) of patients, clopidogrel carboxylic acid was detected. In 40% (22/56) of patients, the ADP-induced aggregation response was within the normal range despite clopidogrel treatment. In 14% (3/22) of these patients, neither clopidogrel nor its main metabolite could be detected. Two of these patients agreed to ingest 75 mg/d clopidogrel under observation and to undergo blood sampling after 2, 12, and 24 hours. Clopidogrel carboxylic acid and a significant inhibition of platelet aggregation were detected even after 24 hours in both patients, confirming noncompliance as the reason for the lack of inhibition of ADP-induced platelet aggregation observed in the initial measurements. In the subgroup of patients who had taken clopidogrel within 4 hours before blood sampling, a large range of carboxylic acid concentrations was detected, indicating a high variability of drug metabolism among patients. In conclusion, determining clopidogrel metabolite plasma concentrations could be a useful tool for identifying poor compliance and variable metabolism in clopidogrel-treated patients. Nevertheless, in the majority of clopidogrel-treated patients, the variability of platelet response is not caused by noncompliance.