Ansgar Weltermann

The post-thrombotic syndrome: risk factors and impact on the course of thrombotic disease

Summary.u2002 Background:u2002The post‐thrombotic syndrome (PTS) is a frequent complication of deep vein thrombosis (DVT). Patients with recurrent ipsilateral DVT have an increased risk of PTS; other risk factors are unknown. Objectives:u2002To establish risk factors of PTS and its impact on venous thrombotic disease. Patients:u2002We prospectively followed 406 patients after a first symptomatic DVT for a median of 60u2003months. Patients with recurrent DVT, a natural inhibitor deficiency, the lupus anticoagulant, cancer, long‐term anticoagulation, an observation time <u200318u2003months and DVT‐recurrence prior PTS‐assessment were excluded. Study outcomes were occurrence of PTS and recurrent symptomatic DVT. Results:u2002PTS was assessed after 44u2003±u200323u2003months (meanu2003±u2003SD) using a clinical classification score. PTS developed in 176 of 406 patients (43.3%). Severe PTS was rare (1.4%). Proximal DVT was the strongest risk factor of PTS [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.3–3.7]. Male gender (OR 1.6, 95% CI 1.0–2.8) and elevated D‐dimer levels (OR 1.9, 95% CI 1.0–3.9) were weaker risk factors. Factor V Leiden, factor II G20210A or high factor VIII did not confer an increased risk of PTS. At 4u2003years, the cumulative probability of recurrence was 7.4% (95% CI 3.2–11.7) among patients with PTS when compared with 1.6% (95% CI 0–3.5; Pu2003<u20030.02) among patients without PTS. The risk of recurrence was 2.6‐fold (95% CI 1.2–5.9) increased when PTS was present. Conclusions:u2002Proximal DVT, male gender, and high D‐dimer levels are independently associated with the development of PTS in patients with a first DVT. Patients with PTS have an increased risk of recurrent venous thromboembolism.

The risk of recurrent venous thromboembolism among patients with high factor IX levels

Summary.u2002 High factor IX (FIX) is a risk factor of deep vein thrombosis. The impact of high FIX on the risk of recurrent venous thrombosis is unknown. We prospectively followed 546 patients after anticoagulation for a first spontaneous venous thromboembolism. Patients with a natural coagulation inhibitor deficiency, lupus anticoagulant or cancer were excluded. At 3u2003years, the likelihood of recurrence was 23% among patients with high FIX (exceeding the 75th percentile) compared with 11% among patients with lower levels. Among patients with high FIX, the relative risk of recurrence was 2.2 (95% CI: 1.3–3.6) before and was 1.6 (95% CI: 1.0–2.8) after adjustment for age, gender, duration of anticoagulation, FV Leiden, FII G20210A, high FVIII and hyperhomocysteinemia. Compared with patients with low factor IX (<u2003138 IUu2003dL−1) and low FVIII (≤u2003234 IUu2003dL−1), the relative risk of recurrence was 1.5 among patients with high FIX and low FVIII, 2.7 among patients with low FIX and high FVIII and 6.6 among patients with high FIX and high FVIII. High levels of FIX confer an increased risk of recurrent venous thromboembolism and enhance the risk of recurrence among patients with high FVIII.

Comparison between idiopathic deep vein thrombosis of the upper and lower extremity regarding risk factors and recurrence.

Summary.u2002 Background:u2002The pathogenesis and natural course of idiopathic upper extremity deep vein thrombosis (UEDVT) are unclear. Objective:u2002To compare patients with UEDVT and with idiopathic lower extremity deep vein thrombosis (LEDVT) regarding risk factors and recurrence. Methods:u2002We followed 50 patients with first idiopathic UEDVT and 841 patients with first idiopathic LEDVT for an average of 59 and 46u2003months, respectively. We excluded patients with natural inhibitor deficiency, lupus anticoagulant, cancer, pregnancy, isolated pulmonary embolism (PE), or long‐term antithrombotic treatment. The endpoint was recurrent venous thromboembolism (VTE). Results:u2002In comparison to LEDVT patients, UEDVT patients were younger (38u2003±u200313u2003years vs. 49u2003±u200316u2003years, Pu2003<u20030.001), slimmer (body mass index: 24u2003±u20034 vs. 27u2003±u20035, Pu2003<u20030.001), less frequently had a family history of VTE (18% vs. 31%, Pu2003=u20030.06) or concomitant PE (8% vs. 31%, Pu2003=0.001), were less frequently carriers of factor V Leiden (12% vs. 30%, Pu2003=u20030.009), and had lower thrombin generation marker levels (D‐dimer, 283u2003±u2003361u2003ngu2003mL−1 vs. 456u2003±u2003446u2003ngu2003mL−1, Pu2003<u20030.001; peak thrombin, 298u2003±u2003101u2003nm vs. 363u2003± 111u2003nm, Pu2003=u20030.001). Recurrence occurred in two of 50 patients with UEDVT (4%) and in 129 of 841 patients with LEDVT (15%). After 5u2003years, the likelihood of recurrence was 2% [95% confidence interval (CI) 0–6] among UEDVT patients and 19% (95% CI 16–22; Pu2003=u20030.02) among LEDVT patients. As compared to LEDVT patients, the adjusted risk of recurrence was 0.26 (95% CI 0.06–1.05; Pu2003=u20030.059) in UEDVT patients. Conclusion:u2002The pathogenesis and natural course of the disease differ between patients with idiopathic UEDVT and LEDVT.

Chemotherapy-induced thrombin generation via procoagulant endothelial microparticles is independent of tissue factor activity

Summary.u2002 Background:u2002Cisplatin‐based chemotherapy predisposes cancer patients to thromboembolic events.

Prediction of recurrent venous thromboembolism by the activated partial thromboplastin time

Summary.u2002 Background:u2002Venous thromboembolism (VTE) is a multi‐factorial disease. Extensive thrombophilia screening is costly and often inconclusive. Simple laboratory methods are required to predict the risk of recurrence. Objective:u2002To assess if measurement of activated partial thromboplastin time (APTT) allows stratification of patients with VTE into high‐ and low‐risk categories with regard to recurrence. Patients and methods:u2002We prospectively followed 918 patients with a first unprovoked VTE and studied the relationship between recurrence and an APTT after discontinuation of anticoagulation. APTT was expressed as a ratio of test to reference coagulation times. Study endpoint was symptomatic recurrent VTE. Results:u2002Venous thromboembolism recurred in 101 (11%) patients. Patients without recurrence had a greater APTT ratio than those with recurrence (0.97u2003±u20030.09 vs. 0.93u2003±u20030.09, Pu2003=u20030.001). After 4u2003years, probability of recurrent VTE was 8.5% (95% CI: 5.5–11.5%) among patients with a ratio equal to or >u20030.95 and 15.6% (95% CI: 11.4–19.9%) among patients with a lower ratio (Pu2003=u20030.005). Compared with patients with an APTT ratio <u20030.95, the relative risk (RR) of recurrence among patients with a ratio equal to or >u20030.95 was 0.56 (95% CI: 0.38–0.84, Pu2003=u20030.005) before and 0.58 (95% CI: 0.39–0.87, Pu2003=u20030.009) after adjustment for sex, age, factor V Leiden, and factor II G20210A. Conclusions:u2002Measurement of APTT allows stratification of patients with VTE into high‐ and low‐risk categories with regard to recurrence.

Circulating tissue factor-exposing microparticles

Upon stimulation or apoptosis, eukaryotic cells shed membrane vesicles of submicron size. These so-called microparticles (MPs) are detected and characterized based on the exposure of antigens characteristic of their respective parental cells and on the increased distribution of negatively charged phospholipids to the outer membrane layer. Among the various hypothesized functions of MPs in both health and disease, one of the most studied is their possible role in hemostasis and thrombosis. In this context, special attention is paid to tissue factor (TF) exposed on a variety of MPs. MPs may have outstanding functional because of their ability to display active TF due to an abundance of negatively charged phospholipids on their surface. The rapid accumulation of TF-bearing MPs (TF+MPs) in a developing thrombus as well as the increased numbers and thrombogenic activity of TF+MPs in prothrombotic disorders indicate an important role in the pathogenesis of thrombosis. Nevertheless, isolation, quantification and antigenic characterization of TF+MPs proved challenging and a lively scientific debate is ongoing with respect to a reliable method to determine the cellular source of MP in vivo. Standardization of preanalytical procedures and development of more sensitive technologies are needed to improve our current understanding of the role of circulating TF+MPs in thrombosis.

Genetic variation in heme oxygenase 1 (HMOX1) and the risk of recurrent venous thromboembolism.

BACKGROUND/OBJECTIVEnProducts of heme oxygenase 1 (HO1) possess antithrombotic properties, and impairment of HO1 activity may contribute to thrombus formation. Transcriptional activity of long GT-repeat alleles in HO1 gene (HMOX1) is lower as compared with short alleles. We hypothesize that these long alleles are associated with decreased HO1 anticoagulant activity and, thus, an increased risk of thrombosis..nnnDESIGN/METHODSnIn a prospective cohort study, we followed 860 patients with a first VTE, and investigated the impact of a promoter GT-dinucleotid length polymorphism in HOMX1 on the risk of recurrent venous thromboembolism (VTE).nnnRESULTSnAllele groups short (S), medium (M) and long (L) of the promoter GT-dinucleotide length polymorphism were distinguished. L-alleles, but not M- or S-alleles, were found to be more frequent among patients with recurrence. Heterozygous carriers of L-alleles had a two-fold higher relative risk of recurrence [(RR 2.2 (95% CI: 1.4-3.4)] as compared to wild type, which was independent of other thrombotic risk factors. At five years, the cumulative probability of recurrence was 18% (95% CI: 15%-22%) in patients without an L-allele compared to 32% (95% CI: 19%-46%) in patients heterozygous for the L-allele (P = .001).nnnCONCLUSIONnPatients with first VTE and long GT-repeat alleles in HMOX1 have an increased risk of recurrence. Genetically determined alterations in HO1 function may represent a new pathomechanism in VTE.

Chemotherapy-induced thrombosis: a role for microparticles and tissue factor?

Chemotherapy is an independent risk factor of thromboembolic events in cancer patients. Various pathogenetic mechanisms have been hypothesized in the past, but until now their individual contribution to the risk of thrombosis has been hardly investigated in clinical trials. In recent years, studies increasingly suggested an association between the prothrombotic state in cancer patients and circulating tissue factor-exposing microparticles. In this review, we discuss the roles of tissue factor and microparticles with regard to chemotherapy-induced hypercoagulability.

Tissue factor exposing microparticles in inflammatory bowel disease

BACKGROUNDnCirculating procoagulant microparticles (MPs) are thought to be involved in the pathogenesis of venous thromboembolism in patients with inflammatory bowel disease (IBD). However, the exposure of tissue factor, the primary initiator of coagulation activation, on microparticles (TF(+)MPs) and its association with hemostasis activation has not yet been studied in IBD patients.nnnMETHODSnIn this case-control study 49 IBD patients (28 Crohns disease, 21 ulcerative colitis) and 49 sex- and age-matched, healthy controls were included. Clinical disease activity (Crohns Disease Activity Index and Clinical Activity Index, respectively) was assessed and IBD-related data were determined by chart review. Numbers, cellular origin and procoagulant activity of TF(+)MPs in plasma were determined using flow cytometry and a chromogenic activity assay. D-dimer and high-sensitive C-reactive protein (CRP) served as markers for coagulation activation and inflammation, respectively. The primary endpoint was the number of TF(+)MPs in IBD patients compared to controls.nnnRESULTSnMedian number (interquartile range) of TF(+)MPs was higher in IBD patients than in controls (14.0 (11.9-22.8)×10(3)/mL vs. 11.9 (11.9-19.1)×10(3)/mL plasma, P=0.029). This finding was due to generally higher plasma levels of MPs from platelets and leukocytes in IBD patients. However, the number of TF(+)MPs was neither correlated with their procoagulant activity and D-dimer nor with disease activity and CRP.nnnCONCLUSIONSnIncreased numbers of circulating TF(+)MPs represent a new facet of hemostatic abnormalities in IBD. However, the lack of association with activation of the coagulation system and disease activity questions their pathogenetic role for venous thromboembolism in this patient group.

The long-term recurrence risk of patients with unprovoked venous thromboembolism: an observational cohort study

Essentials Long‐term recurrence risk of venous thromboembolism (VTE) is uncertain. We performed a prospective cohort study of 839 patients with first unprovoked VTE. VTE recurrence risk is high, particularly in men with proximal thrombosis or pulmonary embolism. Sex and VTE site determine the recurrence risk and should be considered for patient counseling.