N. J. G. M. Veeger

A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin

See also Keeling D. Thrombophilia screening or screaming. This issue, pp 1191–2.

Low incidence of venographically detected deep vein thrombosis after knee arthroscopy without thromboprophylaxis: a prospective cohort study

H. B . ETTEMA,* M. R . HOPPENER , N. J . G . M. VEEGER , H . R . B ÜLLER and J . VAN DER MEER *Department of Orthopaedic Surgery and Traumatology, Isala Clinics (De Weezenlanden Hospital), Zwolle; Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam; and Division of Haemostasis and Thrombosis, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

Lipid levels do not influence the risk of venous thromboembolism Results of a population-based cohort study

Studies on the association between lipid profile and venous thromboembolism (VTE) are inconsistent. This could be caused by classical lipoproteins being inferior to apolipoproteins as markers for VTE risk. Therefore, we examined whether apolipoproteins are more strongly related to VTE than lipoproteins. For this analysis we used the PREVEND prospective community based observational cohort study. Levels of apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), total cholesterol (TC), high-density lipoprotein (HDL), non-HDL, low-density lipoprotein (LDL), triglycerides (TG), lipoprotein(a), ApoB/ApoA1 and TC/HDL ratio were assessed. Subjects with VTE were identified using databases of the national registries of hospital discharge diagnoses, death certificates, and the regional anticoagulation clinic. Out of 7,627 subjects, 110 developed VTE during a median follow-up of 10.5 years. In both univariate and multivariable analyses no significant associations between apolipoproteins and overall VTE were observed. Of the classical lipoproteins, TC, non-HDL, LDL, TG, and TC/HDL ratio were significantly associated with overall VTE in univariate analysis. Significant associations were no longer present in multivariable analysis. TGL and LDL were significantly associated with unprovoked VTE in univariate analysis. After adjustment for age and sex this significance was lost. No significant associations between (apo-) lipoproteins and provoked VTE were found. We conclude that apolipoproteins are not better in predicting VTE risk than the classical lipoproteins. Our population-based cohort study does not show an association between both apolipoproteins and the classical lipoproteins and VTE risk.

Early detection of patients with a poor response to vitamin K antagonists: the clinical impact of individual time within target range in patients with heart disease

CSX patients (P < 0.001). The difference in MONO–PLT aggregates in response to ADP between CSX and the other groups was no longer present after EST (Fig. 1). Significant differences among groups persisted after adjustment for possible confounding clinical and EST variables, including induction of myocardial ischemia. In this study, we show that, in CSX patients, EST induces a reduction in platelet CD41 and CD62P expression, whereas both receptors increase in CAD patients, with CD62P also increasing in controls. Moreover, in CSX patients the increase of platelet receptor expression and of leukocyte–platelet aggregate formation in response to ADP stimulation was consistently lower after than before EST, whereas it was either increased or unchanged in the two other groups (Fig. 1). These results suggest that, in CSX patients, platelets after EST experience changes that make them less reactive, compared to rest conditions and compared with platelets of both patients with obstructive stable CAD and healthy subjects. Our data are in agreement with, and help to explain, the lower platelet reactivity to collagen/ADP in the whole blood found in CSX patients after stress tests, in contrast with the absence of variations in controls and an increase in CAD patients [3–5]. In apparent contrast with all the other results, the MONO– PLT aggregate formation in response to ADP was higher at rest in CSX patients than in the two other groups. The reasons for this finding remain to be clarified, but we cannot exclude that it might be related to an abnormally increased monocyte reactivity.

Insulin resistance and risk of venous thromboembolism

Summary.  Background:  Obesity is an established risk factor for venous thromboembolism (VTE), but it is uncertain how this is mediated. Insulin resistance has a central role in the pathophysiology of the metabolic effects of obesity.

High thrombin-activatable fibrinolysis inhibitor levels may protect against recurrent fetal loss

Thrombin-activatable fibrinolysis inhibitor (TAFI) is a procarboxypeptidase that suppresses fibrinolysis by removing C-terminal lysine residues from partially degraded fibrin [1]. These residues are involved in binding of plasminogen and tissue-type plasminogen activator, and in plasmin formation. TAFI is activated by thrombin, mainly in complex with thrombomodulin, and by plasmin. TAFI inhibits tissue plasminogen activator-induced fibrinolysis [2]. High TAFI levels might enhance the development of thrombosis, and consequently fetal loss as a result of placental thrombosis. Recently, we demonstrated that high TAFI levels are not associated with an increased risk of fetal loss [3]. On the contrary, our data suggested a decline of this risk with increasing TAFI levels. We hypothesized that high TAFI levels during normal pregnancy protect against fetal loss [4,5]. This effect might be more pronounced in pregnant women who are at increased risk of fetal loss because of thrombophilic defects. Here, we present the results of an additional analysis of data from our previously reported study, to test this hypothesis. The study population contained female subjects from four pooled retrospective family cohort studies [6–9]. These studies were designed to estimate the absolute risk of venous thromboembolism (VTE), associated with either hereditary deficiencies of antithrombin, protein C or protein S, the prothrombin 20210A mutation, elevated factor VIII:C levels, or hyperhomocysteinemia. Probands in each of these studies were consecutive patients with documented VTE or premature atherosclerosis (age, < 50 years), and one of these thrombophilic defects. Relatives, who were 15 years of age or older, were identified by pedigree analysis and were enrolled after informed consent was obtained. The studies were approved by the institutional review boards of the participating hospitals. In addition to the above-mentioned thrombophilic defects, subjects were tested for FV Leiden, and TAFI activity was measured. The assays used have been described elsewhere [3]. Detailed information on obstetric history was obtained, by using a questionnaire and reviewing medical records. Clinical data were collected prior to blood sampling. Women were evaluable if they had been pregnant before the end of the study. Women with only terminated or ectopic pregnancies were excluded from analysis. Fetal loss was defined as early fetal loss if it had occurred

Fetal loss in women with hereditary thrombophilic defects and concomitance of other thrombophilic defects: a retrospective family study

Please cite this paper as: Korteweg F, Folkeringa N, Brouwer J, Erwich J, Holm J, van der Meer J, Veeger N. Fetal loss in women with hereditary thrombophilic defects and concomitance of other thrombophilic defects: a retrospective family study. BJOG 2012;119:422–430.

Methionine‐loading and random homocysteine tests have no added value in risk assessment for venous and arterial thrombosis

Hyperhomocysteinemia (HHcy) is a risk factor for venous thrombosis (VT) and arterial thrombosis (AT) [1,2]. To identify subjects at risk of thrombosis, measurements of fasting and methionine-loading (postload) homocysteine (Hcy) levels are usually recommended. Alternatively, random Hcy measurements may simplify the procedure. In this approach, random Hcy levels <10 and >20 lmol L indicate normohomocysteinemia (NHcy) and HHcy, respectively, while succeeding measurements of fasting and postload Hcy remain required at levels of 10–20 lmol L. Previous reports did show an increased risk of VT and AT in subjects with postload HHcy [3–5]. However, both fasting and postload Hcy were measured, independent of whether subjects had fasting HHcy or not. We performed a retrospective study to accurately identify HHcy, associated with an increased risk of VT or AT, by comparing different diagnostic strategies. Postload Hcy was not measured when relatives already had fasting HHcy because it would not change their classification as HHcy. Subjects were derived from a family study, which has been described in detail previously [6,7]. Briefly, 713 relatives (15 years or older, response rate 90%) were enrolled to evaluate the concept of multicausality of VT. Probands were consecutive patients with documented VT, in whom an inherited antithrombin, protein C or protein S (index) deficiency was recognized. Relatives were tested for all currently known thrombophilic defects and HHcy in addition to these deficiencies. Clinical data and blood sampling was collected at date of enrollment. Follow-up time started at age 15 years and ended at the date of enrollment or at the date of thrombosis. Therefore, our study was retrospective and relatives were not treated for HHcy with B-vitamins. According to predefined cutoff levels, HHcy and NHcy relatives were identified and their absolute risks of thrombosis were compared. Women and men were equally distributed. Median age at enrollment (i.e. end of study) was 42 years (range 15–92). VT had occurred in 102 relatives (14%) at a median age of 31 years (16–80). AT had occurred in 48 relatives (7%) at a median age of 57 years (26–80). Median time interval between VT or AT and homocysteine measurement was 14 years (0–47) and 5 years (0–37), respectively.Median random, fasting and postload Hcy levels were 11.9 lmol L (5.5–62.7), 12.3 lmol L (5.6–42.7) and 38.3 lmol L (17.5–110.7), respectively. Since its implementation in July 2001, random Hcy testing had been performed in 532 relatives (Fig. 1). Another 181 relatives had been tested for HHcy with only fasting and postload Hcy measurements (before July 2001). Comparing relatives with random Hcy >20 lmol L vs. <10 lmol L, annual incidences of VT were 0.38% [95% confidence interval (CI), 0.17– 0.76] and 0.41% (0.22–0.68), respectively; relative risk (RR) 0.9; 95% CI, 0.4–2.3. For AT, these were 0.22% (0.07–0.52) vs. 0.14% (0.04–0.32); RR 1.7; 0.5–5.7. Relatives with random Hcy between 10 and 20 lmol L (63%) had successively fasting and postload Hcy tested, as had relatives who were screened before July 2001. Of these, 113 were lost due to logistic problems. Of the remaining 405 relatives, 26 (6%) had fasting HHcy (>18.5 lmol L) and 30 (8%) postload HHcy (>58.8 lmol L). Antithrombin, protein C and protein S deficiencies and other thrombophilic defects, and classical risk factors for AT (diabetes mellitus, hyperlipidemia, hypertension and smoking) were equally distributed over NHcy relatives and relatives with fasting/postload HHcy. Table 1 shows the annual incidences of VT and AT in relatives with NHcy and HHcy. Fasting HHcy revealed an increased risk of VT (RR 2.6; 1.3–4.8) and AT (RR 3.7; 1.5– 8.4). In contrast, relatives with NHcy and postload HHcy showed no differences in risks of VT or AT; RR 0.8 (0.2–1.9) and 1.1 (0.2–3.9), respectively. Because our study cohort was built upwith a high risk thrombophilic population, we repeated our analysis after excluding all deficient relatives. The annual incidence of VT in non-deficient relatives without fastingHHcy was 0.20% (0.12–0.33), which increased to 1.13% (0.45–2.33) in non-deficient relatives with fasting HHcy; RR 5.5 (2.1–13.1). In non-deficient relatives with postload HHcy, the annual incidence of VT was 0.27% (0.03–0.97), compared to 0.19% Correspondence: Willem Lijfering, Division of Haemostasis, Thrombosis and Rheology, Department of Hematology, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. Tel.: +31 50 3612791; fax: +31 50 3611790; e-mail: w.lijfering@ int.umcg.nl

Fetal loss in women with hereditary thrombophilic defects and concomitance of other thrombophilic defects: a retrospective family study: Fetal loss and multiple thrombophilic defects

Please cite this paper as: Korteweg F, Folkeringa N, Brouwer J, Erwich J, Holm J, van der Meer J, Veeger N. Fetal loss in women with hereditary thrombophilic defects and concomitance of other thrombophilic defects: a retrospective family study. BJOG 2012;119:422–430.