Jan van der Meer

Comparison of Low-Molecular-Weight Heparin With Unfractionated Heparin Acutely and With Placebo for 6 Weeks in the Management of Unstable Coronary Artery Disease Fragmin in Unstable Coronary Artery Disease Study (FRIC)

BACKGROUND Low-molecular-weight heparin has a number of pharmacological and pharmacokinetic advantages over unfractionated heparin that make it potentially suitable, when used in combination with aspirin, for the treatment of unstable coronary artery disease. METHOD AND RESULTS Patients with unstable angina or non-Q-wave myocardial infarction (1482) were included in the study, which had two phases. In an open, acute phase (days 1 to 6), patients were assigned either twice-daily weight-adjusted subcutaneous injections of dalteparin (120 i.u./kg) or dose-adjusted intravenous infusion of unfractionated heparin. In the double-blind, prolonged treatment phase (days 6 to 45), patients received subcutaneously either dalteparin (7500 i.u. once daily) or placebo. During the first 6 days, the rate of death, myocardial infarction, or recurrence of angina was 7.6% in the unfractionated heparin-treated patients and 9.3% in the dalteparin-treated patients (relative risk, 1.18; 95% confidence interval [CI], 0.84 to 1.66). The corresponding rates in the two treatment groups for the composite end point of death or myocardial infarction were 3.6% and 3.9%, respectively (relative risk, 1.07; 95% CI, 0.63 to 1.80). Revascularization procedures were undertaken in 5.3% and 4.8% of patients in unfractionated heparin and dalteparin groups, respectively (relative risk, 0.88; 95% CI, 0.57 to 1.35). Between days 6 and 45, the rate of death, myocardial infarction, or recurrence of angina was 12.3% in both the placebo and dalteparin groups (relative risk, 1.01; 95% CI, 0.74 to 1.38). The corresponding rates for death or myocardial infarction were 4.7% and 4.3% (relative risk, 0.92; 95% CI, 0.54 to 1.57). Revascularization procedures were undertaken in 14.2% and 14.3% of patients in the placebo and dalteparin groups, respectively. CONCLUSIONS Our results add to previous evidence suggesting that the low-molecular-weight heparin dalteparin administered by twice-daily subcutaneous injection may be an alternative to unfractionated heparin in the acute treatment of unstable angina or non-Q-wave myocardial infarction. Prolonged treatment with dalteparin at a lower once-daily dose in our study did not confer any additional benefit over aspirin (75 to 165 mg) alone.

Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease

Orthotopic liver transplantation (OLT) can be associated with excessive blood loss. As a result, there may be increased risk of adverse outcomes. Activated recombinant factor VII (rFVIIa) has demonstrated the ability to improve hemostasis in a variety of disorders; however, there has been a limited amount of research into its use in OLT. The purpose of this dose‐finding study was to examine the efficacy and safety of rFVIIa in the reduction of bleeding in patients undergoing OLT. In this double‐blind trial, patients with end‐stage liver disease scheduled for OLT were randomized to 1 of 4 parallel study groups. They received a single intravenous bolus of rFVIIa (20, 40, or 80 μg/kg) or placebo prior to surgery. The primary assessment endpoint was the total number of red blood cell (RBC) units transfused perioperatively. Safety was evaluated by adverse events reported. Eighty‐three comparable patients were randomized to receive study product, with 82 ultimately undergoing OLT. There were no significant differences in required RBC units between the placebo and rFVIIa study groups. The number of adverse events was comparable between study groups. In conclusion, rFVIIa has a good safety profile in patients undergoing OLT. However, the doses studied did not have any effect on the number of RBC transfusions required. (Liver Transpl 2005;11:895–900.)

Individual time within target range in patients treated with vitamin K antagonists: main determinant of quality of anticoagulation and predictor of clinical outcome. a retrospective study of 2300 consecutive patients with venous thromboembolism

The efficacy and safety of vitamin K antagonists (VKA) are related to the actual level of anticoagulation (given as the international normalized ratio, INR). It is often difficult to maintain an optimal INR over time. We assessed the clinical impact of the individual time spent within INR target range (ITTR) in 2304 consecutive patients with venous thromboembolism. Annual incidences of recurrent thromboembolism and major bleeding were 6·2% and 2·8% respectively. The relative risk (RR) of thromboembolism was 4·5 [95% confidence interval (CI) 3·1–6·6, P < 0·001] at INR < 2·0, for major bleeding it was 6·4 (2·5–16·1, P < 0·001) at INR > 5·0, compared with INR 2·0–3·0. Patients with ITTR < 45% were at higher risk than those with ITTR > 65% (RR 2·8, 1·9–4·3, P < 0·001), while no difference was demonstrated comparing ITTR 45–65% and ITTR > 65% (RR 1·2, 0·7–1·8, P = 0·54). Annual incidences of recurrent thromboembolism were 16·0%, 4·9% and 4·6% at ITTR < 45%, 45–60% and >65% respectively. For major bleeding these were 8·7%, 2·1% and 1·9% respectively. ITTR < 37% during the first 30 treatment days was highly predictive for the total treatment time ITTR < 45% (RR 24·2, 13·5–43·1, P < 0·001). In conclusion, ITTR can be used to identify patients on VKA at risk of recurrent thromboembolism or major bleeding. Since the 30‐d ITTR is highly predictive for total treatment ITTR, these patients can be identified soon after start of treatment.

High Absolute Risks and Predictors of Venous and Arterial Thromboembolic Events in Patients With Nephrotic Syndrome Results From a Large Retrospective Cohort Study

Background— No data are available on the absolute risk of either venous thromboembolism (VTE) or arterial thromboembolism (ATE) in patients with nephrotic syndrome. Reported risks are based on multiple case reports and small studies with mostly short-term follow-up. We assessed the absolute risk of VTE and ATE in a large, single-center, retrospective cohort study and attempted to identify predictive factors in these patients. Methods and Results— A total of 298 consecutive patients with nephrotic syndrome (59% men; mean age, 42±18 years) were enrolled. Mean follow-up was 10±9 years. Nephrotic syndrome was defined by proteinuria ≥3.5 g/d, and patients were classified according to underlying histological lesions accounting for nephrotic syndrome. Objectively verified symptomatic thromboembolic events were the primary study outcome. Annual incidences of VTE and ATE were 1.02% (95% confidence interval, 0.68 to 1.46) and 1.48% (95% confidence interval, 1.07 to 1.99), respectively. Over the first 6 months of follow-up, these rates were 9.85% and 5.52%, respectively. Proteinuria and serum albumin levels tended to be related to VTE; however, only the predictive value of the ratio of proteinuria to serum albumin was significant (hazard ratio, 5.6; 95% confidence interval, 1.2 to 26.2; P=0.03). In contrast, neither the degree of proteinuria nor serum albumin levels were related to ATE. Sex, age, hypertension, diabetes, smoking, prior ATE, and estimated glomerular filtration rate predicted ATE (P≤0.02). Conclusions— This study verifies high absolute risks of symptomatic VTE and ATE that were remarkably elevated within the first 6 months. Whereas the ratio of proteinuria to serum albumin predicted VTE, estimated glomerular filtration rate and multiple classic risk factors for atherosclerosis were predictors of ATE.

Microalbuminuria and Risk of Venous Thromboembolism

CONTEXT Microalbuminuria (albuminuria 30-300 mg per 24-hour urine collection) is a well-known risk marker for arterial thromboembolism. It is assumed that microalbuminuria reflects generalized endothelial dysfunction. Hence, microalbuminuria may also predispose for venous thromboembolism (VTE). OBJECTIVE To assess whether microalbuminuria is associated with VTE. DESIGN, SETTING, AND PARTICIPANTS Prevention of Renal and Vascular End-stage Disease (PREVEND) study, an ongoing community-based prospective cohort study initiated in 1997. All inhabitants of Groningen, The Netherlands, aged 28 through 75 years (n = 85,421) were sent a postal questionnaire and a vial to collect a first morning urine sample for measurement of urinary albumin concentration. Of those who responded (40,856), a cohort (8592 participants) including more participants with higher levels of urinary albumin concentration completed screening at an outpatient clinic. Screening data were collected on urinary albumin excretion (UAE) and risk factors for cardiovascular and renal disease. MAIN OUTCOME MEASURE Symptomatic and objectively verified VTE (ie, deep vein thrombosis, pulmonary embolism, or both) between study initiation and June 1, 2007. RESULTS Of 8574 evaluable participants (mean [SD] age, 49 [13] years; 50% men), 129 experienced VTE during a mean (SD) follow-up period of 8.6 (1.8) years, corresponding to overall annual incidence of 0.14% (95% confidence interval [CI], 0.11%-0.19%). Annual incidences were 0.12%, 0.20%, 0.40%, and 0.56% in participants with UAE of less than 15 (n = 6013), 15-29 (n = 1283), 30-300 (n = 1144), and greater than 300 (n = 134) mg per 24-hour urine collection, respectively (P for trend <.001). When adjusted for age, cancer, use of oral contraceptives, and atherosclerosis risk factors, hazard ratios associated with UAE levels of 15-29, 30-300, and greater than 300 mg/24 h were 1.40 (95% CI, 0.86-2.35), 2.20 (95% CI, 1.44-3.36), and 2.82 (95% CI, 1.21-6.61), respectively, compared with participants with UAE of less than 15 mg/24 h (global P = .001). Adjusted hazard ratio for microalbuminuria vs normoalbuminuria (UAE <30 mg/24 h) was 2.00 (95% CI, 1.34-2.98; P < .001). Microalbuminuria-related number needed to harm was 388 per year. CONCLUSION Microalbuminuria is independently associated with an increased risk for VTE.

An effective treatment of severe intractable bleeding after valve repair by one single dose of activated recombinant factor VII.

IMPLICATIONS The successful treatment with recombinant factor VIIa of a patient experiencing intractable bleeding after cardiac surgery is described.

High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin

Hereditary deficiencies of protein S, protein C and antithrombin are known risk factors for first venous thromboembolism. We assessed the absolute risk of recurrence, and the contribution of concomitant thrombophilic defects in a large cohort of families with these deficiencies. Annual incidence of recurrence was estimated in 130 deficient patients, with separate estimates for those with each of protein S, protein C, and antithrombin deficiency, and in eight non-deficient patients with prior venous thromboembolism. All patients were also tested for factor V Leiden, prothrombin G20210A, high levels of factors VIII, IX and XI, and hyperhomocysteinemia. There were 81 recurrent events among 130 deficient patients. Median follow-up was 4.6 years. Annual incidences (95% confidence interval) of recurrent venous thromboembolism were 8.4% (5.8-11.7) for protein S deficiency, 6.0% (3.9-8.7) for protein C deficiency, 10.0% (6.1-15.4) for antithrombin deficiency, and overall 7.7% (6.1-9.5). Relative risk of recurrence in patients with a spontaneous versus provoked first event was 1.5 (0.95-2.3). Cumulative recurrence rates at 1, 5 and 10 years were 15%, 38% and 53%. Relative risk of recurrence with concomitant defects was 1.4 (0.7-2.6) (1 defect) and 1.4 (0.8-2.7) (> or =2 defects). Annual incidence was 1.0% (0.03-5.5) in eight non-deficient patients. Annual incidence of major bleeding in deficient patients on oral anticoagulant treatment was 0.5% (0.2-1.0). We conclude that patients with a hereditary protein S, protein C or antithrombin deficiency appear to have a high absolute risk of recurrence. This risk is increased after a first spontaneous event, and by concomitance of other thrombophilic defects.

Hereditary Deficiency of Protein C or Protein S Confers Increased Risk of Arterial Thromboembolic Events at a Young Age Results From a Large Family Cohort Study

Background— Whether hereditary protein S, protein C, or antithrombin deficiency is associated with arterial thromboembolism (ATE) and whether history of venous thromboembolism in these subjects predisposes them to subsequent ATE have yet to be determined. Methods and Results— On the basis of pedigree analysis, we enrolled a total of 552 subjects (52% women; mean age, 46±17 years), belonging to 84 different kindreds, in this retrospective family cohort study. Detailed information on previous episodes of venous thromboembolism, ATE, anticoagulant use, and atherosclerosis risk factors was collected. Primary study outcome was objectively verified symptomatic ATE. Of 552 subjects, 308 had protein S (35%), protein C (39%), or antithrombin (26%) deficiency. Overall, annual incidences of ATE were 0.34% (95% confidence interval [CI], 0.23 to 0.49) in deficient versus 0.17% (95% CI, 0.09 to 0.28) in nondeficient subjects; the hazard ratio was 2.3 (95% CI, 1.2 to 4.5). Because the risk hazards varied over lifetime, we performed a time-dependent analysis. After adjusting for atherosclerosis risk factors and clustering within families, we found that deficient subjects had a 4.7-fold (95% CI, 1.5 to 14.2; P=0.007) higher risk for ATE before 55 years of age versus 1.1 (95% CI, 0.5 to 2.6) thereafter compared with nondeficient family members. For separate deficiencies, the risks were 4.6- (95% CI, 1.1 to 18.3), 6.9- (95% CI, 2.1 to 22.2), and 1.1- (95% CI, 0.1 to 10.9) fold higher in protein S–, protein C–, and antithrombin-deficient subjects, respectively, before 55 years of age. History of venous thromboembolism was not related to subsequent ATE (hazard ratio, 1.1; 95% CI, 0.5 to 2.2). Conclusions— Compared with nondeficient family members, subjects with protein S or protein C deficiency but not antithrombin deficiency have a higher risk for ATE before 55 years of age that is independent of prior venous thromboembolism.

The Pathogenesis of Venous Thromboembolism: Evidence for Multiple Interrelated Causes

Context Venous thromboembolism (VTE) is thought to arise from the interaction of environmental and genetic factors in persons predisposed to VTE. Contribution The authors studied persons with protein S, protein C, or antithrombin deficiency who were first-degree relatives of persons who had VTE. They assessed each relative for environmental exposures and additional thrombophilic defects. They found that risk for VTE increased with the number of defects and with exposure to environmental risk factors. Cautions The findings were not based on the total population of relatives. The authors could not quantify risk for interactions between specific defects and environmental risk factors. Implications The risk for VTE increases with the number of thrombophilic defects and environmental risk factors in persons with a hereditary predisposition to VTE. The study provides evidence that VTE arises from interactions between environmental and genetic risk factors and quantifies the risks. The Editors Venous thromboembolism (VTE) has an incidence of 0.1 to 0.2 per 100 person-years (1, 2). It has been speculated that the development of VTE results from interactions between multiple genetic and environmental risk factors (3). Several inherited or acquired coagulation defects have been identified as VTE risk factors over the past 30 years. Known thrombophilic defects include hereditary deficiencies of protein S, protein C, and antithrombin; factor V Leiden; the prothrombin G20210A mutation; high levels of coagulant factors VIII, IX, and XI; hyperhomocysteinemia; and antiphospholipid antibodies (4). Whether patients with VTE and their relatives should be tested for all of these defects is still debatable. Clinical implications mainly depend on the absolute risk for a first or recurrent episode of VTE in persons with a single defect or in those with a combination of defects. Most common defects are mild risk factors for VTE. In contrast, hereditary deficiencies of protein S, protein C, and antithrombin are strong risk factors but are rare. Although interactions between these deficiencies and 1 or more other thrombophilic defects might increase the risk for VTE, they cannot be studied easily because the prevalence of such combinations is low. Thus far, only a few studies have reported the risk for VTE associated with coinheritance of deficiencies of protein S, protein C, or antithrombin and factor V Leiden or the prothrombin G20210A mutation (510). The results were not consistent, possibly because of small numbers of cases. We performed a retrospective study to assess the contribution of currently known hereditary thrombophilic defects and exogenous risk factors to the absolute risk for VTE in a large series of protein S, protein C, or antithrombin-deficient families. Methods We aimed to assess interactions between known thrombophilic deficiencies and defects, including hereditary deficiencies of protein S, protein C, and antithrombin. Because these deficiencies are strong risk factors for VTE, the effects and clinical impact of interactions with more prevalent and mild thrombophilic defects may be more pronounced than interactions between mild defects. To enroll sufficient numbers of affected persons needed for accurate risk estimates, we identified families with these rare deficiencies. The family cohort study design enabled us to assess the clinical impact of interactions from absolute risk estimates. Participants The study comprised 3 cohorts of families with hereditary deficiencies of protein S, protein C, or antithrombin. Probands were consecutive patients with VTE who had 1 of these deficiencies. Primary care physicians referred patients with clinically suspected VTE to 1 of 2 hospitals in our region of the Netherlands; 50% were referred to the thrombosis outpatient clinic of our university hospital. Previous clinical trials did not show differences between patients who were referred to either hospital for this reason. Because it is common practice in the Netherlands to confirm suspected VTE, the proportion of patients who were not referred was probably small. All patients who had VTE confirmed at our outpatient clinic were tested for protein S, protein C, or antithrombin deficiencies, unless they had extensive malignant disease. After a deficiency was established by repeated measurement and after causative acquired conditions were excluded, the patients first-degree relatives who were older than age 15 years were identified by pedigree analysis and were contacted through the probands. Because the number of antithrombin-deficient probands was small, second-degree relatives with a deficient parent were also identified. Relatives were assessed for deficiency at the time of identification and then were followed for thromboembolic events from age 15 years to the time of testing. All participants provided informed consent. Physicians at our outpatient clinic collected detailed information about previous episodes of VTE, exposure to exogenous risk factors for VTE, and anticoagulant treatment using a validated questionnaire (11) and by reviewing medical records. The use of oral contraceptives and an obstetric history were documented for women. Blood samples were taken after clinical data had been collected. All relatives were tested for 10 thrombophilic deficiencies and defects in addition to their index deficiencies, including deficiencies of protein S, protein C, antithrombin, and plasminogen; factor V Leiden; prothrombin G20210A; high levels of factors VIII, IX, and XI; hyperhomocysteinemia; and lupus anticoagulant. Diagnosis of VTE Venous thromboembolism was considered established if deep venous thrombosis was confirmed by compression ultrasonography or venography, and pulmonary embolism was confirmed by ventilationperfusion lung scanning, spiral computed tomography scanning, or pulmonary angiography. When these techniques were not yet available, VTE was considered established when the patient had received full-dose unfractionated heparin and a vitamin K antagonist for at least 3 months. Venous thromboembolism was considered secondary if it had occurred at or within 3 months after exposure to exogenous risk factors, including major surgery, trauma, immobilization for more than 7 days, oral contraceptives, hormone replacement therapy, pregnancy, and malignant disease. In the absence of these risk factors, VTE was considered primary. Laboratory Studies Protein S and protein C antigen levels were measured by enzyme-linked immunosorbent assay (Dako, Glostrup, Denmark); activity of protein C (Berichrom Protein C, Dade Behring, Marburg, Germany), antithrombin (Coatest, Chromogenix AB, Mlndal, Sweden), and plasminogen (S2251, Chromogenix AB) was measured by chromogenic substrate assays. Levels of protein S, protein C, and antithrombin were expressed as a percentage of the levels measured in pooled plasma set at 100%. Normal ranges were determined in 393 healthy blood donors who had no family history of VTE, were not pregnant, and had not used oral contraceptives for at least 3 months. Protein S deficiency type I was defined by decreased free and total protein S levels, that is, below normal ranges, and protein S deficiency type III was defined by decreased free protein S levels and normal total protein S levels. After we had demonstrated that type III protein S deficiency was not a risk factor for thrombosis, families with this deficiency were excluded from the analysis (12). Protein C deficiency type I and type II were defined by decreased levels or activity of protein C antigen, and antithrombin deficiency was defined by decreased levels of antithrombin activity. Deficiencies were considered inherited if they were confirmed by measuring a second sample that was collected 3 months later and were found in at least 2 family members. Relatives with acquired conditions were excluded. If there was a discrepancy between the results of the 2 tests, a third sample was tested. A deficiency was considered acquired, through use of oral contraceptives or pregnancy, unless it was confirmed at least 3 months after withdrawal of oral contraceptives or delivery, respectively. Factor V Leiden and the prothrombin G20210A mutation were demonstrated by polymerase chain reaction (13, 14). Factors VIII:C, IX:C, and XI:C were measured by 1-stage clotting assays (Amelung GmbH, Lemgo, Germany) and were increased at levels above 150%. Lupus anticoagulant was defined by abnormal values of dilute Russell viper venom time, activated partial thromboplastin time, and tissue thromboplastin inhibition, which normalized by adding phospholipids to the participants plasma (15). Fasting and postmethionine-loading levels of homocysteine were measured by high-performance liquid chromatography (16). Hyperhomocysteinemia was defined as a fasting homocysteine level above 18.5 mol/L, a postloading level above 58.8 mol/L, or both, as described in a Dutch population (17). Blood samples were collected from probands and relatives at least 3 months after VTE. If probands or relatives were receiving long-term treatment with vitamin K antagonists, samples were taken after treatment had been interrupted for at least 2 weeks; in the meantime, nadroparin was given subcutaneously. Additional tests were performed on plasma stored at80C from relatives who had been enrolled at a time when 1 of more of these deficiencies or defects had not yet been recognized as risk factors for VTE. Statistical Analysis We compared the absolute risk for VTE in deficient and nondeficient relatives in each of the 3 cohorts and in the pooled cohorts. Probands were excluded from the analysis to avoid selection bias. Annual incidences were calculated by dividing the number of symptomatic relatives by the total number of observation-years. Ninety-five percent CIs were calculated around the incidence rates by using the Poisson distribution assumption. Observation time was defined as the period from age 15 yea

Diverse placental pathologies as the main causes of fetal death.

OBJECTIVE: To estimate the occurrence of placental causes of fetal death in relation to different gestational ages and their clinical manifestations during pregnancy. METHODS: In a prospective cohort study conducted from 2002 to 2006, we studied 750 couples with singleton intrauterine fetal death after 20 weeks of gestation. Cause of death was classified according to the Dutch Tulip cause of death classification for perinatal mortality. Differences between groups for categorical data were evaluated by the Fisher exact test or &khgr;2 test. RESULTS: The main causes were placental pathology (64.9%), congenital anomaly (5.3%), infection (1.9%), other (4.8%), and unknown (23.1%). The contribution of causes differed over gestational age periods. At lower gestational age, placental and unknown were the most dominant causes of death (34.8% and 41.7%, respectively); at higher gestational age, the relative importance of an unknown cause decreased and a placental cause increased (16.5% and 77.6%) (P<.001). Placental bed pathology was observed in 33.6% of all fetal deaths, with the highest occurrence between 24 0/7 and 31 6/7 weeks and a strong decline after 32 weeks. In contrast, contribution of developmental placental pathology (17.6%) increased after 32 weeks of gestation (P<.001), as did umbilical cord complications (5.2%) and combined placental pathology (5.4%). Solitary placental parenchyma pathology was less frequent (3.1%). Hypertension-related disease was observed in 16.1% (95% confidence interval [CI] 13.6–19.0) of the cohort, small for gestational age fetuses in 37.9% (95% CI 34.1–41.7), and diabetes-related disease in 4.1% (95% CI 2.8–5.8). CONCLUSION: Most fetal deaths were caused by a variety of placental pathologies. These were related to gestational age, and their clinical manifestations varied during pregnancy. LEVEL OF EVIDENCE: II