F. J. M. Van Der Meer

Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study.

Summary.  Background: The incidence of venous thrombosis (VT) for cancer patients is increased compared with patients without cancer, but estimations of the incidence for different types of cancer have rarely been made because of the low incidence of various types of cancer. Large registries offer an opportunity to study the risk of VT in large cohorts of cancer patients, which is essential in decisions on prophylactic anti‐coagulant treatment. Methods: This cohort study estimates the incidence of VT in cancer patients by using record linkage of a Cancer Registry and an Anticoagulation Clinic database in the Netherlands. Cumulative incidences in patients with different types of malignancies were estimated. We calculated relative risks (RRs) in relation to the presence of distant metastases and treatment. Results: Tumors of the bone, ovary, brain, and pancreas are associated with the highest incidence of VT (37.7, 32.6, 32.1, and 22.7/1000/0.5 year). Patients with distant metastases had a 1.9‐fold increased risk [RRadj: 1.9; 95% confidence interval (CI): 1.6–2.3]. Chemotherapy leads to a 2.2‐fold increased risk (RRadj: 2.2; 95% CI: 1.8–2.7) and hormonal therapy leads to a 1.6‐fold increased risk (RRadj: 1.6; 95% CI: 1.3–2.1) compared with patients not using these treatment modalities. Patients with radiotherapy or surgery did not have an increased risk. Conclusions: We compared the overall incidences of VT in the first half year in our study to the risk of major bleeding as described in the literature. For patients with distant metastases, for several types of cancer, prophylactic anti‐thrombotic treatment could be beneficial.

Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT)

Summary.  Background: Reliable risk estimates for venous thrombosis in families with inherited thrombophilia are scarce but necessary for determining optimal screening and treatment policies. Objectives: In the present analysis, we determined the risk of a first venous thrombotic event in carriers of a thrombophilic defect (i.e. antithrombin‐, protein C‐ or protein S deficiency, or factor V Leiden). Patients and methods: The asymptomatic carriers had been tested prior to this study in nine European thrombosis centers because of a symptomatic carrier in the family, and were followed prospectively for 5.7 years on average between March 1994 and January 2001. Annually, data were recorded on the occurrence of risk situations for venous thrombosis and events (e.g. venous thrombosis, death). Results: Twenty‐six of the 575 asymptomatic carriers (4.5%) and seven of the 1118 controls (0.6%) experienced a first deep venous thrombosis or pulmonary embolism during follow‐up. Of these events, 58% occurred spontaneously in the carriers compared with 43% in the controls. The incidence of first events was 0.8% per year (95% CI 0.5–1.2) in the carriers compared with 0.1% per year (95% CI 0.0–0.2) in the controls. The highest incidence was associated with antithrombin deficiency or combined defects, and the lowest incidence with factor V Leiden. Conclusions: The incidence of venous events in asymptomatic individuals from thrombophilic families does not exceed the risk of bleeding associated with long‐term anticoagulant treatment in the literature (1–3%).

Localized measurement of optical attenuation coefficients of atherosclerotic plaque constituents by quantitative optical coherence tomography

Optical coherence tomography (OCT) is a novel, high-resolution diagnostic tool that is capable of imaging the arterial wall and plaques. The differentiation between different types of atherosclerotic plaque is based on qualitative differences in gray levels and structural appearance. We hypothesize that a quantitative data analysis of the OCT signal allows measurement of light attenuation by the local tissue components, which can facilitate quantitative spatial discrimination between plaque constituents. High-resolution OCT images (at 800 nm) of human atherosclerotic arterial segments obtained at autopsy were histologically validated. Using a new, simple analysis algorithm, which incorporates the confocal properties of the OCT system, the light attenuation coefficients for these constituents were determined: for diffuse intimal thickening (5.5/spl plusmn/1.2 mm/sup -1/) and lipid-rich regions (3.2/spl plusmn/1.1 mm/sup -1/), the attenuation differed significantly from media (9.9/spl plusmn/1.8 mm/sup -1/), calcifications (11.1/spl plusmn/4.9 mm/sup -1/) and thrombi (11.2/spl plusmn/2.3 mm/sup -1/) (p<0.01). These proof of principle studies show that simple quantitative analysis of the OCT signals allows spatial determination of the intrinsic optical attenuation coefficient of atherosclerotic tissue components within regions of interest. Combining morphological imaging by OCT with the observed differences in optical attenuation coefficients of the various regions may enhance discrimination between various plaque types.

An international multicenter randomized study of computer‐assisted oral anticoagulant dosage vs. medical staff dosage

Summary.  Background: Increased demand for oral anticoagulants is overwhelming facilities worldwide, resulting in increasing use of computer assistance. A multicenter clinical endpoint study has been performed to compare the safety and effectiveness of computer‐assisted dosage with dosage by experienced medical staff at the same centers. Methods: A randomized study of dosage of two commercial computer‐assisted dosage programs (PARMA 5 and DAWN AC) vs. manual dosage at 32 centers with an established interest in oral anticoagulation in 13 countries. The aim was to recruit a minimum of 16 000 patient‐years randomized to medical staff or computer‐assisted dosage. In total, 13 219 patients participated, 6503 patients being randomized to medical staff and 6716 to computer‐assisted dosage. The safety and effectiveness of computer‐assisted dosage were compared with those of medical staff dosage. Results: In total, 13 052 patients were recruited (18 617 patient‐years). International Normalized Ratio (INR) tests numbered 193 890 with manual dosage and 193 424 with computer‐assisted dosage. The number of clinical events with computer‐assisted dosage was lower (P = 0.1), but in the 3209 patients with deep vein thrombosis/pulmonary embolism, they were reduced by 37 (24%, P = 0.001). Time in target INR range was significantly improved by computer assistance as compared with medical staff dosage at the majority of centers (P < 0.001). Conclusions: The safety and effectiveness of computer‐assisted dosage has been demonstrated using two different marketed programs in comparison with experienced medical staff dosage at the centers with established interest in anticoagulation. Significant prevention of clinical events in patients with deep vein thrombosis/pulmonary embolism and the achievement of target INR in all clinical groups has been observed. The reliability and safety of other marketed computer‐assisted dosage programs need to be established.

VKORC1 and CYP2C9 Genotypes and Phenprocoumon Anticoagulation Status: Interaction Between both Genotypes Affects Dose Requirement

In a prospective follow‐up study of the effects of VKORC1 and CYP2C9 genotypes on the anticoagulation status of patients, we assessed the CYP2C9 and the VKORC1 C1173T genotypes of patients during the initial 6 months of phenprocoumon treatment. We used linear regression models and Cox proportional hazard models to determine the effects of the VKORC1 and CYP2C9 genotypes on phenprocoumon dose requirements, overanticoagulation, and time to achieve stability. Allele frequencies of interest within the cohort (N=281) were 40.8% VKORC1 T‐1173, 12.8% CYP2C9*2, and 6.9% CYP2C9*3. In patients with the VKORC1 CC genotype, carriers of a CYP2C9 polymorphism needed dosages that were nearly 30% lower than those for CYP2C9*1/*1 patients (P<0.001). In patients with a VKORC1 polymorphism, differences between carriers of a CYP2C9 polymorphism and CYP2C9*1/*1 were far smaller and largely not statistically significant. A larger part of the variability in dose requirement was explained by the VKORC1 genotype than by the CYP2C9 genotype (28.7% and 7.2%, respectively). Carriers of a combination of a CYP2C9 polymorphism and a VKORC1 polymorphism had a strongly increased risk of severe overanticoagulation (hazard ratio (HR) 7.20, P=0.002). Only carriers of a CYP2C9*2 allele had a decreased chance to achieve stability compared to CYP2C9*1/*1 patients (HR 0.61, P=0.004). In conclusion, the VKORC1 genotype modifies the effect of the CYP2C9 genotype on phenprocoumon dose requirements. A combination of polymorphisms of both genotypes is associated with a strongly increased risk of overanticoagulation, whereas delayed stabilization is mainly associated with the CYP2C9 genotype.

Daily vitamin K supplementation improves anticoagulant stability

Summary.  Background: One of the causes of unstable anticoagulant control in patients using vitamin K antagonists is a fluctuating intake of vitamin K. Research suggests that patients with a low dietary intake of vitamin K have a less stable anticoagulant control than patients with a higher intake. Objectives: To study whether supplementation with a low daily dose of vitamin K improves anticoagulant control. Methods: We performed a double‐blind, randomized, placebo‐controlled trial. 200 patients of the Leiden anticoagulation clinic, who used the vitamin K antagonist phenprocoumon, were randomized to receive either adjusted‐dose phenprocoumon and 100 μg vitamin K once daily or adjusted‐dose phenprocoumon and a placebo. Treatment duration was 24 weeks. The primary outcome was the percentage of time the International Normalized Ratio was within the therapeutic range. Results: The time in the therapeutic range was 85.5% in the placebo group and 89.5% in the vitamin K group (adjusted difference 3.6%; 95% CI −0.8% to 8.0%). The time below the therapeutic range was 3.1% in the placebo group and 2.1% in the vitamin K group (adjusted difference −0.7%; 95% CI −2.5% to 1.1%) and the time above the therapeutic range was 11.4% in the placebo group and 8.5% in the vitamin K group (adjusted difference −2.9%; 95% CI −6.9% to 1.1%). The relative risk (RR) of a maximal stability in the vitamin K group compared to the placebo group was 1.8 (95%, CI 1.1–2.7). Conclusion: Supplementation of vitamin K antagonists with 100 μg vitamin K improves stability of anticoagulant therapy. Because the risk of side effects is inversely related to anticoagulant stability, such an improvement is likely to reduce the number of bleeding and thrombotic events.

Familial thrombophilia and lifetime risk of venous thrombosis

Summary  Background : We started a large multicenter prospective follow‐up study to provide reliable risk estimates of venous thrombosis in families with various thrombophilic defects.

Hereditary thrombophilia and fetal loss: a prospective follow-up study

Summary.  Background: As the placental vessels are dependent on the normal balance of procoagulant and anticoagulant mechanisms, inherited thrombophilia may be associated with fetal loss. Objectives: We performed a prospective study to investigate the relation between inherited thrombophilia and fetal loss, and the influence of thromboprophylaxis on pregnancy outcome. Patients and methods: Women were enrolled in the European Prospective Cohort on Thrombophilia (EPCOT). These included women with factor (F)V Leiden or a deficiency of antithrombin, protein C or protein S. Controls were partners or acquaintances of thrombophilic individuals. A total of 191 women (131 with thrombophilia, 60 controls) had a pregnancy outcome during prospective follow‐up. Risk of fetal loss and effect of thromboprophylaxis were estimated by frequency calculation and Cox regression modelling. Results: The risk of fetal loss appeared slightly increased in women with thrombophilia without a previous history of fetal loss who did not use any anticoagulants during pregnancy (7/39 vs. 7/51; relative risk 1.4; 95% confidence interval 0.4, 4.7). Per type of defect the relative risk varied only minimally from 1.4 for FV Leiden to 1.6 for antithrombin deficiency compared with control women. Prophylactic anticoagulant treatment during pregnancy in 83 women with thrombophilia differed greatly in type, dose and duration, precluding solid conclusions on the effect of thromboprophylaxis on fetal loss. No clear benefit of anticoagulant prophylaxis was apparent. Conclusions: Women with thrombophilia appear to have an increased risk of fetal loss, although the likelihood of a positive outcome is high in both women with thrombophilia and in controls.

Current perspective of venous thrombosis in the upper extremity

Summary.  Venous thrombosis of the upper extremity is a rare disease. Therefore, not as much is known about risk factors, treatment and the risk of recurrence as for venous thrombosis of the leg. Only central venous catheters and strenuous exercise are commonly known risk factors for an upper extremity venous thrombosis. In this review an overview of the different risk factors, possible treatments and the complications for patients with a venous thrombosis of the upper extremity is given.

Diagnostic strategy for the assessment of rheumatoid vasculitis

Objective: To determine the clinical features associated with histologically proven rheumatoid vasculitis (HRV) and the additional diagnostic value of serological markers in an inception cohort of 81 patients with rheumatoid arthritis (RA) suspected of RV. Methods: The presence and number of recently developed extra-articular manifestations (EAMs) and a weighted EAM score, as well as the levels of serological markers, were compared between 31 patients with RA with histologically proven vasculitis and 50 patients with RA in whom vasculitis could not be documented histologically. The following markers were evaluated: circulating immune complexes, complement components C3 and C4, class-specific rheumatoid factors (IgM RF, IgG RF, IgA RF), antineutrophil cytoplasmic antibodies, antinuclear antibodies, antiendothelial antibodies, circulating intercellular adhesion molecule-1 and -3, circulating vascular cell adhesion molecule and E-selectin, cellular fibronectin, von Willebrand factor antigen, and C reactive protein. The diagnostic value of these markers, in addition to the clinical features, was evaluated with logistic regression analysis. Results: Peripheral neuropathy or purpura/petechiae, or both, were the most important clinical features to discriminate patients with RA with and without histologically proven RV. The presence of a high number of EAMs and a higher weighted EAM score in patients with RA suspected of vasculitis were also associated with an increased probability of histologically proven RV. After adjustment for EAMs, only the combination of an increased serum IgA RF level and a decreased serum C3 level appeared to make an additional contribution to the diagnosis histologically proven RV. Evidence of systemic vasculitis was found in a muscle biopsy of the rectus femoris in 9/14 (64%) patients with vasculitis with neuropathy and in 3/11 (27%) patients with purpura/petechiae and vasculitis of the skin. Conclusions: In the diagnostic process of RV the presence of peripheral neuropathy and/or purpura/petechiae or a high weighted EAM score will increase the probability of histologically proven RV. Of the circulating factors previously suggested to be markers for RV only IgA RF and C3 further increase the probability of histologically proven RV and may be useful to guide diagnostic decisions.