Linda E. Flinterman

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.

Broadening the factor V Leiden paradox: pulmonary embolism and deep-vein thrombosis as 2 sides of the spectrum.

Risk factors for deep-vein thrombosis have been shown not to be always the same as for pulmonary embolism. A well-known example is the factor V Leiden (FVL) paradox: the FVL mutation poses a clearly higher risk for deep-vein thrombosis (DVT) than for pulmonary embolism. We aimed to expand this paradox and therefore present risk estimates for several established risk factors for DVT and pulmonary embolism separately. When such separate risk estimates could not be retrieved from the literature, we calculated these risks in our own data, a large population-based case-control study on venous thrombosis (the MEGA study). Our results showed that the FVL paradox can be broadened (ie, the risk factors oral contraceptive use, pregnancy, puerperium, minor leg injuries, and obesity have an effect comparable with FVL). Furthermore, we found that pulmonary conditions, such as chronic obstructive pulmonary disease, pneumonia, and sickle cell disease, were risk factors with an opposite effect: a higher risk of pulmonary embolism, but little or no effect on DVT. These findings suggest that pulmonary embolism and DVT may not always have the same etiology, and encourage unraveling this phenomenon in further studies.

Long-Term Survival in a Large Cohort of Patients with Venous Thrombosis: Incidence and Predictors

Linda Flinterman and colleagues report on the long-term mortality rate for individuals who have experienced a first venous thrombosis or pulmonary embolism. They describe an ongoing elevated risk of death for individuals who had experienced a venous thrombosis or pulmonary embolism as compared to controls, for up to eight years after the event.

Relationship between Venous and Arterial Thrombosis: A Review of the Literature from a Causal Perspective

Venous thrombosis and arterial thrombosis are traditionally regarded as two different diseases with respect to pathophysiology, epidemiology, and treatment strategies. Research findings of the past few years suggest that this categorical distinction may be too strict. However, whether the described relationship between venous and arterial thrombosis is real or a result of other factors such as confounding, chance, or bias is still unclear. In this review, we discuss the current literature while using causal diagrams to better understand possible causal relations between cardiovascular risk factors, atherosclerosis, arterial thrombosis, and venous thrombosis. Furthermore, we propose study designs to investigate the causal link between venous and arterial thrombosis. In addition, we comment on the effect of statin use on the occurrence of both arterial and venous thrombosis. The possible clinical implications of these findings are discussed.

Recurrent Thrombosis and Survival After a First Venous Thrombosis of the Upper Extremity

Background— Little is known about the consequences of a first venous thrombosis in the upper extremity. We studied the incidence of, survival, and risk factors for recurrence in a follow-up study. Methods and Results— We followed up 224 patients 18 to 70 years of age after a first venous thrombosis of the arm. Information was collected through anticoagulation clinics, the national death registry, discharge letters, and questionnaires. The median follow-up was 3 years, during which time 30 patients experienced a recurrent event, yielding an incidence rate of 43.2 per 1000 person-years. Survival was reduced: 55 of 224 patients died, which was 5.4-fold higher than age- and sex-adjusted population rates (standardized mortality ratio, 5.4; 95% CI, 4.2 to 7.0). The risk of recurrence was 2-fold higher in women than in men (hazard ratio, 1.8; 95% CI, 0.9 to 3.9). A central venous catheter at the time of first thrombosis was associated with a reduced risk of recurrence. A body mass index ≥25 kg/m2 and a first nonsubclavian thrombosis appeared to increase the risk of a recurrent event. Prothrombotic mutation carriers did not appear to have an increased recurrence risk. Conclusions— The risk of recurrence was high, with women, patients with body mass index ≥25 kg/m2, and patients with a first nonsubclavian vein thrombosis having a higher risk of recurrence. Patients with a first venous thrombosis of the arm have a poor vital prognosis.

Genetic Variations Associated with Recurrent Venous Thrombosis

Background—The prediction of recurrent venous thrombosis using individual genetic risk predictors has proven to be challenging. The aim of this study was to assess whether multiple genetic single nucleotide polymorphism (SNP) analysis would predict recurrent venous thrombosis. Methods and Results—Patients with a first venous thrombosis were followed for a recurrent venous thrombosis up to 2009 (MEGA follow-up study), which occurred in 608 out of 4100 patients (2.7%/year). Thirty-one common thrombosis-associated single nucleotide polymorphisms (SNPs) were associated with the risk of recurrence. A genetic risk score (GRS) for each individual was calculated by summing the number of risk-increasing alleles for each of the 31 SNPs and for a simplified model consisting of 5 SNPs: rs6025, rs1799963, rs8176719, rs2066865, and rs2036914. The risk of recurrence associated with the GRS was calculated continuously and after stratification in a low and high score. All individual SNPs were at most mildly associated with recurrence risk. Regarding the 31-SNP GRS, recurrence risk was highest in patients with ≥31 and lowest in patients with <21 risk alleles. The discriminative power of the 5-SNP GRS was similar to that of the 31-SNP GRS. The 6-year cumulative incidence of recurrence was high for individuals with ≥5 (20.3%; 95% confidence interval, 16.5–24.1) and low for individuals with ⩽1 (9.4%; 95% confidence interval, 6.7–12.1) risk alleles. Predictive power improved after stratification into provoked and unprovoked first events and sex. Conclusions—Multiple genetic SNP analysis is useful in the prediction of recurrent thrombosis, even more so when combining this model with clinical risk factors.

Predictive value of factor VIII levels for recurrent venous thrombosis: results from the MEGA follow-up study

Prediction of recurrent venous thrombosis remains a challenge in the clinic.

Impact of incident venous thromboembolism on risk of arterial thrombotic diseases

Background— Growing evidence supports an association between venous thromboembolism (VTE) and arterial thrombotic diseases (ie, myocardial infarction and ischemic stroke). We aimed to study the association between VTE and future arterial events and to determine the population attributable risk of arterial events by VTE in a large prospective cohort recruited from the general population. Methods and Results— In 1994 to 1995 and 1993 to 1997, 81 687 subjects were included in the Tromsø Study and in the Diet, Cancer and Health Study and followed up to the date of incident venous and arterial events (myocardial infarction or ischemic stroke), death or migration, or to the end of the study period (2010 and 2008, respectively). There were 1208 cases of VTE and 90 subsequent arterial events during a median follow-up of 12.2 years. An association between VTE and future arterial events was found in all women and men aged <65 years but not in men aged >65 years. Women <65 years old with VTE had 3.3-fold higher risk of arterial disease (adjusted hazard ratio, 3.28; 95% confidence interval, 1.69–6.35) compared with women of the same age without VTE. The corresponding hazard ratio in men aged <65 years was 2.06 (95% confidence interval, 1.32–3.20). Only 0.9% of the arterial events were attributed to VTE, and the VTE explained 63.8% of the risk of arterial events among VTE patients. Conclusions— Our findings imply that women and young men with VTE have higher risk of arterial thrombotic disease than those without VTE. However, only 1% of the arterial thrombotic events in the population are attributed to VTE.

Body height, mobility, and risk of first and recurrent venous thrombosis.

Tall people have an increased risk of a first venous thrombosis. Sedentary lifestyle has been shown to act synergistically with body height, especially during long‐haul flights.

Increased risk of CVD after VT is determined by common etiologic factors

Patients with venous thrombosis (VT) have an increased risk of subsequent CVD (CVD), but the underlying pathophysiology is unclear. Using data from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis follow-up study, 4480 patients with VT, 2926 partner control participants, and 2638 random digit dialing (RDD) control participants were followed-up between 1999 and 2008. Incidence rates and hazard ratios with 95% confidence intervals (95% CIs) of CVD (defined as myocardial infarction or ischemic stroke) were calculated for patients vs controls. Measurable confounders (age, sex, body mass index, smoking, chronic disease, malignancy, genetic thrombophilia, and procoagulant markers) were adjusted for when comparing patients with RDD controls. Unmeasured lifestyle-related factors were also considered by comparing patients with their partners. During a median follow-up time of 5 years, 124 CVD events occurred. Incidence of CVD per 1000 person-years was 3.2 (95% CI, 2.5-4.0) in patients, 2.2 (95% CI, 1.5-3.0) in partners, and 1.6 (95% CI, 0.9-2.6) in RDD controls. Crude hazard ratio was 2.2 (95% CI, 1.2-3.8) in patients compared with RDD controls and 1.5 (95% CI, 1.0-2.3) in patients compared with partners. After adjustment for all confounders, these risks attenuated to 1.8 (95% CI, 0.8-4.2) and 1.3 (95% CI, 0.7-2.5) for patients compared with RDD control participants and partners, respectively. In conclusion, individuals with VT had an increased risk of CVD. This could be explained by common etiologic factors.