Rainer Vormittag

Prediction of venous thromboembolism in cancer patients

The risk of venous thromboembolism (VTE) is increased in cancer patients. To improve prediction of VTE in cancer patients, we performed a prospective and observational cohort study of patients with newly diagnosed cancer or progression of disease after remission. A previously developed risk scoring model for prediction of VTE that included clinical (tumor entity and body mass index) and laboratory (hemoglobin level and thrombocyte and leukocyte count) parameters was expanded by incorporating 2 biomarkers, soluble P-selectin, and D-Dimer. Of 819 patients 61 (7.4%) experienced VTE during a median follow-up of 656 days. The cumulative VTE probability in the original risk model after 6 months was 17.7% in patients with the highest risk score (≥ 3, n = 93), 9.6% in those with score 2 (n = 221), 3.8% in those with score 1 (n = 229), and 1.5% in those with score 0 (n = 276). In the expanded risk model, the cumulative VTE probability after 6 months in patients with the highest score (≥ 5, n = 30) was 35.0% and 10.3% in those with an intermediate score (score 3, n = 130) as opposed to only 1.0% in patients with score 0 (n = 200); the hazard ratio of patients with the highest compared with those with the lowest score was 25.9 (8.0-84.6). Clinical and standard laboratory parameters with addition of biomarkers enable prediction of VTE and allow identification of cancer patients at high or low risk of VTE.

High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients - results from the Vienna Cancer and Thrombosis Study (CATS)

Cancer patients are at high risk for venous thromboembolism (VTE). Laboratory parameters with a predictive value for VTE could help stratify patients into high- or low-risk groups. The cell adhesion molecule P-selectin was recently identified as risk factor for VTE. To investigate soluble P-selectin (sP-selectin) in cancer patients as risk predictor for VTE, we performed a prospective cohort study of 687 cancer patients and followed them for a median (IQR) of 415 (221-722) days. Main tumor entities were malignancies of the breast (n = 125), lung (n = 86), gastrointestinal tract (n = 130), pancreas (n = 42), kidney (n = 19), prostate (n = 72), and brain (n = 80); 91 had hematologic malignancies; 42 had other tumors. VTE occurred in 44 (6.4%) patients. In multivariable analysis, elevated sP-selectin (cutoff level, 53.1 ng/mL, 75th percentile of study population) was a statistically significant risk factor for VTE after adjustment for age, sex, surgery, chemotherapy, and radiotherapy (hazard ratio = 2.6, 95% confidence interval, 1.4-4.9, P = .003). The cumulative probability of VTE after 6 months was 11.9% in patients with sP-selectin above and 3.7% in those below the 75th percentile (P = .002). High sP-selectin plasma levels independently predict VTE in cancer patients. Measurement of sP-selectin at diagnosis of cancer could help identify patients at increased risk for VTE.

D-Dimer and Prothrombin Fragment 1 + 2 Predict Venous Thromboembolism in Patients With Cancer: Results From the Vienna Cancer and Thrombosis Study

PURPOSE Venous thromboembolism (VTE) is a well-recognized complication of cancer. Laboratory parameters might be useful to assess the VTE risk in patients with cancer. The aim of this study was to investigate D-dimer and prothrombin fragment 1 + 2 (F 1 + 2), which reflect activation of blood coagulation and fibrinolysis, for prediction of cancer-associated VTE. PATIENTS AND METHODS In a prospective, observational, cohort study of 821 patients with newly diagnosed cancer or progression of disease who did not recently receive chemotherapy, radiotherapy, or surgery were enrolled and followed for a median of 501 days (interquartile range, 255 to 731 days). The malignancies in these patients were as follows: breast (n = 132), lung (n = 119), stomach (n = 35), lower gastrointestinal tract (n = 106), pancreas (n = 46), kidney (n = 22), and prostate (n = 101) cancers; high-grade glioma (n = 102); malignant lymphoma (n = 94); multiple myeloma (n = 17); and other tumor types (n = 47). The study end point was occurrence of objectively confirmed symptomatic or fatal VTE. RESULTS VTE occurred in 62 patients (7.6%). The cutoff level for elevated D-dimer and elevated F 1 + 2 was set at the 75th percentile of the total study population. In multivariable analysis that included elevated D-dimer, elevated F 1 + 2, age, sex, surgery, chemotherapy, and radiotherapy, the hazard ratios (HRs) of VTE in patients with elevated D-dimer (HR, 1.8; 95% CI, 1.0 to 3.2; P = .048) and elevated F 1 + 2 (HR, 2.0; 95% CI, 1.2 to 3.6; P = .015) were statistically significantly increased. The cumulative probability of developing VTE after 6 months was highest in patients with both elevated D-dimer and elevated F 1 + 2 (15.2%) compared with patients with nonelevated D-dimer and nonelevated F 1 + 2 (5.0%; P < .001). CONCLUSION High D-dimer and F 1 + 2 levels independently predict occurrence of VTE in patients with cancer.

High platelet count associated with venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS).

Summary.  Background: In cancer patients, laboratory parameters that predict venous thromboembolism (VTE) are scarce. Increased platelet count has been found to be a risk factor for VTE in cancer patients receiving chemotherapy (CHT). We have assessed high platelet count as a risk predictor for VTE in patients with cancer undergoing discriminative anti‐cancer treatments and investigated whether platelet count correlates with thrombopoietin (TPO) levels. Design and methods: The Cancer and Thrombosis Study (CATS) is an ongoing prospective observational study of patients with newly diagnosed cancer or progression of disease, which started in October 2003. Occurrence of VTE and information on the patients’ anti‐cancer treatment during follow‐up were recorded. Results: Between October 2003 and February 2008, 665 patients with solid tumors were included (314 female/351 male, mean age 62 years). VTE occurred in 44 patients (18 female/26 male, mean age 62 years). The cumulative probability of VTE after 1 year was 34.3% in patients with a platelet count (PC) above the 95th percentile representing 443 × 109/L compared with 5.9% in those below 443 × 109/L. High platelet count [hazard ratio (HR): 3.50, 95% confidence interval (CI): 1.52–8.06, P = 0.0032], soluble P‐selectin [HR: 2.66, 95% CI: 1.42–4.96, P = 0.0021] and surgery [HR: 4.05, 95% CI: 1.74–9.46, P = 0.0012] were statistically significant risk factors for VTE in multivariable analysis along with leucocyte count, age, gender, radio‐ and CHT. We found no correlation between platelet count and TPO levels. Conclusions: High PC is a clinically important, independent risk predictor for VTE in cancer patients. PC was not found to be associated with TPO levels.

High Factor VIII Levels Independently Predict Venous Thromboembolism in Cancer Patients: The Cancer and Thrombosis Study

Objective—Patients with cancer are at an increased risk for venous thromboembolism (VTE). Clotting factor VIII activity (FVIII) has been established as risk factor of primary and recurrent VTE. We investigated FVIII as predictive parameter of VTE in cancer patients. Methods and Results—The prospective observational Cancer and Thrombosis Study (CATS) includes patients with newly diagnosed cancer or disease progression, study end point is symptomatic VTE. FVIII was measured on a Sysmex CA 7000 analyzer. Data on 840 patients (median age: 62 years, 25th to 75th percentile 53 to 68, 378 women) were available for analyses, of these 111 patients had hematologic malignancies and 729 solid cancer. During a median observation time of 495 days 62 events occurred. Cumulative probability of VTE after 6 months was 14% in patients with elevated FVIII-levels and 4% in those with normal levels (P=0.001). The association was strongest in younger patients: whereas in 40-year-old patients a 2-fold VTE risk per factor VIII increase of 20% was observed (HR=2.0 [95% CI: 1.5 to 2.7], P<0.0001), this association was still present but attenuated in older patients. Conclusions—FVIII is independently associated with an increased risk of VTE in cancer patients. The association between FVIII and VTE risk declines with increasing age.

Venous thromboembolism and survival in patients with high-grade glioma

Patients with malignancy, particularly patients with high-grade glioma (HGG; WHO grade III/IV), have an increased risk of venous thromboembolism (VTE). It has been suggested that VTE predicts survival in cancer patients. The aim of our study was to investigate the occurrence of symptomatic VTE and its impact on survival in patients with HGG. Consecutive patients (n = 63; 36 female, 27 male; median age, 58 years) who had neurosurgical intervention between October 2003 and December 2004 were followed after surgery until October 2005. Objectively confirmed VTE was recorded as an event. All patients had received thrombosis prophylaxis with low-molecular-weight heparin (LMWH) during the immediate postoperative period. Subsequently, 56 patients received radiochemotherapy, 6 radiotherapy, and 1 chemotherapy only. Patients were followed over a median time period of 348 days. Fifteen patients (24%) developed VTE. Pulmonary embolism was diagnosed in nine patients (60%) and was fatal twice. The cumulative probability of VTE was 21% after three months and 26% after 12 months. The highest frequency of VTE was observed in patients with biopsy and subtotal tumor resection (n = 37; multivariate hazard ratio, 3.58; 95% CI = 0.98-13.13; P = 0.054) compared with patients with total resection. Survival did not significantly differ among patients with and without VTE and was 53% after 12 months in both groups. Patients with HGG, particularly those with biopsy and subtotal resection, are at high risk to develop VTE postoperatively. Thrombosis was not associated with a significant reduction of survival.

The presence of IgG antibodies against β2‐glycoprotein I predicts the risk of thrombosis in patients with the lupus anticoagulant

Summary.  Background: Lupus anticoagulant (LA) is a strong risk factor of thrombosis. However, a subgroup of patients positive for LA is unaffected by thrombosis and currently no predictive markers are available to identify patients positive for LA at increased risk for thrombosis. Objective: The aim of the study was to investigate whether anti‐beta‐2‐glycoprotein I (anti‐β2GPI) or anticardiolipin antibodies (ACA) are associated with an increased risk of thrombosis in patients persistently positive for LA. Patients and methods: A cohort of 87 consecutive patients persistently positive for LA was investigated, 55 with and 32 without a history of thrombosis. Immunoglobulin G (IgG) and M (IgM) antibodies against β2GPI and cardiolipin were determined by enzyme‐linked immunoassay. Results: Patients positive for LA with thrombosis had significantly higher levels of anti‐β2GPI IgG (median 16.7 standard units, interquartile range 3.0–75.2, P = 0.002) and of ACA IgG (41.1 IgG phospholipid units per mL, 8.9–109.0, P = 0.002) than those without thrombosis (2.6, 1.4–7.9 and 9.7, 4.6–22.1, respectively). Levels of anti‐β2GPI IgM and ACA IgM did not differ significantly between LA patients with and without thrombosis (P = 0.25 and 0.12, respectively). Elevated anti‐β2GPI IgG was associated with an increased risk for thrombosis (OR = 4.0, 95% CI 1.2–13.1), especially for venous thromboembolism (OR = 5.2, 95% CI 1.5–18.0). Conclusions: Increased levels of anti‐β2GPI IgG were associated with thrombosis. We conclude that anti‐β2GPI IgG levels above normal predict an increased risk of thrombosis in patients persistently positive for LA.

Low‐density lipoprotein receptor‐related protein 1 polymorphism 663 C > T affects clotting factor VIII activity and increases the risk of venous thromboembolism

Background: Clotting factor (F) VIII is an independent risk factor for primary and recurrent venous thromboembolism (VTE). The causes for high plasma FVIII levels are not fully understood, but an involvement of genetic factors has been demonstrated. A multifunctional endocytic receptor, low‐density lipoprotein receptor‐related protein 1 (LRP1), mediates cellular uptake and subsequent degradation of FVIII and may contribute to variations in FVIII levels. Objective: We assessed the association of a genetic variation of LRP1 (663C > T) with basal FVIII levels and the risk of venous thrombosis in a group of high‐risk patients and in healthy controls. Patients and methods: One hundred and fifty‐two patients with a history of recurrent VTE (median age 56 years, 47% women) were compared with 198 age‐ and sex‐matched controls (median age 53 years, 50% women). The LRP1 663C > T genotype was analyzed by mutagenic separated polymerase chain reaction assay and heterozygosity was confirmed by sequence analysis. Results: LRP1 663C > T genotype distribution differed significantly between patients (663CC n = 138, 663CT n = 14) and controls (663CC n = 190, 663CT n = 8; P = 0.048). In multivariable linear regression analysis including LRP1 663C > T, ABO blood group, von Willebrand factor antigen, C‐reactive protein and age, LRP1 663CT was independently associated with FVIII activity (P = 0.02). LRP1 663CT was also associated with increased odds for VTE following adjustment for blood group O, FV Leiden and the prothrombin variation 20210G > A in multivariate analysis (odds ratio 3.3, 95% CI 1.3–8.5). Conclusions: According to our data the LRP1 663C > T polymorphism influences plasma FVIII levels independently of blood group, C‐reactive protein and von Willebrand factor and is significantly associated with the risk of VTE.

Circulating procoagulant microparticles in patients with venous thromboembolism

Circulating microparticles (MPs) are small vesicles released from the membrane of almost all cells as a result of cell activation or apoptosis [1–4]. They have a size of less than 1 μmand theirmembrane consists mainly of phospholipids and proteins. MPs are generated under physiological conditions in healthy individuals and display an integral function in the process of coagulation, inflammation, cell remodelling and proliferation [4,5]. MPs play an important role in the initiation and propagation of coagulation [1]. Increasing evidence suggests that MPs are involved in the pathomechanism of thrombotic disease [1–4]. It has been demonstrated that MPs initiate thrombin generation [5]. One major hallmark is the exposure of phosphatidylserine (PS) on MPs that enables the assembly of clotting factors on their surface necessary for the formation of the prothrombinaseand tenase-complex [6–10]. In resting cells aminophospholipids such as PS aremainly sequestrated in the inner leaflet of the plasmamembrane, whereas sphingomyelin and phosphatidylcholine are exposed to the vascular compartment [11]. When cells are stimulated, the asymmetric distribution of phospholipids is disturbed resulting in the externalization of PS on the outer leaflet. Furthermore,MPs have been found to express tissue factor (TF), and thus to provide an environment favourable to initiation and support of coagulation [12,13].

Thrombosis risk and survival in cancer patients with elevated C‐reactive protein

Summary.  Background: The incidence of venous thromboembolism (VTE) is increased among cancer patients. Objective: We assessed serum levels of C‐reactive protein (CRP) in order to study their prognostic significance for VTE and survival in the prospective observational Cancer and Thrombosis Study (CATS). Patients and methods: This study includes patients with recently diagnosed cancer or progression of disease after remission. Occurrence of VTE and information on the patients’ anti‐cancer‐treatment are recorded. Observation ends with occurrence of objectively confirmed VTE, death or after 2 years. CRP levels were determined by an immunonephelometric method. Results: We included 705 consecutive patients with solid tumors. During the observation period, VTE occurred in 43 (6.1%) patients and 413 (58.6%) died. The cumulative probability of VTE was 6.6% after 1 year. In univariate analysis, CRP (as metric variable, per double increase) was associated with VTE [hazard ratio (HR) 1.2, 95% confidence interval (CI) 1.1–1.3 P = 0.048]. However, in multivariable analysis including chemotherapy, surgery and radiotherapy, metastasis, cancer‐site and sP‐selectin the association with VTE (HR 1.0, 95% CI 0.9–1.2 P = 0.932) was no longer observed. CRP was clearly associated with worse survival probability with a HR of 1.3 (95% CI 1.2–1.3, P < 0.0001) in multivariable analysis. The cumulative survival after 12 months was 43% in patients with CRP above the 75th percentile (1.8 mg dL−1) and 82% in those below the 75th percentile. Conclusions: In cancer patients elevated CRP was not independently associated with VTE. CRP was significantly associated with worse survival.