Abnormally high levels of expression of annexin II on APL cells increase the production of plasmin, a fibrinolytic protein. Overexpression of annexin II may be a mechanism for the hemorrhagic complications of APL.

In ambulatory patients with solid cancer, routine thromboprophylaxis to prevent venous thromboembolism is not recommended. Several risk prediction scores to identify cancer patients at high risk of venous thromboembolism have been proposed, but their clinical usefulness remains a matter of debate. We evaluated and directly compared the performance of the Khorana, Vienna, PROTECHT, and CONKO scores in a multinational, prospective cohort study. Patients with advanced cancer were eligible if they were due to undergo chemotherapy or had started chemotherapy in the previous three months. The primary outcome was objectively confirmed symptomatic or incidental deep vein thrombosis or pulmonary embolism during a 6-month follow-up period. A total of 876 patients were enrolled, of whom 260 (30%) had not yet received chemotherapy. Fifty-three patients (6.1%) developed venous thromboembolism. The c-statistics of the scores ranged from 0.50 to 0.57. At the conventional positivity threshold of 3 points, the scores classified 13–34% of patients as high-risk; the 6-month incidence of venous thromboembolism in these patients ranged from 6.5% (95%CI: 2.8–12) for the Khorana score to 9.6% (95%CI: 6.6–13) for the PROTECHT score. High-risk patients had a significantly increased risk of venous thromboembolism when using the Vienna (subhazard ratio 1.7; 95%CI: 1.0–3.1) or PROTECHT (subhazard ratio 2.1; 95%CI: 1.2–3.6) scores. In conclusion, the prediction scores performed poorly in predicting venous thromboembolism in cancer patients. The Vienna CATS and PROTECHT scores appear to discriminate better between low- and high-risk patients, but further improvements are needed before they can be considered for introduction into clinical practice.

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The association of thrombosis, obstetric morbidity, and hemocytopenias with antiphospholipid antibodies is termed antiphospholipid syndrome. Annexin 2 is a profibrinolytic endothelial cell surface receptor that binds plasminogen, its tissue activator (tPA), and beta-2-glycoprotein-I, the main antigen for antiphospholipid antibodies. Here we evaluate annexin 2 as a target antigen in antiphospholipid syndrome. Serum samples from 434 individuals (206 patients with systemic lupus erythematosus without thrombosis, 62 with antiphospholipid syndrome, 21 with non-autoimmune thrombosis, and 145 healthy individuals) were analyzed by ELISA and immunoblotting for antiphospholipid and annexin 2 antibodies. IgG was purified and the effect of anti-annexin 2 antibodies on human umbilical vein endothelial cell activation and cell surface plasmin generation were evaluated. Anti-annexin 2 antibodies (titer >3SD) were significantly more prevalent in patients with antiphospholipid syndrome (22.6%, venous 17.5%, arterial 34.3% and mixed thrombosis 40.4%), than in healthy individuals (2.1%, p<0.001), patients with non-autoimmune thrombosis (0%, p=0.017) or patients with lupus without thrombosis (6.3%, p<0.001). Anti-annexin 2 antibodies enhanced the expression of tissue factor, a procoagulant protein, on endothelial cells (6.4 fold ± 0.13 SE), and blocked the fibrinolytic cofactor activity of purified placental annexin 2 in a tissue plasminogen activator-dependent plasmin generation assay (19 – 71%), independently of beta-2-glycoprotein-I. Similarly, cell surface plasmin generation on human umbilical vein endothelial cells was inhibited by 34–83%. We conclude that antibodies against the fibrinolytic receptor annexin 2 are significantly associated with thrombosis in antiphospholipid syndrome, and that anti-annexin 2 antibodies activate endothelial cells and inhibit endothelial cell surface-localized plasmin generation. We propose that these mechanisms contribute to the prothrombotic tendency in antiphospholipid syndrome.