Development of a thalassemia‐related thrombosis risk scoring system
Authors: Ali T. Taher, Maria Domenica Cappellini, Khaled M. Musallam
Journal: American Journal of Hematology (2019)

A hypercoagulable state has been recognized in patients with beta-thalassemia, with several disease- and management-related factors implicated.1, 2 Ineffective erythropoiesis and chronic hemolysis lead to the production of thrombogenic red blood cells and microparticles which increase the risk of thrombosis. These findings were mostly noted in patients who do not receive regular transfusion therapy (non-transfusion-dependent thalassemia) and who do not accordingly have the protective "wash out" effect of exogenous transfusions.3 The degree of anemia, as an indicator of ineffective erythropoiesis severity, was significantly associated with the risk of thrombosis in observational studies.4 Levels <9 to 10 g/dL (which indicate considerable ineffective erythropoiesis in non-transfusion-dependent patients and suboptimal transfusion therapy in transfusion-dependent patients) showed highest thrombosis risk.4, 5 Splenectomy has also been established as a leading cause of thrombotic events in beta-thalassemia patients, owing to the role of the spleen in scavenging thrombogenic red blood cells and to increased numbers of activated platelets in splenectomized patients.5, 6 Iron overload (serum ferritin ≥800-1000 μg/L) in these patients has also been associated with high thrombosis rates, in view of the damaging effects of toxic iron species on the endothelium and vasculature, as well as to secondary development of multiorgan failure (heart, liver, and endocrine dysfunction).5, 7 Advancing age prolongs the exposure of patients to these risk factors, and higher rates of thrombosis have been reported in older beta-thalassemia patients (>35 years).5, 8, 9 Although the independent contribution of these individual risk factors to the overall thrombosis risk in beta-thalassemia is well known, their collective impact in an individual patient remains unclear. When "beta-thalassemia" per se needs to be considered as a thrombosis risk factor in a patient evaluated in the in-patient, out-patient, obstetric, or surgical settings; it will be essential to have a collective picture so that the disease is appropriately considered alongside other conventional inherited or acquired risk factors in local thrombosis prophylaxis guidelines. With this background, we herein provide a thalassemia-related thrombosis risk scoring system (TRT-RSS) to aid practitioners in categorizing patients for thrombosis risk based on their underlying disease characteristics, and hence support management decisions. The TRT-RSS is aimed at predicting first thrombotic events in patients without prior incidents and provides long-term risk (over 10 years) assessment considering the chronic, lifelong nature of the disease. For this work, we analyzed data form all beta-thalassemia patients registered at and attending our centers in January 2005 and who had available follow-up data for 10 years (until December 2014). We excluded patients who had a documented thrombotic event prior to January 2005, since our analysis was aimed at a first thrombotic event in patients without prior history of thrombosis. A total of 216 patients were included in this analysis. Data was collected as part of now completed clinical studies, and which were approved by the Institutional Review Board at both institutions. All patients had signed an informed consent form for participating in the original studies in accordance with the Declaration of Helsinki. We collected baseline (2005) data from medical charts on age, splenectomy status, transfusion status (patients receiving at least one transfusion every 6 weeks considered regularly transfused), hemoglobin level (pre-transfusion in transfused patients), and ferritin level (average of 3 months for hemoglobin and serum ferritin levels). We also collected data on documented thrombotic events during the 10 years of observation, which were diagnosed per local standard practice using compression ultrasonography, contrast venography, or angiography evidence of thrombus. We then randomly split the sample into two cohorts, cohort 1 (learning cohort) comprised of 105 patients (mean age 33.3 ± 11.5 year, 51.4% females), and cohort 2 (validation cohort) comprised of 111 patients (mean age 33.4 ± 11.6 year, 54.1% females). For each patient in cohort 1, we assigned a TRT-RSS Total Score by adding individual scores of each risk factor according to Table 1. For each risk factor, a weighted-score was selected based on the odds ratio for thrombosis reported in previous studies of beta-thalassemia patients,5 rounded to the nearest 0.5. The 10-year incidence of thrombosis in cohort 1 was 22.9% (24/105). The mean and median TRT-RSS Total Score were higher in patients who developed thrombosis than those who did not (mean 12.9 ± 2.1 vs 6.2 ± 3.6, independent samples t test P < .001; median 11.8 vs 6.5, Mann-Whitey U test P < .001). On logistic regression analysis, each one-point increase in the TRT-RSS Total Score was associated with a 2.7-fold (95% confidence interval [CI]: 1.7-4.5, P < .001) increased odds of thrombosis. To determine TRT-RSS Total Score thresholds of relevance, we constructed a receiver operating characteristic curve (area under the curve: 0.95, 95% CI: 0.92-0.99, P < .001) which showed that the threshold of <9.5 is associated with 100% sensitivity (threshold that predicts no patient would develop thrombosis) and a threshold of >13.5 is associated with 100% specificity (threshold that predicts all patients would develop thrombosis). As such, we assigned the following TRT-RSS risk categories: low risk <9.5, intermediate risk 9.5-13.5, and high risk >13.5 (Table 1). We then calculated the TRT-RSS Total Scores for all patients in cohort 2 and assigned patients to the established TRT-RSS risk categories. A total of 68 (61.3%) patients were low risk, 25 (22.5%) were intermediate risk, and 18 (16.2%) were high risk. The 10-year incidence of thrombosis in cohort 1 was 24.3% (27/111). The incidence of thrombosis was 1.5% (1/68), 40% (10/25), and 88.9% (16/18) in TRT-RSS low-, intermediate-, and high-risk patients. The concordance Kappa for predicting thrombosis was 0.892 (P < .001) indicating high agreement between predicted and observed thrombosis risk. We provide our colleagues with a simple and practical tool to better understand their patients' thalassemia-related risk for thrombosis through a collective consideration of key risk factors. We chose to only include essential risk factors that can give an overall picture of disease activity, that reflect long duration of exposure to pathogenic mechanisms, and that contribute to the development of underlying mechanisms promoting thrombosis. These parameters should be readily available during patient assessment, even in resource-poor settings. The TRT-RSS should be evaluated at the moment of decision making to provide an insight on the contribution of thalassemia to thrombosis risk and should be interpreted in the context of other conventional risk factors in local risk scoring systems and prophylaxis guidelines for medical and surgical patients. For example, a young, non-splenectomized, well-transfused patient with adequate iron control should not be considered any different than a non-thalassemic patient and evaluated for conventional risk factors for thrombosis as per standard prophylaxis guidelines. However, in a patient with opposite characteristics, the physician should give considerable weight for the diagnosis of thalassemia in such patient when being evaluated for potential prophylaxis. We do take this opportunity to invite colleagues to consider TRT-RSS as a risk indicator in future comprehensive risk assessment models for medical and surgical patients. Of course, the TRT-RSS can also identify patients that require thalassemia management optimization, to improve the anemia, decrease iron overload, or manage known consequence of splenectomy such as thrombocytosis and hence decrease the risk for developing thrombosis. Finally, in a constantly evolving disease course, assessment should be frequently repeated over time or with notable changes in treatment. None to disclose.