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Clinical, genetic factors increase likelihood of thrombotic events in sickle cell disease
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Thrombotic events may be frequent among patients with sickle cell disease, according to findings presented at the ASH Annual Meeting and Exposition.
Certain risk factors, including HbSS/SB0 thalassemia, recurrent hospitalizations, kidney disease, higher systolic blood pressures and higher aspartate transaminase concentrations, increase the likelihood of an event in these patients, study results demonstrate.
“Sickle cell disease is an inherited red blood cell disorder that leads to vaso-occlusion, endothelial damage and activation of pro-coagulant pathways,” the researchers wrote. “Recent studies have demonstrated that thrombotic episodes occur at a 3- to 100-fold higher rate in sickle cell disease versus non-sickle cell disease populations, but the risk factors for thrombosis are not clear.”
Andrew Srisuwananukorn, MD, a resident at the University of Illinois at Chicago, and colleagues examined the prevalence of thrombosis and factors that predicted its occurrence in a longitudinal cohort of patients with sickle cell disease. The researchers examined data from 1,193 patients treated at their institution between January 2008 and December 2017.
The researchers used electronic medical records to obtain clinical and laboratory data on the first outpatient encounter during the study period. The Kruskal-Wallis and Chi-square test was used to compare linear and categorical variables, respectively; Cox proportional hazard models were adjusted for age, sex, sickle cell disease genotype and use of hydroxyurea.
During a median follow-up period of 5.6 years (interquartile range, 2.3 to 9.3 years), 210 patients with sickle cell disease (17.6%) experienced a thrombotic event. There were 347 arterial or venous thromboses, including 75 strokes and 272 venous thromboembolisms after January 1, 2008.
Patients who had a thrombotic event were slightly older (average age, 27 years; range, 21 to 39 years) than those who did not (average age, 23 years; range, 15 to 35 years). There were more men than women in the group that had a thrombotic event (64% vs. 36%) and in the group that did not (55% vs. 45%). HbSS/SB0 thalassemia was the most common sickle cell disease genotype among patients who experienced a thrombotic event (n = 176; 83.8%) and among those who did not (n = 655; 66.6%).
Patients who experienced a thrombotic event had a higher yearly hospitalization rate (n = 5; range, 1 to 16) than patients who did not (n = 1; range, 0 to 3) and were more likely to use hydroxyurea (78% vs. 50%). Aspartate transaminase concentrations and serum creatinine levels were both higher in patients who had a thrombotic event (37 u/L and 0.7 mg/dL, respectively) than in those who did not (35 u/L and 0.6 mg/dL, respectively). The difference was statistically significant for both outcomes (P = .006 for aspartate transaminase concentrations and P < .0001 for serum creatinine levels). In Cox proportional hazards analysis, HbSS/S0 thalassemia (HR, 3.0; P < .0001), hospitalizations (10/year increment HR, 1.3; P < .0001), and higher serum creatinine (natural log HR, 1.6; P = .01) independently correlated with thrombotic events.
All VTE events occurred in a subset of 174 patients, including deep vein thrombosis (n = 153; 56%), pulmonary embolism (n = 98; 36%), concurrent deep vein thrombosis and pulmonary embolism (n = 17; 6%) and right atrial thrombus (n = 4; 1%). In patients who experienced deep vein thrombosis, 116 occurred in the upper extremities and 54 occurred in the lower extremities. Most (n = 92) deep vein thrombosis cases in the upper extremities and all incidences of right atrial thrombi resulted from the use of a catheter.
In Cox proportional hazards analysis, independent risk factors for VTE in the observation period were increased frequency of hospitalization (10/year increment HR, 1.3; P < .0001), higher systolic blood pressure (10 mm Hg increase HR, 1.2; P = .002), HbSS/S0 thalassemia (HR, 2.1; P = .004), and higher aspartate transaminase concentrations (natural log HR, 1.6; P = .01).
Warfarin was used by most patients (n = 115; 66%) as an anticoagulant during the initial VTE. Other anticoagulants used included oral direct factor Xa inhibitors (n = 29; 17%) and low-molecular weight heparin (n = 16; 9%). Fourteen patients (8%) did not use any therapy.
Among patients who received anticoagulation therapy, more than half (n = 83; 52%) were treated with initial therapy for 3 to 6 months; 47 patients (29%) were treated for more than 6 months and 30 (19%) were treated for less than 3 months. Recurrent VTE developed in 31 patients, or 18% of all patients who experienced an initial VTE, though the recurrent VTE did not correlate with either the kind of anticoagulation therapy used or the length of therapy.
The researchers also examined whether genetic risk variants for thrombosis correlated with thrombotic events in African-American patients with sickle cell disease. Among a subset of 329 patients who had genome-wide genotyping done, the correlation with thrombosis of two variants in thrombomodulin, THBD rs2567617 (MAF, 0.25; OR, 1.5; P = .049) and rs1998081 (MAF, 0.24; OR, 1.5; P = .059), was replicated after adjusting for age, sex, sickle cell disease genotype and treatment with hydroxyurea.
Thrombotic events in patients with sickle cell disease “are common,” according to Srisuwananukorn and colleagues.
“HbSS/S0 thalassemia, frequent hospitalizations, kidney disease and higher systolic blood pressures and aspartate transaminase concentrations were risk factors for thrombosis,” the researchers wrote. “Genome-wide marker array analysis points to a potential role of thrombomodulin in sickle cell disease-related thrombotic events based on replicated risk variants in THBD. Future studies integrating clinical, laboratory and genetic risk factors may improve our understanding for thrombosis and guide intervention practices in sickle cell disease.” - by Julia Ernst, MS
Srisuwananukorn A, et al. Abstract 9. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures: The researchers report no relevant financial disclosures.