Introduction: Transferrin is responsible for safe iron transport in the blood and iron delivery to cells through transferrin receptor-mediated endocytosis. Several prominent publications recently reported that elevated transferrin concentration is a risk factor for thrombosis based on in vitro studies and animal models, but with no evidence from human subjects.(1-3) In contrast, we have published evidence that transferrin obtained under basal circumstances is a predictor of decreased thrombosis over years of follow-up in Chuvash erythrocytosis, a congenital disorder of increased hypoxia sensing(4) and in high-altitude Bolivians.(5) Whether increased basal transferrin is a hazard for thrombosis in sickle cell disease (SCD) patients is not known.(6)

Methods: We prospectively collected clinical data obtained under basal circumstances as part of routine care for a cohort of 309 patients aged 15-45 years who were enrolled in the Chicago site of the Sickle Cell Disease Implementation Consortium (SCDIC) and followed for five years. Thrombotic events that occurred over the five years after enrollment were recorded. We analyzed data for the 212 patients who had a total iron binding capacity (TIBC) measurement in the medical record at enrollment. The TIBC is a measure of the capability of transferrin to bind iron and directly reflects the transferrin concentration. We calculated the transferrin concentration from the TIBC.

Results: The median age of the patients at enrolment was 29 years and 58% were females. Sickle cell genotype was HbSS or HbSβ0-thalassemia in 75%, HbSC in 19%, and HbSβ+-thalassemia in 6%. Forty-nine percent of the patients were receiving hydroxyurea. A thrombotic event was recorded in the medical record after study enrollment in 67 (31.6%) of the 212 patients with baseline transferrin result available. Of the 67 patients with thrombosis during follow-up, 47 (70.1%) had venous thrombosis (pulmonary embolism, deep vein thrombosis, or unclassified venous thrombosis), 12 (17.9 %) had arterial thrombosis (silent ischemic infarct, transient ischemic attack, or stroke) and 8 (11.9 %) had both arterial and venous thrombosis. Of the baseline clinical and laboratory data, only female gender (71.6% versus 55.2%, P=0.024) and lower transferrin (geometric mean of 186 (146-238) mg/dL versus 201 (157-258) mg/dl (P=0.038) correlated significantly with the prospective occurrence of thrombosis in univariate analysis. In a multivariate logistic regression analysis both female gender (odds ratio 1.98, 95% CI 1.06-3.72, P=0.034) and lower natural log transferrin (odds ratio, 0.28, 95 % CI 0.08-0.98, P = 0.046) displayed independent relationships with prospective occurrence of thrombosis. The normal range of TIBC is 240 to 450 mg/dL. Twenty-seven of 62 patients (43.5%) with TIBC below the normal range experienced a thrombosis while 1 of 8 (12.5%) with TIBC above the normal range experienced a thrombosis.

Discussion: Transferrin, the hepatocyte-produced plasma iron carrier protein, is induced by both hypoxia and iron deficiency via HIF-1.(7) Transferrin tightly binds iron and prevents free iron from accumulating in the plasma. SCD is associated with both extravascular and intravascular hemolysis and with increased abnormal fractions of free plasma hemoglobin, heme and iron.(8) Free plasma iron, or iron not bound to transferrin, has thrombogenic potential.(9) Various factors can affect the transferrin concentration in patients with SCD. Chronic inflammation and iron overload due to repeated blood transfusions are associated with decreased transferrin concentrations, while lower iron stores lead to higher transferrin concentrations. Our data indicate that increased transferrin is not part of the mechanism of increased thrombotic risk in SCD but rather that it may be a marker of protection from thrombosis related to binding of free iron by transferrin and to lower prevalence of inflammation, proteinuria, renal failure, and iron overload. A limitation to our study is that the presence of a central venous catheter increases the risk of thrombosis, but this information was not collected as part of SCDIC.

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