Coagulopathy in Sickle Cell Disease

Sickle cell disease (SCD) results from a single base pair change in the β-globin subunit, yet the downstream effects and complex manifestations that result are protean and variable. The abnormal HbS is insoluble when deoxygenated and polymerizes causing deformation of and damage to the red blood cell (RBC) membrane resulting in cells that are less deformable, prone to hemolysis, and more adhesive with increased phosphatidylserine surface exposure. Heterotypic cellular interactions between the sickle RBCs, endothelium, leukocytes, and platelets, predominantly in the postcapillary venules, result in the pathognomonic vasoocclusion and ischemia reperfusion injury. Over-activation of the innate immune system secondary to ischemia-re perfusion and damage-associated molecular pattern molecules (DAMS) such as heme, result in tissue damage and contribute to activation of coagulation cascade and platelets.

The chronic activation of coagulation and platelets results in a clinically significant but underappreciated prothrombotic state with increased incidence and recurrence of venous thromboembolic events (VTEs—deep venous thrombosis and PE’s-pulmonary embolism). Up to 25% of individuals with SCD will have developed a VTE by adulthood, with the median age of first VTE occurring at 29.99 years, a significantly younger age than the general population. The age at which VTE occurs is comparable with the age observed in individuals with high-risk thrombophilia. The risk of VTE in SCD is compounded by additional risk factors such as by recurrent hospitalizations, increased periods of immobility, frequent use of central venous catheters, and infection, and in these situations may be classified as a provoked rather than an unprovoked VTE. Increased mortality has been observed in adults with SCD and thrombosis, and the recurrence rate in non–catheter-associated VTE is 25%. There is an increased prevalence of pulmonary embolism found in SCD patients at autopsy, especially those with sudden death, and it has been suggested that pulmonary embolism may underlie development of some cases of pulmonary hypertension. Additionally, both retrospective and prospective analyses of patients with acute chest syndrome report increased pulmonary embolism. Use of administrative discharge databases further corroborates the increased incidence of pulmonary embolism in adults with SCD when compared with age- and race-matched controls. In the pediatric SCD population, central venous catheter placement increases the risk of deep vein thrombosis. Pregnancy-related VTE is also increased in women with SCD with an odds ratio of 6.7 (95% CI, 4.4–10.1) in one series. The Royal College of Obstetricians and Gynecologist guidelines recommend low-molecular-weight heparin be administered to women with SCD while in hospital and 7 days postdischarge following vaginal delivery or for a period of 6 weeks following caesarean section ( https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg61 ).