Role of the Hemostatic System on Sickle Cell Disease Pathophysiology and Potential Therapeutics

Abstract

SynopsisRecent studies suggest that sickle cell disease is a hypercoagulable state contributing to the vasoocclusive events in microcirculation resulting in acute and chronic sickle cell related organ damage. In this article, we will review the existing evidence for contribution of hemostatic system perturbation to sickle cell disease pathophysiology. We will also review the data showing increased risk of thromboembolic events, particularly newer information on the incidence of VTE. Finally, the potential role of platelet inhibitors and anticoagulants in SCD will be briefly reviewed.Keywords sickle cell; thromboembolism; hypercoagulable; anti-platelets; anticoagulants IntroductionSickle cell disease (SCD) is the result of homozygous or compound heterozygous inheritance of mutation in the β-globin gene. The resulting substitution of the hydrophilic amino acid glutamic acid at the sixth position by the hydrophobic amino acid valine, leads to the production of hemoglobin S (HbS). HbS polymerizes when deoxygenated and this polymerization is associated with cell dehydration and increased red cell density [1][2][3] . The dense, rigid and sickling red cells lead to vaso-occlusion and impaired blood flow 2,4 , and is thought to underlie acute (painful episodes, acute chest syndrome) and chronic (avascular necrosis, renal insufficiency) complications of the disease. Also, intracellular polymerization ultimately damages the red cell membrane and leads to chronic and episodic extra-vascular and intravascular hemolytic anemia, hemolysis linked nitric oxide (NO) dysregulation and endothelial dysfunction 5 resulting leg ulcer, pulmonary hypertension (PHTN), priapism and stroke 6 .Corresponding author: Ted Wun, MD. Authors contact information Address/Phone/Fax (for both authors): University of California, Davis Cancer Center, 4501 X St., Ste. 3016, Sacramento, CA 95817, Phone: (916) Fax: (916) 734-7946, zahra.pakbaz@ucdmc.ucdavis.edu, ted.wun@ucdmc.ucdavis.edu ZP has no conflict of interest.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptSeveral investigators have reported increased thromboembolic events and alteration in hemostatic system in SCD both under steady state and during acute events. This suggests that perturbation in hemostatic system may contribute to SCD pathophysiology. Changes that have been described include increased expression of tissue factor on blood monocytes 7-9 and endothelial cells 10,11 , abnormal exposure of phosphatidylserine on the red cell surface 12,13 and i...

Sickle cell disease is associated with iron mediated hypercoagulability

“…Patients with SCD not only have evidence of a hypercoagulable state at baseline, but also have an accentuated response during VOC [2]. The hypercoagulable state stems from numerous abnormalities including of activated platelets, increased red cell phosphatidylserine expression, and increased red cell microparticles [1]. Our viscoelastic methodology to determine coagulation kinetics mirrored these previous findings with a significant difference between normal controls and patients with SCD.…”

“…In sum, the degree of plasmatic hypercoagulability and involvement of iron were successfully determined with our viscoelastic techniques. Previous work has well documented the hypercoagulable state in patients with SCD [1,2]. Patients with SCD not only have evidence of a hypercoagulable state at baseline, but also have an accentuated response during VOC [2].…”

“…Sickle cell disease (SCD) is associated with significant thrombotic complications at all ages, including stroke and pulmonary embolism as recently reviewed [1]. Several hemostatic anomalies that document hypercoagulability have been identified in SCD patients, including increased parameter values of thrombin generation as identified by calibrated automated thrombography, excess platelet activation and aggregation, increased formation of thrombin-antithrombin complexes, and increased D-dimer formation to name a few [1,2].…”

“…Several hemostatic anomalies that document hypercoagulability have been identified in SCD patients, including increased parameter values of thrombin generation as identified by calibrated automated thrombography, excess platelet activation and aggregation, increased formation of thrombin-antithrombin complexes, and increased D-dimer formation to name a few [1,2]. Vaso-occlusive crisis (VOC) has been documented to make these abnormalities even greater than steady-state values [1,2]. Of hemostatic interest, patients with SCD often receive multiple red blood cell transfusions and become iron overloaded, eventually requiring chelation therapy with agents such as desferoxamine or desferrioxamine [3].…”

Orphan drugs for sickle vaso-occlusion: dawn of a new era of targeted treatment

“…74 Changes include thrombin activation, altered levels of anticoagulant proteins, impaired fibrinolysis, and platelet activation. Platelet activation may be particularly problematic as it may contribute to cell-cell interactions that may impact sickle erythrocyteendothelial cell adhesion and subsequent vaso-occlusion.…”