title: Thrombin generation and cell-dependent hypercoagulability in sickle cell disease.
abstract: Essentials Sickle cell disease is increasingly being recognized as a chronic hypercoagulable state. Thrombin generation is elevated in the whole blood, but not the plasma of sickle cell patients. Whole blood thrombin generation inversely correlates to erythrocyte phosphatidylserine exposure. Acquired protein S deficiency is likely explained by binding of protein S to sickle red cells. Click to hear Dr Hillery discuss coagulation and vascular pathologies in mouse models of sickle cell disease.
  
  
  
  Introduction Sickle cell disease (SCD) is a hypercoagulable state with chronic activation of coagulation and an increased incidence of thromboembolic events. However, although plasma pre-thrombotic markers such as thrombin-anithrombin complexes and D-dimer are elevated, there is no consensus on whether global assays of thrombin generation in plasma are abnormal in patients with SCD. Based on our recent observation that normal red blood cells (RBCs) contribute to thrombin generation in whole blood, we hypothesized that the cellular components in blood (notably phosphatidylserine-expressing erythrocytes) contribute to enhanced thrombin generation in SCD. Methods Whole blood and plasma thrombin generation assays were performed on blood samples from 25 SCD patients in a non-crisis 'steady state' and 25 healthy race-matched controls. Results Whole blood thrombin generation was significantly elevated in SCD, whereas plasma thrombin generation was paradoxically reduced compared with controls. Surprisingly, whole blood and plasma thrombin generation were both negatively correlated with phosphatidylserine exposure on RBCs. Plasma thrombin generation in the presence of exogenous activated protein C or soluble thrombomodulin revealed deficiencies in the protein C/S anticoagulant pathway in SCD. These global changes were associated with significantly lower plasma protein S activity in SCD that correlated inversely with RBC phosphatidylserine exposure. Conclusion Increased RBC phosphatidylserine exposure in SCD is associated with acquired protein S deficiency. In addition, these data suggest a cellular contribution to thrombin generation in SCD (other than RBC phosphatidylserine exposure) that explains the elevated thrombin generation in whole blood.
authors.affiliation: Department of Medicine, Chapel Hill, NC, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Whelihan
authors.affiliation: Department of Medicine, Chapel Hill, NC, USA.
authors.forename: M Y
authors.initials: MY
authors.lastname: Lim
authors.affiliation: Department of Medicine, Chapel Hill, NC, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Mooberry
authors.affiliation: Department of Medicine, Chapel Hill, NC, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Piegore
authors.affiliation: Department of Medicine, Chapel Hill, NC, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ilich
authors.affiliation: Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: A
authors.initials: A
authors.lastname: Wogu
authors.affiliation: Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Medicine, Chapel Hill, NC, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Monroe
authors.affiliation: Department of Medicine, Chapel Hill, NC, USA.
authors.forename: K I
authors.initials: KI
authors.lastname: Ataga
authors.affiliation: Department of Biochemistry, University of Vermont, Burlington, VT, USA.
authors.forename: K G
authors.initials: KG
authors.lastname: Mann
authors.affiliation: Department of Medicine, Chapel Hill, NC, USA. nigel_key@med.unc.edu.|Department of Pathology and Laboratory Medicine, Chapel Hill, NC, USA. nigel_key@med.unc.edu.
authors.forename: N S
authors.initials: NS
authors.lastname: Key
mesh_terms: D000328:Adult; D001741:Black or African American; D000755:Anemia, Sickle Cell / Q000097:blood*; D000990:Antithrombin III / Q000378:metabolism; D001777:Blood Coagulation / Q000502:physiology; D001792:Blood Platelets / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D004912:Erythrocytes / Q000166:cytology*; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000096:biosynthesis; D006801:Humans; D008297:Male; D010718:Phosphatidylserines / Q000097:blood / Q000737:chemistry*; D017293:Protein S / Q000378:metabolism; D018455:Protein S Deficiency / Q000097:blood*; D011516:Prothrombin / Q000378:metabolism; D013917:Thrombin / Q000096:biosynthesis*; D018180:Thrombomodulin / Q000097:blood; D019851:Thrombophilia / Q000150:complications; D013927:Thrombosis / Q000378:metabolism; D055815:Young Adult; D017086:beta-Thalassemia / Q000097:blood
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; D010718:Phosphatidylserines; D017293:Protein S; C546931:THBD protein, human; D018180:Thrombomodulin; C036309:fibrin fragment D; D000990:Antithrombin III; D011516:Prothrombin; D013917:Thrombin
keywords: anemia; erythrocyte; phosphatidylserine; protein S; sickle cell; thrombin