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Decreased protein S activity in sickle cell disease
A Marfaing-Koka1, C Boyer-Neumann, M Wolf
1Laboratoire d'Hématologie, Hôpital Bicêtre, Le Kremlin, France.
Insights
Sickle cell disease (SCD) patients show deficiencies in protein S (PS) and protein C (PC), crucial coagulation inhibitors. These abnormalities in PS and PC may contribute to thrombotic events in SCD.
Area of Science:
- Hematology
- Coagulation Science
Background:
- Sickle cell disease (SCD) involves complex vaso-occlusion.
- Thrombotic events are a significant complication in SCD.
Purpose of the Study:
- To investigate physiological coagulation inhibitors, specifically antithrombin III (AT III), protein C (PC), and protein S (PS), in individuals with SCD.
- To compare these inhibitors in homozygous SCD patients, heterozygous carriers, and healthy controls.
Main Methods:
- Studied three groups: 27 homozygous SCD patients (crisis or steady state), 23 heterozygous patients, and 30 healthy controls.
- Assessed total and free PS antigen, PS activity, and C4bBP antigen.
- Measured PC levels and fibrinogen D-dimers.
Main Results:
- Heterozygous subjects showed normal inhibitor levels compared to controls.
- Homozygous SCD patients exhibited abnormalities in PS and, to a lesser extent, PC.
- Reduced free PS antigen and PS activity were observed, with PS activity significantly lower than free antigen.
- High fibrinogen D-dimer concentrations were associated with these PS/PC abnormalities.
Conclusions:
- Protein S deficiency, potentially due to adsorption onto abnormal sickle cell membranes or microvesicles, is present in SCD.
- Discrepancies in PS activity may indicate proteolytic inactivation by thrombin.
- These coagulation abnormalities likely contribute to the thrombotic risk in sickle cell disease.
Abstract:
In sickle cell disease (SCD), vaso-occlusion is a complex process involving cellular, vascular and humoral factors and possibly thrombotic events. We studied three physiological inhibitors of the coagulation system, antithrombin III (AT III), protein C (PC) and protein S (PS), in three groups of subjects: 27 homozygous patients observed either in crisis or in a steady state, 23 heterozygous patients and 30 healthy subjects. PS study included the measurement of total and free PS antigen, PS activity and C4bBP antigen. In heterozygous subjects the results were similar to those of controls, but in homozygous subjects abnormalities of PS and to a lesser extent PC were observed. Values of PC were extremely variable with 10 cases lower than the normal range (2 SD of the mean) and 17 others within this range. In all cases total PS antigen was slightly reduced (77 +/- 18%, M +/- SD) with a more marked decrease of free antigen (59 +/- 17%) and normal values of C4bBP. Levels of PS activity were greatly reduced and lower than those of free antigen with a mean ratio of PS activity to free antigen of 0.6. These abnormalities were associated with significantly high concentrations of fibrinogen D-dimers. PS deficiency in SCD may be at least partly due to adsorption of free PS to aminophospholipids abnormally expressed on sickle cells membranes, microvesicles and activated platelets, while the discrepancy between PS activity and free antigen could reflect proteolytic inactivation of PS by traces of thrombin.