Fetal hemoglobin in sickle cell disease: relationship to erythrocyte phosphatidylserine exposure and coagulation activation

Abstract

In sickle cell disease (SCD), loss of erythrocyte membrane phospholipid asymmetry occurs with the exposure of phosphatidylserine (PS), which provides a docking site for coagulation proteins. In vivo sickling/desickling, with resulting red cell membrane changes and microvesicle formation, appears to be one of the factors responsible for PS exposure. We evaluated children with SCD homozygous for sickle hemoglobin (SS disease) and controls (n = 65) and demonstrate that high levels of fetal hemoglobin (assessed as F cells) are associated with decreased microvesicle formation, PS exposure, and thrombin generation. F cells correlated inversely with both microvesicles and PS positivity (P < .000001) in SS disease. Multiple regression analyses using various hematologic parameters as independent variables, and either microvesicles or PS positivity as the dependent variable, showed a strong relationship only with F cells. Additionally, plasma prothrombin fragment F1.2 levels (a marker for thrombin generation) correlated with both PS positivity (P < .001) and F cells (P < .01). An F-cell level of approximately 70% was associated with normal levels of prothrombin fragment F1.2 and with microvesicle formation indistinguishable from control values. We suggest that the use of such surrogate biologic markers in conjunction with F-cell numbers may provide valuable insights into the biology and consequences of in vivo sickling.

Increased adhesive properties of platelets in sickle cell disease: roles for αIIbβ3‐mediated ligand binding, diminished cAMP signalling and increased phosphodiesterase 3A activity

“…Such a correlation indicates that levels of this polymerization‐inhibiting haemoglobin may directly or indirectly affect platelet activation. Accordingly, high levels of fetal haemoglobin have been associated with decreased phosphatidylserine exposure on erythrocytes in SCD and, in turn, decreased generation of TB (Setty et al , 2000).…”

“…Given that platelet α IIb β 3 activation and cAMP levels appear to be associated with levels of fetal haemoglobin, it is possible that the increase in fetal haemoglobin that generally occurs during HC therapy may be responsible for lower platelet activation and adhesive properties. Whilst there is currently no evidence to suggest that HC therapy reduces TB generation, it is conceivable that the increased HbF levels associated with HC diminish phosphatidylserine exposure on red cells, resulting in a reduced activation of coagulation (Setty et al , 2000). Evidence exists to suggest that HC has NO donor properties (King, 2004) and relatively higher intraplatelet levels of cGMP were observed in patients on HC therapy.…”

Microparticles in sickle cell anaemia: promise and pitfalls

“…Some of these studies, however, noted substantial numbers of PS‐negative MPs and some noted the presence of TF+ MMP and/or EMP in sickle blood (addressed below). Table does not include additional reports in which the MP definition is unclear or enumeration is indeterminate (Wun et al , ; Setty et al , ; Westerman et al , ; Tantawy et al , ; Antwi‐Baffour, ). To date, the rich repertoire of other MP sources (e.g., granulocytes, mast cells, T cells, organ‐specific parenchymal cells, microglial cells) is unstudied in the sickle context, despite reasonable expectation of relevance.…”

“…Predictably, in SCD, total and CD71+ RMP correlate with reticulocyte count (Westerman et al , ; van Beers et al , ), and total RMP correlate positively with plasma Hb and lactate dehydrogenase, and inversely with HbF level (Setty et al , ; van Beers et al , ). Numbers of PMP and MMP may also show this relationship to HbF (Westerman et al , ; Nebor et al , ).…”

Interplay between coagulation and vascular inflammation in sickle cell disease

“…This process is mediated via an electrostatic interaction between negatively charged PS and positively charged γ‐carboxyglutamic acid domains present in the clotting proteins, including FVII, FIX, FX and prothrombin (FII) (Owens & Mackman, ). Analysis of blood from sickle cell patients demonstrated a positive correlation between PS‐positive red blood cells and F1·2, D‐dimers, and plasmin‐antiplasmin complex (Setty et al , , ). Interestingly, no positive correlation has been found between PS‐positive platelets and these markers of coagulation activation, which suggests that sickle red blood cells, rather than platelets, contribute to the hypercoagulable state in SCD (Setty et al , ).…”