Impaired platelet prostacyclin receptor activity: a monozygotic twin study discordant for spinal cord injury.
Coronary artery disease (CAD) has been reported to occur prematurely in individuals with spinal cord injury (SCI). Although persons with SCI have metabolic abnormalities that may predispose them to CAD, other potential aetiologies may also be operative. Increased platelet aggregation, among other factors, initiates thrombus formation at the site of the vessel injury, which may acutely obstruct arterial blood flow. Prostacyclin is known to have a beneficial effect to inhibit platelet aggregation and prevent thrombus formation. Platelets were studied from 12 pairs of monozygotic twins, one co-twin with SCI. Each twin pair had similar patterns of platelet aggregation with adenosine diphosphate (ADP), thrombin or collagen, as well as inhibition of platelet aggregation by prostacyclin (PGE1/I2) and synthesis of cyclic adenosine mono phosphate (AMP) by the prostanoid. However, the twin pairs differed in their response to PGE1/I2 inhibition of platelet-stimulated thrombin generation that was completely inhibited in non-SCI platelets but not in SCI platelets. Scatchard analysis of the binding of 3H-prostaglandin E1, a stable prostacyclin receptor probe, showed the presence of one high-affinity (Kd1=8.1 +/- 2.8 nM; nl=168 +/- 35 sites per platelet) and one low-affinity (Kd2=1.1 +/- 0.22 microM; n2=1772 +/- 220 sites per cell) prostacyclin receptor in normal platelets, whereas in SCI platelets there was a significant loss (P<0.00l) of high-affinity receptor sites (Kd1=6.34 +/- 1.80 nM; n1=42 +/- 11 sites per platelet) with no significant change in the low-affinity receptor sites (Kd2=1.2 +/- 0.23 microM; n2=1860 +/- 412 sites per cell). These discordant platelet findings in identical twin pairs raises the possibility of an environmental aetiology for accelerated CAD in those with SCI. The loss of inhibitory effect of PGI2 on thrombin generation in the twin with SCI appears to be because of loss of platelet high-affinity prostanoid receptors, which may contribute to atherogenesis in individuals with SCI.
Kahn
N
N
Mount Sinai School of Medicine, New York, NY 10029, USA, and Veterans Affairs Medical Center, Bronx, NY 10468, USA.
Sinha
A
A
Bauman
W
W
D000527:Alprostadil / Q000494:pharmacology; D001161:Arteriosclerosis / Q000378:metabolism; D001786:Blood Glucose; D001792:Blood Platelets / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D005215:Fasting; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000378:metabolism*; D013917:Thrombin / Q000096:biosynthesis; D014316:Tritium; D014430:Twins, Monozygotic
D001786:Blood Glucose; D007328:Insulin; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D014316:Tritium; D011464:Epoprostenol; D000242:Cyclic AMP; D013917:Thrombin; D000527:Alprostadil