Platelet activation in clinical haemodialysis: LMWH as a major contributor to bio-incompatibility?
BACKGROUND
The sum of undesirable side effects, occurring during haemodialysis (HD), is called bio-incompatibility. Concerning platelets, both an increase in the expression of the cell surface marker P-selectin (CD62p) and release of the intracellular granule product platelet factor 4 (PF4) have been described. However, as PF4 is also abundantly present on endothelium-bound proteoglycans, it is questionable whether the HD-induced increase is exclusively attributable to release from platelets. With respect to the cause of HD-induced bio-incompatibility, interest has been focused mainly on the extracorporeal circuit (ECC), especially the dialyser, whereas only little attention has been paid to other parts of the ECC and the mode of anticoagulation applied. To address the cause and origin of platelet activation and PF4 release during clinical HD, two complementary clinical studies were performed.


METHODS
In study I, the relative influence of the various parts of the ECC was evaluated by measuring the expression of CD62p, platelet aggregation and levels of PF4 and serotonin at various sampling points. In study II, low-molecular-weight heparin (LMWH) was administered 10 min before the actual start of HD, in order to separate the effects from LMWH and the ECC on platelet activation.


RESULTS
In study I, CD62p expression increased across the entire length of the ECC, including the roller pump and dialyser (median at t(5) from 26% to 43%, P = 0.008; median at t(30) from 28% to 48%, P = 0.007). Increments in PF4 and aggregation of platelets were relatively modest. Platelet serotonin content, which was below reference values in healthy controls, and plasma serotonin concentration, which was above reference values, did not change. In study II, PF4 levels increased markedly after the injection of LMWH (from 12 IU/ml at t(-10) to 75 IU/ml at t(0), P = 0.018), whereas CD62p expression remained stable until the start of HD.


CONCLUSIONS
Platelet activation, as measured by the up-regulation of CD62p, is an early process, occurring not only within the dialyser, but across the entire length of the ECC. As CD62p remained unaltered after the administration of LMWH 10 min before the actual start of HD, this kind of activation is independent of LMWH. Considering PF4 however, a sharp increment was observed after the administration of LMWH and before the start of HD. This finding suggests that the PF4 release observed early in clinical HD is largely independent from the ECC, and is probably the result of LMWH-induced detachment from the endothelium. As the platelet serotonin content was relatively reduced and the plasma serotonin levels were elevated, platelets from chronic HD patients might be depleted due to chronic repetitive activation. Based on these data, it appears first, that PF4 is an inferior marker of platelet activation in clinical HD and second, that LMWH is a major contributor to HD-induced bio-incompatibility.
Gritters
Mareille
M
Department of Nephrology, VU University Medical Centre, PO Box 7075, 1007 MB Amsterdam, The Netherlands. m.gritters@vumc.nl
Borgdorff
Piet
P
Grooteman
Muriel P C
MP
Schoorl
Marianne
M
Schoorl
Margreet
M
Bartels
Piet C M
PC
Tangelder
Geert-Jan
GJ
Nubé
Menso J
MJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001792:Blood Platelets / Q000737:chemistry; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation; D010978:Platelet Factor 4 / Q000378:metabolism; D006435:Renal Dialysis / Q000295:instrumentation; D051437:Renal Insufficiency / Q000209:etiology / Q000628:therapy; D012701:Serotonin / Q000032:analysis
D006495:Heparin, Low-Molecular-Weight; D019007:P-Selectin; D012701:Serotonin; D010978:Platelet Factor 4