Fibrinogen fragments and platelet dysfunction in uremia.
BACKGROUND
The uremic state is characterized by subnormal platelet aggregation. Fibrinogen fragments, usually absent in normal human blood, but present in uremic plasma, may play a role in uremic platelet dysfunction.


METHODS
To examine this hypothesis, we investigated the availability and function of fibrinogen receptors [glycoprotein (GP) IIb-IIIa] on uremic and normal platelets, as well as the effect of fragments obtained from chymotrypsin digestion of human fibrinogen on normal platelets. The availability of fibrinogen receptors was examined using anti-GP IIb-IIIa antibodies and flow cytometry, whereas receptor function was assessed by the receptor's ability to mediate fibrinogen binding and platelet aggregation.


RESULTS
Platelet aggregation and the availability of GP IIb-IIIa were lower in uremic patients when compared with normal controls. Flow cytometric analysis showed that fibrinogen fragments decreased the binding of anti-CD61, an activation-independent anti-GP IIIa monoclonal antibody, to resting normal platelets. These fragments also reduced the binding of PAC-1, an activation-dependent anti-GP IIb-IIIa monoclonal antibody, to adenosine diphosphate (ADP)-activated normal platelets. In addition, the binding of radiolabeled fibrinogen to activated normal platelets and platelet aggregation in response to ADP were both decreased by fibrinogen fragments.


CONCLUSIONS
These findings suggest that fibrinogen fragments impair platelet function by occupying fibrinogen receptors prior to cell activation, thus preventing the binding of intact fibrinogen to platelets after subsequent stimulation. These observations also suggest a plausible mechanism by which endogenous fibrinogen fragments present in uremic plasma may contribute to platelet dysfunction.
Kozek-Langenecker
S A
SA
Department of Anesthesiology, University of Vienna, Austria.
Masaki
T
T
Mohammad
H
H
Green
W
W
Mohammad
S F
SF
Cheung
A K
AK
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000911:Antibodies, Monoclonal; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002918:Chymotrypsin / Q000378:metabolism; D005340:Fibrinogen / Q000032:analysis* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology; D015539:Platelet Activation / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D012016:Reference Values; D014511:Uremia / Q000097:blood*
D000911:Antibodies, Monoclonal; D010446:Peptide Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D002918:Chymotrypsin