The role of the porcine von Willebrand factor: baboon platelet interactions in pulmonary xenotransplantation.
BACKGROUND
Porcine von Willebrand factor (pvWF) has been shown to bind to human glycoprotein Ib (GPIb) and cause activation of human (or primate) platelets in the absence of shear stress. Pulmonary xenografts develop disseminated intravascular coagulation (DIC) and microvascular thrombosis within hours of reperfusion, and the aberrant interaction between pvWF and human platelets may be a possible cause of xenograft-associated DIC.


METHODS
Experimental baboons (n=3) received mouse anti-human GPIb monoclonal antibody before undergoing orthotopic pulmonary xenotransplantation with porcine lungs expressing human membrane cofactor protein (CD46).


RESULTS
Blocking the pvWF-GPIb interaction with a monoclonal antibody to GPIb prevented the agglutination of human and baboon platelets by pvWF in vitro. In vivo, the anti-GPIb antibody prevented platelet deposition and prevented the increases in D-Dimers (P=0.011) seen in control xenograft recipients (n=5). However, there was no difference in elevations of prothrombin times (PT) or improvement in the vasoconstriction associated with the loss of xenograft function.


CONCLUSIONS
This study indicates that the DIC associated with the hyperacute dysfunction of pulmonary xenografts is a complex phenomenon that is affected by, but not solely dependent on, activation of platelets. Aberrant interactions between pvWF and GPIb play a significant role in DIC associated with pulmonary xenotransplantation.
Gaca
Jeffrey G
JG
Department of Surgery, Duke University Medical Center, Durham, NC, USA.
Lesher
Aaron
A
Aksoy
Olcay
O
Ruggeri
Zaverio M
ZM
Parker
William
W
Davis
R Duane
RD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001792:Blood Platelets / Q000502:physiology*; D019281:Dimerization; D004211:Disseminated Intravascular Coagulation / Q000209:etiology / Q000503:physiopathology; D005338:Fibrin Fibrinogen Degradation Products / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000503:physiopathology; D016040:Lung Transplantation / Q000009:adverse effects; D051379:Mice; D010215:Papio / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000276:immunology / Q000502:physiology; D013552:Swine / Q000502:physiology*; D014183:Transplantation, Heterologous / Q000009:adverse effects; D014841:von Willebrand Factor / Q000502:physiology*
D000911:Antibodies, Monoclonal; D005338:Fibrin Fibrinogen Degradation Products; D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor