Ginkgo biloba Extracts and Intracranial Hemorrhages

I collected these articles on cases of intracranial hemorrhages associated with the use of Ginkgo biloba extract. The main constituents of Ginkgo extracts are bilobalide and ginkgolides A, B, C, and J. They're antagonists of platelet-activating factor (PAF) receptors (the drug, "BN 52021," as the authors of this randomly-chosen abstract mention, is ginkgolide B: http://www.ncbi.nlm.nih.gov/pubmed/7956274). Here are some of the articles that report on or discuss the association of the use of Ginkgo biloba extracts with intracranial hemorrhages:

http://www.ncbi.nlm.nih.gov/pubmed/9800751

http://www.ncbi.nlm.nih.gov/pubmed/9798614

http://www.ncbi.nlm.nih.gov/pubmed/9091822 (a hyphema is a hemorrhage into the anterior chamber of the eye)

http://www.ncbi.nlm.nih.gov/pubmed/11161079

http://www.ncbi.nlm.nih.gov/pubmed/15277097

http://www.ncbi.nlm.nih.gov/pubmed/16050865

http://www.ncbi.nlm.nih.gov/pubmed/16170143

http://www.ncbi.nlm.nih.gov/pubmed/15693702

http://www.ncbi.nlm.nih.gov/pubmed/12421514

http://www.ncbi.nlm.nih.gov/pubmed/15660071 (bleeding association, but not intracranial)

http://www.ncbi.nlm.nih.gov/pubmed/12399731 (hyphema)

http://www.ncbi.nlm.nih.gov/pubmed/15377145

http://www.ncbi.nlm.nih.gov/pubmed/16044448

http://www.ncbi.nlm.nih.gov/pubmed/13679551

http://www.ncbi.nlm.nih.gov/pubmed/15629177

http://www.ncbi.nlm.nih.gov/pubmed/12122516

It didn't take me very long to collect those. In some cases, the bleeding event may have occurred because of other medications combined with the Ginkgo extract, etc. It's strange, but, for some reason, I've seen a few articles showing that Ginkgo extracts don't seem to reliably influence the INR (International Normalized Ratio, a standardized measurement of the prothrombin time). This one showed no measurable effect on the coagulation cascade (http://www.ncbi.nlm.nih.gov/pubmed/12890165) in healthy, young people, but my sense of the way PAF signalling works is that it doesn't really get going until there's some inflammatory stimulus.

So the issue is not really the role that PAF-receptor antagonism plays in the absence of inflammation but the impact that PAF-receptor antagonism has in the face of the activation of the coagulation cascade, particularly by pro-inflammatory cytokines and other mediators in a disease state. The prothrombin time is also notoriously insensitive, and a significant change may not occur in the INR until the plasma prothrombin concentration has been reduced by something like 50 percent. I mean that the absence of a change in the INR, in response to PAF-receptor antagonism, is not evidence of the absence of an effect of PAF-receptor antagonism on coagulation or platelet-activation-associated parameters.

Obviously there are risks of bleeding from a lot of treatments, particularly in elderly people. Even in the use of warfarin, though, with all the information and research on it, doctors frequently have difficulty managing the degree of anticoagulation. I mean that, under the best of circumstances (when a doctor is monitoring the INR and other coagulation parameters), doctors and patients can have a difficult time keeping the INR stable and preventing overanticoagulation by warfarin. To the extent that the impact of PAF-receptor antagonism on coagulation and platelet activation cannot be measured in vivo (as in the studies showing "no impact" on coagulation or platelet activation, etc.), there is no way of knowing the effect PAF-receptor antagonism is having in any one individual.