70 y m reports to the emergency room with a past medical history of hypertension and high cholesterol complaining of headache. He is not one to have headaches and his wife reports that he is a little “off”. He reports to you that he had some numbness of his tongue but that symptom has resolved. His medications include metoprolol, aspirin and zocor. His vital signs are stable. His sensation and strength are all intact. His reflexes are equivocal. What do you do?
Head CT is performed as quickly as possible and you find a large subdural bleed with midline shift. Neurosurgery is contact immediately…oh yeah…he is on aspirin…how do I stop the effects of the world’s best known drug?
It never ceases to amaze me how little research is out there especially when we try to subscribe to certain practice standards. Let’s talk a few minutes to discuss one such practice in the arena of intracranial hemorrhage. Aspririn effectively knocks cyclooxygenase-I (COX-1) enzyme irreversibly by protein acetylation. As a result, thromboxane A2 is made which is an important factor involved with platelet aggregation. As a result, the “stickiness” of your platelets is irreversibly effected. Unlike aspirin, NSAIDs similiarly block this reaction but in a reversible way (so not as large a concern). Plavix irreversibly inhibits the P2Y12 ADP receptor and remains active after cessation of treatment for a number of days (normalizing after 5-7 days). Some studies have demonstrated increased bleeding with plavix relative to aspirin. Despite that we have decided to give them both together because we know that they have the potential to prevent cardiac events.
So how do we reverse these potentially dangerous drugs that seemed so amazing to the heart and stroke prevention health of a patient. We know that patient outcomes are all influenced by hematoma size, growth, location and speed to evacuation when appropriate. It is important to halt the bleeding in its tracks to restore hemostasis. Unfortunately there is no specific antidote for either medication.
The neurosurgical community recommends the use of platelets as a means of restoring normal hemostasis in asprin therapy. Recommendations made by Beshay et al. (2010), suggest reversing the aspirin effect by giving one dose of platelet transfusion (1 single donor or 5 pooled concentrates). The idea is that the new platelets present will not be effected by the already metabolized aspirin and they will join ranks with the newest platelets to constitute an improved clotting ability. In vitro, this has been shown to be a possible solution by Vilahur et al. that platelet dysfunction due to clopidogrel can be corrected with 10 platelet concentrate units after a 300-mg clopidogrel loading or 12.5 units after a 600mg loading dose. The study was created in response to the need to correct cardiovascular surgical bleeding in patients taking combination of aspirin and plavix. It may be assumed that if it works in the chest it should work in the head. So what effect do platelets have on intracranial hemorrhage? The answer is that we don’t have any great evidence. Creutzfeldt et al (2009) performed a retrospective analysis on the question and did not identify improved outcomes (functional status or mortality). The authors contribute these findings to the retrospective quality of the study, single institution as well as small sample size. A similiar study was conducted in 2 different institutions looking at patients older than 50 and its effect on mortality. Both retrospective arms (with platelet therapy and without it) had mortality rates around 17%. That being said, it still stands as the standard of care for antiplatelet reversal therapy, listed below:
Aspirin – 1 single donor or 5 pooled concentrates of platelets
Plavix – 2 single donor or 10 pooled concentrates of platelets
What about desmopressin? It improves hemostais by promoting VWF as well as Factor VIII. Desmopressin has consistently acts in the surgical literaterature as a means of stopping post-operative bleeding. Reiter et al (2007) showed the DDAVP improved platelet aggregation from GPIIb/IIIa inhibitors + aspirin at 1.5-2.0 hours after transfusion was stopped. Desmopressin has not been studied in the intracranial hemorrhage community. It is unlikely to cause for bad outcomes unless a noted allergy exists. Dosing either IV or intranasally has shown to be equally effective (N=8). Even thought here is a paucity of evidence it should be strongly considered in your patients taking antiplatelet therapy with intracranial bleeding at the dosing listed below:
Desmopressin – 0.3 ug/kg every 12 hours for 48 hours IV or intranasally
Recombinant factor VIIIa has also been showing promise in reversing aspirin. There is little literature addressing traumatic ICH in patients on antiplatelet therapy. There are many more studies to be done. At the end of the day, this author would recommend giving a combination of platelets as well as desmopressin in a patient suffering from an ICH on antiplatelet therapy. What do you all think? Please let me know.
Michael Meguerdichian, MD
Beshay et al., Emergency reversal of anticoagulation and antiplatelet therapies in neurosurgical patients: A review, J Neurosurg, 2010; 112: 307-318.
Campbell, PG et al., Emergency Reversal of Antiplatelet Agents in Patients Presenting with an Intracranial Hemorrhage: A Clinical Review, World Neurosurgery 2010; 74 (2/3): 279-285.
Creutzfeldt, et al., Prior Antiplatelet Therapy, Platelet Infusion Therapy, and Outcome after Intracerebral Hemorrhage, Journal of Stroke and Cerebrovascular Diseases, 2008; Vol. 18 (3): 221-228
Downey, et al., Does Platelet Administration Affect Mortality in Elderly Head‐Injured Patients Taking Antiplatelet Medications?, American Surgeon, 2009; Vol 75(11): 1100‐1103.
Flordal PA, Sahlin S: Use of desmopressin to prevent bleeding complications in patients treated with aspirin. Br J Surg, 1993; 80:723-724.
Reiter et al., Desmopressin antagonizes the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors and aspirin, The American Society of Hematology 2003; Vol 102 (15):4594-4599.
Vilahur, G et al., Normalization of platelet reactivity in clopidogrel-treated subjects, Journ of Thrombosis and Haemostasis, 2006; 5:82-90.