*Long message ahead*

CYP3A4 is a huge family of CYPs that interestingly have a platelet enzyme as part of it: Thromboxane Synthetase. 

This enzyme is responsible for the production of Thromboxane A2 which is a potent visoconstrictor. TXA2 is associated with the lack of reperfusion in the ichemic brain.

Selective inhibition of thromboxane synthase may alleviate ischemic brain damage by reducing cerebral TXA2 concentrations and elevating cerebral blood flow, which relieves neurons from hypoxia. 

(You can find more information in the link below) :)

If the patient has immune thrombocytopenia, I would believe the production of platelets by the megakaryocytes should increase. If its normal, and the diagnostic is made based on bleeding events rather than peripheral platelet count, it is reasonable to:

1 - check for peripheral platelet count. If normal, see 2.

2 - Consider these platelets are having a hard time to respond to proaggregant stimuli and further become activated to perform their normal function. Due to the brain fog report, possibly Thromboxane synthase is not inhibited, cause vasoconstriction would lead to less blood flow to the neurons, therefore reducing their activity due to ischemia.

Moreover, Thromboxane Synthase activity is dependent on PGH2 levels, which occur in response to injury. The lack of platelet aggregation in a thrombocytopenic patient may also upregulate the production of PGH, in an attempt from the injured cells to get platelets to activate. PGH2 is rapidly converted to TXA2 by platelets and other cells, but no activation of the platelets occur in the scenario you presented....while vasoconstriction is likely to occur.

In summary, these are my thoughts. 

1. Platelets are not becoming activated, injury and bleeding persist.

2. Cells adjacent to the injury sites (where bleeding is taking place) start signalling to claim for platelets. Thus, they are raising PGH2 production and further TXA2 levels produced by thromboxane synthetase. present in platelets and other inflammatory cells.

3. TXA2 cannot trigger platelet aggregation as it should (Possibly because the thromboxane receptors in the platelets surface are inhibited or silenced.). Therefore,bleeding continues.

4. ThromboxaneA2 acts on endothelial cells, generating vasoconstriction. Brain vessels are constricted, reducing perfusionto neurons and generating ichemia, thus making it hard for the patient to have long conversations and having a "Brain Fog."

Happy science! 

http://www.ncbi.nlm.nih.gov/pubmed/2718203

Thank you for educating me and supplying a resource! Your explanation has prompted this patient's team of specialists to conduct testing to see if what you suggest is the cause. "Happy Science" indeed!

Hi Jennifer. 

Anytime! Thank you for keeping me on the loop of what's happening. I'm glad my thoughts helped the team in some way. 

If you still consider that thromboxane receptors might not be working on the patient platelets and TXA2 levels are high enough to generate vasoconstriction in the brain, here are two suggestions on experiments that can provide a quick answer to help diagnostics:

1. Obtain patient platelet rich plasma and perform platelet aggregation assays (light transmission aggregometry is the current gold standard for this) using the thromboxane receptor agonist U-46619. U-46619 mimics thromboxane A2 and PGH2 in platelets. If this molecule does not make platelets to aggregate, the receptor function is compromised.

2. To make sure that vasoconstriction due to increased TXA2 levels is really a possibility for the brain fog, I suggest getting plasma or urine samples from the patient and determine the levels of TXB2 (direct metabolite of TXA2) you can find in each. (Cayman Chemicals has kits for this and they are pretty sensitive!).

If you can't see aggregation induced by U-46619, and patients TXB2 levels are high, this hypothesis might actually be true. Please let me know how the case develop. Thanks again for letting me know. 

Sincerely,

Andre

Thank you again, I will let you know.

Update: This patient underwent an aortic aneurysm removal by one of the renal arteries. Additionally, the surgeons had specially made "stents" for all arteries going to organs in this area. Two of the top three surgeons in the US met at Emory to perform the surgery. The patient is doing well, however his platelet levels almost required a blood transfusion the week before the surgery but were fine the day of surgery. Anesthesia did not produce any adverse effects. Patient and wife unconcerned about platelet and blood related issues, as surgery was their main concern. It is disheartening to hear, but perhaps they need time to digest recent events. Thank you again for all the information you provided!

Glad to hear he is fine after surgery. My best wishes to his family and the group of specialists that composed the team who successfully helped to solve the problem!

Keep in touch Jennifer!

Best,

Andre