Cerebrovascular Disease/Stroke

=Objectives=

Define

 * Therapeutic INR
 * An INR (international normalized ratio, it is a measurement of the extrinsic pathway of coagulation) that balances the risk of embolic events with the risk of bleeding and side effects. Patients at risk of a stroke typically set a goal of 2.5 (range 2.0 to 3.0), though this may vary based on a patient's risk factors such as presence of an anti-phospholipid antibody, mechanical heart valve, etc.  The range of an INR in a normal person is 0.8-1.2.


 * Amyloid angiopathy
 * Changes in the cerebral vasculature integrity due to thickening of arterial media; associated with increased risk of lobar hemorrhage. Chemical mediators of homostasis affected.  Hemorrhages due to amyloid angiopathy have a high rate of recurrance (20%), may occur within weeks of initial hemorrhage.  Linked to production of amyloid associated with Alzheimers changes.  Prevalence increases with age.

Discuss factors that increase stroke risk in the elderly
Three types of strokes exist: ischemic, cardioembolic, and hemorrhagic.
 * cardioembolic (20% of all strokes)
 * Atrial fibrilation is the most important risk factor for cardioembolic strokes (5% annualized risk). Factors that exacerbate stroke risk in the presence of AF include: Congestive heart failure, hypertension history, age over 75, diabetes, and stroke or TIA history.
 * Additional less common risks include rheumatic heart disease, coagulopathy (eg protein C def), prosthetic valves, and paradoxical emboli (PFO).


 * hemorrhagic (15% of all strokes)
 * hypertension, berry aneurysm, smoking,


 * ischemic stroke (remaining 65%)
 * Risks for ischemic stroke include atherosclerosis, especially carotid artery stenosis. Diabetes, smoking, hyperlipidemia, excessive EtOH, and hypertension are other risk factors.

List the major side effects of common stroke prevention therapies

 * Warfarin:
 * 1% annual major bleeding complication, including intracranial hemorrhage. bleeding from falls & minor trauma.
 * Epidermal necrosis. (Fun fact: antidote is vitamin K (phytonadione) or fresh frozen plasma)
 * Pregnancy category X.
 * Antiplatlet agents
 * Aspirin: gastritis and ulcers. (prophylactic proton-pump-inhibitor)
 * clopidrogrel: diarrhea or rash (5%), bleeding risks, expensive
 * dipyridamole/aspirin: bleeding, headache, diarrhea
 * Carotid Endoarterectomy (CEA): a defined set of patients with carotid artery stenosis will benefit from CEA. The perioperative mortality of surgery is ~ 6%.

Describe particular benefits and perils of anticoagulation in the elderly

 * Anticoagulation has a clear benefit for patients with atrial fibrillation and at least one additional risk factor. Anticoagulation has significant risks of major bleeding complications from minor falls, trauma, and emergency surgeries.  These risks are approximately 1% per patient per year. Aspirin therapies have risk of gastritis.

Drug List

 * Aspirin: acetylates platelet cyclooxygenase, which irreversible inhibits the formation of platlet thromboxane A2 (a platelet aggregator). Also inhibits endothelial prostacyclin (therby inhibiting an anti-aggregating and vasodilating molecule).
 * ER-dipyridamole/aspirin (Aggrenox): an antiplatelet agent that inhibits the uptake of adenosine by a variety of cells, including those of the vascular endothelium. adenosine inhibits platelet aggregation.  Also acts to increase NO, prostocyclin and inhibit phosphodiesterases (via unknown mechanism).
 * Clopidogrel (Plavix): irreversible inhibitor of the ADP receptor on platelets, and thus prevents the activation of glycoprotein IIb/IIIa that leads to fibrinogen bindin to the platelets; prevents platelet aggregation.
 * Warfarin (Coumadin): interferes with the hepatic synthesis of vitamin K-dependent coagulation factors II (prothrombin), VII, IX, X. Prolongs PT and aPTT.
 * tPA (alteplase, Activase): recombinant DNA form of the enzyme human tissue-type plasminogen activator. Fibrinolytic.

=Links & References=
 * Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
 * Drug references from Dynamed & Harrison's Internal Medicine, Chapter 364, Cerebrovascular Disease.