1. Stroke mechanisms in AF: Rationale for anticoagulant therapy
B:Vascular biology
Stroke mechanisms in AF: Rationale for anticoagulant therapy
Prothrombotic states in AF
Content Points:
AF is associated with increased levels of several markers of a procoagulant state:
- Coagulation factor VIII1 - Prothrombin fragment 1,22
- Fibrinogen1,2,3 - Thrombin-antithrombin complex4,5
- D-dimer1,3-5
- Tissue plasminogen activator antigen (suggestive of altered fibrinolytic balance, since most of this antigen is complexed with plasminogen activator inhibitor-1 [PAI-1])2
AF is also associated with platelet activation, as measured by increased levels of the following markers:
- P-selectin ß-thromboglobulin1,4 - Platelet factor 41,4
However, enhancement of the coagulation system is not the result of platelet activation, suggesting that stasis-related clot formation in the left atrial appendage (LLA) is a more important mechanism.6
1Gustafsson C, Blomback M, Britton M, et al. Coagulation factors and the increased risk of stroke in nonvalvular atrial fibrillation. Stroke. 1990;21:47-51.
2Feng D, D'Agostino RB, Silbershatz H, et al. Hemostatic state and atrial fibrillation (the Framingham Offspring Study). Am J Cardiol. 2001;87:
3Leong F, Blann AD, Lip GYH. Effect of degree of blood pressure on the hypercoagulable state in chronic atrial fibrillation. Am J Cardiol. 2000;86:
4Heppell RM, Berkin KE, McLenachan JM, Davies JA. Haemostatic and haemodynamic abnormalities associated with left atrial thrombosis in non-rheumatic atrial fibrillation. Heart. 1997;77:
5Mitusch R, Siemens HJ, Garbe M, et al. Detection of a hypercoagulable state in novalvular atrial fibrillation and the effect of anticoagulant therapy. Thromb Haemost. 1996;75:
6Nagao T, Hamamoto M, Kanda A, et al. Platelet activation is not involved in acceleration of the coagulation system in acute cardioembolic stroke with nonvalvular atrial fibrillation. Stroke. 1995;26:

2. Potential prothrombotic mechanisms in AF: ↓ NO production
Content Points:
Cai et al studied nitric oxide (NO) production in the left atrial endocardium of pigs with experimentally induced AF.1
As shown, basal NO levels were significantly lower in the left atrium and LAA in animals with AF compared with controls without AF (P < 0.01 for both comparisons). This was accompanied by a 46% decrease in expression of NO synthase (NOS) in the left atrium of animals with AF compared with controls (P < 0.01, data not shown).
AF did not cause significant changes in NO levels of NOS expression in the right atria or ascending aorta.
The investigators concluded that organized atrial contraction is required to maintain normal endocardial expression of NO. Since NO has important antithrombotic effects, the investigators speculate that decreased NO bioavailability may contribute to clot formation.
1Cai H, Li Z, Goette A, Mera F, Honeycutt C, Feterik K, et al. Downregulation of endocardial nitric oxide synthase expression and nitric oxide production in atrial fibrillation: Potential mechanisms for atrial thrombosis and stroke. Circulation. 2002;106:

3. Potential prothrombotic mechanisms in AF: LAA stasis Content Points:
The Stroke Prevention in Atrial Fibrillation (SPAF) clinical trial program was sponsored by the National Institute of Neurological Disorders and Stroke and consisted of six multicenter clinical trials of antithrombotic therapy (warfarin, aspirin) in patients with AF.1
SPAF III was an evaluation of a risk stratification scheme developed from the SPAF I and II data, and compared dose-adjusted warfarin (INR 2-3) with fixed-dose, low-intensity warfarin plus aspirin in high-risk patients. There was a 74% risk reduction for dose-adjusted warfarin vs the combination anticoagulation regimen.
To explore the mechanism of clot formation, investigators used TEE to assess flow velocity in the LAA in a cohort of 721 patients.2
Peak antegrade flow velocity (Avp) was used as a measure of LAA emptying.
Among patients with Avp<20 cm/s, 20 to 30 cm/s, and >30 cm/s, the frequencies of LAA thrombi were 17%, 6%, and 6%, respectively.
When patients treated with adjusted-dose warfarin and those with noncardioembolic stroke were excluded from the analysis, reduced Avp was shown to be predictive of cardioembolic events (as shown on the slide).
In high-risk patients, the frequency of LAA thrombus and cardioembolic events increased more than 2.5-fold when Avp was <20 cm/s.
These findings demonstrate that reduced LAA flow velocity is important in the genesis of clots.
1Hart RG. Lessons from the Stroke Prevention in Atrial Fibrillation trials. Ann Intern Med. 2003;138:
2Goldman ME, Pearce LA, Hart RG, Zabalgoitia M, Asinger RW, Safford R, Halperin JL, for the Stroke Prevention in Atrial Fibrillation Investigators. Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (the Stroke Prevention in Atrial Fibrillation [SPAF-III] study). J Am Soc Echocardiogr. 1999;12:

4. Stroke mechanisms in AF: Proposed unifying model Content Points:
Cardiovascular risk factors such as elevated blood pressure, coronary artery disease (CAD), and diabetes likely account in large part for the hypercoagulable state associated with AF.1 However, the observation that markers of coagulation activity increase when the duration of AF is >12 hours suggests that AF per se may contribute to enhancement of coagulation.2
The role of cardiovascular risk factors in decreased NO bioavailability in the coronary vascular endothelium is well established.3 Thus, it is reasonable to speculate that they may also contribute to the downregulation of endocardial NOS.4 However, mechanical factors secondary to disorganized atrial contraction may also play a role.4 Decreased NO bioavailability, in turn, leads to an environment conducive to platelet adhesion to the endocardium and an altered fibrinolytic balance (increased PAI-1).
Since activation of the coagulation system with subsequent thrombin formation is the primary pathogenic mechanism, the result is a fibrin-rich clot.
1Feng D, D'Agostino RB, Silbershatz H, Lipinska I, Massaro J, Levy D, et al. Hemostatic state and atrial fibrillation (the Framingham Offspring Study). Am J Cardiol. 2001;87:
2Sohara H, Amitani S, Kurose M, Miyahara K. Atrial fibrillation activates platelets and coagulation in a time-dependent manner: a study in patients with paroxysmal atrial fibrillation. J Am Coll Cardiol. 1997;29:
3Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: The role of oxidant stress. Circ Res. 2000;87:
4Cai H, Li Z, Goette A, Mera F, Honeycutt C, Feterik K, et al. Downregulation of endocardial nitric oxide synthase expression and nitric oxide production in atrial fibrillation: Potential mechanisms for atrial thrombosis and stroke. Circulation. 2002;106:

5. Effect of anticoagulation intensity on post-stroke survival in patients with AF
Content Points:
Hylek et al retrospectively studied the frequency and severity of incident ischemic strokes in a cohort of 13,559 patients with AF.1
As shown, the 30-day survival among patients who were not taking warfarin or aspirin when they had an ischemic stroke was significantly worse compared with patients who were on antithrombotic medication (aspirin or warfarin).
Survival among patients who were taking warfarin and who had an INR <2.0 was also significantly worse as compared with warfarin patients who had an INR >2.0.
Survival among patients who were taking aspirin was comparable to survival among patients who were taking warfarin and who had an INR <2.0.
The investigators concluded that INR >2.0 markedly reduces the severity of stroke.
1Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, Singer DE. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med. 2003;349:

6. AFFIRM: Effect of anticoagulation intensity on stroke risk
Content Points:
The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) results support the critical importance of maintaining a therapeutic anticoagulation level.1
AFFIRM included 4060 patients with recurrent AF that (in the clinical judgment of the investigators) was likely to cause illness or death and warranted long-term treatment. Study subjects were randomized to one of the two treatment strategies and were followed for a mean of 3.5 years with a maximum of 6 years.
- In the rhythm control group, continuous anticoagulation was encouraged, but could be stopped if sinus rhythm had been maintained for at least 4 weeks.
- In the rate control group, continuous anticoagulation was mandated by the study protocol.
Rate control group: As shown, of 77 ischemic strokes, 52 (69%) occurred in patients who had discontinued warfarin or were taking warfarin but had an INR <2.0.
Rhythm control group: Of 80 ischemic strokes, 61 (79%) occurred in patients who had discontinued warfarin or were taking warfarin but had an INR <2.0.
1The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347: