ASPIRIN: the best NSAID

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Understanding thrombi & coagulation

AHA Scientific Statement

Guide to Anticoagulant Therapy: Heparin

 

A Statement for Healthcare Professionals From the American Heart Association

Jack Hirsh, MD; Sonia S. Anand, MD; Jonathan L. Halperin, MD; Valentin Fuster, MD, PhD


Key Words: AHA Scientific Statement • anticoagulants • heparin

Just the coagulation part of lengthly, technical article reproduced here--Heparin omitted. 

 

http://circ.ahajournals.org/cgi/content/full/103/24/2994?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&searchid=1130151345754_3351&stored_search=&FIRSTINDEX=0&minscore=5000&search_url=http%3A%2F%2Fcirc.ahajournals.org%2Fcgi%2Fsearch&journalcode=circulationaha 

Circulation. 2001;103:2994.)
2001 American Heart Association, Inc.


Introduction:

Thrombi are composed of fibrin and blood cells and may form in any part of the cardiovascular system, including veins, arteries, the heart, and the microcirculation. Because the relative proportion of cells and fibrin depends on hemodynamic factors, the proportions differ in arterial and venous thrombi.1 2 Arterial thrombi form under conditions of high flow and are composed mainly of platelet aggregates bound together by thin fibrin strands.3 4 5 In contrast, venous thrombi form in areas of stasis and are predominantly composed of red cells, with a large amount of interspersed fibrin and relatively few platelets. Thrombi that form in regions of slow to moderate flow are composed of a mixture of red cells, platelets, and fibrin and are known as mixed platelet-fibrin thrombi.4 5 When a platelet-rich arterial thrombus becomes occlusive, stasis occurs, and the thrombus can propagate as a red stasis thrombus. As thrombi age, they undergo progressive structural changes.6 Leukocytes are attracted by chemotactic factors released from aggregated platelets2 or proteolytic fragments of plasma proteins and become incorporated into the thrombi. The aggregated platelets swell and disintegrate and are gradually replaced by fibrin. Eventually, the fibrin clot is digested by fibrinolytic enzymes released from endothelial cells and leukocytes. The complications of thrombosis are caused either by the effects of local obstruction of the vessel, distant embolism of thrombotic material, or, less commonly, consumption of hemostatic elements.

Arterial thrombi usually form in regions of disturbed flow and at sites of rupture of an atherosclerotic plaque, which exposes the thrombogenic subendothelium to platelets and coagulation proteins; plaque rupture may also produce further narrowing due to hemorrhage into the plaque.7 8 9 10 11 Nonocclusive thrombi may become incorporated into the vessel wall and can accelerate the growth of atherosclerotic plaques.9 12 13 When flow is slow, the degree of stenosis is severe, or the thrombogenic stimulus is intense, the thrombi may become totally occlusive. Arterial thrombi usually occur in association with preexisting vascular disease, most commonly atherosclerosis; they produce clinical tissue ischemia either by obstructing flow or by embolism into the distal microcirculation. Activation both of blood coagulation and of platelets is important in the pathogenesis of arterial thrombosis. These 2 fundamental mechanisms of thrombogenesis are closely linked in vivo, because thrombin, a key clotting enzyme generated by blood coagulation, is a potent platelet activator, and activated platelets augment the coagulation process. Therefore, both anticoagulants and drugs that suppress platelet function are potentially effective in the prevention and treatment of arterial thrombosis, and evidence from results of clinical trials indicates that both classes of drugs are effective.

Venous thrombi usually occur in the lower limbs; although often silent, they can produce acute symptoms due to inflammation of the vessel wall, obstruction of flow, or embolism into the pulmonary circulation. They can produce long-term complications due to venous hypertension by damaging the venous valves. Activation of blood coagulation is the critical mechanism in pathogenesis of venous thromboembolism, whereas platelet activation is less important. Anticoagulants are therefore very effective for prevention and treatment of venous thromboembolism, and drugs that suppress platelet function are of less benefit.

Intracardiac thrombi usually form on inflamed or damaged valves, on endocardium adjacent to a region of myocardial infarction (MI), in a dilated or dyskinetic cardiac chamber, or on prosthetic valves. They are usually asymptomatic when confined to the heart but may produce complications due to embolism to the cerebral or systemic circulation. Activation of blood coagulation is more important in the pathogenesis of intracardiac thrombi than platelet activation, although the latter plays a contributory role. Anticoagulants are effective for prevention and treatment of intracardiac thrombi, and in patients with prosthetic heart valves, the efficacy of anticoagulants is augmented by drugs that suppress platelet function.

Widespread microvascular thrombosis is a complication of disseminated intravascular coagulation or generalized platelet aggregation. Microscopic thrombi can produce tissue ischemia, red cell fragmentation leading to a hemolytic anemia, or hemorrhage due to consumption of platelets and clotting factors. Anticoagulants are effective in selected cases of disseminated intravascular coagulation.


Clinical Consequences of Thrombosis:

It has been estimated that venous thromboembolism is responsible for more than 300 000 hospital admissions per year in the United States14 and that pulmonary embolism (PE) causes or contributes to death in 12% of hospitalized patients and is responsible for 50 000 to 250 000 deaths annually in the United States. The burden of illness produced by venous thromboembolism includes death from PE (either acute or, less commonly, chronic), long-term consequences of the postthrombotic syndrome, the need for hospitalization, complications of anticoagulant therapy, and the psychological impact of a potentially chronic, recurrent illness.

Arterial thrombosis is responsible for many of the acute manifestations of atherosclerosis and contributes to the progression of atherosclerosis. The burden of illness from atherosclerosis is enormous. As a generalized pathological process, atherosclerosis affects the arteries supplying blood to the heart, brain, and abdomen or legs, causing acute and chronic myocardial ischemia, including sudden death, MI, unstable angina, stable angina, ischemic cardiomyopathy, chronic arrhythmia, and ischemic cerebrovascular disease (including stroke, transient ischemic attacks, and multi-infarct dementia). In addition, atherosclerosis can cause renovascular hypertension, peripheral arterial disease with resulting intermittent claudication and gangrene, and bowel ischemia, and it can compound the complications of diabetes mellitus and hypertension. Thromboembolism that originates in the heart can cause embolic stroke and peripheral embolism in patients with atrial fibrillation (AF), acute MI, valvular heart disease, and cardiomyopathy.

The second version of "A Guide to Anticoagulant Therapy" was published in 1994. Since then, the following important advances have been made: (1) low-molecular-weight heparin (LMWH) preparations have become established anticoagulants for treatment of venous thrombosis and have shown promise for the treatment of patients with acute coronary syndromes; (2) direct thrombin inhibitors have been evaluated in venous thrombosis and acute coronary syndromes; (3) important new information has been published on the optimal dose/intensity for therapeutic anticoagulation with coumarin anticoagulants; and (4) the dosing of heparin for adjunctive therapy in patients with acute coronary syndromes has been reduced because conventional doses cause serious bleeding when combined with thrombolytic therapy or glycoprotein (GP) IIb/IIIa antagonists.

Whenever possible, the recommendations in this review of anticoagulant therapy are based on results of well-designed clinical trials. For some indications or clinical subgroups, however, recommendations are of necessity based on less solid evidence and are therefore subject to revision as new information emerges from future studies.


 

Aspirin use associated with lower mortality, but doesn't raise bleeding risk. 2002 study

 

J Vasc Surg. 2002 Mar;35(3):413-21

Benefits, morbidity, and mortality associated with long-term administration of oral anticoagulant therapy to patients with peripheral arterial bypass procedures: a prospective randomized study.

Johnson WC, Williford WO; Department of Veterans Affairs Cooperative Study #362.

[WARFARIN is
COUMADIN (crystalline warfarin sodium) is an anticoagulant which acts by inhibiting vitamin K-dependent coagulation factors. Chemically, it is 3-( -acetonylbenzyl)-4-hydroxycoumarin and is a racemic mixture of the R- and S-enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. The crystallization of warfarin sodium virtually eliminates trace impurities present in amorphous warfarin. Its empirical formula is C19 H15 NaO4.—rxlist.com]
BACKGROUND: The benefits of the long-term administration of oral anticoagulant therapy remain unclear in patients with lower extremity arterial bypass surgery. We studied the effect of warfarin plus aspirin therapy (WASA) versus aspirin therapy alone (ASA) on patient mortality, morbidity and bypass patency rates in a randomized clinical trial. METHODS: In a multicenter, prospective, nonmasked clinical trial, 831 patients who underwent peripheral arterial bypass surgery were compared in a long-term treatment program of WASA (target international normalized ratio of 1.4 to 2.8; 325 mg/day) with ASA (325 mg/day). The primary end point was bypass patency, and mortality and morbidity were the secondary endpoints. RESULTS: There were 133 deaths in the WASA group (31.8%) and 95 deaths in the ASA group (23.0%; risk ratio, 1.41; 95% confidence interval, 1.09 to 1.84; P =.0001). Major hemorrhagic events occurred more frequently in the WASA group (WASA, n = 35; ASA, n = 15; P =.02). In the prosthetic bypass group, there was no significant difference in patency rate in the 8-mm bypass subgroup, but there was a significant difference in patency rate in the 6-mm bypass subgroup (femoral-popliteal; 71.4% in the WASA group versus 57.9% in the ASA group; P =.02). In the vein bypass group, patency rate was unaffected (75.3% in the WASA group versus 74.9% in the ASA group). CONCLUSION: The long-term administration of warfarin therapy when combined with aspirin therapy has only a few selected indications for improvement of bypass patency and is associated with an increased risk of morbidity and mortality. 

 

Notice the pro industry slant of no difference in results being turned into “a few selected indications for improvement” and the ignoring of the fatal outcome for 6-mm bypass subgroup.  Moreover for the 8-mm bypass subgroup there was 2.5 more deaths (adjusting for the difference of 2:1 for the two groups).  17% more deaths should be considered significant, but it wasn’t for the 8-mm subgroup. —jk.

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