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(Circulation. 2002;106:1748.)
© 2002 American Heart Association, Inc.

Editorial

Acute Pulmonary Embolism

Don’t Ignore the Platelet

Piotr Sobieszczyk, MD; Michael C. Fishbein, MD; Samuel Z. Goldhaber, MD

From the Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (P.S., S.Z.G.); and the Department of Pathology and Laboratory Medicine, UCLA Medical Center, Los Angeles, Calif (M.C.F.).

Correspondence to Samuel Z. Goldhaber, MD, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail sgoldhaber{at}partners.org

Key Words: Editorials • platelets • embolism • thrombosis • pulmonary heart disease

Acute pulmonary embolism (PE) remains a dreaded and frequent cardiovascular emergency, with an estimated annual incidence of almost 200 000 cases in the United States alone.¹ Despite therapeutic advances, ² the International Cooperative Embolism Registry of 2454 patients³ reported a surprisingly high 90-day all-cause mortality of 17.4%. The cause of death in 45% of patients was PE itself. Recurrent PE, fatal or nonfatal, occurred in 8% of patients within 90 days. It is clear that a novel therapeutic pharmacological strategy with a safe and easy-to-administer agent is needed to reduce adverse outcomes from this common illness. Clinical and experimental evidence suggests that antiplatelet agents, usually overlooked in the treatment of PE, may fulfill this role by preventing the initiation and propagation of the venous thrombus and by minimizing the adverse physiological consequences of PE.

Venous thrombosis has been traditionally associated with red blood cell and fibrin-rich "red clot," whereas arterial thrombi superimposed on atherosclerotic lesions are rich in platelets, giving the appearance of "white clot." This simple but somewhat dogmatic concept has had important therapeutic implications: "red clot" has been traditionally treated with heparin and warfarin, while platelet inhibition has been utilized for acute coronary syndromes caused by "white clot." However, careful morphological analysis of thrombi formed in veins reveals tangled pale strands of aggregated platelets and fibrin within the mass of red blood cells.⁴ Experimentally induced venous thrombus in the presence of radiolabeled platelets shows early platelet accumulation at the "head" of the venous thrombus.^5,6 As the thrombi age, acquisition of platelets slows and the clots become "red," predominantly composed of fibrin and erythrocytes.

Venous thromboembolism activates platelets, leading to release of vasoactive agents such as serotonin, adenosine diphosphate, prostaglandins, and thromboxane A₂.^7–9 PE causes increased urinary excretion of thromboxane B₂, a marker of platelet activation in early phases of thrombus formation.¹⁰ Physiological responses to platelet activation include pulmonary hypertension, bronchoconstriction, and right ventricular failure.¹¹ These adverse consequences result from reduction of blood flow through the pulmonary vasculature due to mechanical obstruction and local pulmonary vasoconstriction due to platelet-mediated release of humoral substances. Aspirin is a potent inhibitor of thromboxane A₂ synthesis, and antiplatelet agents may reduce the adverse physiological response to PE caused by humoral mediators.

Experimental evidence supports adjunctive antiplatelet therapy for the treatment of PE. Pretreatment of rabbits with aspirin before experimentally induced PE reduced mortality and attenuated tachycardia, pulmonary hypertension, and systemic arterial hypotension. The likely mechanism is inhibition of prostaglandin and serotonin release by activated platelets.^12,13 In a canine model of PE, pretreatment with the cyclooxygenase inhibitor indomethacin prevented the expected increase in thromboxane B2, pulmonary dead space, and pulmonary vascular resistance.¹⁴ However, in another canine study, treatment with aspirin or indomethacin approximately 60 minutes after induction of PE with autologous blood clot exacerbated pulmonary hypertension and worsened gas exchange.¹⁵ Methodological differences may explain the difference between the results of these 2 studies.

The Antiplatelet Trialists’ Collaboration reviewed data from 80 trials involving 10 000 surgical or immobilized patients and compared rates of deep venous thrombosis (DVT) and PE in patients treated with antiplatelet agents or placebo.¹⁶ Of the 80 trials, 55 tested aspirin as the antiplatelet agent. Most of the other trials tested dipyridamole, ticlopidine, or hydroxychloroquine. Overall, antiplatelet therapy reduced the rate of venous thromboembolism. DVT was detected in 25% of patients treated with an antiplatelet agent, compared with 34% of controls. The Antithrombotic Trialists’ Collaboration reviewed data from 64 535 patients in 32 trials. Antiplatelet therapy (agents not specified) significantly reduced the risk of clinically overt fatal or nonfatal PE from 0.61% in controls to 0.46% in the treatment arm.¹⁷

In the Pulmonary Embolism Prevention Trial of 13 356 patients with hip fractures, antiplatelet therapy was tested by randomizing patients to low-dose aspirin (160 mg daily for 5 weeks) or placebo.¹⁸ Low-dose aspirin reduced the rate of fatal PE by 58%, all PE by 43%, and symptomatic DVT by 29%.

Novel antiplatelet agents may provide additional safe and effective treatment strategies for acute PE. Clopidogrel, a thienopyridine derivative, inhibits platelet aggregation by irreversibly blocking the platelet ADP receptor. Clinical effectiveness of this antiplatelet agent has been tested in 2 large clinical trials. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial randomized 19 185 patients with known atherosclerotic disease to either daily aspirin or clopidogrel. After a mean follow-up of 2 years, patients treated with clopidogrel had an annual risk of ischemic stroke, myocardial infarction, or vascular death of 5.3% compared with 5.8% in the aspirin arm.¹⁹

More recently, the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial investigated the benefits of long-term adjunctive therapy with clopidogrel in addition to aspirin in 12 562 patients with non-ST-elevation acute coronary syndromes.²⁰ After 9 months of treatment, patients randomized to the clopidogrel plus aspirin arm had a 20% reduction in risk of myocardial infarction, stroke, or cardiovascular death compared with patients treated with aspirin alone. There was an absolute increase in major bleeding of 0.9% and a near doubling in minor bleeding from 8.6% with aspirin alone to 15.3% in the combined treatment arm. However, there was no significant increase in life-threatening bleeding, suggesting relative safety of the combined clopidogrel-aspirin antiplatelet regimen.

The integrin glycoprotein IIb/IIIa receptor on the platelet surface binds circulating fibrinogen or von Willebrand factor and cross-links platelets. Glycoprotein IIb/IIIa receptor antagonists inhibit this final common pathway of platelet aggregation. Their role in management of acute coronary syndromes is well established.²¹ They are routinely used with intravenous unfractionated heparin and aspirin therapy.²² Their safety and efficacy with concomitant thrombolytic therapy, enoxaparin, and unfractionated heparin has been assessed in several large trials.^23–25 To date, the IIb/IIIa glycoprotein platelet antagonists have not been tested as therapy in acute venous thromboembolism. With respect to combined antiplatelet therapy and warfarin, recent trials indicate that increased bleeding may occur.^26,27

Acute PE can lead to catastrophic cardiovascular collapse because of adverse mechanical and humoral effects on the pulmonary vasculature. Current therapies focus on using anticoagulants to prevent thrombus propagation and, occasionally, to dissolve or remove clot with thrombolysis or embolectomy, respectively. However, persistent high mortality and recurrence rates demonstrate that current management has not yet minimized adverse clinical outcomes. Antiplatelet agents, so far untested in acute PE, provide additional antithrombotic protection. Moreover, they can significantly attenuate pulmonary vasoconstriction, bronchospasm, and hypoxia associated with PE. Their safety and efficacy in managing arterial thrombotic illnesses indicate their promising role in acute PE. We advocate setting up a large clinical trial to determine whether antiplatelet therapy administered in addition to anticoagulation can reduce the mortality and morbidity of acute PE.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

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