linical Presenta tation Ar erial Clinical Pr esentation of Ar t erial hromb ombosis vs hromb ombosis T hrombosis vs.

V enous T hrombosis
By Rebecca Jensen, MT(ASCP)
INTRODUCTION Thrombosis can occur in the venous or arterial circulation and develops as a result of a complex interaction among circulating coagulation proteins, platelets, and the blood vessel wall. Arterial thrombosis, in fact, is the most common cause of death in North America as it is the etiology of most acute myocardial infarctions (MI) and cerebral vascular accidents. These entities represent the two most common forms of cardiovascular disease. Venous thromboembolic disease is the third most common form of cardiovascular disease in North America and typically presents as deep venous thrombosis and pulmonary embolus. The prevalence of thromboembolic events is increasing, due in part to the longer average life span of the population. The clinical presentation of patients with arterial or venous thrombosis varies significantly and the etiology of thrombus formation in the two circulations is distinctly different with few exceptions. This article will present the most common clinical manifestations of arterial and venous thrombosis and discuss the possible factors than contribute to thromboembolism. STATISTICS According to current estimates from the American Heart Association 7,500,000 Americans have suffered myocardial infarction, and 4,600,000 have suffered stroke. Recent studies have shown that cardiovascular diseases as a group are responsible for 40% of all deaths in the United States and claim almost as many lives each year as the next seven leading causes of death combined. It is estimated that 1,100,000 Americans will suffer an MI annually. Approximately 650,000 of these will represent first MIs and 450,000 will be recurrent attacks. Greater than 45% of individuals who suffer from MI in a given year will die from it. The average age for first MI is 65.8 years for men and 70.4 for women. Annually, greater than 250,000 persons in the United States are diagnosed with venous thromboembolism. Deep venous thrombosis and pulmonary embolism account for 300,000 to 600,000 hospitalizations and approximately 100,000 deaths annually in the United States. Approximately 15% to 30% of the patients who experience a pulmonary

Numb umber V olume 16 Number 8 August 2002

Clinical Presentation of Arterial Thrombosis vs. Venous Thrombosis ................................. 1 Current Literature Review .... 7 Suggested Reading .................. 7 Current Literature Abstracts.. 8 New Product Information ...... 10 Self-Assessment ....................... 12

Objective: The reader will be able to discuss the clinical presentations of arterial and venous thrombosis and the factors that contribute to thrombotic risk in these two circulations.

CLINICAL HEMOSTASIS REVIEW 7700 E. Wrightstown Rd., Ste. 106 Tucson, Arizona 85715 chr@coagulation.com 520.722.0797

EDITOR IN CHIEF Rebecca Jensen, MT(ASCP) CLINICAL ADVISORS Dorothy M. Adcock, MD Alexander Duncan, MD, ChB H. James Day, MD, FACP Don W. Hill, MD, FACP CONTRIBUTOR Lynne Stevens, MT(ASCP) ASSISTANT TO THE EDITOR Kendra Sagar

Clinical Hemostasis Review, is published by Esoterix Coagulation, Inc. and is circulated to selected physicians and laboratorians. Copyright 2002. Esoterix Coagulation is part of the ESOTERIX, Inc family of laboratories providing esoteric testing in numerous disease corridors. The opinions expressed in the articles are those of the author(s) and do not necessarily reflect the opinions or recommendations of the advertisers, editors, or publisher. The Publisher reserves copyright and renewal on all published material and such material may not be reproduced in whole or in part without written permission from the publisher. Consult the full prescribing information on any drugs or devices discussed. All correspondence should be directed to the attention of the Editor, Clinical Hemostasis Review, 7700 E. Wrightstown Road, Ste. 106, Tucson, AZ 85715. Subscription Rate: $65.00/year, 14 issues, prepaid. Outside the USA additional postage is required: Canada and Mexico $20/year, all other destinations $50/year. Single copies $7.00. Subscriptions are to be paid in USA dollars only. Subscriptions not accompanied by payment will be assessed a billing charge. To assure prompt delivery of your issues, please notify us of any address corrections. Six weeks are required to effect a change. Missing copies not received by mail will be provided free of charge if we are notified no later than two months after the issue date. After this deadline, we will charge subscribers $5.00 per issue. ISSN 0894-1025

embolism die, many before therapeutic intervention can be administered. PATHOPHYSIOLOGY OF ARTERIAL THROMBOSIS The arterial circulation is a high flow, high-pressure environment. Arterial thrombosis generally develops as a result of underlying vascular abnormalities, typically atherosclerotic vascular disease and less frequently in individuals with vasculitis. Atherosclerosis is a disease affecting medium and large sized arteries and is rarely found in arteries smaller than 500 microns in diameter. The aorta as well as femoral, coronary, carotid, cerebral, and renal arteries are typically affected. The clots formed in arterial thrombosis are called white clots due to their composition of fibrin and platelets. Thrombotic stroke occurs when thrombosis occurs in the cerebral arteries. The majority of MIs occur as a result of rupture or fissure of atherosclerotic plaques with subsequent exposure of thrombogenic factors. Currently it is thought that atherosclerosis is a response to the endothelial cell injury and that a variety of factors may trigger the atherosclerotic process. Once injured, circulating platelets interact with the subendo-thelium and atherosclerotic plaque, subsequently activating the clotting process leading to clot formation. PRESENTATION OF ARTERIAL THROMBOSIS A number of clinical findings can precede MI including high blood pressure and angina. About 20% of MIs are preceded by long-standing angina. Although initial MI presentation may be sudden and intense, most individuals experience mild pain or discomfort that develops more slowly. Pain associated with MI typically lasts longer than 10 minutes and frequently occurs with other symptoms including: chest discomfort, upper body discomfort, shortness of breath, nausea, or lightheadedness. The chest discomfort or pain generally disseminates from the center of the chest and may dissipate and return. The pain may be crushing, squeezing, or feels like an uncomfortable pressure. The discomfort in other areas of the upper body can be found in the neck, back, jaw, stomach, or frequently in one or both arms. Sudden cardiac arrest, defined as
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an abrupt stopping of the heart, strikes acutely and is not heralded by any warning signs. Sudden loss of responsiveness including no pulse and no normal breathing are the presenting symptoms. In adult victims of sudden cardiac arrest, approximately 90% have atherosclerotic disease in two or more major arteries. If sudden cardiac arrest victims are not recessitated successfully, brain damage begins to occur within four to six minutes after the heart stops. The clinical manifestations of a stroke occur suddenly and include: numbness of the face, arm, leg (particularly on one side of the body), severe headache, blurred vision, aphasia, dizziness or loss of coordination, or confusion. Transient ischemic attacks (TIAs) precede strokes approximately 10% of the time. The symptoms are the same as a stroke but only are sustained for a few minutes. In individuals who have had one or more TIAs, approximately 36% later have a stroke. FACTORS CONTRIBUTING TO ARTERIAL THROMBOSIS While the identification and treatment of patients with venous thrombosis has improved substantially in recent years, the diagnosis and treatment of individuals with arterial thrombosis remains complex. Similar to venous thrombosis, a confluence of genetic, behavioral, and environmental risk factors is required to initiate the atherosclerotic process that underlies arterial thrombosis. Numerous clinical disorders other than abnormalities of hemostatic parameters have been linked to arterial thrombosis including: inflammation, fibrinolytic defects, in, heparin-induced thrombocytopenia, hyperhomocysteinemia, diabetes mellitus, hyperlipidemia, and hypertension. A number of clinical conditions and lifestyle choices represent an acquired risk for arterial thrombosis. The presence of antiphospholipid antibodies can lead to a hypercoagulable state and place a patient at risk for arterial thrombosis. Other clinical conditions can result in alterations of the endothelium such as hyperhomocysteinemia, radiation treatment, and chemotherapy. Other disorders can result in vasculitis which can predispose to arterial clot formation. Furthermore, lifestyle choices that

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can lead to increased risk of arterial thrombosis include cigarette smoking, lack of physical exercise, and obesity. LABORATORY DETECTION OF RISK FACTORS FOR ARTERIAL THROMBOSIS The selection of laboratory assays best suited to detect arterial thrombotic risk is not well defined in contrast to the well-established risk factors for venous thrombotic disease. Risk factors such as the deficiency states of antithrombin, protein C, and protein S, as well as the polymorphisms associated with factor V Leiden and prothrombin mutation have not proven to increase risk of arterial thrombosis in the general population although their role in venous thrombotic risk has been demonstrated in numerous studies. Some subgroups of patients however have shown an increased risk of arterial thrombosis when there is a confluence of risk factors such as cigarette smoking and the presence of factor V Leiden. Congenital factors that demonstrate increased risk of arterial thrombosis include hyperhomocysteinemia and lipoprotein(a). The indications for diagnostic studies in patients at risk for arterial thrombosis are limited but include: patients who are 45 years of age or less, those with multiple thrombotic episodes, those that have thrombosis in the absence of obvious atherosclerosis, and those patients with venous thrombosis. Young patients with stroke or transient ischemic attacks are frequently found to have antiphospholipid antibodies. The laboratory evaluation for patients presenting with arterial thrombosis should include tests for the evaluation of antiphospholipid antibodies. The comprehensive screen for antiphospholipid antibodies includes an activated partial thromboplastin time (APTT), APTT mixing studies, dilute Russell's viper venom time, hexagonal phospholipid neutralization, platelet neutralization procedure, anticardiolipin antibodies (including IgG, IgM, and IgA subclasses), beta-2 glycoprotein I antibody (including IgG, IgM, and IgA subclasses), antiphosphotidylserine antibody (IgG, IgM), and antiprothrombin antibody (IgG, IgM). The evaluation should also include tests for homocysteine. Homocysteine can be evaluated by measuring plasma

or urine homocysteine levels or by the detection of the genetic alterations responsible for elevated homocysteine levels. The most common polymorphisms responsible for alterations of the homocysteine metabolism are MTHFR C667T and A1998C. Evaluation may also include assays to detect levels of lipoprotein(a). PATHOPHYSIOLOGY OF VENOUS THROMBOSIS There are significant differences in the pathology of blood clots between the venous and arterial systems. The venous circulation is a low flow, lowpressure system. Clots that develop in the venous system, sometimes called red clots, are generally relatively large in size and are composed predominantly of fibrin enmeshed with cellular components including red blood cells. Stasis and changes in blood composition that induce hypercoagulability are significant contributors to clot formation in the venous system. Importantly, venous thrombosis can occur spontaneously in individuals with genetic abnormalities associated with hypercoagulability. PRESENTATION OF VENOUS THROMBOSIS The potential and sometimes fatal consequence of pulmonary embolism as a result of thrombus formation gives emphasis to the importance of rapid recognition of venous thrombosis. Both deep vein thrombosis and pulmonary embolism may be difficult to diagnose as the clinical findings are often nonspecific. Diagnosis of deep vein thrombosis as well as pulmonary embolism requires objection confirmation to reach definitive diagnosis. The strategies for diagnosis, treatment, and prevention of venous thrombosis have advanced significantly in the past 20 years. Venous thrombosis most commonly occurs in the lower extremities; however, in certain cases it affects veins of the upper extremities, liver, spleen, intestines, and kidneys. Superficial vein thrombosis is characterized by pain, erythema, tenderness, and heat at the site of the affected area. The extent of superficial vein thrombosis can be determined by palpation of the vein, and rarely will thrombi found in superficial veins embolize, with the exception of those that have propagated into deep veins.
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Deep vein thrombosis of the proximal (iliac, femoral, or popliteal) veins is suggested by erythema, heat, tenderness, and unilateral leg swelling. Other symptoms that may be observed include distention of the superficial veins and prominent superficial collateral veins. Approximately one-half of untreated individuals with proximal vein thrombosis will develop pulmonary embolism although this may not always be clinically evident. Calf vein thrombosis is manifested by calf pain and posterior calf tenderness. The risk of significant pulmonary embolism with calf vein thrombosis is low. It is estimated that 10% to 20% of calf vei thrombi propagate into proximal veins leading to increased risk of embolization. The vast majority of pulmonary emboli are thought to be from deep vein thrombosis of the lower extremities or pelvis and may be detected using sensitive techniques. Once thromboemboli are released into the venous circulation, they are distributed to both lungs in approximately 65% or cases. The lower lobes of the lungs are involved four times more frequently than the upper lobes. Most often, thromboemboli lodge in large or medium sized pulmonary arteries, and fewer than 35% reach the smaller pulmonary arteries. Acute pulmonary emboli begin to lyse immediately upon reaching the lungs. Smaller thrombi are lysed completely within several weeks in most patients. As the clot lysis occurs, pulmonary circulation improves and the physiologic alterations are lessened. Conversely, massive emboli can result in death within minutes or hours. Rarely, recurrent thromboemboli may reach the lungs causing progressive pulmonary arterial obstruction. Sharp chest pain and dyspnea are hallmark symptoms of pulmonary embolism although symptoms may vary in duration and intensity. Tachynea is a common symptom and restlessness and anxiety can accompany pulmonary emboli as well. Typcially cyanosis only occurs following massive pulmonary embolism. Symptoms vary due to the extent of the pulmonary vascular occlusion or pre-embolic cardiopulmonary function. Small thromboemboli, however, may be symptomatic.

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Pulmonary hypertension may be observed as a result of increase pulmonary vascular resistance. Some degree of pulmonary hypertension is reported in most pulmonary emboli, but if greater than 30% to 50% of the pulmonary arterial tree is obstructed, significant pulmonary hypertension is frequently seen. When severe, pulmonary hypertension causes dull substernal chest discomfort. Pulmonary infarction occurs in less than 10% of cases of pulmonary emboli and is most commonly observed in patients with a previously abnormal pulmonary circulation. Non-invasive tests including ultrasonography and quantitative D-dimer assays have been used to evaluate patients for deep vein thrombosis. The Ddimer assay has a high negative predictive value if results are below an appropriately established cut off level. The ventilation/perfusion scan is the primary test utilized for diagnosis of pulmonary embolism. Pulmonary angiography can be used to confirm or exclude the presence of pulmonary embolism. FACTORS CONTRIBUTING TO VENOUS THROMBOSIS A number of clinical conditions may exist which predispose an individual to venous thrombosis including: malignancy, pregnancy, post-surgical state (especially knee replacement or hip surgery), infection, advancing age, trauma, estrogen use, and myeloproliferative disease. For many patients no inherited or clinical condition know to increased risk of thrombosis can be found. The primary hereditary factors responsible for venous thrombosis include mutations of the prothrombin gene, activated protein C resistance, qualitative and quantitative deficiencies of protein C, antithrombin, and protein S. Hyperhomocysteinemia and antiphospholipid antibodies are acquired risk factors for venous thrombosis. Activated protein C resistance is caused by a mutation in the factor V gene in approximately 90% of cases and named factor V Leiden. The factor V Leiden mutation is present in 3% to 6% of the Caucasian population and is discovered in 20% to 60% of individuals with recurrent thrombosis. To date, it is the most common cause of inherited thrombophilia. The prothrombin muta-

tion is the second most common genetic cause of venous thrombosis and the mutation is present in almost 3% of the Caucasian population. Approximately 18% of patients with thrombosis are discovered to have the prothrombin gene mutation. Abnormalities of protein C and protein S are discovered in 8% to 10% of patients with thrombosis. The incidence of antiphospholipid antibodies in patients with venous thrombosis is reported as 2% to 3%. Antithrombin deficiency is relatively rare, occurring in approximately 1% of patients with venous thrombosis. LABORATORY DIAGNOSIS OF VENOUS THROMBOSIS The laboratory evaluation of venous thrombotic disease should be preceded by a thorough patient history to determine whether the patient has concomitant clinical conditions that may predispose for thrombosis. Presently, a number of studies suggest that the patient evaluation includes a complete blood count with peripheral blood smear, Factor V Leiden, antithrombin, protein S, protein C, tests for antiphospholipid antibodies, lipoprotein (a), homocysteine, and prothrombin mutation 20210. Additional tests that may be beneficial include factor VIII, IX, and XI levels and platelet activation studies. CONCLUSION The high incidence of venous and arterial thrombotic events underscores the importance of rapid and accurate detection of causes of thrombosis. The laboratory can play a significant role in identifying genetic risk factors for thromboembolic disease. Individuals with genetic mutations predisposing for thrombosis and lifestyle choices that increase their risk should be educated about the signs and symptoms for venous or arterial thrombosis. KEYWORDS: venous thrombosis, deep vein thrombosis, pulmonary emboli, stroke, myocardial infarction, transient ischemic attack, sudden cardiac death.

REFERENCES
American Heart Associaton. 2002 Heart and stroke statistical update. www.aha.com. Accessed November 27, 2002. Bates SM, Ginsberg JS. Diagnosis of deep vein thrombosis during pregnancy. In: Ginsberg J, Kearon C, Hirsh J (Eds). Critical Decisions in Thrombosis and Hemostasis. London: BC Decker Inc. 1998:32-38. Bergqvist D, Lindgren B, Matzsch T. Costeffectiveness of preventing postoperative deep vein thrombosis. In: Hull R, Pineo GF (Eds). Disorders of Thrombosis. Philadelphia, PA: WB Saunders Co; 1996:228-33. Berqvist D. New approaches to prevention of deep vein thrombosis. Thromb Haemost. 1997;78:684. Bick R, Jakway J, Baker W. Deep vein thrombosis: Prevalence of etiologic factors and results of management in 100 consecutive patients. Semin Thromb Hemost. 1992;18(2):267. Carter CJ. Pathogenesis of arterial thrombosis. In: Hull R, Pineo GF (Eds). Disorders of Thrombosis. Philadelphia, PA: W.B. Saunders Company; 1996:18-30. Comerota A. Myths, mystique, and misconceptions of venous disease. J Vasc Surg. 2001;34:765. Creager MA, Beckman JA. Assessment of arterial and venous thrombosis. In: Loscalzo J, Schafer AI, (Eds). Thrombosis and Hemorrhage, 2nd Edition. Baltimore: Williams and Wilkins; 1998:491-516. Cushman M, Ridker PM. Novel risk factors for arterial thrombosis. In: Kitchens CS, Alving BM, Kessler CM, (Eds). Consultative Hemostasis and Thrombosis. Philadelphia, PA: WB Saunders Company; 2002:31124. Davies MJ. Pathology of arterial thrombosis. British Medical Bulletin. 1994;50:789. deBoer K, Buller H, ten Cate J, Levi M. Deep vein thrombosis in obstetric patients: Diagnosis and risk factors. Thromb Haemost. 1992;67(1):4. Fritsma G. Laboratory results that predict arterial thrombosis. Clin Lab Sci. 2001;14:262. Goldhaber SZ. Pulmonary embolism and deep venous thrombosis: Epidemiology, diagnosis, therapy, and prevention. Hemostasis and Thrombosis Update. Temple University:1996.

CLINICAL HEMOSTASIS REVIEW

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Haire WD. Deep venous thrombosis and pulmonary embolus. In: Kitchens CS, Alving BM, Kessler CM, eds. Consultative Hemostasis and Thrombosis. Philadelphia, PA: WB Saunders Company; 2002:197-224. Hansson P, Welin L, Tibblin G, et al. Deep vein thrombosis and pulmonary embolism in the general population. Arch Intern Med. 1997;157:1665. Hashemi HA, Katz ML, Comerota AJ. Diagnosis of acute deep vein thrombosis. Hem/ Onc Annals. 1993;1:107. Heit J, Silverstein M, Mohr D, et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost. 2001;86:452. Hirsh J, Hoak J. Management of deep vein thrombosis and pulmonary embolism. Circulation. 1996;93:2212. Hull RD, Feldstein W, Pineo GF. Cost effectiveness of diagnosis of deep vein thrombosis in symptomatic patients. Thromb Haemost. 1995;74:189. Jackson E, Skerrett PJ, Ridker PM. Epidemiology of arterial thrombosis. In: Colman RW, ed. Hemostasis and Thrombosis Basic Principles and Clinical Practice, 4th edition. Philadelphia, PA: Lippincott Williams and Wilkins; 2001:1179-96. Jensen R. Determining the etiology of a thrombotic episode. Clinical Hemostasis Review. 1999;13(10):1. Jensen R. Risk factors associated with arterial thrombosis. Clinical Hemostasis Review. 1999;13(2):1. Kahn SR, et al. Clinical prediction of deep vein thrombosis in patients with leg symptoms. Thromb Haemost. 1999;81:353. Kearon C. Diagnosis of recurrent deep vein thrombosis. In: Ginsberg J, Kearon C, Hirsh J (Eds). Critical Decisions in Thrombosis and Hemostasis. London: BC Decker Inc. 1998:27-31. Meade TW, Miller GJ, Rosenberg RD. Characteristics associated with the risk of arterial thrombosis. Verstrate M, Fuster V, Topol EJ (Eds). Cardiovascular Thrombosis: Thrombocardiology and Thromboneurology, Second Edition. Philadelphia, PA: Lippincott-Raven Publishers. 1998: 77-89. Meade TW, Miller GJ, Rosenberg RD. Characteristics associated with the risk of arterial thrombosis and the prethrombotic state. In:

Fuster V, Verstraete M, (eds). Thrombosis in Cardiovascular Disorders. Philadelphia, PA: W.B. Saunders; 1992:79-98. Merck Online Manual. http:// www.merck.com/pubs/mmanual/. Accessed November 27, 2002. Perrier A, Bounameaux H. Cost-effective diagnosis of deep vein thrombosis and pulmonary embolism. Thromb Haemost. 2001;86:475-87. Quinn C, Hill J, Hassouna H. A guide for diagnosis of patients with arterial and venous thrombosis. Clin Lab Sci. 2000;13:229. Reiner AP, Siscovick DS, Rosendaal FR. Hemostatic risk factors and arterial thrombotic disease. Thromb Haemost. 2001;85:584-95. Stein PD. Clinical features of deep venous thrombosis and pulmonary embolism. In: Hull R, Pineo GF (Eds). Disorders of Thrombosis. Philadelphia, PA: WB Saunders Co; 1996:234-8. Thromas DP, Roberts HR. Hypercoagulability in venous and arterial thrombosis. Ann Intern Med. 1997;126:638. Turpie AGG. Secondary prevention of deep vein thrombosis and pulmonary embolism. In: Verstraete M, Fuster V, Topol EJ, (Eds). Cardiovascular Thrombosis, 2nd edition. New York, NY: Lippincott-Raven; 1998:68390. Wheeler HB, Hirsh J, Wells P, Anderson FA. Diagnostic tests for deep vein thrombosis: Clinical usefulness depends on probability of disease. Arch Intern Med. 1994;154:1921. Wheeler HB. Diagnosis of deep vein thrombosis. Am J Med. 1994;18. Wheeler HB. Diagnosis of deep vein thrombosis: Using the right test for the right purpose. Arch Intern Med. 1991;151:2145.

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