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VVVVVolume 16 Nolume 16 Nolume 16 Nolume 16 Nolume 16 Numbumbumbumbumber 8er 8er 8er 8er 8August 2002August 2002August 2002August 2002August 2002

Clinical Presentation of ArterialThrombosis vs. VenousThrombosis ................................. 1

Current Literature Review .... 7

Suggested Reading .................. 7

Current Literature Abstracts.. 8

New Product Information ...... 10

Self-Assessment ....................... 12

By Rebecca Jensen, MT(ASCP)

Objective: The reader will be able to discuss the clinical presentations ofarterial and venous thrombosis and the factors that contribute to thromboticrisk in these two circulations.

INTRODUCTIONINTRODUCTIONINTRODUCTIONINTRODUCTIONINTRODUCTIONThrombosis can occur in the venous or

arterial circulation and develops as a resultof a complex interaction among circulat-ing coagulation proteins, platelets, and theblood vessel wall. Arterial thrombosis, infact, is the most common cause of death inNorth America as it is the etiology of mostacute myocardial infarctions (MI) and cere-bral vascular accidents. These entitiesrepresent the two most common forms ofcardiovascular disease. Venous throm-boembolic disease is the third most com-mon form of cardiovascular disease in NorthAmerica and typically presents as deepvenous thrombosis and pulmonary embo-lus. The prevalence of thromboembolicevents is increasing, due in part to thelonger average life span of the population.

The clinical presentation of patientswith arterial or venous thrombosis variessignificantly and the etiology of thrombusformation in the two circulations is dis-tinctly different with few exceptions. Thisarticle will present the most common clini-cal manifestations of arterial and venousthrombosis and discuss the possible fac-tors than contribute to thromboembolism.

STATISTICSSTATISTICSSTATISTICSSTATISTICSSTATISTICSAccording to current estimates from

the American Heart Association 7,500,000Americans have suffered myocardial inf-arction, and 4,600,000 have sufferedstroke. Recent studies have shown thatcardiovascular diseases as a group areresponsible for 40% of all deaths in theUnited States and claim almost as manylives each year as the next seven leadingcauses of death combined.

It is estimated that 1,100,000 Ameri-cans will suffer an MI annually. Approxi-mately 650,000 of these will representfirst MI’s and 450,000 will be recurrentattacks. Greater than 45% of individualswho suffer from MI in a given year will diefrom it. The average age for first MI is 65.8years for men and 70.4 for women.

Annually, greater than 250,000 per-sons in the United States are diagnosedwith venous thromboembolism. Deepvenous thrombosis and pulmonary em-bolism account for 300,000 to 600,000hospitalizations and approximately100,000 deaths annually in the UnitedStates. Approximately 15% to 30% of thepatients who experience a pulmonary

CLINICAL HEMOSTASIS REVIEWCLINICAL HEMOSTASIS REVIEWCLINICAL HEMOSTASIS REVIEWCLINICAL HEMOSTASIS REVIEWCLINICAL HEMOSTASIS REVIEW7700 E. Wrightstown Rd., Ste. 106Tucson, Arizona 85715chr@coagulation.com520.722.0797

EDITOR IN CHIEFEDITOR IN CHIEFEDITOR IN CHIEFEDITOR IN CHIEFEDITOR IN CHIEFRebecca Jensen, MT(ASCP)

CCCCCLINICAL ADVISORSLINICAL ADVISORSLINICAL ADVISORSLINICAL ADVISORSLINICAL ADVISORSDorothy M. Adcock, MDAlexander Duncan, MD, ChBH. James Day, MD, FACPDon W. Hill, MD, FACP

CONTRIBUTORCONTRIBUTORCONTRIBUTORCONTRIBUTORCONTRIBUTORLynne Stevens, MT(ASCP)

ASSISTANT TO THE EDITORASSISTANT TO THE EDITORASSISTANT TO THE EDITORASSISTANT TO THE EDITORASSISTANT TO THE EDITORKendra Sagar

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embolism die, many before therapeu-tic intervention can be administered.PATHOPHYSIOLOGY OF ARTERIALPATHOPHYSIOLOGY OF ARTERIALPATHOPHYSIOLOGY OF ARTERIALPATHOPHYSIOLOGY OF ARTERIALPATHOPHYSIOLOGY OF ARTERIALTHROMBOSISTHROMBOSISTHROMBOSISTHROMBOSISTHROMBOSIS

The arterial circulation is a highflow, high-pressure environment. Ar-terial thrombosis generally develops asa result of underlying vascular abnor-malities, typically atherosclerotic vas-cular disease and less frequently in in-dividuals with vasculitis. Atherosclero-sis is a disease affecting medium andlarge sized arteries and is rarely found inarteries smaller than 500 microns indiameter. The aorta as well as femoral,coronary, carotid, cerebral, and renalarteries are typically affected. The clotsformed in arterial thrombosis are called“white clots” due to their compositionof fibrin and platelets.

Thrombotic stroke occurs whenthrombosis occurs in the cerebralarteries.

The majority of MIs occur as a resultof rupture or fissure of atheroscleroticplaques with subsequent exposure ofthrombogenic factors. Currently it isthought that atherosclerosis is a re-sponse to the endothelial cell injury andthat a variety of factors may trigger theatherosclerotic process. Once injured,circulating platelets interact with thesubendo-thelium and atheroscleroticplaque, subsequently activating the clot-ting process leading to clot formation.PRESENTATION OF ARTERIALPRESENTATION OF ARTERIALPRESENTATION OF ARTERIALPRESENTATION OF ARTERIALPRESENTATION OF ARTERIALTHROMBOSISTHROMBOSISTHROMBOSISTHROMBOSISTHROMBOSIS

A number of clinical findings canprecede MI including high blood pres-sure and angina. About 20% of MI’s arepreceded by long-standing angina.Although initial MI presentation maybe sudden and intense, most individu-als experience mild pain or discomfortthat develops more slowly. Pain associ-ated with MI typically lasts longer than10 minutes and frequently occurs withother symptoms including: chest dis-comfort, upper body discomfort, short-ness of breath, nausea, or lighthead-edness. The chest discomfort or paingenerally disseminates from the centerof the chest and may dissipate andreturn. The pain may be crushing,squeezing, or feels like an uncomfort-able pressure. The discomfort in otherareas of the upper body can be found inthe neck, back, jaw, stomach, or fre-quently in one or both arms.

Sudden cardiac arrest, defined as

an abrupt stopping of the heart, strikesacutely and is not heralded by any warn-ing signs. Sudden loss of responsive-ness including no pulse and no normalbreathing are the presenting symp-toms. In adult victims of sudden cardiacarrest, approximately 90% have ath-erosclerotic disease in two or moremajor arteries. If sudden cardiac arrestvictims are not recessitated success-fully, brain damage begins to occurwithin four to six minutes after theheart stops.

The clinical manifestations of astroke occur suddenly and include:numbness of the face, arm, leg (par-ticularly on one side of the body), se-vere headache, blurred vision, aphasia,dizziness or loss of coordination, orconfusion. Transient ischemic attacks(TIAs) precede strokes approximately10% of the time. The symptoms are thesame as a stroke but only are sustainedfor a few minutes. In individuals whohave had one or more TIAs, approxi-mately 36% later have a stroke.FACTORS CONTRIBUTING TOFACTORS CONTRIBUTING TOFACTORS CONTRIBUTING TOFACTORS CONTRIBUTING TOFACTORS CONTRIBUTING TOARTERIAL THROMBOSISARTERIAL THROMBOSISARTERIAL THROMBOSISARTERIAL THROMBOSISARTERIAL THROMBOSIS

While the identification and treat-ment of patients with venous thrombo-sis has improved substantially in recentyears, the diagnosis and treatment ofindividuals with arterial thrombosis re-mains complex. Similar to venousthrombosis, a confluence of genetic,behavioral, and environmental risk fac-tors is required to initiate the athero-sclerotic process that underlies arterialthrombosis. Numerous clinical disor-ders other than abnormalities of hemo-static parameters have been linked toarterial thrombosis including: inflam-mation, fibrinolytic defects, in, hep-arin-induced thrombocytopenia,hyperhomocysteinemia, diabetes mel-litus, hyperlipidemia, and hypertension.

A number of clinical conditionsand lifestyle choices represent an ac-quired risk for arterial thrombosis. Thepresence of antiphospholipid antibod-ies can lead to a hypercoagulable stateand place a patient at risk for arterialthrombosis. Other clinical conditionscan result in alterations of the endothe-lium such as hyperhomocysteinemia,radiation treatment, and chemo-therapy. Other disorders can result invasculitis which can predispose to arte-rial clot formation.

Furthermore, lifestyle choices that

4 4 4 4 4 CLINICAL HEMOSTASIS REVIEW AUGUST 2002

can lead to increased risk of arterialthrombosis include cigarette smoking,lack of physical exercise, and obesity.LABORATORY DETECTION OF RISKLABORATORY DETECTION OF RISKLABORATORY DETECTION OF RISKLABORATORY DETECTION OF RISKLABORATORY DETECTION OF RISKFACTORS FOR ARTERIALFACTORS FOR ARTERIALFACTORS FOR ARTERIALFACTORS FOR ARTERIALFACTORS FOR ARTERIALTHROMBOSISTHROMBOSISTHROMBOSISTHROMBOSISTHROMBOSIS

The selection of laboratory assaysbest suited to detect arterial thromboticrisk is not well defined in contrast to thewell-established risk factors for venousthrombotic disease. Risk factors such asthe deficiency states of antithrombin,protein C, and protein S, as well as thepolymorphisms associated with factor VLeiden and prothrombin mutation havenot proven to increase risk of arterialthrombosis in the general populationalthough their role in venous throm-botic risk has been demonstrated innumerous studies. Some subgroups ofpatients however have shown an in-creased risk of arterial thrombosis whenthere is a confluence of risk factors suchas cigarette smoking and the presenceof factor V Leiden.

Congenital factors that demonstrateincreased risk of arterial thrombosis in-clude hyperhomocysteinemia andlipoprotein(a).

The indications for diagnostic stud-ies in patients at risk for arterial thrombo-sis are limited but include: patients whoare 45 years of age or less, those withmultiple thrombotic episodes, those thathave thrombosis in the absence of obvi-ous atherosclerosis, and those patientswith venous thrombosis. Young patientswith stroke or transient ischemic attacksare frequently found to have antiphos-pholipid antibodies.

The laboratory evaluation for pa-tients presenting with arterial thrombo-sis should include tests for the evalua-tion of antiphospholipid antibodies. Thecomprehensive screen for antiphos-pholipid antibodies includes an activatedpartial thromboplastin time (APTT), APTTmixing studies, dilute Russell's vipervenom time, hexagonal phospholipidneutralization, platelet neutralizationprocedure, anticardiolipin antibodies(including IgG, IgM, and IgA subclasses),beta-2 glycoprotein I antibody (includ-ing IgG, IgM, and IgA subclasses),antiphosphotidylserine antibody (IgG,IgM), and antiprothrombin antibody (IgG,IgM).

The evaluation should also includetests for homocysteine. Homocysteinecan be evaluated by measuring plasma

or urine homocysteine levels or by thedetection of the genetic alterations re-sponsible for elevated homocysteinelevels. The most common polymor-phisms responsible for alterations ofthe homocysteine metabolism areMTHFR C667T and A1998C. Evaluationmay also include assays to detect levelsof lipoprotein(a).PATHOPHYSIOLOGY OF VENOUSPATHOPHYSIOLOGY OF VENOUSPATHOPHYSIOLOGY OF VENOUSPATHOPHYSIOLOGY OF VENOUSPATHOPHYSIOLOGY OF VENOUSTHROMBOSISTHROMBOSISTHROMBOSISTHROMBOSISTHROMBOSIS

There are significant differences inthe pathology of blood clots betweenthe venous and arterial systems. Thevenous circulation is a low flow, low-pressure system. Clots that develop inthe venous system, sometimes calledred clots, are generally relatively largein size and are composed predomi-nantly of fibrin enmeshed with cellularcomponents including red blood cells.Stasis and changes in blood composi-tion that induce hypercoagulability aresignificant contributors to clot forma-tion in the venous system. Importantly,venous thrombosis can occur sponta-neously in individuals with genetic ab-normalities associated with hyperco-agulability.PRESENTATION OF VENOUSPRESENTATION OF VENOUSPRESENTATION OF VENOUSPRESENTATION OF VENOUSPRESENTATION OF VENOUSTHROMBOSISTHROMBOSISTHROMBOSISTHROMBOSISTHROMBOSIS

The potential and sometimes fatalconsequence of pulmonary embolismas a result of thrombus formation givesemphasis to the importance of rapidrecognition of venous thrombosis. Bothdeep vein thrombosis and pulmonaryembolism may be difficult to diagnoseas the clinical findings are often non-specific. Diagnosis of deep vein throm-bosis as well as pulmonary embolismrequires objection confirmation to reachdefinitive diagnosis. The strategies fordiagnosis, treatment, and prevention ofvenous thrombosis have advanced sig-nificantly in the past 20 years.

Venous thrombosis most com-monly occurs in the lower extremities;however, in certain cases it affects veinsof the upper extremities, liver, spleen,intestines, and kidneys. Superficial veinthrombosis is characterized by pain,erythema, tenderness, and heat at thesite of the affected area. The extent ofsuperficial vein thrombosis can be de-termined by palpation of the vein, andrarely will thrombi found in superficialveins embolize, with the exception ofthose that have propagated into deepveins.

Deep vein thrombosis of the proxi-mal (iliac, femoral, or popliteal) veins issuggested by erythema, heat, tender-ness, and unilateral leg swelling. Othersymptoms that may be observed in-clude distention of the superficial veinsand prominent superficial collateralveins. Approximately one-half of un-treated individuals with proximal veinthrombosis will develop pulmonary em-bolism although this may not always beclinically evident.

Calf vein thrombosis is manifestedby calf pain and posterior calf tender-ness. The risk of significant pulmonaryembolism with calf vein thrombosis islow. It is estimated that 10% to 20% ofcalf vei thrombi propagate into proxi-mal veins leading to increased risk ofembolization.

The vast majority of pulmonaryemboli are thought to be from deepvein thrombosis of the lower extremi-ties or pelvis and may be detected usingsensitive techniques. Once thrombo-emboli are released into the venouscirculation, they are distributed to bothlungs in approximately 65% or cases.The lower lobes of the lungs are in-volved four times more frequently thanthe upper lobes. Most often,thromboemboli lodge in large or me-dium sized pulmonary arteries, andfewer than 35% reach the smaller pul-monary arteries.

Acute pulmonary emboli begin tolyse immediately upon reaching thelungs. Smaller thrombi are lysed com-pletely within several weeks in mostpatients. As the clot lysis occurs, pulmo-nary circulation improves and the physi-ologic alterations are lessened. Con-versely, massive emboli can result indeath within minutes or hours. Rarely,recurrent thromboemboli may reachthe lungs causing progressive pulmo-nary arterial obstruction.

Sharp chest pain and dyspnea arehallmark symptoms of pulmonary em-bolism although symptoms may vary induration and intensity. Tachynea is acommon symptom and restlessness andanxiety can accompany pulmonaryemboli as well. Typcially cyanosis onlyoccurs following massive pulmonaryembolism. Symptoms vary due to theextent of the pulmonary vascular occlu-sion or pre-embolic cardiopulmonaryfunction. Small thromboemboli, how-ever, may be symptomatic.

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REFERENCESREFERENCESREFERENCESREFERENCESREFERENCESAmerican Heart Associaton. 2002 Heartand stroke statistical update. www.aha.com.Accessed November 27, 2002.

Bates SM, Ginsberg JS. Diagnosis of deepvein thrombosis during pregnancy. In:Ginsberg J, Kearon C, Hirsh J (Eds). CriticalDecisions in Thrombosis and Hemosta-sis. London: BC Decker Inc. 1998:32-38.

Bergqvist D, Lindgren B, Matzsch T. Cost-effectiveness of preventing postoperative deepvein thrombosis. In: Hull R, Pineo GF (Eds).Disorders of Thrombosis. Philadelphia,PA: WB Saunders Co; 1996:228-33.

Berqvist D. New approaches to prevention ofdeep vein thrombosis. Thromb Haemost.1997;78:684.

Bick R, Jakway J, Baker W. Deep vein throm-bosis: Prevalence of etiologic factors and re-sults of management in 100 consecutive pa-tients. Semin Thromb Hemost.1992;18(2):267.

Carter CJ. Pathogenesis of arterial thrombo-sis. In: Hull R, Pineo GF (Eds). Disorders ofThrombosis. Philadelphia, PA: W.B.Saunders Company; 1996:18-30.

Comerota A. Myths, mystique, and miscon-ceptions of venous disease. J Vasc Surg.2001;34:765.

Creager MA, Beckman JA. Assessment ofarterial and venous thrombosis. In: LoscalzoJ, Schafer AI, (Eds). Thrombosis and Hem-orrhage, 2nd Edition. Baltimore: Williamsand Wilkins; 1998:491-516.

Cushman M, Ridker PM. Novel risk factorsfor arterial thrombosis. In: Kitchens CS,Alving BM, Kessler CM, (Eds). ConsultativeHemostasis and Thrombosis. Philadel-phia, PA: WB Saunders Company; 2002:311-24.

Davies MJ. Pathology of arterial thrombosis.British Medical Bulletin. 1994;50:789.

deBoer K, Buller H, ten Cate J, Levi M. Deepvein thrombosis in obstetric patients: Diag-nosis and risk factors. Thromb Haemost.1992;67(1):4.

Fritsma G. Laboratory results that predictarterial thrombosis. Clin Lab Sci.2001;14:262.

Goldhaber SZ. Pulmonary embolism anddeep venous thrombosis: Epidemiology, di-agnosis, therapy, and prevention. Hemosta-sis and Thrombosis Update. TempleUniversity:1996.

Pulmonary hypertension may beobserved as a result of increase pulmo-nary vascular resistance. Some degreeof pulmonary hypertension is reportedin most pulmonary emboli, but if greaterthan 30% to 50% of the pulmonaryarterial tree is obstructed, significantpulmonary hypertension is frequentlyseen. When severe, pulmonary hyper-tension causes dull substernal chestdiscomfort.

Pulmonary infarction occurs in lessthan 10% of cases of pulmonary emboliand is most commonly observed in pa-tients with a previously abnormal pul-monary circulation.

Non-invasive tests including ultra-sonography and quantitative D-dimerassays have been used to evaluate pa-tients for deep vein thrombosis. The D-dimer assay has a high negative predic-tive value if results are below an appro-priately established cut off level. Theventilation/perfusion scan is the primarytest utilized for diagnosis of pulmonaryembolism. Pulmonary angiography canbe used to confirm or exclude the pres-ence of pulmonary embolism.FACTORS CONTRIBUTING TOFACTORS CONTRIBUTING TOFACTORS CONTRIBUTING TOFACTORS CONTRIBUTING TOFACTORS CONTRIBUTING TOVENOUS THROMBOSISVENOUS THROMBOSISVENOUS THROMBOSISVENOUS THROMBOSISVENOUS THROMBOSIS

A number of clinical conditions mayexist which predispose an individual tovenous thrombosis including: malig-nancy, pregnancy, post-surgical state(especially knee replacement or hipsurgery), infection, advancing age,trauma, estrogen use, and myeloprolif-erative disease. For many patients noinherited or clinical condition know toincreased risk of thrombosis can befound.

The primary hereditary factors re-sponsible for venous thrombosis includemutations of the prothrombin gene,activated protein C resistance, qualita-tive and quantitative deficiencies ofprotein C, antithrombin, and protein S.Hyperhomocysteinemia andantiphospholipid antibodies are ac-quired risk factors for venous thrombo-sis. Activated protein C resistance iscaused by a mutation in the factor Vgene in approximately 90% of casesand named factor V Leiden. The factorV Leiden mutation is present in 3% to6% of the Caucasian population and isdiscovered in 20% to 60% of individualswith recurrent thrombosis. To date, it isthe most common cause of inheritedthrombophilia. The prothrombin muta-

tion is the second most common ge-netic cause of venous thrombosis andthe mutation is present in almost 3% ofthe Caucasian population. Approxi-mately 18% of patients with thrombosisare discovered to have the prothrombingene mutation. Abnormalities of pro-tein C and protein S are discovered in8% to 10% of patients with thrombosis.The incidence of antiphospholipid anti-bodies in patients with venous throm-bosis is reported as 2% to 3%. Anti-thrombin deficiency is relatively rare,occurring in approximately 1% of pa-tients with venous thrombosis.LABORATORY DIAGNOSIS OFLABORATORY DIAGNOSIS OFLABORATORY DIAGNOSIS OFLABORATORY DIAGNOSIS OFLABORATORY DIAGNOSIS OFVENOUS THROMBOSISVENOUS THROMBOSISVENOUS THROMBOSISVENOUS THROMBOSISVENOUS THROMBOSIS

The laboratory evaluation of venousthrombotic disease should be precededby a thorough patient history to deter-mine whether the patient has concomi-tant clinical conditions that may predis-pose for thrombosis. Presently, a num-ber of studies suggest that the patientevaluation includes a complete bloodcount with peripheral blood smear, Fac-tor V Leiden, antithrombin, protein S,protein C, tests for antiphospholipidantibodies, lipoprotein (a), homocys-teine, and prothrombin mutation 20210.Additional tests that may be beneficialinclude factor VIII, IX, and XI levels andplatelet activation studies.CONCLUSIONCONCLUSIONCONCLUSIONCONCLUSIONCONCLUSION

The high incidence of venous andarterial thrombotic events underscoresthe importance of rapid and accuratedetection of causes of thrombosis. Thelaboratory can play a significant role inidentifying genetic risk factors for throm-boembolic disease. Individuals withgenetic mutations predisposing forthrombosis and lifestyle choices thatincrease their risk should be educatedabout the signs and symptoms forvenous or arterial thrombosis.

KEYWORDS: KEYWORDS: KEYWORDS: KEYWORDS: KEYWORDS: venous thrombosis, deepvein thrombosis, pulmonary emboli,stroke, myocardial infarction, transientischemic attack, sudden cardiac death.

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Kahn SR, et al. Clinical prediction of deep veinthrombosis in patients with leg symptoms.Thromb Haemost. 1999;81:353.

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