Venous Thromboembolism: An Overview.

By Kushen Ramessur

School of Biosciences

University of Westminster

London ,W1 W 6UW. UK

Email: kush@servihoo.com

For comments please email: bioanalyst@hotmail.com

 

 

Venous Thromboembolism (VTE) is considered as a major global health problem (Schafer, 2003) and is associated with substantial mortality and morbidity in the absence of treatment (Dalen & Alpert, 1975). Its incidence rises with age and is above 10 percent for those over 80 years old (Hansson et al., 1997).

Epidemiology of VTE:

In the United Kingdom and Northern Europe the incidence of VTE is 1 per 10 000 person per year (Kesteven, 2000). In the United States the annual incidence is 1 per 1000 person and every year 107 000 new cases of deep vein thrombosis (DVT) and 94 000 new cases of pulmonary embolism (PE) are diagnosed in the States (Kroegel & Reissig, 2003). According to Heit, (2002) 30 percent of VTE patients will die within 30 days after diagnosis and despite improved prophylaxis, the incidence of VTE has not significantly changed since 1980. Almost one third of the surviving patients will develop recurrent venous thromboembolism within the next 8 years (Prandoni et al., 1996).

Several recent studies were also done to investigate the possible link between VTE and long haul aeroplane flights. But a consensus has yet to be found and researchers like Badrinath (2002) are in favour of the idea that air travel could be a significant contributing factor in pulmonary embolism whereas Mant (2001) and Weir (2001) concluded that the risk is low.

Pathophysiology:

The formation and propagation of the thrombus depends on abnormalities of blood flow, blood vessel wall and blood clotting components. They are collectively known as the Virchow's triad (Turpie et al., 2002). Abnormalities in blood flow and in blood clot formation usually occur after prolonged immobility or confinement to bed (Turpie et al., 2002). The most important risk factors are haemostatic and environmental.

The risk factors as reviewed by Gray in 2002 include:

Environmental factors:

Prolonged immobility

Prolonged confinement to bed or lower limb paralysis

Surgery, particularly lower limb orthopaedic operations, and major pelvic or abdominal operations

Trauma
For example, hip fractures and acute spinal injury

Obesity

Smoking

Acquired Factors:

Major medical illnesses such as acute myocardial infarction, ischaemic stroke, congestive cardiac failure, acute respiratory failure

Oestrogen use in pharmacological doses
For example, oral contraception pills, hormone replacement therapy

Cancer, especially metastatic adenocarcinomas

History of venous thromboembolism

Acquired hypercoagulable states
Lupus anticoagulant and antiphospholipid antibodies, hyperhomocysteinaemia, dysfibrinogenaemia, myeloproliferative disorders such as polycythaemia rubra vera

Genetic factors:

Inherited hypercoaguable states
Activated protein C resistance (factor V Leiden mutation), protein C deficiency, protein S deficiency, antithrombin deficiency, prothrombin gene mutation.

Deep vein thrombosis of the lower limb is seen in a quarter of patients with acute myocardial infarct and more than half of those with acute ischaemic stoke. But in over 50 percent of those with a first episode of DVT no predisposing factors could be found (Turpie et al., 2002).

Clinical presentation and assessment:

About 30% of patients with DVT eventually develop PE and thus a good clinical assessment of the patient is important, for the correct diagnosis and treatment of the patient (Kearon, 2001). Most venous thrombi are clinically silent (Harris et al., 1975) and about one third of the patients with symptoms have the classic picture of pain, swelling, tenderness along the distribution of the deep legs veins, venous distension or cyanosis (Hirsh & Lee, 2002). However, the other conditions like superficial thrombophelitis, cellulites, ruptured Baker's cyst and other musculoskeletal conditions also, cause venous obstruction or perivascular inflammation (Turpie, Chin & Lip, 2002) thus making the diagnosis of VTE even more difficult.

Diagnosis of deep vein thrombosis:

The first clinical model to assess the clinical likelihood of DVT was developed by Wells and colleagues (Well, Hirsh, Anderson et al., 1995). Based on their clinical presentations patients are classified as either having low-, intermediate- or high risk of having DVT. The simplified version of the clinical model for predicting pretest probability for DVT is currently used in many hospitals. But this clinical model cannot be used as a stand-alone test and DVT has to be confirmed using other alternative diagnostic methods like venography, I-fibrinogen scanning, impedence plethysmography and Doppler ultrasound (Babior & Stossel, 1994).

Pulmonary embolism diagnosis:

The empirical clinical assessment is based on the prospective investigation of pulmonary embolism diagnosis (PIOPED) and McMaster risk studies (Hull, Hirsh, Carter et al., 1985) to grade the clinical probability of PE into either low, intermediate- or high risk.

However, 3 other research groups have recently published explicit prediction rules for determining the clinical probability of P.E. (Miniati, Prediletto, Formichi et al., 1999). Wells and colleagues (Wells, Ginsberg, Anderson et al., 1998) also, use sign and symptoms in the grading. The clinical diagnosis is usually confirmed using pulmonary angiography, helical computed tomography or ventilation-perfusion scan.

However, this conventional way of diagnosing DVT and P.E. has many shortcomings.

Only about 25% of patients with compatible symptoms have DVT confirmed by venous ultrasonography or venography (Hirsh & Lee, 2002).

Phlebography is costly in terms of human resources, cannot be repeated and is a poor choice for monitoring patients with serial examinations (Weinmann, 1994).

Inspite of having sensitivity above 90 percent magnetic resonance venography cannot be used routinely for the diagnosis of DVT because of its high cost and availability (Spritzer, Norconk, Sostman et al., 1993).

Traditional computed tomography (CT) is not suitable for the evaluation of suspected P.E. as it cannot give an optimum opacity of the pulmonary arteries in the time required to complete the imaging (Kearon, 2003).

Helical CT sensitivity and specificity when used to diagnose P.E. was 69 % and 86% respectively (deMonye & Pattynama, 2001).

Normal CT seen alone cannot be used to exclude P.E. (Lorut, Ghassains, Herellou et al., 2000; Ost, Rozenshtein, Saffran et al., 2001).

Inspite of the fact that pulmonary angiography is the gold standard for the diagnosis of P.E.. It has many side effects, difficult to interpret, costly and a mortality rate of 0.5%. (Stein, Athanasoulis, Alavi et al., 1992). It is not also recommended for patients with renal impairment and in coma (PIOPED investigators, 1990).

Pregnancy very often causes a left leg swelling due to compression of the left ileac vein by the gravid uterus. Therefore, any iliac vein thrombosis can be missed by compression ultrasonography (Hirsh & Lee, 2002).

1-2 % of patients with an initially normal ultrasonography develop DVT within 1 week after initial diagnosis (Cogo, Lensing, Koopman et al., 1998).

DVT can lead to P.E. and 93% deaths occur within 2.5 hours after the onset of the symptoms (Mavromatis & Kessler, 2001).

Thus, ongoing research continued for years to find a diagnostic method, which is quick, highly sensitive and specific enough to diagnose DVT and PE within minutes. The test should also be reliable with a positive predictive value of 85% or above to diagnose VTE or a negative predictive value of above 95% to exclude P.E. The recurrence of VTE must not be more than 2% during the follow up period (Kearon, 2003). The diagnostic test should also cost less than the currently available tests.

For decades, Laboratory markers of ongoing fibrinolysis and procoagulant activity were extensively studied about their possible use in the diagnosis of VTE (Mavromatis & Kessler, 2001). In recent years, D-dimer emerged as a useful marker for the exclusion of venous thromboembolism (Perrier et al., 1999). However, it must be noted that D-dimer present in the circulation was already assayed for decades as an indicator of whether blood clot is being formed and broken down in the body (Dempfle, 2000).

Several studies have established that there is a link between D-dimer levels and VTE (Becker et al., 1996; Moser, 1994) and the following results were obtained:

Plasma D-dimer concentration is elevated in patients with venous thrombosis (Bournameaux et al., 1992) or pulmonary embolism (Bournameaux, 1991).

Venous thrombosis is unlikely to be present if D-dimer levels are not raised (Bournameaux, 1994) but all positive result requires confirmation by more specific imaging based tests (Goldhaber & Morpurgo, 1992).

An elevated level of D-dimer occurs with pulmonary embolism (Lee & Ginsberg, 1998) and the degree of elevation is proportional to the extent of the pulmonary embolism (Galle et al., 2002; deMonye et al., 2002).

Increased plasma concentrations of D-dimer may predict thrombotic events (Fowkes et al., 1993; Herren at al., 1994).

Elevated D-dimer correlated with the severity of disease (Lassila et al., 1993)

Plasma D-dimer concentration raises more than 100 fold during deep vein thrombosis (Cushman et al., 2003).

Increased D-dimer levels remained increased for at least 1 week (Kline et al., 2000)

D-dimer levels are also higher in the presence of inherited thrombophilia factors like factor V Leiden, prothrombin 20210A or elevated factor VIIIc. However, D-dimer is still associated with thrombosis irrespective if those factors are present or not (Cushman et al, 2003).

All detection methods use monoclonal antibodies that recognise epitopes specific to the cross-linked D-dimer fragments among the other various fibrin degradation products (Lee & Ginsberg, 1998). The different assays differ in the type of antibody used, D-dimer epitope structure recognised and the way the antigen-antibody complexes are measured. Some methods are quantitative whereas others are qualitative (Farell et al., 2000)

The four main D-dimer assay methods used are

Microplate ELISA

Latex agglutination

Immunofiltration (Membrane ELISA)

Whole blood agglutination

Conclusion:

Despite improvement in treatment the incidence of venous thromboembolism is still very high in the world. The conventional methods of diagnosing VTE had many shortcomings and D-dimer assays gave some promising results. However, many shortcomings like low sensitivity and specificity of the test use of different cut-off values by different manufacturers have to be overcome before it can be used as a diagnostic test for excluding VTE. Also, some methods like ELISA are still too expensive for its use in a routine diagnostic laboratory.

References:

Babior BM & Stossel TP. (1994). Haematology a pathophysiological approach. 3^rd Ed. Churchill Livingstone. New York.

Badrinath P (2002). Air travel and venous thromboembolism - the jury is still out. CMAJ; 166(7): 885-886

Becker DM, Philbrick JT, Bachhuber TL and Humphries JE (1996). D-dimer testing and acute venous thromboembolism: a short cut to accurate diagnosis? Arch Intern Med; 156: 939-946.

Bounameaux H.(1991). Treatment of deep venous thrombosis .J Mal Vasc. 1991;16(2):195.

Bounameaux HP, Cirafici P, de Moerloose PA, Slosman D, Reber G and Linger PF.(1991). Measurement of D-dimer in plasma as diagnostic aid in suspected pulmonary embolism. Lancet; 337: 196-200.

Bounameaux H, de Moerloose P, Perrier A, reber G.(1994). Plasma measurement of D-dimer as diagnostic aid in suspected venous thromboembolism: an overview. Thromb Haemost; 71: 1-6.

Cogo A, Lensing AW, Koopman MM et al.(1998). Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study. British medical journal; 316: 17-20.

Cushman M, Folsom AR, Wang L et al.(2003). Fibrin fragment D-dimer and the risk of future venous thrombosis. Blood; 10(14): 1243-1248.

Dalen JE & Alpert JS (1975). Natural history of pulmonary embolism. Prog cardiovascular disease; 17: 259-270.

de Monye W, Pattynama PM.(2001). Contrast-enhanced spiral computed tomography of the pulmonary arteries: an overview. Semin Thromb Hemost. ;27(1):33-9

De Monye W, Sanson BJ, Mac Gillavry MR, Pattynama PM, Buller HR, van den Berg-Huysmans AA, Huisman MV; ANTELOPE-Study Group.(2002). Embolus location affects the sensitivity of a rapid quantitative D-dimer assay in the diagnosis of pulmonary embolism. Am J Respir Crit Care Med ;165(3):345-8

Dempfle CE. (2000). Use of D-dimer assays in the diagnosis of venous thrombosis. Semin Thromb Hemost; 26(6): 631-641.

Farell S, Hayes T, Shaw M.(2000). A negative SimpliRED D-dimer assay result does not exclude diagnosis of deep vein thrombosis or pulmonary embolism in emergency department patients, Ann Emerg Med; 35(2): 121-125.

Fowkes FG, Lowe GD, Housley E et al.(1993). Cross-linked fibrin degration products, progression of peripheral arterial diseases and the risk of coronary heart disease. Lancet; 342: 84-86.

Galle C, Papazyan JP, Miron MJ, Slosman D, Boumameaux H, Perrier A.(2002). Prediction of pulmonary embolism extent by clinical findings, D-dimer level and deep vein thrombosis shown by ultrasound. Thromb Haemost;86:1156-60. 2002

Goldhaber SZ, Morpurgo M.(1992). Diagnosis, treatment, and prevention of pulmonary embolism. Report of the WHO/International Society and Federation of Cardiology Task Force. JAMA;268(13):1727-33. Review

Gray HW (2002). The natural history of venous thromboembolism: impact on ventilation / perfusion scan reporting. Semin. Nucl. Med.; 32(3): 159-172

Hirsh J & Lee AYY.(2002). How we diagnose and treat deep vein thrombosis?Blood;99(9): 3102- 3110

Harris WH, Salzman EW, Athanasoulis C et al. (1975). Comparison of (sup125)I fibrinogen count screening with phlebography for detection of venous thrombi after elective hip surgery. NEJM; 292: 665-667.

Hansson P, Welin L, Tibblin G & Eriksson H. (1997). Deep vein thrombosis and pulmonary embolism in the general population. Arch Intern Med; 157: 1665-1670.

Heirt JA, Minor TA, Andrews JC et al. (1999). Determinants of plasma fibrin D-dimer sensitivity for acute pulmonary embolism as defined by pulmonary angiography. Arch Pathol Lab Med; 123: 235-240.

Herrren T, Stricker H, Haeberli A. Do DD, Staub PW.(1994). Fibrin formation and degradation in patients with arteriosclerosis disease. Circulation; 90: 2679-2686.

Hull RD, Hirsh J, Carter CJ, Raskob GE, Gill GJ, Jay RM, Leclerc JR, David M, Coates G. (1985). Diagnostic value of ventilation-perfusion lung scanning in patients with suspected pulmonary embolism.Chest ;88(6):819-28.

Kearon C. (2001). Natural history of venous thromboembolism. Semin Vasc Med; 1:27-37.

Kearon C. (2003). Diagnosis of pulmonary embolism. CMAJ; 168(2).

Kesteven P. (2000). Traveller's thrombosis. Thorax;55(Suppl 1):S32-6.

Kline JA, Johns KL, Colucciello SA et al. (2000). New diagnostic tests for pulmonary embolism. Ann Emerg Med; 35: 168-180.

Kroegel C & Reissig A.(2003). Principle mechanisms underlying venous thromboembolism: Epidemilology, risk factor, pathophysiology and pathogenesis. Respiration; 70(1): 7-30.

Lassila R, Peltonen S, Lepantalo M, Saarinen O, kauhamen P, Manninem V.(1993). Severity of peripheral atherosclerosis is associated with fibrinogen and degradation of cross-linked fibrin. Arteriosles Thromb; 13: 1738-1742.

Lee AYY & Ginsberg JS.(1998). Laboratory diagnosis of venous thromboembolism. Baillieres clinical haematology; 11: 587-604.

Lorut C, Ghossains M, Horellou MH, Achkar A, Fretault J, Laaban JP.(2000). A noninvasive diagnostic strategy including spiral computed tomography in patients with suspected pulmonary embolism. Am J Respir Crit Care Med.;162(4 Pt 1):1413-8

Mant MJ (2001). Air travel and thromboembolism. CMAJ; 165(8): 1006

Mavromatis BH & Kessler CM. (2001). D-dimer testing: the role of the clinical laboratory in the diagnosis of pulmonary embolism. Journal of clinical pathology; 54(9): 664-668.

Miniati M, Prediletto R, Formichi B, Marini C, Di Ricco G, Tonelli L, Allescia G, Pistolesi M. (1999). Accuracy of clinical assessment in the diagnosis of pulmonary embolism. Am J Respir Crit Care Med;159(3):864-71.

Moser KM, Fedullo PF, Littlejohn JK et al.(1994). Frequent asymtomatic pulmonary embolism in patients with deep vein thrombosis. JAMA; 271: 223-225.

Ost D, Rozenshtein A, Saffran L, Snider A.(2001). The negative predictive value of spiral computed tomography for the diagnosis of pulmonary embolism in patients with nondiagnostic ventilation-perfusion scans.Am J Med.;110(1):16-21

Perrier A, Desmarais S, Miron MJ et al.(1999). Non-invasive diagnosis of venous thromboembolism in outpatient. Lancet; 353: 190-195.

PIOPED investigators (1990). Value of the ventilation/ perfusion scan in acute pulmonary embolism. JAMA; 263: 2752- 2759.

Prandoni P, Lensing AW, Cogo A et al. (1996).The long term clinical course of acute DVT. Ann Intern Med; 125: 1-7.

Schafer AI (2003). Warfarin for venous thromboembolism- walking the dosing tight rope. NEJM; 348:15:1-2.

Spritzer CE, Norconk JJ Jr, Sostman HD, Coleman RE. (1993). Detection of deep venous thrombosis by magnetic resonance imaging. Chest.;104(1):54-60

Scurr JH, Smith PD, Machin S. (2001). Deep Vein Thrombosis in airline passengers- the incidence of deep vein thrombosis and the efficacy of elastic compression stockings. Cardio Vasc Surg.; 9(2): 159- 162

Stein PD, Athanasoulis C, Alavi A, Greenspan RH et al.(1992). Complications and validity of pulmonary angiography in acute pulmonary embolism. Circulation; 85: 462- 468.

Turpie AGC, Chin BSP & Lip GYH.(2002): Venous thromboembolism : Pathophysiology, clinical features and prevention. British medical journal; 325: 887- 890

Weinmann, Eran E, Sulzman EW.(1994). Medical progress in deep vein thrombosis. NEJM; 331(24): 1630-1641.

Weir E. (2001). The weak connection between venous thromboembolism and air travel CMAJ ; 164 (7).

Wells PS, Hirsh J , Anderson DR et al (1995). Accuracy of clinical assessment of pretest probability of deep vein thrombosis in clinical management. Lancet; 345: 1326-1330.

Wells PS, Hirsh J, Anderson DR, Lensing AW, Foster G, Kearon C, Weitz J, D'Ovidio R, Cogo A, Prandoni P, Girolami A, Ginsberg JS. (1998). A simple clinical model for the diagnosis of deep-vein thrombosis combined with impedance plethysmography: potential for an improvement in the diagnostic process.
J Intern Med.;243(1):15-23.