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Home , Deep vein thrombosis, Phlebitis, Thrombophlebitis, Thrombosis, Venous thrombosis

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Superficial or deep ? Superficial thrombophlebitis () and thrombosis (DVT) are both common conditions and they share some clinical features and risk factors. It is important to differentiate between the two disorders because they are managed differently. In part one of this two-part article, the clinical features and the of phlebitis and DVT are examined. Part two will examine the management options for each condition. Dr Nabil Aly Consultant , DME, University Hospital Aintree, Liverpool, Lower Lane, Liverpool L9 7AL email [email protected]

Superficial thrombophlebitis to obtain valid estimates of its affects individuals older than 40 is a common inflammatory- frequency. The exact incidence years and the male-to-female thrombotic process that may of DVT is also unknown because ratio is 1.2:1, indicating that occur spontaneously or as a most studies are limited by the males have a higher risk of DVT of medical or inherent inaccuracy of the clinical than females.2,3 surgical interventions. It has diagnosis of peripheral venous the same pathophysiology disorders. More importantly, and pathogenesis as deep vein most DVTs are occult and usually Pathophysiology thrombosis (DVT) and shares resolve spontaneously without most of its risk factors. complication; therefore, some Microscopic thrombosis is a Although uncommon, a DVTs are never diagnosed. normal part of the dynamic superficial thrombophlebitis can The existing data probably balance of haemostasis. In 1846, sometimes progress through underestimate the true incidence the German pathologist Virchow perforating to adjacent deep of DVT, but the incidence of recognised that if this dynamic veins. Therefore, not surprisingly, (including balance was altered by venous the incidence of associated DVT) in hospitalised patients is stasis, abnormal coagulability, or DVT and pulmonary considerably higher and varies vessel wall , microthrombi (PE) in people with superficial from 20 to 70%.2 could propagate to form thrombophlebitis is relatively high.1 Age is not an independent macroscopic thrombi. In the However, ruling out a DVT in risk factor for superficial absence of a triggering event, this clinical setting is difficult and thrombophlebitis, but the neither nor abnormal often further testing is required incidence of other recognised risk coagulability alone causes to evaluate for a DVT. No single factors increases with age. This clinically important thrombosis, physical finding or combination of leads to an overall increased risk but vascular endothelial symptoms and signs is sufficiently with increasing age.1 does reliably cause accurate to establish the diagnosis. The overall incidence of formation. The initiating injury venous thromboembolic diseases triggers an inflammatory response is increasing as the population that results in immediate Epidemiology ages. It rises markedly in persons adhesion at the site of injury. 60 years and older, and may be as Further platelet aggregation is Superficial thrombophlebitis is high as 900 cases per 100,000 by mediated by A2 and so common that it is difficult the age of 85 years.3 DVT usually by .

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Platelet aggregation due to However, not all venous thrombi venous thromboembolic disease, thromboxane A2 is inhibited pose equal embolic risk and and up to 30% of patients reversibly by non-steroidal anti- isolated vein thrombi carry a with DVT or PE may have a inflammatory drugs (NSAIDs) limited risk of PE.2 . 5,6 Evaluation and irreversibly by , for should be but these drugs do not affect considered in patients younger thrombin-mediated platelet Aetiology than 55 years with an idiopathic aggregation. Therefore, for this episode of DVT, patients with reason, neither treatment is very Risk factors for superficial recurrent thrombosis, and effective for preventing or treating thrombophlebitis include a patients with a family history of venous thrombosis. history of local trauma, prior thromboembolism.3 The diagnosis The formation, propagation, similar episodes, of DVT is confirmed in only 20- and dissolution of venous (veins that have become enlarged 30% of emergency admissions thrombi represent a balance and tortuous without phlebitis), with clinically suspected DVT, between thrombogenesis and the prolonged travel, hormone use, and a clinical study evaluating body’s protective mechanisms tobacco use or family history of 1102 acutely ill, immobilised (specifically, the circulating . However, admitted general medical inhibitors of the absence of identifiable risk patients, found four factors to be and the fibrinolytic system). factors has no prognostic value. independently associated with The development of venous The most important clinically an increased risk for venous thrombosis is best understood as identifiable risk factors are thromboembolism (VTE): the activation of coagulation in a prior history of superficial presence of an infectious areas of reduced blood flow, which thrombophlebitis and/or DVT. disease, age >75 years, , explains why the most successful The risk of DVT in a patient and history of prior VTE. Most of prophylactic regimens are with superficial thrombophlebitis these factors were asymptomatic anticoagulation and minimisation is remote. One case-series and diagnosed by of of venous stasis. study found that it occurred both lower extremities.7 very occasionally if the DVT thrombophlebitis extended above DVT of the lower extremity the knee.4 Clinical features usually begins in the deep veins The clinical evaluation of of the calf around the valve cusps patients with suspected DVT Patients with superficial or within the soleal plexus. A is via an assessment of risk thrombophlebitis often describe minority of cases arise primarily in factors. Specific risk factors for a history of a gradual onset of the iliofemoral system as a result venous thromboembolic disease localised tenderness, followed of direct vessel wall injury, such as (mainly DVT and/or pulmonary by the appearance of an area of from hip or intravenous embolism; PE) include increasing along the path of a . The vast majority age, prolonged immobility, . Patients may also of calf vein thrombi dissolve surgery, trauma, malignancy, complain of a hard, painful “knot” completely without and , oestrogenic in a previous varicose vein. approximately 20% propagate and hormone The classic signs of DVT, proximally, which usually occurs therapy, congestive failure, including Homans’ sign ( on before embolisation.2 The process , and passive dorsiflexion of the ), of adherence and organisation of diseases that alter blood viscosity oedema, tenderness, and warmth, a venous thrombus does not begin (eg, , sickle-cell are difficult to ignore, but they are until 5-10 days after thrombus disease, and multiple myeloma), of low predictive value and can formation. Until this process has and inherited thrombophilias. occur in other conditions such as been established fully, the non- At least one established risk musculoskeletal injury, , adherent disorganised thrombus factor is present in approximately and venous insufficiency.6 Many may propagate and/or embolise. 75% of patients who develop DVT patients are asymptomatic;

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Box : Clinical features of DVT and thrombophlebitis

Superficial thrombophlebitis DVT Inspection Inspection Erythema, oedema, and pain are common Oedema is principally unilateral Swelling may result from acute venous Erythema and local pain may occur obstruction (as in DVT) or venous reflux Venous distension and prominence of the Normal veins are distended visibly at the foot, subcutaneous veins , and occasionally in the popliteal fossa Palpation Palpation Tenderness, if present, is usually confined to the Superficial thrombophlebitis is characterised by calf muscles or along the course of the deep veins the finding of a palpable, indurated, cordlike, in the medial tender, subcutaneous venous segment Homans’ sign: discomfort in the calf muscles Palpation of a painful or tender area may reveal a on forced dorsiflexion of the foot with the knee firm, thickened, thrombosed vein straight and it is neither sensitive nor specific: it Palpable thrombosed vessels are virtually always is present in less than 1/3 of DVT patients, but is superficial found in more than 50% of patients without DVT however, the history may include: this test, the propagation of a without coexisting varicose unilateral oedema, non-specific palpable wave suggests that veins and with no other obvious leg pain in about 50% and a fluid-filled vessel with open or aetiology (eg, intravenous tenderness in 75%, which could incompetent valves connects the catheters, intravenous drug abuse, also be found in 50% of patients two locations. and soft tissue injury) had an without objectively confirmed associated DVT.4 DVT.6 The value of various The pain and tenderness Differential diagnosis diagnostic tests and imaging associated with DVT does studies in predicting the not usually correlate with the Superficial thrombophlebitis presence of DVT depends on the size, location, or extent of the should be differentiated from likelihood of disease in each risk thrombus. But, the signs and DVT, Table 1. Others conditions group.6 A well-validated clinical symptoms of DVT are related to be differentiated may include prediction rule can be used for to the degree of obstruction to Baker’s cyst, postphlebitic risk stratification of patients with venous outflow and syndrome with or without suspected DVT. For example. The of the vessel wall. Darkened, chronic venous insufficiency, and Wells clinical prediction guide discoloured, stained skin or non- lymphoedema. It is also often enables to reliably healing ulcers are typical signs of confused with cellulitis. stratify their patients into high-, chronic venous stasis, particularly Although the risk of DVT moderate-, or low-risk of DVT.9 It along the medial ankle and in patients with superficial incorporates risk factors, clinical the medial lower leg. Chronic thrombophlebitis is remote, those signs, and the presence or absence varicosities or with superficial thrombophlebitis of alternative diagnoses. also may be observed and extending to the saphenofemoral Used in combination with bedside manoeuvre, such as the junction are at higher risk for D-dimer or Doppler ultrasound Perthes percussive test, can help associated DVT.4 In one case- tests, a prediction rule can reduce to assess if venous segments series, about 40% of patients with the need for contrast venography, are interconnected.8 During superficial thrombophlebitis, as well as the likelihood of false-

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positive or false-negative test D-dimer levels only remain laboratory studies. Some of results.6 elevated in DVT for about seven these states include resistance to Blood tests rarely are helpful days and patients presenting later activated (most often in the diagnosis of superficial than that in the course, after clot due to Leiden), protein thrombophlebitis, except in those organisation and adherence have C deficiency, deficiency, patients at risk for an underlying occurred, may have low levels of III deficiency, hypercoagulable state. D-dimer D-dimer. Therefore, the D-dimer antiphospholipid antibodies and/ is a unique degradation product test should be used to rule out or prothrombin gene 2010-a produced by -mediated DVT rather than confirm it. mutation (factor II mutation). proteolysis of cross-linked Many different D-dimer These are rare causes of DVT that is often measured assays are available, with varying and are primarily indicated when in the evaluation for DVT and sensitivities and specificities, DVT is diagnosed in patients PE. It has an important role in and physicians should know younger than 50 years, when the diagnosing DVT,10,11 but its their hospital’s D-dimer assay. there is a confirmed family history value in detecting superficial Most studies have confirmed the of a hypercoagulable state or a thrombophlebitis is of little clinical utility of D-dimer testing, familial deficiency, when venous clinical use.12 and most clinical algorithms thrombosis is detected in unusual incorporate their use. sites, and in the clinical setting of D-dimer testing The laboratory based enzyme -induced skin . D-dimer fibrin fragments are linked immunosorbent assay The present in fresh fibrin clot and (ELISA) is currently advocated (PT) and activated partial in fibrin degradation products of in the literature as the best thromboplastin time (aPTT) cross-linked fibrin. Monoclonal D-dimer test for excluding VTE are not useful in the diagnostic antibodies specific for the in a hospital setting. Stein et al evaluation of patients D-dimer fragment are used to reported that ELISA for D-dimer with suspected superficial differentiate fibrin-specific clot has an overall sensitivity of 96% thrombophlebitis or DVT, and from non–cross-linked fibrin for DVT and 95% for PE.15 A most patients have a normal and from . These recent meta-analysis showed that PT and aPTT. Mahmoodi et al specific attributes of the D-dimer the qualitative assays (SimpliRED found that microalbuminuria was antibodies account for their D-dimer and Clearview Simplify independently associated with high sensitivity for venous D-dimer) have a lower sensitivity an increased risk for VTE and thromboembolism.13 However, (that is, a higher number of false the risk of VTE rose in tandem D-dimer level may be elevated in negatives) but higher specificity with the rate of urinary albumin any medical condition where clots (that is, a lower number of false excretion.16 The annual incidence form, such as in trauma, recent positives) than the quantitative of VTE was 0.12% among surgery, haemorrhage, cancer, and assays (Cardiac D-dimer and participants with <15 mg albumin sepsis. Many of these conditions Triage D-dimer). The latter seem, per 24-hour urine collection are associated with higher risk for therefore, better suited to rule out compared with 0.40% among DVT. DVT in suspected patients as they those with 30–300 mg albumin D-dimer is sensitive for decrease the pre-test probability per 24 hours. Adjusted hazard proximal vein DVT but less of VTE more effectively.13 The ratio for microalbuminuria versus so for calf vein DVT. A large same meta-analysis concluded normoalbuminuria (ie, <30 mg/24 study, in low-risk patients with that the quantitative D-dimer h) was 2 (P <0.001). low pretest probability for tests (Cardiac D-dimer and Triage DVT, confirmed that a negative D-dimer) have similar sensitivity Imaging studies SimpliRED (A rapid qualitative to ELISA for D-dimer. Proper diagnosis of venous RBC agglutination assay) system disease often requires D-dimer result rules out DVT and Other laboratory tests both functional and anatomic ultrasonography was not required Several common hypercoagulable information about the venous in these patients.14 In addition, states can be identified through circulation. Diagnosing DVT and

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committing patients to the risks of Superficial thrombophlebitis in vein DVT).11,13 anticoagulation therapy without lower extremity varicose veins The negative predictive value confirmatory objective testing is has an extremely low incidence of (NPV) for proximal vein DVT is unacceptable. DVT.17 99% and overall specificity is 95%. The standard procedure The incidence of VTE following for evaluating patients with Compression ultrasonography normal imaging tests, such as suspected DVT has been contrast Technological advances in compression ultrasonography venography. Nowadays, non- ultrasonography have permitted in patients suspected of DVT, is invasive studies have essentially the combination of real-time around 1-2%.13 replaced venography as the ultrasonographic imaging with initial diagnostic test of choice. Doppler flow studies (duplex Contrast venography The reasons for that include ultrasonography). The major For a long time the standard allergic reactions to contrast ultrasonographic criterion for test for evaluating patients with material, contrast-induced detecting venous thrombosis is suspected DVT has been contrast DVT, technical difficulties, failure to compress the vascular venography, a inadequate studies, inter- , presumably because of the against which non-invasive studies observer variability, and lack of presence of occluding thrombus. for DVT are compared. However, availability. Contrast venography The absence of the normal phasic the current use of contrast is either contraindicated or non- Doppler signals arising from the venography is limited by the risk of diagnostic in as many as 20–25% changes to venous flow provides pain, superficial thrombophlebitis, of patients, and compression indirect evidence of venous hypersensitivity or toxic ultrasonography is considered occlusion. reactions to contrast agents and the most appropriate study in Duplex ultrasonography is interobserver variability.6 As a suspected lower extremity DVT.11 also helpful to differentiate venous result, noninvasive studies have Controversy still exists over the thrombosis from haematoma, essentially replaced venography as use of noninvasive studies such Baker’s cyst, abscess, and other the initial diagnostic test of choice. as duplex ultrasonography for the causes of leg pain and oedema. diagnosis of suspected calf vein Ultrasound assessment has IPG DVT, as it is relatively insensitive several limitations: its accuracy In many studies, impedance for calf vein thrombosis.11 In depends on the operator; it plethysmography (IMG) has ambulatory outpatients with cannot distinguish between an old been shown to be sensitive suspected DVT, the sensitivity clot and a new clot; and it is not and specific for proximal vein of duplex ultrasonography for accurate in detecting DVT in the thrombosis.18 It is insensitive proximal vein thrombosis is pelvis or the small vessels of the for calf vein thrombosis, non- 97%, and it remains the initial calf, or in detecting DVT in the occluding proximal vein diagnostic test of choice. CT presence of or significant thrombus, and iliofemoral vein venography is the best diagnostic oedema. Causes of false-positive thrombosis above the inguinal modality for suspected iliofemoral examinations include superficial ligament. IPG cannot distinguish DVT. All patients with superficial thrombophlebitis, popliteal cysts, between thrombotic occlusion thrombophlebitis above the and abscess.6 In addition, venous and extravascular compression knee should undergo duplex thrombi proximal to the inguinal of the vein. False-positive ultrasonography as the initial ligament are difficult to visualise results occur in the setting of diagnostic modality of choice to and non-occluding thrombi may significant congestive cardiac rule out DVT. For patients with be difficult to detect. Many studies failure and raised central venous superficial thrombophlebitis have confirmed the diagnostic pressure as well as in severe below the knee, duplex sensitivity and specificity of duplex arterial insufficiency. When ultrasonography is only indicated ultrasonography for proximal vein directly compared, duplex for consistent thrombosis. Sensitivity of duplex ultrasonography has superior with a DVT (eg, asymmetrical ultrasonography for proximal vein sensitivity and specificity over swelling, erythema, and pain). DVT is 97% but only 73% for calf IPG.18

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CT venography reliable guide to a peripheral 2000; 82: 171–5 The primary utility of CT venous condition. The value 9. Anand SS, Wells PS, Hunt D, et al. Does this patient have deep vein venography is for the diagnosis of of various diagnostic tests and thrombosis? JAMA 1998; 279(14): iliofemoral DVT. Ultrasonography imaging studies in predicting the 1094–9 is limited to the diagnosis of DVT presence of DVT depends on the 10. American Academy of Family in the venous system distal to the likelihood of disease in each risk Physicians, American College inguinal ligament. The iliac veins group. A well-validated clinical of Physicians [Guideline]. Current Diagnosis of Venous cannot usually be visualised by prediction rule can be used for Thromboembolism in : ultrasonography, and a different risk stratification of patients with A Clinical Practice Guideline. The diagnostic modality must be used. suspected DVT. Nowadays, non- Joint American Academy of Family In the Prospective Investigation of invasive studies have essentially Physicians/American College of Diagnosis replaced venography as the initial Physicians Panel on Deep Venous II (PIOPED II) study, the diagnostic test of choice for Thrombosis/Pulmonary Embolism. Annals of Family 2007; 5: addition of CT venography to CT evaluating patients with suspected 57–62 of the chest increased DVT. 11. Buller HR, Ten Cate-Hoek AJ, Hoes the diagnostic sensitivity for AW, et al. Safely ruling out deep venous thromboembolic disease Conflict of interest: none venous thrombosis in primary care. than CT angiography alone.19 declared Ann Intern Med 2009; 150: 229–35 12. Gillet JL, Ffrench P, Hanss M, et al. Predictive value of D-dimer assay in MRV References superficial thrombophlebitis of the Magnetic resonance venography lower limbs. J Mal Vasc 2007; 32: (MRV) is the diagnostic test 1. Verlato F, Zucchetta, Prandoni P, 90–5 of choice for suspected iliac et al. An unexpectedly high rate of 13. Geersing JG, Janssen KJM, pulmonary embolism in patients with vein or inferior vena caval Oudega R, et al Excluding venous superficial thrombophlebitis of the thromboembolism using point of thrombosis when CT venography thigh. J Vasc Surg. 1999; 30: 1113–5 care D-dimer tests in outpatients: a is contraindicated or technically 2. Carter CJ. The natural history and diagnostic meta-analysis. BMJ 2009; inadequate. In suspected calf epidemiology of venous thrombosis. 339: b2990 vein thrombosis, MRV is more Prog Cardiovasc Dis 1994; 36: 423–38 15. Stein PD, Hull RD, Patel KC, et al. 3. Silverstein MD, Heit JA, Mohr DN, sensitive than any other non- D-dimer for the exclusion of acute et al. Trends in the incidence of venous thrombosis and pulmonary invasive study. However, cost, and pulmonary embolism: a systematic review. Ann lack of general availability, and embolism: a 25-year population- Intern Med 2004; 140: 589–602 technical issues limit its use. based study. Arch Intern Med 16. Mahmoodi BK, Gansevoort 1998;158: 585-93 RT, Veeger NJ, et al. Micro- 4. Campbell B. Varicose veins and their albuminuria and risk of venous Conclusion management. BMJ 2006; 333: 287– thromboembolism. JAMA 2009; 301: 292 1790–716. 5. Ramzi DW, Leeper KV. DVT 17. Bergqvist D, Jaroszewski H. Deep Superficial thrombophlebitis and and pulmonary embolism: Part II. vein thrombosis in patients with DVT are two common peripheral Treatment and prevention. Am Fam superficial thrombophlebitis of the venous conditions. Both are Physician 2004; 69: 2841–8 leg. Br Med J (Clin Res Ed) 1986; 292: 6. Ramzi DW, Leeper KV. DVT sharing the basic pathophysiology, 658–9 and pulmonary embolism: Part I. 18. Heijboer H, Büller HR, Lensing AW, pathogenesis and most of the risk Diagnosis. Am Fam Physician 2004; et al. A comparison of real-time factors. The overall incidence of 69(12): 2829–36 compression ultrasonography with venous thromboembolic diseases is 7. Alikhan R, Cohen AT, Combe impedance plethysmography for the increasing as the population ages, S, et al. Risk factors for venous diagnosis of deep-vein thrombosis but the risk of DVT in patients thromboembolism in hospitalized in symptomatic outpatients. N Engl J patients with acute medical illness: with superficial thrombophlebitis Med 1993; 329: 1365–9 analysis of the MEDENOX Study. 19. Stein PD, Fowler SE, Goodman LR, is remote. The two conditions Arch Intern Med 2004; 164; 2386 Gottschalk A, Hales CA, Hull RD. share few clinical signs, which are 8. Kim J, Richards S, Kent PJ. Clinical Multidetector computed tomography common to many other entities, examination of varicose veins--a for acute pulmonary embolism. N and visual appearance is not a validation study. Ann R Coll Surg Engl Engl J Med 2006; 354: 2317–27

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