Superficial Thrombophlebitis

Background

Superficial thrombophlebitis is a common inflammatory-thrombotic disorder in which a thrombus develops in a vein located near the surface of the skin. Most superficial veins that develop thrombosis also have phlebitis, in contrast to deep venous thrombosis (DVT), a sometimes asymptomatic condition in which phlebitis may be absent. (See Etiology and Workup.)

Although superficial thrombophlebitis usually occurs in the lower extremities, it also has been described in the penis and the breast (Mondor disease). Superficial thrombophlebitis can also develop anywhere that medical interventions occur, such as in the arm or neck (external jugular vein) when intravenous (IV) catheters are used. (See Etiology, Presentation, and Workup.)

Thrombosis and thrombophlebitis of the superficial venous system receive little attention in medical and surgical textbooks. However, thrombophlebitis is encountered frequently, and although it is usually a benign, self-limiting disease, it can be recurrent and tenaciously persistent, at times causing significant incapacitation. (See Epidemiology and Prognosis.)

When affecting the great saphenous vein (GSV; also referred to as the greater or long saphenous vein), thrombophlebitis will sometimes progress into the deep venous system. Damage to deep venous valves leads to chronic deep venous insufficiency (often referred to as postphlebitic syndrome), as well as to recurrent pulmonary embolism (PE) and an increased risk of death.^[1]

Causes and sites of development

Superficial thrombophlebitis can occur spontaneously, especially in the lower extremities in the GSV, or as a complication of medical or surgical interventions. Although the etiology is frequently obscure, superficial venous thrombosis is most often associated with one of the components of the Virchow triad; ie, intimal damage (which can result from trauma, infection, or inflammation), stasis or turbulent flow, or changes in blood constituents (presumably causing increased coagulability). (See Etiology.)

In each type of superficial thrombophlebitis, the condition presents as redness and tenderness along the course of the vein, usually accompanied by swelling. Bleeding also can occur at the site of a varicose vein. (See Presentation.)

Although unusual, superficial thrombophlebitis may occur in the small saphenous vein (SSV; also referred to as the lesser saphenous vein), which empties into the popliteal vein.

Superficial thrombophlebitis can also occur in the external jugular vein, if it has been used for an infusion site. Superficial thrombophlebitis of the upper extremities usually occurs at infusion sites or sites of trauma.

Diagnosis and treatment

Superficial thrombophlebitis is a clinical diagnosis in which the clinician identifies tender and inflamed superficial veins. However, ruling out DVT in the clinical setting is difficult; further testing is often required to evaluate for this condition. (See Presentation and Workup.)

Treatment for superficial thrombophlebitis is aimed at patient comfort and at preventing superficial phlebitis from involving the deep veins. (See Treatment and Medication.)

Superficial phlebitis with infection, such as phlebitis originating at an IV catheter site, is referred to as septic thrombophlebitis, a clinical entity requiring diagnostic and therapeutic approaches that are different from those applied to sterile phlebitis.

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Pathophysiology

Microscopic thrombosis is a normal part of the dynamic balance of hemostasis. In 1846, the German pathologist Virchow recognized that if this dynamic balance were altered by venous stasis or turbulence, abnormal coagulability, or vessel wall injuries, then microthrombi could propagate to form macroscopic thrombi.

In the absence of a triggering event, neither venous stasis nor abnormal coagulability alone causes clinically important thrombosis, but vascular endothelial injury does reliably result in thrombus formation. The initiating injury triggers an inflammatory response that results in immediate platelet adhesion at the injury site. Further platelet aggregation is mediated by thromboxane A2 (TxA2) and by thrombin. A more detailed visual of the coagulation pathway can be seen in the image below.

View Image

Blood coagulation (thrombin) and protein C pathways. Courtesy of Wikimedia Commons ©John H Griffin, PhD.

Platelet aggregation due to TxA2 is inhibited irreversibly by aspirin and reversibly by other nonsteroidal anti-inflammatory drugs (NSAIDs); thrombin-mediated platelet aggregation, on the other hand, is not affected by NSAIDs, including aspirin. This is why aspirin and other NSAIDs are somewhat effective in preventing arterial thrombosis, where platelet aggregation is mediated via TxA2, as seen in patients with stroke and myocardial infarction (MI), but are not very effective in preventing venous thrombophlebitis, where it is believed that clot formation is more of a result of thrombin activation.

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Etiology

Risk factors

The most important clinically identifiable risk factors for thrombophlebitis are a prior history of superficial phlebitis, DVT, and PE. Some common risk markers include recent surgery or pregnancy, prolonged immobilization, and underlying malignancy.

Phlebitis also occurs in diseases associated with vasculitis, such as polyarteritis nodosa (periarteritis nodosa) and Buerger disease (thromboangiitis obliterans). Buerger noted phlebitis in 8 of 19 patients, and Shionoya reported it in 43% of the 255 patients he followed.^{[2, 3]} After 2010, a medically emergent cutaneous thombophlebitis began to be noted more frequently, after an increase in use of levamisole (an antihelminth) for bulking cocaine in the US. In a review of the literature by Pearson et al, cutaneous thrombosis was noted in 84% of patients presenting with levamisole-induced vasculopathy.^{[4, 5]}

Pregnancy

The increased likelihood of developing thrombophlebitis occurs through most of pregnancy and for approximately 6 weeks after delivery. This is partly due to increased platelet stickiness and partly due to reduced fibrinolytic activity.

The association between pregnancy and thrombophlebitis is of particular concern to women who carry the factor V Leiden or prothrombin C-20210-a gene, because they already have a predisposition to clotting, which would also be exacerbated by pregnancy.^[6]

Estrogen therapy

High-dose estrogen therapy is another risk factor. Case-controlled and cohort studies based on clinical signs and symptoms of thrombosis suggest that by taking high-estrogen oral contraceptives, a woman may increase her risk of thrombosis by a factor of 3-12 times, though the absolute risk remains low. Newer low-dose oral contraceptives are associated with a much lower risk of thrombophlebitis, though the absolute risk has not been well quantified.^[7]

Additional risk factors

Other recognized markers of risk for venous thromboembolic disease include the following:

• Varicose veins
• Obesity
• Age older than 60 years (however, there are fewer complications in this age group)
• Cigarette smoking
• IV drug abuse
• Hypercoagulable states (eg, factor V Leiden mutation, prothrombin gene mutation, and protein S deficiency)
• Systemic lupus erythematosus
• Acquired immunodeficiency syndrome (AIDS) - Lupus anticoagulant
• Drug-induced lupus anticoagulant
• Antithrombin III deficiency
• Behçet disease
• Blood type A
• Burns
• Catheters (indwelling venous infusion catheters)
• Chemotherapy
• Congestive heart failure
• Estrogen replacements (high dose only)
• Fibrinogen abnormality
• Fractures
• Hemolytic anemias
• Heparin-associated thrombocytopenia
• Homocysteinemia
• Homocystinuria
• Hyperlipidemias
• Immobilization
• Malignancy
• MI
• Phenothiazines
• Plasminogen abnormality
• Plasminogen activator abnormality
• Polycythemia
• Postoperative
• Protein C deficiency
• Protein S deficiency
• Resistance to activated protein C
• Thrombocytosis
• Trauma
• Ulcerative colitis
• Venography
• Venous pacemakers
• Venous stasis
• Warfarin - First few days of therapy
• Caustic materials, such as lighter fluid, injected intravenously^[8]

Traumatic thrombophlebitis

Superficial venous thrombosis following an injury usually occurs in an extremity, manifesting as a tender cord along the course of a vein juxtaposing the area of trauma. Ecchymosis may be present early in the disease, indicating extravasation of blood associated with injury to the vein; this may turn to brownish pigmentation over the vein as the inflammation resolves.

Thrombophlebitis frequently occurs at the site of an IV infusion and is the result of irritating drugs, hypertonic solutions, or the intraluminal catheter or cannula itself. This is by far the most common type of thrombophlebitis encountered. Usually, redness and pain signal its presence while the infusion is being given, but thrombosis may manifest as a small lump days or weeks after the infusion apparatus has been removed. It may take months to completely resolve.

The features of iatrogenic form of traumatic (chemical) phlebitis may be deliberately produced by sclerotherapy during the treatment of varicose veins.

Thrombophlebitis in varicose vein

Superficial thrombophlebitis frequently occurs in varicose veins. It may extend up and down the saphenous vein or may remain confined to a cluster of tributary varicosities away from the main saphenous vein.

Although thrombophlebitis may follow trauma to a varix, it often occurs in varicose veins without an antecedent cause.

Thrombophlebitis in a varicose vein develops as a tender, hard knot and is frequently surrounded by erythema. At times, bleeding may occur as the reaction extends through the vein wall. It frequently is observed in varicose veins surrounding venous stasis ulcers.

Superficial thrombophlebitis along the course of the GSV is observed more often to progress to the deep system.

Infection-related thrombophlebitis

Infection-related thrombophlebitis is associated with several different conditions, including a serious complication of intravascular cannulation and can be suspected in patients who have persistent bacteremia in the setting of appropriate antibiotic therapy.^[9] It is characterized by perivascular inflammation with or without evidence of purulence within the venous lumen. It also frequently is associated with bloodstream infection.

In 1932, DeTakats suggested that dormant infection in varicose veins was a factor in the development of thrombophlebitis occurring following operations or after injection treatments, trauma, or exposure to radiation therapy.^[10]

Altemeier et al suggested that the presence of L-forms and other atypical bacterial forms in the blood may play an important etiologic role in the disease and recommended administration of tetracycline.^[11]

Migratory thrombophlebitis

Jadioux described migratory thrombophlebitis in 1845, determining it to be an entity characterized by repeated thromboses developing in superficial veins at varying sites but occurring most commonly in the lower extremity. Although numerous etiologic factors have been proposed for this condition, none have been confirmed.

The association of carcinoma with migratory thrombophlebitis was first reported by Trousseau, in 1856. Sproul noted migratory thrombophlebitis to be especially prevalent with carcinoma of the tail of the pancreas.^[12]

Thrombophlebitis of superficial veins of breast and anterior chest wall (Mondor disease)

Mondor disease is a rare condition. Thrombophlebitis is usually located in the anterolateral aspect of the upper portion of the breast or in the region extending from the lower portion of the breast across the submammary fold toward the costal margin and the epigastrium.

A characteristic finding is a tender, cordlike structure that may be best demonstrated by tensing the skin via elevation of the arm.

The cause of Mondor disease is unknown, but a search for malignancy is indicated. Mondor disease is more likely to occur after breast surgery, with the use of oral contraceptives, and with protein C deficiency.

Thrombophlebitis of the dorsal vein of the penis, generally caused by trauma or repetitive injury, is also referred to as Mondor disease.^{[13, 14]}

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Epidemiology

Superficial thrombophlebitis is a common condition worldwide.

In the author's experience, superficial thrombophlebitis most frequently occurs in the age group ranging from young adulthood to middle age. However, Markovic et al reported that a common risk factor is age older than 60 years, though fewer complications occur in this age group.^[15]

As previously mentioned, pregnancy, puerperium, and high-dose estrogen therapy are recognized risk factors for phlebitis. However, there are no intrinsic, sex-linked risks for the disease.

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Prognosis

The prognosis in superficial thrombophlebitis is usually good. Superficial phlebitis is rarely associated with PE, though it can occur, particularly if the process extends into a deep vein. However, individuals with superficial venous thrombosis do not seem to have a great tendency to develop DVT. In contrast, patients with DVT are frequently found to have superficial venous thrombosis.

The patient should be told to expect the disease process to persist for 3-4 weeks or longer. If it occurs in the lower extremity in association with varicose veins, it has a high likelihood of recurrence unless excision is performed.

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Patient Education

Because thrombophlebitis tends to recur if the vein has not been excised, instructing the patient in ways to prevent stasis in the vein is usually advisable. The use of elastic stockings may be indicated, especially if the patient plans to stand in an upright position for long periods. Slight elevation of the foot of the bed, avoidance of long periods of standing in an upright position, and avoidance of prolonged inactivity is recommended.

For patient education information, see Varicose Veins, Deep Vein Thrombosis (Blood Clot in the Leg, DVT), and Phlebitis.

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History

Patients with superficial thrombophlebitis often give a history of a gradual onset of localized tenderness, followed by the appearance of an area of erythema along the path of a superficial vein. Patients may also have a history of the following:

• Local trauma
• Similar prior episodes
• Varicose veins
• Prolonged travel
• Hormone use
• Tobacco use
• Family history of blood coagulopathies
• Enforced stasis

Although patients should be asked about these risk factors for hypercoagulability, the absence of identifiable risk factors has no prognostic value.

Traumatic thrombophlebitis

Ask about trauma, needlesticks, indwelling intravenous (IV) catheters, drug (eg, phenytoin) or hypertonic solution (10% calcium chloride) infusion, and sclerotherapy.

Thrombosed varicose veins

Ask about history of varicose veins, previous history of thrombosed varices, and any injury to the leg that has the varices. One should ascertain whether there was a thrombosed vein and should determine the timing of erythema and pain.

Thrombosed hemorrhoids

The history should focus on previous occurrences of thromboses and surgical intervention, as well as on the timing of symptoms.

Migratory thrombophlebitis

Also known as Trousseau’s sign of malignancy, migratory thrombophlebitis is described as thrombophlebitis that travels, often from one leg to the other. It has a strong association with adenocarcinoma of the pancreas and lung; therefore, the history should be directed toward finding malignancy.

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Physical Examination

Visual appearance is not a reliable guide to a peripheral venous condition, because the clinical findings of venous disease (erythema, edema, and pain) are common to many other entities. Swelling may result from acute venous obstruction (as in deep venous thrombosis [DVT]) or from deep or superficial venous reflux, or it may be caused by an unrelated disease condition, such as hepatic insufficiency, renal failure, cardiac decompensation, infection, trauma, or environmental effects. Lymphedema may be primary or it may be secondary to overproduction of lymph due to severe venous hypertension.

Normal veins are distended visibly at the foot, the ankle, and, occasionally, the popliteal fossa, but not in the rest of the leg. Normal veins may be visible as a blue, subdermal, reticular pattern, but dilated superficial leg veins above the ankle usually are evidence of venous pathology.

Darkened, discolored, stained skin or nonhealing ulcers are typical signs of chronic venous stasis, particularly along the medial ankle and the medial lower leg. Chronic varicosities or telangiectasias also may be observed.

Palpation

Palpation of a painful or tender area may reveal a firm, thickened, thrombosed vein. Palpable thrombosed vessels are virtually always superficial.

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Complications

Complications in superficial thrombophlebitis include the following:

• Extension into the deep venous system
• Hyperpigmentation over the affected vein
• Persistent, firm nodule in subcutaneous tissues at the site of the affected vein
• Conversion to suppurative thrombophlebitis

Complications of suppurative phlebitis include the following:

• Metastatic abscess formation
• Bloodstream infection
• Septic emboli

Death from superficial thrombophlebitis without complication is unusual; however, if superficial thrombophlebitis extends into the deep venous system, it can be a source of pulmonary emboli.^[16]

Complications can also result if the recanalization of thrombosed veins results in a valveless channel from destruction of the fragile valves by the inflammatory process. The lack of valves in the vein can lead to a prolonged venous circulation time and often to chronically elevated ambulatory venous pressure within the legs. This often results in a clinical postphlebitic syndrome of chronic pain, edema, hyperpigmentation, ulceration, and an increased risk of recurrent thrombophlebitis.

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Approach Considerations

Key questions in cases of superficial thrombophlebitis concern the location and extent of the thrombosis, as well as its proximity to the deep venous system at the saphenofemoral or saphenopopliteal junction.

Patients who present with spontaneous thrombophlebitis without a previous indwelling intravenous (IV) catheter or other precipitating cause should be considered for evaluation for a hypercoagulable state. Certainly, all patients with a past history of another thromboembolic event should undergo a workup as well.

Migratory thrombophlebitis, especially without good cause, may be an indication for a more detailed evaluation of the patient to determine whether a malignant lesion exists. This evaluation should include selective application of serum carcinoembryonic antigen (CEA) testing, prostate-specific antigen (PSA) testing, colonoscopy, computed tomography (CT), and mammography.

Imaging studies

A combination of functional and semianatomic or anatomic techniques allows a complete understanding of most venous system pathology. Functional tests are extremely useful as measures of whole-leg or regional venous function, but they can detect only regionally significant reflux or a significant impediment to venous outflow, which would predispose to the development of a thrombus.

Anatomic imaging of the venous system can detect small amounts of local and regional reflux, as well as the presence of an obstructing or nonobstructing thrombus. Unfortunately, anatomic imaging often fails to identify important functional deficits.

Histologic findings

Histologic findings include inflammatory reaction in the vein wall and thrombus in the lumen of the vein.

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Laboratory Studies

Blood tests rarely are helpful in the diagnosis of thrombophlebitis, except in those patients at risk for an underlying hypercoagulable state. Several common hypercoagulable states, including the following, can be identified through laboratory studies:

• Resistance to activated protein C (most often due to factor V Leiden)
• Protein C deficiency
• Protein S deficiency
• Antithrombin III deficiency
• Antiphospholipid antibodies
• Prothrombin gene 2010-a mutation (factor II mutation)

Schönauer et al reported a high factor VIII concentration to be an independent risk factor for superficial thrombophlebitis.^[17] In another study, de Godoy and Braile reported that 5.5% of patients with repetitive superficial thrombophlebitis were positive for protein S deficiency.^[18] Other authors have reported that factor V Leiden and the prothrombin gene mutation significantly increase the risk of superficial thrombophlebitis.

The prothrombin time (PT) and activated partial thromboplastin time (aPTT) are not useful in the diagnostic evaluation of patients with suspected superficial or deep thrombophlebitis. Most patients with thrombophlebitis have a normal PT and aPTT, and active thrombophlebitis is not uncommon in patients with a therapeutically elevated international normalized ratio (INR) due to warfarin therapy.

A low white blood cell (WBC) count lowers the likelihood of an infectious process and raises the likelihood of phlebitis. An elevated WBC count is not specific, because normal and elevated WBC counts are common in patients with thrombophlebitis. Chronic venous insufficiency (venous congestion due to reflux) and superficial thrombophlebitis or deep venous thrombosis (DVT) can mimic leg cellulitis very closely, and true cellulitis (with an elevated WBC count) is a frequent complication of both diseases.

D-dimer is a unique degradation product produced by plasmin-mediated proteolysis of cross-linked fibrin that is often measured in the evaluation for DVT and pulmonary embolism (PE). However, it is of little clinical use for detecting thrombophlebitis.^[19]

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Venography

Venography is rarely required to diagnose superficial thrombophlebitis. The modality is also not necessary to exclude the diagnosis of DVT, which can be excluded with duplex scanning.

Invasive contrast venography, once the criterion standard for evaluation of the venous system, has fallen out of favor because of its invasiveness, as well as its use of ionizing radiation and IV contrast. In addition, it can lead to venous scarring and thrombophlebitis. If information on the pelvic veins or iliac venous outflow tract is required, CT venography, if available, is usually preferable.

Magnetic resonance venography (MRV) is a noninvasive test that probably is more sensitive and more specific than ultrasonography (US) in the detection of deep venous thrombophlebitis; however, this is not readily available and is not practical at most institutions.

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Ultrasonography

Duplex US evaluation is the diagnostic study of choice for venous thrombosis. Thrombosed veins may appear thickened or inflamed on US, but the most accurate diagnostic finding is a lack of compressibility of the vein using the scan head (see the image below). An experienced sonographer should be able to diagnose superficial thrombophlebitis with a high sensitivity and specificity.^[20]

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Thrombosis of great saphenous vein and tributaries. Note lack of full compressibility of vein secondary to intraluminal thrombus. Courtesy of Wikimedi....

All patients with superficial thrombophlebitis above the knee should undergo duplex US as the initial diagnostic modality of choice to rule out DVT. When the patient has superficial thrombophlebitis below the knee, duplex US is only indicated for signs and symptoms consistent with DVT (eg, asymmetrical swelling, erythema, pain). Superficial thrombophlebitis in lower-extremity varicose veins has an extremely low incidence of DVT.^[21]

After an initial diagnosis of superficial thrombophlebitis, especially in the thigh region, a follow-up duplex US examination in 48-72 hours should be performed to look for progression of disease after treatment is initiated. A finding of no clot extension indicates successful therapy. Thrombus extension or encroachment toward the deep venous system should prompt more aggressive treatment.

Results from a study by Quéré et al indicated that in patients with symptomatic superficial venous thrombosis, compression US of an affected limb’s entire venous system provides valuable treatment information.^[22] The investigation involved 844 patients from the Prospective Observational Superficial Thrombophlebitis (POST) study, all of whom had symptomatic superficial venous thrombosis. A complete lower limb scan of both legs using compression US was performed on all of the patients, with imaging of the superficial and deep venous systems.

Among the report’s findings were that concomitant DVT was present in 198 patients (23.5%) and that 41.8% of those individuals had proximal DVT.^[22] Superficial venous thrombosis was not contiguous with DVT in 83 (41.9%) of the 198 patients.

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Diagnosis in Pregnancy

Venous thrombophlebitis and PE are common during all trimesters of pregnancy and for 6-12 weeks after delivery.

Superficial varicosities and superficial phlebitis, along with associated DVT, are also common during pregnancy because of a pregnancy-related reduction in intrinsic plasminogen activator activity. Failure to treat the mother properly is the most common cause of fetal demise.

The diagnostic approach, as follows, should be exactly the same in a pregnant patient as in a nonpregnant one:

• Duplex US is safe in pregnancy
• If indicated, a nuclear perfusion lung scan may be performed safely in pregnancy
• If indicated, heparin may be used in pregnancy
• If indicated, fibrinolytics may be used in pregnancy

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Approach Considerations

The treatment of superficial venous thrombosis depends on the condition’s etiology, extent, and symptoms. Duplex ultrasonography (US) gives an accurate appraisal of the extent of disease and thus allows the administration of a more rational therapy.

For the superficial, localized, mildly tender area of thrombophlebitis that occurs in a varicose vein, treatment with mild analgesics, such as aspirin, and the use of some type of elastic support usually are sufficient. Patients are encouraged to continue their usual daily activities. If extensive varicosities are present or if symptoms persist, phlebectomy of the involved segment may be indicated.

More severe thrombophlebitis, as indicated by the degree of pain, redness, and the extent of the abnormality, should be treated with elevation of the extremity and the application of massive, hot, wet compresses. The latter measure seems to be more effective when a large, bulky dressing, including a blanket and plastic sheeting followed by hot water bottles, is used, taking care to avoid burning the patient.

Anticoagulants are usually not indicated in superficial thrombophlebitis unless the process extends into the deep venous system^[23] or persistent inflammation is present in an affected area.^[24]

In the case of thrombosis of a hemorrhoid, evacuation of the thrombus, though very painful, usually provides rapid relief. Magnesium sulfate compresses may also be used to alleviate swelling and pain, though surgery is sometimes necessary to remove the clot from the hemorrhoid.

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Compression Stockings

Long-leg, heavy-gauge elastic stockings or multiple elastic (Ace) bandages are indicated when the patient becomes ambulatory.

Gradient compression stockings are an often-overlooked adjunctive therapy that is both benign and effective. These highly elastic stockings provide a gradient of compression that is highest at the toes (at least 30-40 mm Hg) and gradually decreases to the level of the thigh. This amount of compression reduces capacitive venous volume by approximately 70% and increases the measured velocity of blood flow in the deep veins by a factor of 5 or more. Gradient compression hose also have been shown to increase local and regional intrinsic fibrinolytic activity.

In the early phases of superficial thrombophlebitis in the leg, dangling the extremity without external support from stockings or elastic bandages leads to leg swelling and increased pain.

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Pharmacologic Therapy

Current treatment options are aimed at resolving symptoms, preventing recurrence and most importantly, and preventing extension to the deep venous system, which may potentially result in a thromboembolism. Previous treatment options were based on a Cochrane review published in 2007 that showed that nonsteroidal anti-inflammatory drugs (NSAIDs) and low-molecular-weight heparin (LMWH) are the first options.^[25]

A second Cochrane review published in 2013 added, among others, a large randomized control study that included more than 3000 patients with superficial thrombophlebitis and compared fondaparinux with placebo. The investigators found fondaparinux to be a good option for treatment of superficial thrombophlebitis and prevention of some of its associated complications.^[26]

Fondaparinux

Fondaparinux is a newer anticoagulant that was derived from the binding region of heparin and antithrombin. It is an inhibitor of factor Xa, and its main uses are the same as those of heparin—more specifically, prevention and treatment of venous thrombosis and pulmonary embolism (PE). Fondaparinux is not shown to interact with platelets and platelet factor 4 and thus theoretically should not cause heparin-induced thrombocytopenia (HIT). Its main advantage over heparin or LMWH is that its bioavailability and half-life (15-17 hours) allow once-daily dosing.

As noted (see above), fondaparinux has been shown to achieve significant reductions in the extension of superficial thrombophlebitis into the deeper venous systems and the rate of recurrence in general, as well as to reduce the symptoms of venous thromboembolism when compared to placebo^[26] ; however, there was no difference with respect to the rates of major bleeding. To date, no studies have been done to compare the efficacy of fondaparinux with that of heparin or LMWH in superficial thrombophlebitis.

Use of the lowest dosage of fondaparinux (2.5 mg/day subcutaneously) for 45 days was shown by Decousus et al to suffice for prevention of extension, recurrence, and embolization of superficial venous thrombosis.^[27] Another advantage to this anticoagulant medication is that the dosage studied for superficial venous thrombosis does not have to be monitored. At this dosage, fondaparinux has not been shown to affect activated partial thromboplastin time (aPTT), prothrombin time (PT), or bleeding time.^[28]

Fondaparinux should be avoided in patients with kidney function compromise, active bleeding, bacterial endocarditis, and body weight below 50 kg. One downside to the use of fondaparinux is that there is currently no antidote, especially for the low dosage used for superficial thrombophlebitis treatment. Also, because this agent is cleared by the renal system, prolonged administration warrants renal function monitoring and should be discontinued if creatinine clearance is less than 30 mL/min.

Low-molecular-weight heparin

The 2007 Cochrane review cited above suggested that anticoagulation with LMWH is better in reducing local signs and symptoms, along with reducing propagation to deep venous thrombosis (DVT).^[25] In addition, LMWH is useful in preventing the progression of thrombosis and is recommended when there is evidence of DVT.

Patients with contraindications to anticoagulation or those receiving adequate anticoagulation treatment who have progression of thrombosis should be considered for saphenous ligation at the junction with the deep venous system.

Nonsteroidal anti-inflammatory drugs

The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) is similar to that of LMWH in reducing the risk of extension of superficial thrombophlebitis into the deep venous system along with decreasing recurrence. In addition, NSAIDs are often more practical and more easily administered than LMWH. No NSAID has not been shown to be superior to others in the treatment of superficial thrombophlebitis.

Antibiotics

Antibiotics are not routinely indicated for treatment of superficial thrombophlebitis, in that the erythema and tenderness are local inflammatory reactions, not allergic reactions. However, if suppurative thrombophlebitis may be present, then antibiotics should cover skin flora and anaerobic organisms, especially if an abscess is present. One should also consider coverage with vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) if the local population warrants this.

Local thrombolytics

No adequate studies have been performed on the use of local thrombolytics, and they were excluded from the Cochrane Database of Systematic Reviews article. Therefore, at this time, their use is not recommended.

Related studies

Patients who present with thrombosis of the great saphenous vein (GSV) or the small saphenous vein (SSV) should be considered for anticoagulation or ligation of the vein, given that a high incidence (6-44%) of concurrence or progression to DVT has been reported in such patients. In a study, Ascher et al reported that 65.6% of patients who presented with GSV thrombosis were found to have associated DVT.^[29]

A meta-analysis of the prevalence of DVT and PE in patients with superficial vein thrombosis found a weighted mean prevalence of 18.1% for DVT and 6.9% for PE in patient with superficial thrombophlebitis. The authors concluded that in selected patients with superficial thrombophlebitis, screening for DVT or PE may be warranted.^[30]

Optimal treatment of saphenous vein thrombosis remains controversial. As noted by Wichers et al in a systematic review, a lack of randomized trials has prevented evidence-based recommendations in this area.^[16]

In a small, randomized trial of 60 patients with GSV thrombosis, Lozano et al compared treatment using LMWH with surgical saphenous ligation.^[31] Patients in the LMWH group experienced no episodes of DVT or PE but had a 10% incidence of recurrent superficial venous thrombosis. Among the patients treated surgically, two pulmonary emboli (6.7%) were found, and one episode of recurrent superficial venous thrombosis (3.3%) occurred.

In a larger randomized trial (Stenox study), no statistical difference in the incidence of DVT or PE was found between patients with superficial venous thrombosis who were treated with placebo, with NSAIDs, or with two doses of LMWH. In the study, 436 patients were randomized to one of the three groups; all patients wore compression stockings.

The study’s placebo group had a higher incidence of recurrent superficial venous thrombosis than did the other patients. Interestingly, the results in the group treated with NSAIDs were the same as those in the patients treated with LMWH.

Similar to the outcome of the above study, Wichers et al concluded, after a systematic review of the literature, that LMWH or NSAID therapy appears to reduce the incidence of superficial venous thrombosis extension or recurrence.^[16] Larger trials are likely required to demonstrate differences in the incidence of DVT.

Treating patients with some form of low- or intermediate-dose anticoagulation appears reasonable at this time; this should be followed by repeat duplex ultrasonography to look for progression at regular intervals for a few weeks to a month. In patients with stable nonprogressing thrombus, anticoagulation therapy can probably be discontinued in the absence of other risk factors.

SURPRISE trial

The SURPRISE trial was a randomized, open-label, blinded outcome event adjudication trial that compared rivaroxaban 10 mg once daily with fondaparinux 2.5 mg once daily in 472 patients with superficial vein thrombosis who were at risk for venous thromboembolism (VTE) and complications.^[32]  Both groups were treated for 45 + 5 days and had an observational period of 90 + 10 days.

The investigators looked at primary efficacy outcome as a composite endpoint of deep venous thrombosis (DVT), pulmonary embolism (PE), progression of superficial vein thrombosis towards the saphenofemoral junction, recurrence of superficial venous thrombosis and all-cause mortality at day 45.^[32] The trial was designed to show noninferiority of rivaroraxaban compared to fondaparinux in terms of primary endpoints and risk of major bleeding.

The investigators found that the primary efficacy outcome occurred in 3.3%  of patients receiving rivaroxaban and 1.8% of patients receiving fondaparinux.^[32] On the basis of this finding, the absolute difference between rivaroxaban and fondaparinux was 1.53% (P = .025 for noninferiority). Rivaroxaban 10 mg once daily was shown to be noninferior to fondaparinux 2.5 mg once daily for treatment of superficial venous thrombosis. The incidence of clinically significant nonmajor bleeding was 2.5% at 45 days and 2.5% at 90 days for rivaroxaban versus 0.4% at 45 days and 0.9% at 90 days for fondaparinux.

Noninferiority was shown for rivaroxaban with no statisically significantly increased rate of major bleeding as compared with fondaparinux.^[32] No data were collected on comparative quality of life between the two medication regimens. This is an important consideration, in that rivaroxaban is given orally once daily and fondaparinux as a subcutaneous injection once daily. The authors state that this consideration will have to be addressed in further studies.

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Excision and Ligation

With persistence or spread of the process, the thrombophlebitic vein may be excised.^[33] Patients who demonstrate signs and symptoms of septic thrombophlebitis require urgent venous excision to control the septic focus. This is usually performed through a direct incision over the vein, allowing removal of the infected thrombosed segment along with wide debridement of any surrounding infected or necrotic tissue. Cultures are sent to guide antibiotic therapy.

Surgical treatment may also be considered for patients with saphenous thrombophlebitis. This is most often considered if the process extends upward toward the femoral or popliteal vein despite anticoagulation or in a patient with a contraindication to systemic anticoagulation.

Whether surgical ligation or anticoagulation is the best initial treatment for saphenous vein thrombosis without deep venous involvement remains controversial. If saphenous ligation is chosen, high ligation at the saphenofemoral or saphenopopliteal junction is recommended, with ligation of any branches near the junction. For saphenopopliteal procedures, US mapping for guidance is recommended because of the variability in location of the saphenopopliteal anatomy.

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Puncture and Evacuation

A painful section of a superficial vein containing a palpable intravascular coagulum may be treated by puncture incision with an 18-gauge needle and evacuation of the clot after local anesthesia. This procedure often produces marked rapid relief and rapid resolution of the inflammation.

Puncture and evacuation is less effective in the first week after the onset of symptoms, because the vessel wall is thickened and the coagulum itself is more cohesive during the early phase of phlebitis.

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Treatment of Septic and Suppurative Thrombophlebitis

If thrombophlebitis is associated with a cannula or a catheter, the device should be immediately removed and cultured. If the patient is in a septic state, appropriate antibiotics should be given. If suppurative thrombophlebitis is suspected, immediate and complete excision of all of the involved veins is indicated. The wound may be left packed open for secondary closure or skin grafting at a later date. The use of appropriate systemic antibiotics is always indicated.

If the suppurative process involves one of the deep veins, aggressive antimicrobial and anticoagulant therapy are necessary.

If a venous segment involved in superficial thrombophlebitis is suspected to be a source of bacteremia but does not require excision, it can be aspirated in order to culture the contents of the venous lumen. This may be helpful in immunocompromised patients with phlebothrombosis and positive blood cultures.

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Long-Term Monitoring

Follow-up should be performed 2-3 days after treatment for superficial thrombophlebitis, either with an office visit or by telephone, to be sure that the patient is progressing in a satisfactory manner.

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Medication Summary

Some anti-inflammatory drugs may be of benefit in the treatment of superficial thrombophlebitis. Salicylates, indomethacin, and ibuprofen have been reported to be effective. In addition, salicylates, ibuprofen, and dipyridamole have been used as antithrombotic agents, but their effectiveness has not been documented in this setting.^[34]

Because thrombophlebitis is primarily due to inflammation and fibrin clot, antithrombotic or antiplatelet-aggregating agents would seem to have little value. Anticoagulants are usually not indicated unless the process extends into the deep venous system.^[23]

Additionally, in rare cases in which persistent inflammation is present in an area of superficial thrombophlebitis, a brief course of low-molecular-weight heparin (LMWH) can be used as an alternative to excision of the vein in order to bring the inflammation under control. This treatment alternative may be necessary for management of superficial thrombophlebitis associated with pregnancy.

Antibiotics are usually not necessary in superficial thrombophlebitis unless the process is suppurative. In persistent cases or even as early definitive therapy, excision of the inflammatory process is effective. The wounds usually heal well with primary closure; the inflammatory process, except in suppurative phlebitis, is usually nonbacterial and localized and is removed completely.

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Ibuprofen (Ibu, Advil, Motrin)

• Dosing, Interactions, etc.

Clinical Context:  Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

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Indomethacin (Indocin)

• Dosing, Interactions, etc.

Clinical Context:  Indomethacin, which inhibits prostaglandin synthesis, is rapidly absorbed. Metabolism of the drug occurs in the liver by demethylation, deacetylation, and glucuronide conjugation.

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Naproxen (Aleve, Anaprox, Naprelan, Naprosyn)

• Dosing, Interactions, etc.

Clinical Context:  Naproxen inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in decrease of prostaglandin synthesis.

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Class Summary

Along with LMWHs, nonsteroidal anti-inflammatory drugs (NSAIDs) are considered first options to resolve symptoms and prevent extension of thromboembolism.

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Enoxaparin (Lovenox)

• Dosing, Interactions, etc.

Clinical Context:  Enoxaparin was the first LMWH released in the United States and is the only LMWH now approved by the US Food and Drug Administration (FDA) for both treatment and prophylaxis of deep venous thrombosis (DVT).

It is widely used in pregnancy, although clinical trials are not yet available to demonstrate that it is as safe as unfractionated heparin.

When enoxaparin is used, there is no utility in checking the aPTT (the drug has a wide therapeutic window, and aPTT does not correlate with the anticoagulant effect).

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Dalteparin (Fragmin)

• Dosing, Interactions, etc.

Clinical Context:  Dalteparin is indicated for the prevention of DVT, which may lead to pulmonary embolism (PE). It enhances the inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, dalteparin preferentially increases the inhibition of factor Xa. The average duration of treatment is 7-14 days.

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Heparin

• Dosing, Interactions, etc.

Clinical Context:  The initial bolus used for inflammatory or septic thrombosis is lower than that needed for spontaneous DVT and PE, because most patients with inflammatory or septic thrombophlebitis do not have underlying hypercoagulability.

Patients withDVT and PE require more aggressive therapy because DVT is a manifestation of an active hypercoagulable state.

Do not check aPTT until 6 hours after the initial bolus, as an extremely high or low value during this time should not provoke any action.

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Class Summary

Heparin is essential for patients with superficial thrombophlebitis that is progressive and for those with particular risk factors for progression or recurrence. Heparin should always be used when thrombophlebitis involves the great saphenous vein. Heparin is the mainstay of treatment when deep system involvement is suggested, but anticoagulation alone does not guarantee a successful outcome. The disease may progress despite full and effective heparin anticoagulation.

Heparin works by activating antithrombin III to slow or prevent the progression of venous thrombosis. Heparin does not dissolve existing clots.

Fractionated LMWHs have largely replaced unfractionated heparin in the treatment of superficial phlebitis. LMWHs offer several distinct advantages over unfractionated heparin, including the following:

- They may be used in the outpatient setting

- They do not require measurement of the activated partial thromboplasting time (aPTT)

- They produce more reliable anticoagulation

- They are associated with a lower risk of bleeding

When unfractionated heparin is used, an aPTT of at least 1.5 times the control value is necessary for a therapeutic effect. To achieve this, unfractionated heparin must be given intravenously in adequate doses. Low-dose, subcutaneous unfractionated heparin should not be used, as it is not an effective therapy for thrombophlebitis and does not provide effective prophylaxis against progression of the disease.

Warfarin should not be used in the acute treatment of superficial phlebitis, because the early risk of increased thrombogenesis outweighs any convenience of oral therapy.

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Ceftriaxone (Rocephin)

• Dosing, Interactions, etc.

Clinical Context:  Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity. It has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. This agent arrests bacterial growth by binding to 1 or more penicillin-binding proteins. When used for the treatment of phlebitis, ceftriaxone should be administered intravenously rather than intramuscularly.

Ceftriaxone is effective in the treatment of superficial phlebitis and bacterial septicemia caused by Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, viridans group streptococci, Escherichia coli, Enterobacter cloacae, Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Morganella morganii, Serratia marcescens, Acinetobacter calcoaceticus, Bacteroides fragilis, and various Peptostreptococcus species.

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Cephalexin (Keflex)

• Dosing, Interactions, etc.

Clinical Context:  Cephalexin is a first-generation cephalosporin that may be used as adjunctive therapy in superficial phlebitis if infection is possible but unlikely, and if the only likely organisms would be skin flora, including staphylococci and streptococci.

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Class Summary

These agents are not routinely useful in nonseptic superficial phlebitis. Antibiotics are indicated whenever infection is suspected to play a role and whenever phlebitis of the great saphenous vein above the knee threatens to approach the saphenofemoral junction. The choice of antibiotics should be guided by blood culture results whenever possible, but empiric therapy should at a minimum provide coverage for group A streptococci and for Staphylococcus aureus.

Superficial phlebitis must not be confused with septic phlebitis, which can be life threatening. If septic phlebitis is suspected, the selection of antibiotics is critically important and depends upon the clinical setting.

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