AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Many innate conditions may predispose patients to thrombophlebitis by means of a variety of hypercoagulopathy syndromes. Traumatic events can also initiate a thrombophlebitic reaction. In addition, the persistence of significant reflux into a vein that has been treated with a sclerosing agent can lead to phlebitis. More commonly, phlebitis occurs if perforator veins in the region of sclerotherapy are not diagnosed and treated.

Pathophysiology

Hypercoagulable states

A number of primary and secondary hypercoagulable states can be assessed by obtaining an appropriate patient history and review of systems. Prior to 1993, only 3 inherited hypercoagulable factors had been recognized: antithrombin III, protein C, and protein S. More recently, heritable defects were identified in 10-15 genes that code for 1 or more of the following coagulation factors: (1) factor V, (2) prothrombin, (3) homocysteine pathway enzymes, (4) free protein S, (5) activated protein C (APC), (6) lupuslike inhibitor, and (7) anticardiolipin antibodies.

In the general population, the prevalence of an inherited thrombotic syndrome is presently estimated to be 1 individual in 2500-5000; the prevalence increases to 4% in patients with a past history of thrombosis.¹ A past history of deep venous thrombosis (DVT) increases the likelihood of new postoperative venous thrombosis from 26% to 68%, whereas a past history of both DVT and pulmonary embolism (PE) is predictive of a near 100% incidence of thrombosis.² Further detail regarding hypercoagulable conditions is beyond the scope of this article. The most common conditions are discussed below. For additional information, the reader is referred to multiple review articles on hypercoagulable conditions.^{1, 3, 4}

Resistance to APC (see Inherited factor deficiency) is the most common genetic risk factor associated with venous thrombosis. Most cases are due to a point mutation in the factor V gene (factor V Leiden [FVL]), which subsequently prevents the cleavage and disruption of activated factor V by APC and thus promotes ongoing clot development. In approximately 3-8% of white adults, this mutation is heterozygous, but many of these individuals have no history of thrombosis. Double heterozygosity with FVL and protein C, protein S, or antithrombin deficiency is reported, and affected individuals have an increased risk of thrombosis. Women with FVL heterozygosity who are also taking oral contraceptives have a 35-fold increase in the risk of thrombosis.

Oral contraceptive use and estrogen replacement therapy

The mechanism for thromboembolic disease in women who use oral contraceptives is multifactorial. Both estrogens and progestogens are implicated in promoting thrombosis, even with low-dose therapy.^{5, 6, 7} All study results indicate that the increased risk occurs predominately when the preparations are actually used and perhaps for a week or so after their discontinuation.^{8, 9} However, the total correction of potentially hemostatic changes that occur during oral contraceptive therapy requires 4 weeks of abstinence.¹⁰

The highest rate of thromboembolism occurs with the use of large doses of estrogen^{5, 6, 7, 8, 11}; some studies show an 11-fold increase in thromboembolism.^{8, 12} Nevertheless, the risk of postoperative PE still appears to be increased in women who use oral contraceptive agents, even with minimal amounts of estrogen.¹³

The incidence of DVT associated with oral contraceptive use varies on the type and concentration of estrogen. The potency among native estrogens, estrone and estradiol, ethinyl estradiol, and estrogens in oral contraceptive agents differs by at least 200-fold.¹⁴ In patients who receive hormone replacement therapy with 0.625-mg conjugated equine estrogens and 2.5-mg medroxyprogesterone, the risk of DVT is 2-3.6 times higher than that of nonusers.¹⁵

Oral contraceptives are responsible for about 1 case of superficial venous thrombosis (SVT) or DVT per 500 women users per year.¹⁶ This incidence of symptomatic thrombosis may be a low estimate of true hypercoagulability; a plasma fibrinogen chromatographic study demonstrated a 27% incidence of silent thrombotic lesions in 154 new users of either mestranol 100 mg or ethinyl estradiol 50 mg.¹⁷

As a group, people who take oral contraceptives have numerous alterations in their coagulation system that promote a hypercoagulable state. These alterations include hyperaggregable platelets, decreased endothelial fibrinolysis¹⁸, decreased negative surface charge on vessel walls and blood cells¹⁹, elevated levels of procoagulants, reduced RBC filterability²⁰, increased blood viscosity secondary to elevated RBC volume²¹, and decreased levels of antithrombin III.^{22, 23, 24} An alteration in any of these factors, alone or in combination, may predominate in women who are taking oral contraceptives. The extent of the derangement in the hemostatic system determines whether thrombosis occurs.

The most important factors that prevent clot propagation are antithrombin III and vascular stores of tissue plasminogen activator (t-PA).^{22, 25, 26, 27} Antithrombin III levels are 20% lower in some women who are taking oral contraceptive agents²⁵ or estrogen replacement medications.²⁸ In women who use oral contraceptive agents and have thromboembolic events, releasable t-PA is decreased 25-fold in 90%^{22, 25, 26}, and the venous walls in 51.6% have an abnormally low plasminogen activator content.²⁷ Therefore, a certain subgroup of women who are taking birth control pills may have a particular risk for thromboembolic disease.

In addition, the distensibility of the peripheral veins may increase with the use of systemic estrogens and progestins.²⁹ This increased distensibility may promote valvular dysfunction and a relative stasis in blood flow, which enhance the hypercoagulable state.

A therapeutic alternative that should be considered for women in whom estrogen replacement cannot be discontinued is transdermal 17-beta-estradiol. The direct delivery of estrogen into the peripheral circulation eliminates the first-pass effect of liver metabolism. This delivery method decreases hepatic estrogen levels, with subsequent minimization of the estrogen-induced alteration of coagulation proteins. Thus, the use of transdermal estrogen is recommended for patients with an increased risk of thromboembolism because alterations in blood clotting factors have not been demonstrated during such treatment.³⁰

Tamoxifen use

Unusual and poorly understood complications of tamoxifen use are thrombophlebitis and DVT. These complications occur in as many as 1% of treated patients.^{31, 32} Results from the evaluation of various coagulation parameters and factors, including the sex hormone–binding globulin level, antithrombin III fibrinogen level, platelet count, protein C level, and fibrinopeptide A level, are normal.^{32, 33, 34, 35, 36}

Pregnancy

During pregnancy, an increase in most procoagulant factors and a reduction in fibrinolytic activity occur. Plasma fibrinogen levels gradually increase after the third month of pregnancy to double those of the nonpregnant state. In the second half of pregnancy, levels of factors VII, VIII, IX, and X also increase.³⁷ Decreased fibrinolytic activity is probably related to a decrease in the level of circulating plasminogen activator.³⁸ In addition, a 68% reduction in protein S levels is measured during pregnancy and in the postpartum period.³⁹ Protein S levels do not return to the reference range until 12 weeks after delivery. These changes are necessary to prevent hemorrhage during placental separation.

The hypercoagulable condition of the immediate antepartum period is responsible, in large part, for the development of superficial thrombophlebitis and DVT in 0.15% and 0.04% of this patient population, respectively.⁴⁰ Even more important is the immediate postpartum period, during which the incidences of superficial thrombophlebitis and DVT increase to 1.18% and 0.15%, respectively. Fifty percent of the cases of DVT develop by the second day after delivery. Because normalization of most coagulation factors generally occurs by postpartum day 3⁴¹, additional factors are suspected in the 21% of patients in whom a DVT subsequently develops 2-3 weeks after delivery. Maternal age is also linked to venous thrombosis; the rate is approximately 1 case per 1000 women younger than 25 years, and the rate increases to 1 case per 1200 women older than 35 years.¹¹

Two thirds of patients in whom postpartum DVT develops have varicose veins. Thus, in addition to the potential adverse effects on the fetus, sclerotherapy should be avoided near term until coagulability returns to normal 6 weeks after delivery.

Inherited factor deficiency

Although endothelial damage is speculated to be necessary for symptomatic thrombosis to occur, venous thrombosis may be associated with a deficiency in 1 of several anticoagulant factors.⁴² In otherwise healthy patients younger than 45 years who are referred for evaluation of venous thrombosis, the prevalence of antithrombin III, protein C, and protein S deficiency is approximately 5% for each.⁴³

Antithrombin III deficiency occurs in 1 person per 2000-5000 people in the general population.^{44, 45} Acquired antithrombin III deficiency can occur with liver disease and as a result of oral contraceptive use. Antithrombin III combines with coagulation factors, blocking biologic activity and inhibiting thrombosis.

Protein C and protein S, 2 vitamin K–dependent proteins, are other important anticoagulant factors. Protein S is a cofactor for the effect of APC on factors Va and VIIIa. In the United States, the prevalence of heterozygous protein C deficiency is estimated to be 1 case per 60-300 healthy adults.⁴⁶ More than 95% of the patients are asymptomatic. However, a significant deficiency in either protein can predispose an individual to DVT. In fact, 75% of patients with homozygosity for protein S deficiency have venous thrombosis before they are aged 35 years.⁴⁷

Although factor deficiency can cause venous thrombosis, a genetic alteration in factor V, which results in APC resistance, is at least 10 times more common than other alterations. This genetic alteration is found in approximately one third of patients referred for an evaluation of DVT.^{48, 49, 50} Precipitating factors for thrombosis, such as pregnancy and use of oral contraceptives, were present in 60% of these patients. APC resistance is discussed in Hypercoagulable states.

Defects in the fibrinolytic system, specifically plasminogen, occur in as much as 10% of the healthy population.⁵¹ When the defects occur alone, the risk of thrombosis is small. Under certain circumstances, abnormal plasminogen levels may also predispose an individual to thrombosis.

Lupuslike anticoagulants are present in 16-33% of patients with lupus erythematosus, as well as in many patients with a variety of autoimmune disorders.^{52, 53, 54} Thrombosis may occur in 30-50% of patients with circulating lupuslike anticoagulants.^{54, 55, 56}

Travel-related venous thrombosis

Although the relationship between air travel and DVT was first recognized in 1954⁵⁷, PE was noted to occur in Londoners confined in air raid shelters during World War II. In 1993, Lord and McGrath reported findings of 45 patients in whom venous thrombosis was related to travel (37 by air and 8 by road or rail).⁵⁸ Clinical risk factors included previous thromboembolism (31%) and varicose veins (20%). Hypercoagulable factors were detected in 47% of the patients by using the assays available in 1993.

Lord reported that in 122 additional patients, thromboembolism was associated with prolonged travel.^{59, 60} Hypercoagulable factors were isolated in 72% of patients who were tested. The most common factor was protein C resistance, which was found in 47% of patients.

At least one clinical or laboratory risk factor was present prior to travel in more than 80% of patients who developed DVT after long-haul flights (>8 h), and SVT was diagnosed in 12% of this study group.⁶¹ In most cases, the risk factors could be identified by medical history without any laboratory testing. The most common risk factors were estrogen use, history of thrombosis, and the presence of factor V Leiden.

Malignancy

Hypercoagulability occurs in association with a number of malignancies. Symptoms suggestive of malignancy should be investigated in individuals without other known risk factors for thrombosis.

Other factors

Alteration of the activity of matrix metalloproteinases influences mechanical properties of the vein wall.⁶² Thrombophlebitis may be a complication of intravenous catheters⁶³, medications interfering with the coagulation pathway, or anticoagulant treatment⁶⁴, infections.⁶⁵ Venous function was suggested to be influenced by genetic factors.⁶⁶

Frequency

United States

See Pathophysiology. Exact frequency data for the general population are hard to find. The frequency is influenced by the subgroups of patients studied.

International

The frequency is the same as that in the United States.

Mortality/Morbidity

• DVT causes pain, and it may also be associated with the development of life-threatening PE, if untreated. Similarly, superficial thrombophlebitis is not a complication that should be taken lightly. If untreated, the inflammation and clot may spread through the perforating veins to the deep venous system. This extension may lead to valvular damage and possible pulmonary embolic events.^{67, 68, 69, 70, 71} Propagation of SVT to DVT may occur in up to 15% of patients (Leon, 2005). Superficial thrombophlebitis is associated with an elevated risk of recurrence.⁷²


• Coincidental DVT with SVT is reportedly more common in patients without varicose veins than in those with varicose veins (60% vs 20%). Thus, other innate factors place patients with SVT at additional risk for DVT.


• In a study of 145 patients, superficial thrombophlebitis in 23% of the affected limbs had proximal extension into the saphenofemoral junction (SFJ).⁷³ PE was found in 7 (33.3%) of 21 patients with thrombophlebitis of the greater saphenous vein (GSV) above the knee.⁷⁴ Seventeen of the 21 patients had varicose veins. In this study, clinical symptoms suggestive of PE were present in only 1 of 7 patients. The occurrence of DVT in patients with below-the-knee SVT was 25 (32%) in a study of 78 patients.⁷⁵

Race

No racial predilection is recognized.

Sex

Women have a slight predilection over men because of systemic estrogen use.

Age

Age may be a predisposing factor in SVT and/or DVT. Reportedly, elderly patients have an increased risk of DVT.^{76, 77, 78} The major cause of this increased risk may be the relative pooling of blood in the soleal venous sinuses, which occurs as a result of decreased calf muscle pump infusion.⁷⁹

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Symptoms potentially caused by venous thrombosis are generally nonspecific.

• In superficial thrombophlebitis, acute-onset pain and swelling usually occur over a previous varicose vein.
• • At times, this pain and swelling, which is often associated with warm erythema, can appear even without an obvious underlying varicosity.
  
  
  • Swelling and pain in an upper extremity are suggestive of thrombosis.
  
  
  • Pain associated with SVT is usually localized over the site of thrombosis.
  
  
  • Pain associated with DVT is generally more diffuse and more common in the lower extremities than elsewhere.


• Recent surgery (especially orthopedic surgery), trauma, immobilization, or prolonged bed rest are factors that can contribute to SVT or DVT.


• Inquire about a history or symptoms suggestive of heart disease or congestive heart failure; relevant findings include dizziness, bilateral extremity swelling, and weight gain.


• Inquire about a history of previous thrombosis.


• Obtain a thorough family history.


• Document the patient's age when thrombosis was diagnosed as well as the type of thrombosis (eg, DVT, SVT, PE, myocardial infarction [MI], stroke).


• Obtain an accurate obstetric history in female patients. Recurrent spontaneous abortions may suggest an underlying factor deficiency.


• Because hypercoagulability occurs in association with a number of malignancies, a history or symptoms suggestive of malignancy (eg, fever, bone pain, weight loss, bruising, fatigue) should be investigated in individuals without other known risk factors for thrombosis.


• Inquire about sickle cell disease.


• Risk factors (in the healthy flying population) included factors of immobilization associated with prolonged chair-rest deconditioning, including dehydration, hypovolemia, increased viscosity of the blood, and reduced venous blood flow.⁸⁰

Physical

• The classic findings of SVT are a firm, tender, erythematous fibrous cord, usually in the area of a previous varicose or normal-appearing vein.
• In cases of DVT, mild-to-moderate edema, erythema, and tenderness prevail.
• A discrete cord rarely is palpable in DVT, especially DVT in a lower extremity.
• Patients with venous thrombosis (or cellulitis) may present with a hot, swollen leg.

Causes

See Pathophysiology.

• Trauma to a varicose vein or normal vein is common.


• Predisposing factors include any event that can reduce venous flow; examples include prolonged sitting or immobilization and dehydration (as on a long airline flight), long surgery, or prolonged bed rest.


• Internal trauma to a vein due to an indwelling catheter or even a difficult phlebotomy procedure can also cause venous injury and inflammation.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Vasculitis
Sickle cell disease

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Laboratory evaluation for factor-related hypercoagulability conditions includes the measurement of the following:
• • Protein C and APC resistance
  
  
  • Protein S level
  
  
  • Antithrombin III level
  
  
  • Lupus anticoagulant level
  
  
  • Anticardiolipin antibody level


• See Pathophysiology.

Imaging Studies

• Venous duplex ultrasonography, which is mandatory, helps in diagnosing the thrombosis in the vein and details its extent.
• Venography, which is rarely necessary, may be used to define the extent and propagation of the thrombosis.
• If PE is suspected, appropriate tests such as chest radiography, ventilation perfusion scanning, and/or pulmonary venography may be necessary.

Procedures

• If an occult malignancy is suspected, a thorough workup should be performed. A complete medical workup is required in young adults who have thrombophlebitis but no predisposing factors because an occult malignancy is possible.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The location of the thrombosis directs the treatment.

If progression to DVT is suspected or proven, adequate anticoagulation is imperative to prevent PE and other possible long-term complications of DVT.

• Adequate compression should be maintained, and the patient should ambulate frequently until the pain and inflammation resolve.


• In addition to adequate compression, drainage of the thrombi after their liquefaction (approximately 2 wk after onset of the lesion) hastens the otherwise slow, painful resorption process.⁸¹


• Aspirin or other nonsteroidal anti-inflammatory agents may be helpful in limiting both inflammation and pain.
• • Patients with extensive involvement of leg varices should receive anticoagulants. This treatment is particularly important if the proximal part of the SFJ is involved. In addition to propagation of the thrombus through the SFJ, 11-40% of patients with SVT at the SFJ have evidence of concurrent DVT.^{74, 75, 82, 83} In these patients, anticoagulation for 6 months resolved the DVT and/or SVT and prevented PE. This success occurred despite duplex ultrasonographic evidence of SVT progression to DVT in 2 of 20 patients.⁸²
  
  
  • The use of low-dose low molecular weight heparin (LMWH) in patients with SVT may decrease perivascular inflammation. LMWH limits neutrophil extravasation.⁸⁴ Thus, LMWH has anti-inflammatory properties in addition to anticoagulant properties.
  
  
  • High doses of unfractionated heparin were more effective in preventing thromboembolic combinations than prophylactic doses.⁸⁵
  
  
  • Pycnogenol (an oral antithrombotic agent) was found to decrease the number of thrombotic events during long-haul flights.⁸⁶


• Essaven gel improved the signs and symptoms of SVT of the arms.⁸⁷

Surgical Care

Emergency surgical interventions may be effective in preventing complications of SVT.⁸⁸ Surgical interventions were associated with the lowest incidence of extension of the thrombus and allowed return to work faster than nonsurgical modalities.⁸⁹

• Under the appropriate circumstances, incision and drainage of the clot should be attempted to alleviate pain.


• If the thrombosis extends into the deep venous system, ligation and stripping of the affected vein should be considered.

Consultations

SVT can usually be treated conservatively, as described above, unless extension into the deep venous system is imminent.

Activity

Patients should be encouraged to be ambulatory.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Anticoagulation is necessary only in cases of extensive thrombophlebitis or propagation into the deep venous system. For additional drugs, see the Medication section in Thromboembolism.

Drug Category: Anticoagulants

These agents inhibit thrombin, which prevents formation and/or extension of thrombus and allows recanalization of the blood vessel over time. Oral anticoagulants are the mainstay of long-term outpatient management. Oral anticoagulants competitively interfere with vitamin K metabolism, decreasing plasma concentrations of the active forms of factors II, VII, IX, and X (also proteins C and S). Infants and children tend to require higher maintenance doses and more frequent dosage adjustments than adults.

Drug Name	Enoxaparin (Lovenox)
Description	Prevents DVT, which may lead to PE in patients undergoing surgery who are at risk for thromboembolic complications. Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa. Average duration of treatment is 7-14 d. Greater bioavailability and longer half-life after SC injection than unfractionated heparin. With enoxaparin, monitor CBC count, including platelet count, and monitor effect with anti–factor Xa levels.
Adult Dose	DVT: 1 mg/kg SC q12h or 1.5 mg/kg SC qd Prophylaxis in patients at risk: 30-40 mg SC q12h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to drug or components; history of heparin-associated thrombocytopenia; active major bleeding
Interactions	Digoxin, nicotine, tetracycline, quinine, protamine, and antihistamines may decrease effects; anticoagulants (eg, NSAIDs, aspirin), dextran, dipyridamole, dihydroergotamine, drotrecogin, mezlocillin, piperacillin, ticarcillin, drospirenone and ethinyl estradiol, and sulfinpyrazone may increase toxicity; concomitant administration of argatroban with antiplatelet agents, thrombolytics, and other anticoagulants may increase risk of bleeding; among cephalosporins, coagulation abnormalities are most commonly reported with moxalactam, cefamandole, and cefoperazone, due to possible direct effect on prothrombin time or vitamin K production
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in recent major surgery, lumbar or spinal puncture, or peptic ulcer disease; history of GI bleed, severe HTN, bleeding tendency, or renal dysfunction; in neonates, avoid medications preserved with benzyl alcohol if possible; not for IM use; thrombocytopenia should prompt testing for antibodies (HIT) due to increased risk of bleeding and progression to thrombosis; precaution in uncontrolled hypertension; may in crease risk of bleeding in women over age 60 y

Drug Name	Dalteparin (Fragmin)
Description	Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa. Average duration of treatment is 7-14 d.
Adult Dose	2500-5000 U SC qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; major bleeding; thrombocytopenia
Interactions	Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding; concomitant administration of argatroban with antiplatelet agents, thrombolytics, and other anticoagulants may increase risk of bleeding; among cephalosporins, coagulation abnormalities are most commonly reported with moxalactam, cefamandole, and cefoperazone, due to possible direct effect on prothrombin time or vitamin K production
Pregnancy	B - Usually safe but benefits must outweigh the risks
Precautions	If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMWH; may in crease risk of bleeding in women over age 60 y

Drug Name	Tinzaparin (Innohep)
Description	Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa. Average duration of treatment is 7-14 d.
Adult Dose	175 U/kg SC qd, at same time each day for > 6 days and until patient is adequately anticoagulated with warfarin (INR >2.0 for two consecutive days)
Pediatric Dose	Not established; adult dose suggested
Contraindications	Documented hypersensitivity; major bleeding; thrombocytopenia
Interactions	Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding; concomitant administration of argatroban with antiplatelet agents, thrombolytics, and other anticoagulants may increase risk of bleeding; among cephalosporins, coagulation abnormalities are most commonly reported with moxalactam, cefamandole, and cefoperazone, due to possible direct effect on prothrombin time or vitamin K production
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMWH; 1 mg of protamine sulfate will reverse effect of approximately 100 U of tinzaparin if significant bleeding complications develop; may in crease risk of bleeding in women over age 60 y

Drug Name	Warfarin (Coumadin)
Description	Used for long-term anticoagulation. Warfarin has a half-life of 36-42 h. More difficult to monitor PT and INR in children because of variability in dietary vitamin K intake, effects of other medications, and age; monitor CBC and platelet counts and INR.
Adult Dose	2-5 mg PO/IV qd initially; adjust dose based on INR; usual maintenance, 2-10 mg PO/IV qd
Pediatric Dose	Loading dose: 0.2 mg/kg/d PO Infants: 0.31 mg/kg/d PO (average) 1-5 years: 0.16 mg/kg/d PO 6-10 years: 0.13 mg/kg/d PO
Contraindications	Documented hypersensitivity; hemorrhagic tendencies or blood dyscrasias; recent or contemplated major surgery (especially in the eyes or CNS); open wounds; active bleeding or ulceration of GI, GU, or respiratory tract; CNS bleeding; aneurysm; pericarditis or pericardial effusion; bacterial endocarditis; threatened abortion; risk of poor compliance; spinal puncture; malignant hypertension
Interactions	Numerous medications and herbal supplements (refer to latest PDR for complete list); possible decreased anticoagulant effects occur with coadministration of griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, PO contraceptives, and sucralfate; anticoagulant effects may increase with coadministration of PO antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac
Pregnancy	D - Unsafe in pregnancy
Precautions	Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or protein S deficiency are at risk of skin necrosis; caution in elderly patients, patients with hepatic or renal dysfunction, and those with a history of heparin-induced thrombocytopenia; febrile, hyperlipidemia, hyperthyroidism, steatorrhea, and poor nutritional state may increase PT/INR response

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Follow up patients with SVT at weekly intervals until complete resolution occurs to ensure against its progression to DVT.
• Routinely monitor patients with DVT, especially while they are receiving anticoagulant therapy.

Deterrence/Prevention

• The routine use of graduated support stockings (class I or II), especially when the patient is confined on an airplane or otherwise is extremely important.

Complications

• The progression of SVT to DVT should be prevented.
• DVT should be treated at the first sign of its development.
• Untreated, DVT may result in life-threatening PE.

Prognosis

• SVT and DVT both have an excellent prognosis if treated promptly. Proper treatment should result in rapid resolution.
• After resolution of the acute problem, the following treatment options for the underlying varicose veins should be considered: ambulatory phlebectomy, ligation and stripping, endovenous radiofrequency, and endovenous laser ablation.

Patient Education

• Patients should be educated regarding the risk factors for future thrombotic events.


• The risks and benefits of anticoagulation therapy should also be explained.


• For excellent patient education resources, visit eMedicine's Circulatory Problems Center and Lung and Airway Center. Also, see eMedicine's patient education articles Varicose Veins, Blood Clot in the Legs, Phlebitis, and Pulmonary Embolism.


• The JAMA's patient education information⁹⁰ is referenced in the Bibliography.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Proper diagnosis, therapy, and follow-up help in preventing complications of either SVT or DVT.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Thomas JH. Edgar J Poth lecture. Pathogenesis, diagnosis, and treatment of thrombosis. Am J Surg. Dec 1990;160(6):547-51. [Medline].
2. Kakkar VV, Howe CT, Nicolaides AN, Renney JT, Clarke MB. Deep vein thrombosis of the leg. Is there a "high risk" group?. Am J Surg. Oct 1970;120(4):527-30. [Medline].
3. Samlaska CP, James WD. Superficial thrombophlebitis. II. Secondary hypercoagulable states. J Am Acad Dermatol. Jul 1990;23(1):1-18. [Medline].
4. Schafer AI. The hypercoagulable states. Ann Intern Med. Jun 1985;102(6):814-28. [Medline].
5. Kaplan NM. Cardiovascular complications of oral contraceptives. Annu Rev Med. 1978;29:31-40. [Medline].
6. Durand JL, Bressler R. Clinical pharmacology of the steroidal oral contraceptives. Adv Intern Med. 1979;24:97-126. [Medline].
7. Stolley PD, Tonascia JA, Tockman MS, Sartwell PE, Rutledge AH, Jacobs MP. Thrombosis with low-estrogen oral contraceptives. Am J Epidemiol. Sep 1975;102(3):197-208. [Medline].
8. Vessey M, Mant D, Smith A, Yeates D. Oral contraceptives and venous thromboembolism: findings in a large prospective study. Br Med J (Clin Res Ed). Feb 22 1986;292(6519):526. [Medline].
9. Helmrich SP, Rosenberg L, Kaufman DW, Strom B, Shapiro S. Venous thromboembolism in relation to oral contraceptive use. Obstet Gynecol. Jan 1987;69(1):91-5. [Medline].
10. Robinson GE, Burren T, Mackie IJ, Bounds W, Walshe K, Faint R, et al. Changes in haemostasis after stopping the combined contraceptive pill: implications for major surgery. BMJ. Feb 2 1991;302(6771):269-71. [Medline].
11. Seigel DG. Pregnancy, the puerperium and the steroid contraceptive. Milbank Mem Fund Q. Jan 1972;50(1):Suppl 2:15-23. [Medline].
12. Boston Collaborative Drug Surveillance Programme. Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumours. Report from the Boston Collaborative Drug Surveillance Programme. Lancet. Jun 23 1973;1(7817):1399-404. [Medline].
13. Quinn DA, Thompson BT, Terrin ML, Thrall JH, Athanasoulis CA, McKusick KA, et al. A prospective investigation of pulmonary embolism in women and men. JAMA. Oct 7 1992;268(13):1689-96. [Medline].
14. Mashchak CA, Lobo RA, Dozono-Takano R, Eggena P, Nakamura RM, Brenner PF, et al. Comparison of pharmacodynamic properties of various estrogen formulations. Am J Obstet Gynecol. Nov 1 1982;144(5):511-8. [Medline].
15. Grady D, Hulley SB, Furberg C. Venous thromboembolic events associated with hormone replacement therapy. JAMA. Aug 13 1997;278(6):477. [Medline].
16. Stadel BV. Oral contraceptives and cardiovascular disease (first of two parts). N Engl J Med. Sep 10 1981;305(11):612-8. [Medline].
17. Alkjaersig N, Fletcher A, Burstein R. Association between oral contraceptive use and thromboembolism: a new approach to itsinvestigation based on plasma fibrinogen chromatography. Am J Obstet Gynecol. May 1975;122(2):199-211. [Medline].
18. Siegbahn A, Ruusuvaara L. Age dependence of blood fibrinolytic components and the effects of low-dose oral contraceptives on coagulation and fibrinolysis in teenagers. Thromb Haemost. Dec 22 1988;60(3):361-4. [Medline].
19. Srinivasan S, Solash J, Redner A, Moser C, Farhangian D, Lucas TR, et al. The alteration of surface charge characteristics of the vascular system by oral contraceptive steroids. Contraception. Mar 1974;9(3):291-303. [Medline].
20. Oski FA, Lubin B, Buchert ED. Reduced red cell filterability with oral contraceptive agents. Ann Intern Med. Sep 1972;77(3):417-9. [Medline].
21. Aronson HB, Magora F, Schenker JG. Effect of oral contraceptives on blood viscosity. Am J Obstet Gynecol. Aug 1 1971;110(7):997-1001. [Medline].
22. Dreyer NA, Pizzo SV. Blood coagulation and idiopathic thromboembolism among fertile women. Contraception. Aug 1980;22(2):123-35. [Medline].
23. Sagar S, Stamatakis JD, Thomas DP, Kakkar VV. Oral contraceptives, antithrombin- III activity, and postoperative deep-vein thrombosis. Lancet. Mar 6 1976;1(7958):509-11. [Medline].
24. von Kaulla E, von Kaulla KN. Oral contraceptives and low antithrombin-3 activity. Lancet. Jan 3 1970;1(7636):36. [Medline].
25. Pizzo SV. Venous thrombosis. In: Koepke JA, ed. Laboratory Hematology. Vol 2. New York, NY: Churchill Livingstone; 1984.
26. Miller KE, Pizzo SV. Venous and arterial thromboembolic disease in women using oral contraceptives. Am J Obstet Gynecol. Dec 1 1982;144(7):824-7. [Medline].
27. Astedt B, Isacson S, Nilsson IM, Pandolfi M. Thrombosis and oral contraceptives: possible predisposition. Br Med J. Dec 15 1973;4(5893):631-4. [Medline].
28. Judd HL, Meldrum DR, Deftos LJ, Henderson BE. Estrogen replacement therapy: indications and complications. Ann Intern Med. Feb 1983;98(2):195-205. [Medline].
29. Goodrich SM, Wood JE. The effect of estradiol-17-beta on peripheral venous distensibility and velocity of venous blood flow. Am J Obstet Gynecol. Oct 1 1966;96(3):407-12. [Medline].
30. Alkjaersig N, Fletcher AP, de Ziegler D, Steingold KA, Meldrum DR, Judd HL. Blood coagulation in postmenopausal women given estrogen treatment: comparison of transdermal and oral administration. J Lab Clin Med. Feb 1988;111(2):224-8. [Medline].
31. Lipton A, Harvey HA, Hamilton RW. Venous thrombosis as a side effect of tamoxifen treatment. Cancer Treat Rep. Jun 1984;68(6):887-9. [Medline].
32. Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. Feb 23 1989;320(8):479-84. [Medline].
33. Jordan VC, Fritz NF, Tormey DC. Long-term adjuvant therapy with tamoxifen: effects on sex hormone binding globulin and antithrombin III. Cancer Res. Aug 15 1987;47(16):4517-9. [Medline].
34. Love RR, Surawicz TS, Williams EC. Antithrombin III level, fibrinogen level, and platelet count changes with adjuvant tamoxifen therapy. Arch Intern Med. Feb 1992;152(2):317-20. [Medline].
35. Auger MJ, Mackie MJ. Effects of tamoxifen on blood coagulation. Cancer. Apr 1 1988;61(7):1316-9. [Medline].
36. Bertelli G, Pronzato P, Amoroso D, Cusimano MP, Conte PF, Montagna G, et al. Adjuvant tamoxifen in primary breast cancer: influence on plasma lipids and antithrombin III levels. Breast Cancer Res Treat. Dec 1988;12(3):307-10. [Medline].
37. Bonnar J. Hemostatic function and coagulopathy during pregnancy. Obstet Gynecol Annu. 1978;7:195-217. [Medline].
38. Bonnar J, McNicol GP, Douglas AS. Fibrinolytic enzyme system and pregnancy. Br Med J. Aug 16 1969;3(5667):387-9. [Medline].
39. Comp PC, Thurnau GR, Welsh J, Esmon CT. Functional and immunologic protein S levels are decreased during pregnancy. Blood. Oct 1986;68(4):881-5. [Medline].
40. Aaro LA, Johnson TR, Juergens JL. Acute deep venous thrombosis associated with pregnancy. Obstet Gynecol. Oct 1966;28(4):553-8. [Medline].
41. Beller FK. Thromboembolic disease in pregnancy. In: Anderson A, ed. Thromboembolic Disorders. New York, NY: Harper & Row; 1968.
42. Rick ME. Protein C and protein S. Vitamin K-dependent inhibitors of blood coagulation. JAMA. Feb 2 1990;263(5):701-3. [Medline].
43. Bauer KA. Pathobiology of the hypercoagulable state: clinical features, laboratory evaluation, and management. In: Hoffman R, et al, eds. Hematology: Basic Principles and Clinical Practice. New York, NY: Churchill Livingstone; 1991.
44. Collen D, Schetz J, de Cock F, Holmer E, Verstraete M. Metabolism of antithrombin III (heparin cofactor) in man: effects of venous thrombosis and of heparin administration. Eur J Clin Invest. Feb 1977;7(1):27-35. [Medline].
45. Odegård OR, Abildgaard U. Antithrombin III: critical review of assay methods. Significance of variations in health and disease. Haemostasis. 1978;7(2-3):127-34. [Medline].
46. Miletich J, Sherman L, Broze G Jr. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med. Oct 15 1987;317(16):991-6. [Medline].
47. Engesser L, Broekmans AW, Briët E, Brommer EJ, Bertina RM. Hereditary protein S deficiency: clinical manifestations. Ann Intern Med. May 1987;106(5):677-82. [Medline].
48. Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med. Feb 24 1994;330(8):517-22. [Medline].
49. Peus D, Heit JA, Pittelkow MR. Activated protein C resistance caused by factor V gene mutation: common coagulation defect in chronic venous leg ulcers?. J Am Acad Dermatol. Apr 1997;36(4):616-20. [Medline].
50. Nichols WL, Heit JA. Activated protein C resistance and thrombosis. Mayo Clin Proc. Sep 1996;71(9):897-8. [Medline].
51. Towne JB. Hypercoagulable states and unexplained vascular graft thrombosis. In: Bernhard VM, Towne JB, eds. Complications in Vascular Surgery. St. Louis, Mo: Quality Medical Publishing; 1991.
52. Espinoza LR, Hartmann RC. Significance of the lupus anticoagulant. Am J Hematol. Jul 1986;22(3):331-7. [Medline].
53. Tabachnik-Schor NF, Lipton SA. Association of lupuslike anticoagulant and nonvasculitic cerebral infarction. Arch Neurol. Aug 1986;43(8):851-2. [Medline].
54. Shi W, Krilis SA, Chong BH, Gordon S, Chesterman CN. Prevalence of lupus anticoagulant and anticardiolipin antibodies in a healthy population. Aust N Z J Med. Jun 1990;20(3):231-6. [Medline].
55. Mueh JR, Herbst KD, Rapaport SI. Thrombosis in patients with the lupus anticoagulant. Ann Intern Med. Feb 1980;92(2 Pt 1):156-9. [Medline].
56. Elias M, Eldor A. Thromboembolism in patients with the 'lupus'-type circulating anticoagulant. Arch Intern Med. Mar 1984;144(3):510-5. [Medline].
57. Homans J. Thrombosis of the deep leg veins due to prolonged sitting. N Engl J Med. Jan 28 1954;250(4):148-9. [Medline].
58. Lord RS, McGrath M. Travelers venous thrombosis. Presented at: The International Society of Cardiovascular Surgery Meeting. Lisbon, Portugal: 1993.
59. Lord RS. Air travel-related deep venous thrombosis. Sydney views. Cardiovasc Surg. Apr 2001;9(2):149-50; discussion 153-6. [Medline].
60. Parsi KA, McGrath MA, Lord RS. Traveller's venous thromboembolism. Cardiovasc Surg. Apr 2001;9(2):157-8. [Medline].
61. McQuillan AD, Eikelboom JW, Baker RI. Venous thromboembolism in travellers: can we identify those at risk?. Blood Coagul Fibrinolysis. Oct 2003;14(7):671-5. [Medline].
62. Kowalewski R, Sobolewski K, Wolanska M, Gacko M. Matrix metalloproteinases in the vein wall. Int Angiol. Jun 2004;23(2):164-9. [Medline].
63. Kagel EM, Rayan GM. Intravenous catheter complications in the hand and forearm. J Trauma. Jan 2004;56(1):123-7. [Medline].
64. Siddoway LA. Amiodarone: guidelines for use and monitoring. Am Fam Physician. Dec 1 2003;68(11):2189-96. [Medline].
65. Hochmair M, Valipour A, Oschatz E, Hollaus P, Huber M, Chris Burghuber O. From a sore throat to the intensive care unit: the Lemierre syndrome. Wien Klin Wochenschr. May 2006;118(7-8):243-6. [Medline].
66. Brinsuk M, Tank J, Luft FC, Busjahn A, Jordan J. Heritability of venous function in humans. Arterioscler Thromb Vasc Biol. Jan 2004;24(1):207-11. [Medline].
67. Plate G, Eklöf B, Jensen R, Ohlin P. Deep venous thrombosis, pulmonary embolism and acute surgery in thrombophlebitis of the long saphenous vein. Acta Chir Scand. 1985;151(3):241-4. [Medline].
68. Gjores JE. Surgical therapy of ascending thrombophlebitis in the saphenous system. Angiology. May 1962;13:241-3. [Medline].
69. Bergqvist D, Lindblad B. A 30-year survey of pulmonary embolism verified at autopsy: an analysis of 1274 surgical patients. Br J Surg. Feb 1985;72(2):105-8. [Medline].
70. Bergqvist D, Jaroszewski H. Deep vein thrombosis in patients with superficial thrombophlebitis of the leg. Br Med J (Clin Res Ed). Mar 8 1986;292(6521):658-9. [Medline].
71. Galloway JM, Karmody AM, Mavor GE. Thrombophlebitis of the long saphenous vein complicated by pulmonary embolism. Br J Surg. May 1969;56(5):360-1. [Medline].
72. Schönauer V, Kyrle PA, Weltermann A, Minar E, Bialonczyk C, Hirschl M, et al. Superficial thrombophlebitis and risk for recurrent venous thromboembolism. J Vasc Surg. Apr 2003;37(4):834-8. [Medline].
73. Bendick PJ, Ryan R, Alpers M, et al. Clinical significance of superficial thrombophlebitis. J Vasc Technol. 1995;19:57-61.
74. Verlato F, Zucchetta P, Prandoni P, Camporese G, Marzola MC, Salmistraro G, et al. An unexpectedly high rate of pulmonary embolism in patients with superficial thrombophlebitis of the thigh. J Vasc Surg. Dec 1999;30(6):1113-5. [Medline].
75. Krunes U, Lindner F, Lindner R, Gnutzmann J. Genugt die klinische untersuchung einer varikophlebitis des unterschenkels?. Phlebologie. 1999;28:93-6.
76. Crandon AJ, Peel KR, Anderson JA, Thompson V, McNicol GP. Postoperative deep vein thrombosis: identifying high-risk patients. Br Med J. Aug 2 1980;281(6236):343-4. [Medline].
77. Sue-Ling HM, Johnston D, McMahon MJ, Philips PR, Davies JA. Pre-operative identification of patients at high risk of deep venous thrombosis after elective major abdominal surgery. Lancet. May 24 1986;1(8491):1173-6. [Medline].
78. Coon WW. Epidemiology of venous thromboembolism. Ann Surg. Aug 1977;186(2):149-64. [Medline].
79. Schina MJ Jr, Neumyer MM, Healy DA, Atnip RG, Thiele BL. Influence of age on venous physiologic parameters. J Vasc Surg. Nov 1993;18(5):749-52. [Medline].
80. Greenleaf JE, Rehrer NJ, Mohler SR, Quach DT, Evans DG. Airline chair-rest deconditioning: induction of immobilisation thromboemboli?. Sports Med. 2004;34(11):705-25. [Medline].
81. Sigg K. The treatment of varicosities and accompanying complications; (the ambulatory treatment of phlebitis with compression bandage). Angiology. Oct 1952;3(5):355-79. [Medline].
82. Sacher R. Antithrombin deficiency in special clinical syndromes--Part II: panel discussion #2. Semin Hematol. Oct 1995;32(4 Suppl 2):67-71. [Medline].
83. Chengelis DL, Bendick PJ, Glover JL, Brown OW, Ranval TJ. Progression of superficial venous thrombosis to deep vein thrombosis. J Vasc Surg. Nov 1996;24(5):745-9. [Medline].
84. Downing LJ, Strieter RM, Kadell AM, Wilke CA, Greenfield LJ, Wakefield TW. Low-dose low-molecular-weight heparin is anti-inflammatory during venous thrombosis. J Vasc Surg. Nov 1998;28(5):848-54. [Medline].
85. Marchiori A, Verlato F, Sabbion P, Camporese G, Rosso F, Mosena L, et al. High versus low doses of unfractionated heparin for the treatment of superficial thrombophlebitis of the leg. A prospective, controlled, randomized study. Haematologica. May 2002;87(5):523-7. [Medline].
86. Belcaro G, Cesarone MR, Rohdewald P, Ricci A, Ippolito E, Dugall M, et al. Prevention of venous thrombosis and thrombophlebitis in long-haul flights with pycnogenol. Clin Appl Thromb Hemost. Oct 2004;10(4):373-7. [Medline].
87. De Sanctis MT, Cesarone MR, Incandela L, Belcaro G, Griffin M. Treatment of superficial vein thrombophlebitis of the arm with Essaven gel--a placebo-controlled, randomized study. Angiology. Dec 2001;52 Suppl 3:S63-7. [Medline].
88. Beatty J, Fitridge R, Benveniste G, Greenstein D. Acute superficial venous thrombophlebitis: does emergency surgery have a role?. Int Angiol. Mar 2002;21(1):93-5. [Medline].
89. Belcaro G, Nicolaides AN, Errichi BM, Cesarone MR, De Sanctis MT, Incandela L, et al. Superficial thrombophlebitis of the legs: a randomized, controlled, follow-up study. Angiology. Jul 1999;50(7):523-9. [Medline].
90. Torpy JM, Burke AE, Glass RM. JAMA patient page. Thrombophlebitis. JAMA. Jul 26 2006;296(4):468. [Medline].
91. Ascer E, Lorensen E, Pollina RM, Gennaro M. Preliminary results of a nonoperative approach to saphenofemoral junction thrombophlebitis. J Vasc Surg. Nov 1995;22(5):616-21. [Medline].
92. Campbell B. Varicose veins and their management. BMJ. Aug 5 2006;333(7562):287-92. [Medline].
93. Kupelian AS, Huda MS. Pregnancy, thrombophlebitis and thromboembolism: what every obstetrician should know. Arch Gynecol Obstet. Mar 2007;275(3):215-7. [Medline].
94. Leon L, Giannoukas AD, Dodd D, Chan P, Labropoulos N. Clinical significance of superficial vein thrombosis. Eur J Vasc Endovasc Surg. Jan 2005;29(1):10-7. [Medline].
95. Nachmann MM, Jaffe JS, Ginsberg PC, Horrow MM, Harkaway RC. Sickle cell episode manifesting as superficial thrombophlebitis of the penis. J Am Osteopath Assoc. Feb 2003;103(2):102-4. [Medline].