Medical Terms Learned today

Drug Category: Anticoagulants -- Anticoagulation remains the mainstay of initial treatment for DVT. Regular unfractionated heparin was the standard of care until the recent introduction of low-molecular-weight-heparin (LMWH). Heparin prevents extension of the thrombus and has been shown to significantly reduce but not eliminate the incidence of fatal and nonfatal pulmonary emboli, as well as recurrent thrombosis. The primary reason for this is that heparin has no effect on preexisting nonadherent thrombus. Heparin does not affect the size of existing thrombus and has no intrinsic thrombolytic activity.

Heparin therapy is associated with complete lysis in fewer than 10% of patients studied with venography after treatment.

Heparin therapy has little effect on the risk of developing postphlebitic syndrome. The original thrombus causes venous valvular incompetence and altered venous return leading to a high incidence of chronic venous insufficiency and postphlebitic syndrome.

The anticoagulant effect of heparin is directly related to its activation of antithrombin III. Antithrombin III, the body's primary anticoagulant, inactivates thrombin and inhibits the activity of activated factor X in the coagulation process.

Heparin is a heterogeneous mixture of polysaccharide fragments with varying molecular weights but with similar biological activity. The larger fragments primarily interact with antithrombin III to inhibit thrombin. The low-molecular-weight fragments exert their anticoagulant effect by inhibiting the activity of activated factor X. The hemorrhagic complications attributed to heparin are thought to arise from the larger higher-molecular-weight fragments.

The optimal regimen for the treatment of DVT is anticoagulation with heparin or an LMWH followed by full anticoagulation with oral warfarin for 3-6 months. Some evidence indicates that even longer anticoagulation with warfarin is appropriate in certain cases.

Warfarin therapy is overlapped with heparin for 4-5 days until the international normalized ratio (INR) is therapeutically elevated to 2-3. Heparin must be overlapped with oral warfarin because of the initial transient hypercoagulable state induced by warfarin. This effect is related to the differential half-lives of protein C, protein S, and the vitamin K–dependent clotting factors II, VII, IX, and X. Long-term anticoagulation is definitely indicated for patients with recurrent venous thrombosis and/or persistent or irreversible risk factors.

When IV unfractionated heparin is initiated for DVT, the goal is to achieve and maintain an elevated activated partial thromboplastin time (aPTT) of at least 1.5 times control. Heparin pharmacokinetics are complex; the half-life is 60-90 minutes. After an initial bolus of 80 U/kg, a constant maintenance infusion of 18 U/kg is initiated. The aPTT is checked 6 hours after the bolus and adjusted accordingly. The aPTT is checked every 6 hours until 2 successive aPTTs are therapeutic. Thereafter, the aPTT, the hematocrit level, and platelet count are monitored every 24 hours.

Heparin-induced thrombocytopenia is not infrequent. In this condition, platelet aggregation induced by heparin may trigger venous or arterial thrombosis with significant morbidity and mortality. Unfortunately, the subset of patients who develop thrombosis is unpredictable. All patients who develop thrombocytopenia while taking heparin are at risk. Alternatives include the substitution of porcine for bovine heparin, the use of LMWH, or initiation of therapy with warfarin alone.

LMWH is prepared by selectively treating unfractionated heparin to isolate the low-molecular-weight (<9,000 Da) fragments. Its activity is measured in units of factor X inactivation, and monitoring of the aPTT is not required. The dose is weight adjusted.

LMWH is administered SC, and its half-life permits single- or twice-daily dosing. Its use in the outpatient treatment of DVT and pulmonary embolism has been evaluated in a number of studies.

At the present time, 4 LMWH preparations, Enoxaparin, Dalteparin, Tinzaparin, and Nadroparin, are available. Only Enoxaparin and Tinzaparin have received Food and Drug Administration (FDA) approval for the treatment of DVT in the United States. Tinzaparin has been approved only for in-hospital treatment of DVT. Enoxaparin is approved for inpatient and outpatient treatment of DVT. Nadroparin is approved for DVT treatment in Canada. Dalteparin is only approved for DVT prophylaxis and the treatment of acute coronary syndrome but not for acute DVT.

The increased bioavailability and prolonged half-life of LMWH allows for outpatient treatment of DVT using once - or twice-daily SC treatment regimens. Outpatient treatment of acute DVT with LMWH has been successfully evaluated in a number of studies and is currently the treatment of choice if the patient meets the necessary criteria. Outpatient management is not recommended if the patient has proven or suspected concomitant pulmonary embolism, significant comorbidities, extensive ileofemoral DVT, morbid obesity, renal failure, or poor follow-up.

Drug Name	Heparin (Hep-Lock) -- Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of a clot after a spontaneous fibrinolysis.
Adult Dose	80 U/kg IV bolus, followed by 18-U/kg/h maintenance infusion Monitor aPTT and titrate maintenance dose to effect
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; subacute bacterial endocarditis; severe liver disease; hemophilia; active bleeding; history of heparin-induced thrombocytopenia
Interactions	Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase toxicity
Pregnancy	A - Safe in pregnancy
Precautions	In neonates, preservative-free heparin is recommended to avoid possible toxicity (gasping syndrome) by benzyl alcohol, which is used as preservative; caution in severe hypotension and shock

Drug Name	Warfarin (Coumadin) -- Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders. Dose must be individualized and adjusted to maintain INR at 2-3.
Adult Dose	2-10 mg/d PO
Pediatric Dose	Weight-based dose of 0.05-0.34 mg/kg/d; adjust according to desired INR Infants may require doses at or near high end of this range
Contraindications	Documented hypersensitivity; severe liver or kidney disease; risk of CNS hemorrhage; cerebral aneurysms; open wounds or bleeding of the GI, GU, or respiratory tract
Interactions	Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, PO contraceptives, and sucralfate Medications that may increase anticoagulant effects of warfarin include 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 mellitus; patients with protein C or S deficiency are at risk of skin necrosis

Drug Name	Enoxaparin (Lovenox) -- LMWH used in treatment of DVT and pulmonary embolism as well as DVT prophylaxis. Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. Slightly affects thrombin and clotting time and preferentially increases inhibition of factor Xa. Average duration of treatment is 7-14 d.
Adult Dose	1 mg/kg SC bid; alternatively, administer 1.5 mg/kg SC qd
Pediatric Dose	Not established The following doses have been suggested: <2 months: 0.75 mg/kg/dose bid 2 months to 18 years: 0.5 mg/kg/dose bid
Contraindications	Documented hypersensitivity; major bleeding; history of heparin-induced thrombocytopenia
Interactions	Platelet inhibitors or PO anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding
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 reverses effect of approximately 1 mg of enoxaparin if significant bleeding complications develop

Drug Name	Tinzaparin (Innohep) -- Used in hospitalized patients. 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 d and until patient is adequately anticoagulated with warfarin (INR >2 for 2 consecutive d)
Pediatric Dose	Not established; adult dose suggested
Contraindications	Documented hypersensitivity; major bleeding; heparin-induced thrombocytopenia (current or history of)
Interactions	Platelet inhibitors or PO anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding
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 reverses the effect of approximately 100 U of tinzaparin if significant bleeding complications develop

Drug Category: Thrombolytics -- Significant advantages over conventional anticoagulant therapy include prompt resolution of symptoms, prevention of pulmonary embolism, restoration of normal venous circulation, preservation of venous valvular function, and prevention of postphlebitic syndrome. Thrombolytic therapy does not prevent clot propagation, rethrombosis, or subsequent embolization. Heparin therapy and oral anticoagulant therapy must always follow a course of thrombolysis.

Unfortunately, most patients with DVT have absolute contraindications to thrombolytic therapy. Thrombolytic therapy is also not effective once the thrombus is adherent and begins to organize. Venous thrombi in the legs are often large and associated with complete venous occlusion. The thrombolytic agent that acts on the surface of the clot may not be able to penetrate and lyse the thrombus.

Nevertheless, the data from many published studies indicate that thrombolytic therapy is more effective than heparin in achieving vein patency. The unproven assumption is that the degree of lysis observed on posttreatment venography is predictive of future venous valvular insufficiency and late (5-10 y) development of postphlebitic syndrome. Preliminary evidence suggests that incidence of postphlebitic syndrome at 3 years is reduced by half but certainly not entirely eliminated.

The hemorrhagic complications of thrombolytic therapy are formidable (~3 times higher) and include the small but potentially fatal risk of intracerebral hemorrhage. The uncertainty regarding thrombolytic therapy is likely to continue. Currently, thrombolytic therapy is not routinely recommended for DVT at most centers but should be considered in patients with massive ileofemoral vein thrombosis or in young patients with acute onset of extensive DVT.

Thrombolytic therapy is administered regionally by using a variety of medical devices inserted by means of interventional radiology. These devices are inserted transvenously and advanced to the distal edge of the clot. The thrombolytic agent is injected, and the catheter is slowly advanced as the clot dissolves.

Drug Name	Urokinase (Abbokinase) -- Direct plasminogen activator isolated from human fetal kidney cells grown in culture. Acts on endogenous fibrinolytic system and converts plasminogen to enzyme plasmin. Plasmin degrades fibrin clots, fibrinogen, and other plasma proteins. It is nonantigenic but more expensive than streptokinase, which limits its use. When used for purely local fibrinolysis, it is administered as local infusion directly into area of thrombus and with no bolus. Adjust dose to achieve clot lysis or patency of affected vessel.
Adult Dose	4400 U/kg IV bolus followed by maintenance infusion at 4400 U/kg/h for 1-3 d For regional thrombus-directed therapy, smaller bolus of 250,000 U IV may be given followed by infusion at 500-2000 U/kg/h
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; internal bleeding; recent trauma including cardiopulmonary resuscitation; history of stroke; intracranial or intraspinal surgery or trauma; intracranial neoplasm
Interactions	Thrombolytic enzymes, alone or in combination with anticoagulants and antiplatelets, may increase risk of bleeding complications
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in IM administration of medications and severe hypertension, trauma, or surgery in previous 10 d; avoid dislodging possible deep vein thrombi; do not measure blood pressure in lower extremities; monitor therapy by measuring PT, aPTT, TT, or fibrinogen approximately 4 h after initiation of therapy

Drug Name	Streptokinase (Kabikinase, Streptase) -- Acts with plasminogen to convert plasminogen to plasmin. Plasmin degrades fibrin clots as well as fibrinogen and other plasma proteins. An increase in fibrinolytic activity that degrades fibrinogen levels for 24-36 h takes place with IV infusion of streptokinase.
Adult Dose	250,000 U IV bolus followed by an infusion at 100,000 U/h for 1-3 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; active internal bleeding; intracranial neoplasm; aneurysm; diathesis; severe uncontrolled arterial hypertension
Interactions	Antifibrinolytic agents may decrease effects of streptokinase; heparin, warfarin, and aspirin may increase risk of bleeding
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in severe hypertension, IM administration of medications, and trauma or surgery in the previous 10 d; measure hematocrit, platelet count, aPTT, TT, PT, or fibrinogen levels before therapy; either TT or aPTT should be less than twice the reference range value following infusion of streptokinase and before (re)instituting heparin; do not take blood pressure in the lower extremities because it may dislodge a possible deep vein thrombi; PT, aPTT, TT, or fibrinogen should be monitored 4 h after initiation of therapy

Drug Name	Alteplase, tPA (Activase) -- Thrombolytic agent for DVT or pulmonary embolism. A tissue plasminogen activator (tPA) produced by recombinant DNA and used in the management of acute ischemic stroke (AMI) and pulmonary embolism. Safety and efficacy of this regimen with coadministration of heparin and aspirin during the first 24 h after symptom onset have not been investigated.
Adult Dose	Front-loaded regimen recommended 15 mg IV bolus initially followed by 50 mg IV over the next 30 min and then 35 mg IV over the next 1 h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active internal bleeding; intracranial or intraspinal surgery or trauma; intracranial neoplasm; arteriovenous malformation or aneurysm; history of stroke in last 2 mo; bleeding diathesis; severe uncontrolled hypertension; intracranial hemorrhage when performing pretreatment evaluation (avoid); recent intracranial surgery; suspicion of subarachnoid hemorrhage; serious head trauma or recent previous stroke; uncontrolled hypertension; intracranial neoplasm; seizure at onset of stroke; active internal bleeding; arteriovenous malformation or aneurysm; bleeding diathesis
Interactions	Drugs that alter platelet function (eg, aspirin, dipyridamole, abciximab) may increase risk of bleeding before, during, or after alteplase therapy; may give heparin with and after alteplase infusions to reduce risk of rethrombosis; either heparin or alteplase may cause bleeding complications
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor for bleeding, especially at arterial puncture sites, with coadministration of vitamin K antagonists; control and monitor blood pressure frequently during and following alteplase administration (when managing acute ischemic stroke); do not use >0.9 mg/kg to manage acute ischemic stroke; doses >0.9 mg/kg may cause ICH

	FOLLOW-UP	Section 8 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Further Inpatient Care:

• Most patients with confirmed proximal vein DVT may be safely treated on an outpatient basis. Exclusion criteria for outpatient management are as follows:
  
  • Suspected or proven concomitant pulmonary embolism
    

  • Significant cardiovascular or pulmonary comorbidity
    

  • Ileofemoral DVT
    

  • Contraindications to anticoagulation
    

  • Familial or inherited disorder of coagulation - ATIII, prothrombin 20210A, protein C or protein S deficiency, or factor V Leyden
    

  • Pregnancy
    

  • Morbid obesity
    

  • Renal failure
    

  • Unavailable or unable to arrange close follow-up care

• Patients are treated with a LMWH and instructed to initiate therapy with warfarin 5 mg PO daily. LMWH and warfarin are overlapped for about 5 days until the INR is therapeutic.

• If inpatient treatment is necessary, LMWH is effective and obviates the need for IV infusions or serial monitoring of the aPTT.

• With the introduction of LMWH, selected patients qualify for outpatient treatment only if adequate home care and close medical follow-up can be arranged.

• At some centers, patients with isolated calf vein DVT are treated with full anticoagulant therapy. Most physicians do not treat calf vein DVT with anticoagulation unless proximal extension is objectively documented with close clinical surveillance.

• The aPTT must be monitored every 6 hours while the patient is taking IV heparin until the dose is stabilized in the therapeutic range. Patients treated with LMWH do not require monitoring of the aPTT.

• Platelets also should be monitored. Heparin or LMWH should be discontinued if the platelet count falls below 75,000.

• While the patient is taking warfarin, the prothrombin time (PT, INR) must be monitored daily until the target is achieved, then weekly for several weeks. When the patient is stable, monitor monthly. Inability to monitor INR precludes outpatient treatment of DVT.

• For the first episode of DVT, patients should be treated for 3-6 months. Recurrent episodes should be treated for at least 1 year.

• Significant bleeding (ie, hematemesis, hematuria, gastrointestinal hemorrhage) should be thoroughly investigated because anticoagulant therapy may unmask a preexisting disease (eg, cancer, peptic ulcer disease, arteriovenous malformation).

Further Outpatient Care:

• Treatment for isolated calf vein DVT is best individualized, taking into account local preferences, patient reliability, the availability of follow-up care, and an assessment of ongoing risk factors.

• Patients with suspected or diagnosed isolated calf vein DVT may be discharged safely on a nonsteroidal anti-inflammatory drug (NSAID) or aspirin with close follow-up care and repeat diagnostic studies (ie, ultrasonography) in 7 days to evaluate for proximal extension.

• At certain centers, patients with isolated calf vein DVT are treated with full anticoagulant therapy.

• Patients with suspected DVT but with negative initial noninvasive study results need to be reassessed by their primary care provider within 7 days.

• Patients with ongoing risk factors need to be reevaluated at 1 week to detect proximal extension because of the limited accuracy of noninvasive tests for calf vein DVT.

Transfer:

• Transfer may be necessary for patients with special concerns such as inherited coagulation disorders.

• Transfer may be required depending on local expertise for treatment with thrombolytics, surgical therapy, or insertion of a filter.

Deterrence/Prevention:

• Prophylaxis for DVT is required in all patients with risk factors. DVT prophylaxis for patients scheduled to undergo major surgery is well recognized.

• Recently, a large multicenter double-blind placebo-controlled trial showed that a single subcutaneous 40-mg daily dose of enoxaparin achieved a 63% reduction in the incidence of DVT/pulmonary embolism in general medical patients admitted to the hospital.

Complications:

• Acute pulmonary embolism may still occur despite adequate anticoagulation.

• Hemorrhagic complications are the most common adverse effects of anticoagulant therapy. The risk of major hemorrhage while taking heparin is approximately 5%.

• The treatment of hemorrhage while taking heparin depends on the severity of the bleeding and the extent to which the aPTT is elevated above the therapeutic range. Patients who hemorrhage while receiving heparin are best treated by discontinuing the drug. The half-life is relatively short, and the aPTT usually returns to the reference range within a few hours. Treatment with fresh frozen plasma or platelet infusions is ineffective. For severe hemorrhage, such as intracranial or massive gastrointestinal bleeding, heparin may be neutralized by protamine at a dose of 1 mg for every 100 units. Protamine should be administered at the same time that the infusion is stopped.
  

• The treatment of major hemorrhage associated with LMWH is similar to heparin. However, the half-life of these agents is longer (4-6 h). As with heparin, fresh frozen plasma or platelet transfusions are ineffective. Protamine may be used, but it only reverses 60% of the drug's effects.

• The risk of bleeding on warfarin is not linearly related to the elevation of the INR. The risk is conditioned by other factors, including poor follow-up, drug interactions, age, and preexisting disorders that predispose to bleeding.

• Patients who hemorrhage while receiving oral warfarin are treated by withholding the drug and administering vitamin K. Severe life-threatening hemorrhage is managed with fresh frozen plasma in addition to vitamin K.

• Additional complications include the following:

• Systemic embolism

• Chronic venous insufficiency

• Postphlebitic syndrome (ie, pain and edema in the affected limb without new clot formation)

• Soft tissue ischemia associated with massive clot and very high venous pressures - Phlegmasia cerulea dolens (rare but should be considered a surgical emergency)

Prognosis:

• All patients with proximal vein DVT are at long-term risk of chronic venous insufficiency.

• Approximately 20% of untreated proximal (above the calf) DVTs progress to pulmonary emboli, and 10-20% of these are fatal. With anticoagulant therapy, the mortality rate is decreased 5- to 10-fold.

• DVT confined to the calf virtually never causes clinically significant emboli and thus does not require anticoagulation. However, calf DVTs occasionally propagate into the proximal system. Therefore, patients with suspected calf vein DVTs should be reassessed at 7 days to include a repeat noninvasive study. If propagation into the popliteal or femoral system is detected, they must be fully anticoagulated.

Patient Education:

• Advise women taking estrogen of the risks and common symptoms of thromboembolic disease.

• Discourage prolonged immobility, particularly on plane rides and long car trips.

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

Posted by: Ds20040999 / 7:31 AM