VENOUS THROMBOEMBOLISM (VTE)

Venous thromboembolism (VTE) is a pathological state resulting from clot formation in the
venous circulation and is manifested as deep vein thrombosis (DVT) and pulmonary embolism
(PE).

PATHOPHYSIOLOGY
Hemostasis is controlled by antithrombotic substances secreted by intact endothelium
adjacent to damaged tissue.
a)Thrombomodulin modulates thrombin activity by converting protein C to its activated form
(aPC), which joins with protein S to inactivate factors Va and VIIIa. This prevents coagulation
reactions from spreading to uninjured vessel walls.
b)Circulating antithrombin inhibits thrombin and factor Xa.
c) Heparan sulfate is secreted by endothelial cells and accelerates antithrombin activity.
d) Heparin cofactor II also inhibits thrombin.

e) The fibrinolytic system dissolves formed blood clots; plasminogen is converted to plasmin by
tissue plasminogen activator and urokinase plasminogen activator. Plasmin degrades the fibrin
mesh into soluble end products (fibrin split products or fibrin degradation products).
Alterations in blood vessels, circulating elements in blood, and speed of blood flow can lead to
pathologic clot formation (Virchow triad):
✓ Vascular injury occurs with trauma (especially fractures of the pelvis, hip, or leg),
orthopedic surgery (eg, knee and hip replacement), or indwelling venous catheters.
✓ Hypercoagulable states include malignancy; activated protein C resistance; deficiency of
protein C, protein S, or antithrombin; high concentrations of factor VIII, IX, and/or XI or
fibrinogen; antiphospholipid antibodies; and estrogen use.
✓ Stasis can result from damage to venous valves, vessel obstruction, prolonged
immobility, or increased blood viscosity resulting from medical illness (eg, heart failure,
myocardial infarction), surgery, paralysis (eg, stroke), polycythemia vera, obesity, or
varicose veins.
CLINICAL PRESENTATION
Many patients never develop symptoms from the acute event.
Symptoms of DVT: Unilateral leg swelling, pain, tenderness, erythema, and warmth. Physical
signs may include a palpable cord and a positive Homan sign.
Symptoms of PE: Cough, chest pain or tightness, shortness of breath palpitations, hemoptysis,
dizziness, or lightheadedness. Signs of PE include tachypnea, tachycardia, diaphoresis, cyanosis,
hypotension, shock, and cardiovascular collapse.
Postthrombotic syndrome may produce chronic lower extremity swelling, pain, tenderness,
skin discoloration, and ulceration.

DIAGNOSIS
Assessment should focus on identifying risk factors (eg, increased age, major surgery, previous
VTE, trauma, malignancy, hypercoagulable states, drug therapy).
Radiographic contrast studies (venography, pulmonary angiography) are the most accurate and
reliable method for VTE diagnosis.
Noninvasive tests (eg, compression ultrasound, computed tomography scan, ventilation-
perfusion scan) are often used for initial evaluation of patients with suspected VTE.
Elevated d-dimer blood levels occur in acute thrombosis but also with other conditions (eg,
recent surgery or trauma, pregnancy, cancer). Therefore, a negative test can help exclude VTE,
but a positive test is not conclusive evidence of the diagnosis.
Clinical assessment checklists can be used to determine whether a patient has a high,
moderate, or low probability of DVT or PE.
TREATMENT
Goals of Treatment
The goals are:
to prevent development of PE and postthrombotic syndrome,
to reduce morbidity and mortality from the acute event
to minimize adverse effects
to minimize cost of treatment.

General Approach
Anticoagulation is the primary treatment for VTE; DVT and PE are treated similarly.

After VTE is confirmed objectively, institute rapid acting anticoagulant therapy as soon as
possible.
Anticoagulation is usually initiated with an injectable anticoagulant (unfractionated heparin
[UFH], low-molecular-weight heparin [LMWH], or fondaparinux) and then transitioned to
warfarin maintenance therapy. Injectable anticoagulants can be administered in the outpatient
setting in most patients with DVT and in carefully selected hemodynamically stable patients
with PE. Alternatively, oral rivaroxaban may be initiated in select patients.
The acute phase (~7 days) requires rapidly-acting anticoagulants (UFH, LMWH, fondaparinux,
rivaroxaban) to prevent thrombus extension and embolization.
The early maintenance phase (7 days to 3 months) consists of continued anticoagulation to
reduce risk of long-term sequelae (eg, post-thrombotic syndrome) by allowing formed clot to
be slowly dissolved by endogenous thrombolysis.
Anticoagulation beyond 3 months is aimed at long-term secondary prevention of recurrent VTE.

Nonpharmacologic Therapy
• Graduated compression stockings and intermittent pneumatic compression (IPC) devices
improve venous blood flow and reduce risk of VTE.
• Inferior vena cava filters can provide short-term protection against PE in very high risk
patients with contraindications to anticoagulation therapy or in whom anticoagulant therapy
has failed.

• Encourage patients to ambulate as much as symptoms permit.

• Consider thrombectomy in life- or limb-threatening DVT. For acute PE, catheter based
embolectomy might be suitable for patients who have contraindications to thrombolytic
therapy, have failed thrombolytic therapy, or in whom death is likely before onset of
thrombolysis. Reserve surgical embolectomy for massive PE and hemodynamic instability when
thrombolysis is contraindicated, has failed, or will have insufficient time to take effect.

Pharmacologic Therapy
ALGORITHM FOR THE TREATMENT OF VTE

Note: You may refer the Handbook for a better view of the above algorithm.

A.Unfractionated Heparin
Unfractionated heparin (UFH) prevents growth and propagation of a formed thrombus and
allows endogenous thrombolytic systems to degrade the clot. Because some patients fail to
achieve an adequate response, IV UFH has largely been replaced by LMWH or fondaparinux.
UFH continues to have a role in patients with creatinine clearance less than 30 mL/min (<0.5
mL/s).
When immediate and full anticoagulation is required, a weight-based IV bolus dose followed by
a continuous IV infusion is preferred.
Fixed dosing: 5000-unit bolus followed by 1000-units/h continuous infusion

Weight-based subcutaneous (SC) dosing: initial dose 333 units/kg SC followed by 250 units/kg
every 12 hours)
Warfarin therapy is overlapped for at least 5 days and continued after UFH is discontinued.
Measure aPTT prior to initiation of therapy and 6 hours after the start of therapy or a dose
change. Adjust the heparin dose promptly based on patient response.
Bleeding is the primary adverse effect associated with anticoagulant drugs. The most common
bleeding sites include the gastrointestinal (GI) tract, urinary tract, and soft tissues.
If major bleeding occurs, discontinue UFH immediately and give IV protamine sulfate.
Heparin-induced thrombocytopenia (HIT) is a serious immune-mediated problem that
requires immediate intervention. Thrombocytopenia is the most common clinical
manifestation, but serologic confirmation of heparin antibodies is required for making the
diagnosis.
B.Low-Molecular-Weight Heparin
• Advantages of LMWHs over UFH include:

(1) predictable anticoagulation dose response

(2) improved SC bioavailability
(3) dose-independent clearance
(4) longer biologic half-life
(5) lower incidence of thrombocytopenia

(6) less need for routine laboratory monitoring

• Stable DVT patients who have normal vital signs, low bleeding risk, and no other comorbid
conditions requiring hospitalization can be discharged early or treated entirely on an outpatient
basis. Some patients with PE may also be managed safely as outpatients with LMWH or
fondaparinux. Patients who are unsuitable candidates for outpatient treatment should be
hospitalized.
• Recommended doses (based on actual body weight) of LMWH for treatment of DVT with or
without PE include the following:

✓ Enoxaparin: 1 mg/kg SC every 12 hours or 1.5 mg/kg every 24 hours

✓ Dalteparin: 100 units/kg every 12 hours or 200 units/kg every 24 hours
✓ Tinzaparin: 175 units/kg SC every 24 hours
• Acute treatment with LMWH can be transitioned to long-term warfarin after 5 to 10 days.

• Routine laboratory monitoring is unnecessary. Prior to initiating therapy, obtain a baseline

complete blood cell count (CBC) with platelet count and serum creatinine. Check the CBC every
5 to 10 days during the first 2 weeks of LMWH therapy and every 2 to 4 weeks thereafter to
monitor for occult bleeding. Measuring anti–factor Xa activity is the most widely used method
to monitor LMWH; routine measurement is unnecessary in stable and uncomplicated patients.
• Bleeding is the most common adverse effect of LMWH therapy, but may be less common than
with UFH.If major bleeding occurs, administer protamine sulfate IV, although it cannot
neutralize the anticoagulant effect completely. Protamine sulfate is not recommended if the
LMWH was given more than 12 hours earlier.
• Thrombocytopenia can occur with LMWHs, but the incidence of HIT is three times lower than
with UFH.