14 venous thromboembolismVenous Thromboembolism

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

Patophysiology

PATHOPHYSpa
• Normal hemostasis (Fig. 14–1) maintains integrity of the circulatory system after
blood vessel damage. Vascular injury allows components of the coagulation process
to seal the breach through interaction of activated platelets and the clotting factor
cascade initiated by tissue factor and culminating in formation of a fibrin clot.
• In contrast to physiologic hemostasis, pathologic venous thrombosis occurs in the
absence of gross vein wall disruption and may be triggered by microparticles bearing
tissue factor rather than the tissue factor expressed in vessel walls.
• Platelets are activated and contribute to thrombus formation by two pathways: (1)
exposure
of blood to subendothelial collagen after vascular injury; and (2) thrombin
generation by tissue factor derived from the vessel wall or in blood. A platelet
thrombus develops as activated platelets recruit unstimulated platelets. Platelet
activation releases adenosine diphosphate (ADP), calcium ions, and P-selectin, an
adhesion molecular that facilitates capture of microparticles bearing tissue factor.
Accumulation of tissue factor in the platelet thrombus initiates fibrin clot formation
via the coagulation cascade.
• The tissue factor pathway triggers coagulation by generating a small amount of
thrombin, which converts factors VIII and V to their active cofactor forms (VIIIa,
Va), which then stimulates the tenase and prothrombinase complexes to generate a
large burst of thrombin.
• Finally, thrombin mediates conversion of fibrinogen to fibrin monomers, which
precipitate and polymerize to form fibrin strands. Factor XIIIa covalently bonds
these strands together. Fibrin deposition forms a meshwork that encases aggregated
platelets to form a stabilized clot that seals the site of vascular injury and prevents
blood loss.
• Hemostasis is controlled by antithrombotic substances secreted by intact endothelium
adjacent to damaged tissue. 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. In addition, circulating antithrombin inhibits thrombin and
factor Xa. Heparan sulfate is secreted by endothelial cells and accelerates antithrombin
activity. Heparin cofactor II also inhibits thrombin.
• 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.
Thromboembolism

CLINICAL PRESENTASION
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, reduce morbidity and mortality from the acute event, and minimize
adverse effects and cost of treatment.

GENERAL APPROACH
• Anticoagulation is the primary treatment for VTE; DVT and PE are treated similarly
(Fig. 14–2).
• After VTE is confirmed objectively, institute 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, postthrombotic 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 highrisk
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, catheterbased
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
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 (Table 14–1). Fixed dosing

FIGURE 14–2. Treatment of venous thromboembolism (VTE). (CT, computed

tomography; DVT, deep vein thrombosis; IV, intravenous; LMWH, low-molecular-
weight
heparin; PE, pulmonary embolism; SBP, systolic blood pressure; UFH, unfractionated
heparin.)

(eg, 5000-unit bolus followed by 1000-units/h continuous infusion) produces similar

clinical outcomes.
• Weight-based subcutaneous (SC) UFH (initial dose 333 units/kg SC followed by 250
units/kg every 12 hours) without coagulation monitoring is a less costly option for
select patients; warfarin therapy is overlapped for at least 5 days and continued after
UFH is discontinued.
• The activated partial thromboplastin time (aPTT) with a therapeutic range of 1.5 to
2.5 times the mean normal control value is generally used to determine the degree

of therapeutic anticoagulation. 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. Critical areas include intracranial, pericardial, and intraocular sites, and
adrenal glands. Symptoms of bleeding include severe headache, joint pain, chest pain,
abdominal pain, swelling, tarry stools, hematuria, or the passing of bright red blood
through the rectum. Minor bleeding occurs frequently (eg, epistaxis, gingival bleeding,
prolonged bleeding from cuts, bruising from minor trauma).
• If major bleeding occurs, discontinue UFH immediately and give IV protamine
sulfate by slow IV infusion over 10 minutes (1 mg/100 units of UFH infused during
the previous 4 hours; maximum 50 mg).
• 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. Use of a clinical prediction rule, such as the four Ts score (Thrombocytopenia,
Timing of platelet count fall or thrombosis, Thrombosis, oTher explanation for
thrombocytopenia),
can improve the value of platelet count monitoring and heparin antibody
testing in predicting HIT. Discontinue all heparin if new thrombosis occurs in the
setting of falling platelets in conjunction with a moderate or high four Ts score. Then
initiate alternative anticoagulation with a parenteral direct thrombin inhibitor.
• Long-term UFH has been reported to cause alopecia, priapism, hyperkalemia, and
osteoporosis.

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, and (6) less need for
routine laboratory monitoring.
• LMWH given SC in fixed or weight-based doses is at least as effective as UFH given
IV for VTE treatment. Efficacy and safety are similar with inpatient or outpatient

LMWH administration, once- or twice-daily dosing, and use of different LMWH

preparations.
• 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 (Lovenox): 1 mg/kg SC every 12 hours or 1.5 mg/kg every 24 hours
✓ Dalteparin (Fragmin): 100 units/kg every 12 hours or 200 units/kg every 24 hours
(not approved by the U.S. FDA [Food and Drug administration] for this indication)
✓ Tinzaparin (Innohep): 175 units/kg SC every 24 hours
• Acute treatment with LMWH can be transitioned to long-term warfarin after 5 to
10 days.
• Because LMWH anticoagulant response is predictable when given SC, 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.
• As with other anticoagulants, bleeding is the most common adverse effect of LMWH
therapy, but major bleeding may be less common than with UFH. If major bleeding
occurs, administer protamine sulfate IV, although it cannot neutralize the anticoagulant
effect completely. The recommended dose of protamine sulfate is 1 mg per
1 mg of enoxaparin or 1 mg per 100 anti–factor Xa units of dalteparin or tinzaparin
administered in the previous 8 hours. A second dose of 0.5 mg per 1 mg or 100 anti–
factor Xa units can be given if bleeding continues. Smaller protamine doses can be
used if the LMWH dose was given in the previous 8 to 12 hours. 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.

Fondaparinux
• Fondaparinux sodium (Arixtra) prevents thrombus generation and clot formation
by indirectly inhibiting factor Xa activity through its interaction with antithrombin.
It is approved for prevention of VTE following orthopedic (hip fracture, hip and
knee replacement) or abdominal surgery and for the treatment of DVT and PE (in
conjunction with warfarin).
• Fondaparinux is a safe and effective alternative to LMWH for treatment of DVT or PE.
• Fondaparinux is dosed once daily via weight-based subcutaneous injection: 5 mg if
less than 50 kg, 7.5 mg if 50 to 100 kg, and 10 mg if greater than 100 kg. Fondaparinux
is contraindicated if creatinine clearance is less than 30 mL/min (<0.5 mL/s).
• For VTE prevention, the dose is 2.5 mg SC once daily starting 6 to 8 hours after
surgery.
• Patients receiving fondaparinux do not require routine coagulation testing. Measure
CBC at baseline and periodically thereafter to detect occult bleeding. Monitor for
signs and symptoms of bleeding daily. There is no specific antidote to reverse the
antithrombotic activity of fondaparinux.

Direct Anti-Xa Inhibitors

• Rivaroxaban (Xarelto) and apixaban (Eliquis) are selective inhibitors of both free and
clot-bound factor Xa that do not require antithrombin to exert their anticoagulant effect.
• Neither agent is FDA approved for VTE treatment in the United States, but rivaroxaban
is approved for prevention of VTE following hip or knee replacement surgery; the
rivaroxaban dose is 10 mg orally once daily with or without food. Rivaroxaban should
be initiated at least 6 to 10 hours after surgery once hemostasis has been established and
continued for 12 days (knee replacement) or 35 days (hip replacement).
• Routine laboratory monitoring and dose adjustment are not required because of
predictable pharmacokinetics. Bleeding is the most common adverse effect; patients
should be observed closely for signs or symptoms of blood loss.

Warfarin
• Warfarin inhibits enzymes responsible for cyclic interconversion of vitamin K in the
liver. Reduced vitamin K is a cofactor required for the carboxylation of the vitamin
K–dependent coagulation proteins prothrombin (II); factors VII, IX, and X; and
the endogenous anticoagulant proteins C and S. By reducing the supply of vitamin
K, warfarin indirectly slows their rate of synthesis. By suppressing the production
of clotting factors, warfarin prevents initial formation and propagation of thrombi.
Warfarin has no direct effect on previously circulating clotting factors or previously
formed thrombi. The time required to achieve its anticoagulant effect depends on the
elimination half-lives of the coagulation proteins. Because prothrombin has a 2- to
3-day half-life, warfarin’s full antithrombotic effect is not achieved for 8 to 15 days
after initiation of therapy.
• Start warfarin concurrently with UFH or LMWH therapy. For patients with acute
VTE, UFH, LMWH, or fondaparinux should be overlapped for at least 5 days, regardless
of whether the target international normalized ratio (INR) was achieved earlier.
The UFH or LMWH can then be discontinued once the INR is within the desired
range for 2 consecutive days.
• Guidelines for initiating warfarin therapy are given in Fig. 14–3. The usual initial
dose is 5 to 10 mg. Lower starting doses may be acceptable based on patient factors
such as advanced age, malnutrition, liver disease, or heart failure. Starting doses
greater than 10 mg should be avoided.
• Monitor warfarin therapy by the INR; for most indications, the target INR is 2.5, with
an acceptable range of 2 to 3. After an acute thromboembolic event, measure the INR
at least every 3 days during the first week of therapy. In general, do not make dose
changes more frequently than every 3 days. Adjust doses by calculating the weekly dose
and reducing or increasing it by 5% to 25%. The full effect of a dose changes may not
become evident for 5 to 7 days. Once the patient’s dose response is established, obtain
an INR every 7 to 14 days until it stabilizes, then every 4 to 8 weeks thereafter.
• Hemorrhagic complications ranging from mild to severe and life-threatening can
occur at any body site. The GI tract and nose are the most frequent sites of bleeding.
Intracranial hemorrhage is the most serious complication and often results in
permanent disability and death.
• Management of bleeding and excessive anticoagulation:
✓ Most patients with asymptomatic INR elevations can be safely managed by
withholding
warfarin alone.
✓ When the INR is greater than 4.5 without evidence of bleeding, the INR can be
lowered by withholding warfarin, adjusting the dose of warfarin, and providing
vitamin K to shorten the time to return to normal INR.
✓ If the INR is 5 to 9, warfarin doses may be withheld or may be combined with a
low dose of oral phytonadione (≤2.5 mg).
✓ If the INR is between 4.5 and 10 without bleeding, routine use of vitamin K is not
recommended
because it has not been shown to affect the risk of developing subsequent
bleeding or thromboembolism compared to simply withholding warfarin alone.
✓ For INR is greater than 10 without evidence of bleeding, giving oral phytonadione
2.5 mg is suggested.
✓ Use vitamin K with caution in patients at high risk of recurrent thromboembolism
because of the possibility of INR overcorrection.
✓ Patients with warfarin-associated major bleeding require supportive care and
repletion of coagulation factors; 5 to 10 mg of vitamin K should be administered
via slow IV injection.
FIGURE 14–3. Initiation of warfarin therapy. (INR, international normalized ratio;
PT,
prothrombin time.)

• Nonhemorrhagic adverse effects of warfarin include the rare “purple toe” syndrome
and skin necrosis.
• Because of the large number of food–drug and drug–drug interactions with warfarin,
close monitoring and additional INR determinations may be indicated whenever
other medications are initiated, or discontinued, or an alteration in consumption of
vitamin K–containing foods is noted.
Thrombolytics
• Thrombolytic agents are proteolytic enzymes that enhance conversion of plasminogen
to plasmin, which subsequently degrades the fibrin matrix.
• Removal of the occluding thrombus by fibrinolytic therapy (or surgical means) is
rarely warranted. Patients who present within 14 days of symptom onset with extensive
proximal DVT, good functional status, low bleeding risk, and a life expectancy
of a year or more are candidates for thrombolysis.
• Patients with DVT that involves the iliac and common femoral veins are at highest
risk for postthrombotic syndrome and may have the greatest potential to benefit from
thrombus removal strategies.

• The risk of bleeding associated with catheter-directed drug administration appears

to be less than systemic administration. For DVT, catheter-directed thrombolysis is
preferred if appropriate expertise and resources are available. The same duration and
intensity of anticoagulation therapy is recommended as for DVT patients who do not
receive thrombolysis.
• For patients with massive PE manifested by shock and cardiovascular collapse (~5%
of patients with PE), thrombolytic therapy is considered necessary in addition to
aggressive interventions such as volume expansion, vasopressor therapy, intubation,
and mechanical ventilation. Administer thrombolytic therapy in these patients without
delay to reduce the risk of progression to multisystem organ failure and death.
However, the risk of death from PE should outweigh the risk of serious bleeding
associated with thrombolytic therapy.
• Dosage regimens of thrombolytic agents for treatment of DVT and/or PE:
✓ Alteplase (Activase): For PE, 100 mg by IV infusion over 2 hours
✓ Streptokinase (Streptase): 250,000 units IV over 30 minutes, followed by a
continuous
IV infusion of 100,000 units/h for 24 hours (PE) or 24 to 72 hours (DVT)
✓ Urokinase (Abbokinase): For PE, 4400 IU/kg IV over 10 minutes, followed by 4400
IU/kg/h for 12 to 24 hours
• During thrombolytic therapy, IV UFH may be either continued or suspended; the
most common practice in the United States is to suspend UFH. Measure the aPTT
after completion of thrombolytic therapy. If the aPTT at that time is shorter than
80 seconds, start UFH infusion and adjust to maintain the aPTT in the therapeutic
range. If the posttreatment aPTT is longer than 80 seconds, remeasure it every 2 to
4 hours and start a UFH infusion when the aPTT is shorter than 80 seconds.
PREVENTION
• Nonpharmacologic methods improve venous blood flow by mechanical means and
include early ambulation, graduated compression stockings, IPC devices, and inferior
vena cava filters.
• Pharmacologic options inhibit clotting factor activity or production. Appropriately
selected therapy can significantly reduce the incidence of VTE after hip and knee
replacement, hip fracture repair, general surgery, myocardial infarction, ischemic
stroke, and in appropriately selected hospitalized medical patients.
• Refer to Antithrombotic Therapy and Prevention of Thrombosis, 9th edition: Evidence-
Based Clinical Practice Guidelines published by the American College of Chest
Physicians for detailed information on prophylaxis strategies based on the clinical
situation and level of risk for VTE.

EVALUATION OF THERAPEUTIC OUTCOMES

• Monitor patients for resolution of symptoms, development of recurrent thrombosis,
symptoms of the postthrombotic syndrome, and adverse effects from anticoagulants.
• Monitor hemoglobin, hematocrit, and blood pressure carefully to detect bleeding
from anticoagulant therapy.
• Perform coagulation tests (aPTT, PT, and INR) prior to initiating therapy to establish
the patient’s baseline values and guide later anticoagulation.
• Ask outpatients taking warfarin about medication adherence and symptoms related
to bleeding and thromboembolic complications. Any changes in concurrent medications
should be carefully explored.