You are on page 1of 14

VENOUS THROMBOEMBOLISM

(VTE)
EricWongandSultanChaudhry

Facultyreviewer:Dr.PeterL.Gross,AssociateProfessor,DivisionofHematology
andThromboembolism,DepartmentofMedicine(McMasterUniversity)

Definition
Deep vein thrombosis (DVT) and pulmonary embolism (PE) are
manifestations of the same pathological entity, called venous
thromboembolism (VTE).

An embolus is any intravascular material that migrates from its original location to
occlude a distal vessel. Although the embolus can be a blood clot (thrombus), fat, air,
amniotic fluid, or tumour, a PE is usually caused by a thrombus originating from the deep
veins in the legs (deep venous thrombosis, DVT).

Arterialvs.venousthrombosis

Thromb Haemost. 2011 Apr;105(4):586-96.

The coagulation cascade is an essential part of hemostasis. However, the


same coagulation factors can give rise to clot formation in the circulation
that is inappropriate (i.e. not for hemostasis). Thrombi can form in both
the arteries and veins, but they have different pathophysiology and lead
to different outcomes. This chapter is about venous thrombosis.
Arterial thrombosis

Venous thrombosis (VTE)

Mechanis

Typically from rupture of

Typically from a combination of

atherosclerotic plaques.

factors from Virchows triad.

Location

Left heart chambers, arteries

Venous sinusoids of muscles and


valves in veins

Diseases

Acute coronary syndrome

Deep venous thrombosis

Ischemic stroke
Limb

Pulmonary embolism

claudication/ischemia
Compositi
on

Mainly platelets

Mainly fibrin

Treatment

Mainly antiplatelet agents


(ASA, clopidogrel)

Mainly anticoagulants (heparins,


warfarin)

Etiology

N Engl J Med. 2008 Mar 6;358(10):1037-52.

J Cardiovasc Nurs. 2005 Jul-Aug;20(4):254-9.

Venous thromboembolism is associated with Virchows triad: three


conditions that predispose to thrombus formation.
1.
2.
3.

Hypercoagulability
Stasis
Endothelial damage

VTE often arise from the synergistic effects of multiple risk factors, for
example, when a patient with inherited factor V Leiden mutation uses oral
contraceptives (acquired risk on genetic risk background).
Triad component

Associated risk factors

Hypercoagulabilit

Hereditary factors (inherited thrombophilia)

Factor V Leiden*: Activated factor V (FVa) is a


cofactor for activated factor X, and together, they

Changes in blood
coagulation
pathway, shifting
balance toward
coagulation

lead to thrombin generation from its zymogen,


prothrombin. Thrombin is a serine protease that
cleaves solublefibrinogen into insoluble fibrin and
activates other factors that amplify the coagulation
cascade. To regulate coagulation and protect
against clot formation, activated protein C
(aPC) cleaves and inactivates FVa.Factor V
Leiden is a mutation at one of the aPC cleavage
sites, rendering factor Va resistant to inactivation,
thus predisposing to clot formation and VTE.
Individuals with this mutation are at a 5-fold
increased risk for developing a first VTE.
Prothrombin G20210A*: Mutation at
nucleotide 20210 from guanine to adenine. The
mutation is in the 3 untranslated region of the
prothrombin and therefore does not alter the
structure of the protein, but causes increased
production of prothrombin (factor II). Individuals
with this mutation are at a 2-4 fold increased risk
for developing a first VTE.
Deficiencies in antithrombin (AT), protein
C (PC) and protein S (PS), plasminogen (Pg):
o
AT, PS and PC are the major
anticoagulation proteins and genetic defects
can lead to qualitative or quantitative defects in
their structure predisposing patients to
developing VTE.

*The 2 most common hereditary factors; autosomal


dominant risk inheritance
Acquired factors

Cancer: Cancer cells induce a prothrombotic


state through a variety of mechanisms. Some
cancer cells express (i) procoagulant proteins and
(ii) cause the release of microparticles (soluble
fragments of tumour cell membranes) leading to a
systemic hypercoagulable state. Two common
procoagulant proteins aretissue factor, which
indirectly activates factor X by complexing with
factor VII, and cancer procoagulant, which
directly activates factor X. Tumour-induced hypoxia
and release of inflammatory cytokines have also
been speculated to cause a prothrombotic state.
Pathophysiol Haemost Thromb. 2006;35(1-2):10310.
Best Pract Res Clin Haematol. 2009 Mar;22(1):49-

60.

Stasis
The slowing or
stopping of blood
flow

Chemotherapy: Chemotherapy drugs have


been shown to induce TF in tumor cells as well as
monocytes, downregulation of protein C and S
(natural anticoagulation mechanism), direct
damage to the vascular endothelium, and platelet
activation. Anti-angiogenic agents
(bevacizumab) have platelet and endothelial
activation properties leading to a prothrombotic
state.
Arterioscler Thromb Vasc Biol. 2009 Mar;29(3):31620.
Oral contraceptives and hormone
replacement therapy: Hyperestrogenemia
causes increased hepatic synthesis of procoagulant
proteins and decreased synthesis of anticoagulant
and fibrinolytic proteins.
Thromb Res. 2010 Jul;126(1):5-11.
Pregnancy and postpartum period: High
estrogen like OCP/HRT and stasis due to obstruction
of inferior vena cava by fetus.
Central obesity: Mechanisms include
procoagulant effects of adipocytokines (leptin and
adiponectin), increased activity of coagulation
cascade, increased inflammation, oxidative stress,
and endothelial dysfunction.
Eur J Vasc Endovasc Surg. 2007 Feb;33(2):223-33.
Heparin-induced thrombocytopenia (HIT):
Heparin binds platelet factor 4 (PF4) and exposes a
previously masked epitope, leading to the
production of IgG antibody in some heparin treated
patients. IgG binds to the heparin-PF4 complex,
forming immune complexes that bind and activate
platelets. This leads to a hypercoagulable state and
thrombocytopenia. Platelet activation also induces
endothelial cell injury.
Blood. 2007 Dec 15;110(13):4253-60.
Reduced mobility: Increases length of contact
of coagulation factors with endothelium.
o
Examples: Long-haul air travel,
hospitalization
Polycythemia: Hyperviscosity, due to
excessive overproduction of red blood cells, leads
to stasis of blood in the veins.

Endothelial injury: Stasis directly damages


the endothelium as well as reduces the natural
fibrinolysis.
Congestive heart failure: Failure to pump
blood forward results in venous stasis and elevated
central venous pressure.

Endothelial
damage

Endothelial dysfunction: Shifts the balance between


clot generation and breakdown towards thrombosis

Normal endothelium
is antithrombotic.

due to decreased synthesis of nitric oxide and


prostacyclin and increased endothelin-1.

Hypertension

Cigarette smoking
Endothelial damage: Exposure of subendothelial
tissue factor and collagen, which offer a substrate for
platelet binding, activation and aggregation; leading to
clot formation.

Chronic indwelling central venous


catheter (catheters also directly activate the
intrinsic pathway)

Major surgery

Trauma

PathophysiologyofDVT

Semin Nucl Med. 2001 Apr;31(2):90-101.

Crit Care Clin. 2011 Oct;27(4):869-84, vi.

Circulation. 2003 Jun 17;107(23 Suppl 1):I22-30.

Deep venous thrombosis usually arises in the lower extremities. Most


DVTs form in the calf veins, particularly in the soleus sinusoids and cusps
of the valves.

Venous valves are avascular, which, in conjunction with reduced flow of oxygenated
blood in veins, predisposes the endothelium to be hypoxemic. The endothelium around
valves responds by expressing adhesion molecules that attract leukocytes. These cells
transfer tissue factor to the endothelium, which can complex with activated factor
VII to begin the coagulation cascade via the extrinsic pathway. The main component of
these venous thrombi is fibrin (as product of coagulation cascade) and red blood cells,
which get trapped in the clot. Platelets also contribute, but to a lesser extent.
The skeletal muscle pump helps prevent DVT by moving blood past the valves (i.e.
reducing venous stasis), which washes away activated clotting factors that can otherwise
propagate the initial thrombus.
If a clot forms and does not resolve (see below), it will extend proximally into
the popliteal and femoral veins (proximal veins). 25% of calf DVTs will extend
proximally within 7 days. While calf DVTs are usually asymptomatic and do not give rise

to significant PEs, proximal DVTs are more likely symptomatic and can embolize to form
dangerous PEs.
By the numbers

96% arise in the lower extremities; 4% arise in the upper extremities.


Chest. 2008 Jan;133(1):143-8.
Of symptomatic lower-extremity DVTs, 88% involve the proximal veins; the rest
only involve the calf veins. Almost all lower-extremity DVTs arise from the calf veins
and extend proximally.
Arch Intern Med. 1993 Dec 27;153(24):2777-80.
90% of PEs arise from DVTs.
50% of symptomatic proximal lower-extremity DVTs have asymptomatic PEs.
70% of PEs have asymptomatic DVTs.
28% of symptomatic DVTs will have post-thrombotic syndrome after 5 years.

Resolution and consequences

The initial thrombus can lead to complete resolution, clot


extension/embolization, or organization.

Complete resolution: Fibrinolysis is a dynamic process where plasminogen is


converted into plasmin, an enzyme that degrades fibrin into soluble peptides. Fibrinolysis
starts within hours, and it can lead to complete or partial resolution of the thrombus.
Partial resolution may lead to any one of these 3 consequences.
Clot extension and embolization: Proximal flow of the venous blood sweeps the
thrombus in the same direction, extending it into the proximal veins.
Organization: Thrombi that do not resolve begin to retract within days. At the same
time, inflammatory cells infiltrate the thrombi and cause remodeling. The residual clot is
incorporated into the vessel wall and a layer of endothelial cells forms on top (reendothelialization). This process, called organization, allows some blood flow to resume,
but it destroys valves along the length of the clot and causes scarring of the veins. The
hemodynamic changes to the vein causes post-thrombotic syndrome.
o
Post-thrombotic syndrome is a consequence of DVTs, and the clinical
features include pain, leg edema, and other signs of venous insufficiency. It occurs in
approximately 1/3 of DVT cases. The cause is a combination of venous
obstruction by residual clots or venous scarring and venous reflux due to valve
destruction. Prevention of this sequela includes adequate anticoagulationto prevent
VTE recurrence and compression stockings to improve venous return.

PathophysiologyofPE
Hellenic J Cardiol. 2007 Mar-Apr;48(2):94-107.
Circulation. 2003 Dec 2;108(22):2726-9.

Effectsofmechanicalocclusion

Increased alveolar (physiologic) dead space: decreased perfusion of alveoli distal to


thrombus causes the alveoli to be ventilated but not perfused, resulting in V/Q mismatch
(high V/Q) and increased dead space
o
Increased minute ventilation: patient compensates for dead space and
responds to chemical irritation by hyperventilation.
o
Hypocapnia: increased minute ventilation causes decreased blood CO2
and respiratory alkalosis. Hypocapnia exacerbates alveolar hypoxemia by
causing secondary bronchoconstriction.
Increased pulmonary vascular resistance: due to vascular obstruction by thrombus
and chemical mediators from platelets (see below)
Decreased surfactant and atelectasis: vascular compromise beyond thrombus
reduces surfactant production and thus predisposes distal region to atelectasis

Effectsofchemicalmediators

Platelets from the thrombus secrete chemical mediators such


as histamine and serotonin, which causes pulmonary
vasoconstriction and bronchoconstriction.
Bronchoconstriction leads to alveolar hypoxemia, which in turn causes more
vasoconstriction and increased vascular resistance.

Hemodynamicconsequences

Increased right ventricular afterload: from increased pulmonary vascular


resistance.
o
Right ventricular dilatation and hypertrophy: parasternal heave, loud P2

RV ischemia
o
Right-sided (backward) heart failure: increased jugular venous pressure
(JVP)
Decreased left ventricular filling: because of bowing of interventricular septum to
left side from RV hypertrophy
o
Left-sided (forward) heart failure: hypotension, syncope, cardiogenic shock

Resolution

Intrinsic thrombolytic mechanisms (plasmin) start to lyse clots: D-dimer (breakdown


product of fibrin) levels increase in serum.
Symptomatic PE is treated with anticoagulation therapy (oral or
parenteral), thrombolytic therapy (for massive PE causing cardiogenic shock),
or inferior vena cava filter (if anticoagulation is contraindicated). See Treatment section
for details.
Untreated large PE causes death by acute increase in right ventricular pressure,
leading to RV failure.

ClinicalfeaturesofDVT

Semin Nucl Med. 2001 Apr;31(2):90-101.

JAMA. 1998 Apr 8;279(14):1094-9.

Clinicians accurately diagnose DVT using clinical features in approximately


25% of cases because the signs and symptoms are neither sensitive nor
specific. Therefore, it is important to confirm clinical findings using
additional testing, such as compression ultrasonography. The signs and
symptoms of DVT arise from (i) venous obstruction and
(ii) inflammation of the veins. Patients may also present with features
of pulmonary embolism.
Symptoms

Signs

Mechanism

Asymmetric

Pitting

Swelling and pitting edema are caused by

leg/calf
swelling

edema on
affect side

venous obstruction. Calf circumference is


measured 10cm below the tibial tuberosity.
Normal difference between the two legs
should be less than 1cm; greater than 3cm
difference is considered significant.

Pain,

Localized

Pain, erythema, and tenderness are caused by

erythema

tenderness
along deep

vascular inflammation. Recruitment of


inflammatory cells to thrombus and venous

venous
system

stasis causes phlebitis.

Homans sign

First observed by surgeon Dr. John Homans,


the sign is elicited by passive dorsiflexion of
the ankle. Positive findings include increased
resistance to dorsiflexion or knee flexion, both
in response to irritation of the posterior calf
muscles. This sign is neither sensitive nor
specific.
N Engl J Med. 1946 Aug 1;235(5):163-7.

Dilated

Palpable cord

Dilated superficial veins are caused by

superficial
veins (non-

obstruction of the deep venous system.


Palpable cord refers to palpable superficial

varicose)

veins, which is a sign of superficial phlebitis.

ClinicalfeaturesofPE

Hellenic J Cardiol. 2007 Mar-Apr;48(2):94-107.

JAMA. 2003 Dec 3;290(21):2849-58.

PEs are frequently asymptomatic. Symptomatic patients most commonly


present with dyspnea. Signs of DVT are only found in about 1/3 of PE
patients.
Sympto

Corresponding

Mechanism

ms

sign(s)

Dyspnea

Tachypnea*,

Hyperventilation to compensate for

decreased air entry,


localized rales,

increased dead space and in response to


chemical mediators from

wheezing

platelets.Dyspnea is a symptom
of central, which causes more severe

hemodynamic consequences because


of occlusion of larger vessels. *Most
common symptom and sign, respectively.

Parasternal heave,

Increased pulmonary pressure (from

loud P2, increased


JVP

vasoconstriction) causes right ventricular


overload (loud P2) and right ventricular
dilatation (parasternal heave). Rightsided backward heart failure
causes increased JVP, and eventually
left-sided heart failure (tachycardia).

Palpitatio
ns

Hemodynamic
signs: Tachycardia

See above. Tachycardia is a sympathetic


response to decreased cardiac output.

Pleuritic
chest

Pleural friction rub,


signs of pleural

PE near the pleura (peripheral PE)


causes ischemia to the region, resulting in

pain

effusion (stony
dullness on

inflammation. Since the pleura is


innervated, inflammation will produce

percussion,
decreased fremitus)

localized pleuritic chest pain.


Inflammation also increases the
permeability of the pleural surface,
leading to accumulation of exudative
pleural fluid (pleural effusion).

Hemoptys

PE causes damage to the pulmonary

is and
cough

vasculature, which leads to bleeding into


the airways. Cough is usually
nonproductive, and may be triggered by
irritation of the pleura or the airways.
Am J Med. 2007 Oct;120(10):871-9.

Syncope

Hypotension,

Decreased left ventricular filling, causing

cyanosis

forward heart failure.

DiagnosisofDVT

JAMA. 2006 Jan 11;295(2):199-207. (Discussion of Wells DVT score here)

Chest. 2012 Feb;141(2 Suppl):e351S-418S. (2012 Chest Guidelines)

Diagnosis starts with history (risk factors) and physical, which can be
used to generate a pretest probability using a validated clinical
prediction rule, such as the Wells DVT score (see JAMA reference
above). Patients with high likelihood of DVT can be further tested
with compression ultrasonography, where the length of the proximal
veins (popliteal and femoral) is sequentially compressed with the
ultrasound probe. Normal veins are easily occluded with moderate
external compression, but a DVT will prevent occlusion of the vein lumen.
Ultrasonography is both sensitive and specific for DVTs.

A D-dimer level can be done to rule-out DVT in individuals with low pretest
probability (see discussion in Diagnosis of PE).
Contrast venography is considered the gold standard for diagnosis of DVT, although
this is rarely done because it is invasive, expensive, and not readily available. Contrast is
injected into the dorsal foot vein, and the leg is imaged with CT scan or MRI.

DiagnosisofPE
JAMA. 2003 Dec 3;290(21):2849-58.

Diagnosis is based on history and physical, and confirmed with CT


or V:Q scan if the clinical suspicion is high. The Wells criteria can
be used to determine risk (pretest probability) of PE.
Criteria

Poin
ts

1 Clinical signs/symptoms of DVT

2 No other diagnosis more likely

than PE
3 Tachycardia: heart rate > 100

1.5

4 Immobilization for > 3 days


(e.g. strict bed rest)

1.5

OR
Surgery in the previous 4
weeks
5 Previous DVT or PE

1.5

6 Hemoptysis

7 Malignancy

Low risk (<2): 3% pretest

probability
Moderate (2-6): 20%
High (>6): 63%
Thromb Haemost. 2000
Mar;83(3):416-20.

Note on D-dimer: In low-risk patients with symptoms that suggest PE, a


D-dimer can be used to rule out PE if negative (high sensitivity, low
specificity). D-dimer level is measured in the blood. As explained above, it
is a degradation product of fibrin, which is elevated if a coagulation and
fibrinolysis reaction happens in the body. In PE, endogenous fibrinolytic
mechanisms try to dissolve the clot, which is the basis of an elevated Ddimer. However, the D-dimer level not specific and is elevated in any type
of inflammatory process. Its clinical utility is limited to ruling out PE in
those with a low pretest probability.

Treatment
Chest. 2012 Feb;141(2 Suppl):e419S-94S.

The goals of treatment for VTE are (i) anticoagulation to prevent further
clot generation and (ii) thrombolysis if the thrombus is large enough to
cause hemodynamic compromise.
Anticoagulation: Reduces further clot formation

Anticoagulation with parenteral (intravenous or subcutaneous)


and oral anticoagulants is the mainstay of VTE therapy. Typically, one of
the parenteral agents (e.g. heparin, LMWH, or fondaparinux) or a new oral
anticoagulant (e.g. rivaroxaban) is started first. The patient may be
transitioned to a traditional oral anticoagulant (e.g. warfarin) for chronic
anticoagulation.

Unfractionated heparin (UFH): Inhibits the function of thrombin as well as Xa by


inducing conformational changes in antithrombin, allowing it to bind the enzymes
better.
Low molecular weight heparin (LMWH): Functions similar to UFH, but due to the
smaller average heparin chain length, accelerates the bridging of AT with Xa only, and
not thrombin.
Fondaparinux: A pentasaccharide sequence that directly binds to AT (at an allosteric
site) and induces a conformational change allowing it to bind and inhibit factor Xa only.
Rivaroxaban: A new oral anticoagulant that inhibits factor Xa by binding to its active
site.

Chronic anticoagulation: For prophylaxis against future VTE

Any of the agents for acute anticoagulation can be used for chronic
anticoagulation, but they are less convenient for outpatients due to the
need for daily injections. Oral anticoagulation drugs are the mainstay
for outpatient anticoagulation. Vitamin K antagonists (e.g.

warfarin) were traditionally used, but newer agents, such


as dabigatran and rivaroxaban, can also be used. In addition, aspirin is
an antiplatelet agent that has been shown to reduce VTE events in recent
trials.

Vitamin K antagonists (e.g. warfarin): Warfarin inhibits the vitamin K dependent


synthesis of calcium dependent clotting factors (II, VII, IX and X). Furthermore, warfarin
also inhibits PS and PC (part of the endogenous anticoagulation pathway).
o
The inhibition of PC and PS occurs faster than the other clotting factors,
making warfarin acutely a procoagulant. Therefore, warfarin must be given
concomitantly with acute anticoagulants at first (a process known as overlapping)
to (i) prevent acute procoagulant effect and (ii) allow time for inhibition of vitamin K
dependent factors. Once the patients international normalized ratio (INR) is
therapeutic (2-3), acute anticoagulants can be discontinued.
Warfarin has been the mainstay of chronic VTE therapy for over 50 years, but there
are several issues with its use: (i) increased bleeding risk, (ii) teratogenicity in pregnancy,
(iii) interaction with many foods and drugs, and (iii) close monitoring required because
anticoagulation effect is not reliably predictable by dosage. New antithrombotic
medications have been developed that are potentially safer than warfarin.
o
Direct thrombin inhibitors (e.g. dabigatran): Directly block thrombin
function by blocking the active site. Dabigatran is equivalent to warfarin in both
prevention of recurrent clots and bleeding risk in patients with acute VTE, but it does
not require monitoring due to its predictable therapeutic effect (RE-COVER trial).
N Engl J Med. 2009 Dec 10;361(24):2342-52.

Direct Xa inhibitors (e.g. rivaroxaban): Directly inhibit the function of Xa


by blocking the active site. Unlike warfarin and dabigatran, rivaroxaban does not
require overlapping with heparins. Rivaroxaban is equivalent to warfarin in short- and
long-term prevention of PE in symptomatic patients, but it does not require
monitoring or overlapping, and has significantly lower bleeding risk compared to
warfarin (EINSTEIN-PE trial).
N Engl J Med. 2012 Apr 5;366(14):1287-97.

Aspirin: Although this antiplatelet agent is classically used to prevent arterial


thrombosis, new evidence suggests that it can also be used for recurrent VTE prevention.
Daily aspirin (100mg/day used in trials) can reduce VTE recurrence by approximately
1/3. Aspirin, although not as effective as other anticoagulants, may be used if the patient
is intolerant of anticoagulants.
N Engl J Med. 2012 Nov 22;367(21):2039-41.

Thrombolysis: Breaks down the thrombus

Tissue plasminogen activator (tPA): activates plasminogen (Pg) to plasmin (Pn),


which cleaves the thrombus, generating soluble D-dimer products.

Contraindications to anticoagulation

Thrombectomy: If a large thrombus creates hemodynamic compromise, and there are


contraindications to thrombolysis, the clot can be surgically removed or by
interventional radiology.

Inferior vena cava (IVC) filter: Temporary IVC filters can be placed to stop the
movement of clots from the deep veins of the lower extremity from travelling to the
pulmonary vasculature.

You might also like