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Venous thromboembolism (VTE)

pathophys.org /vte/

Definition

Deep vein thrombosis (DVT)and pulmonary embolism (PE)are manifestations of the same pathological entity,

called venous thromboembolism (VTE) .

An embolusis 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 PEis usually

caused by a thrombus originating from the deep veins in the legs (deep venous thrombosis, DVT).

Arterial vs. venous thrombosis

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)

Mechanism Typically from rupture of atheroscleroticplaques.

Typically from a combination of factors fromVirchows triad.

Location Left heart chambers, arteries Venous sinusoids of muscles and valves in veins

Diseases Acute coronary syndrome

Ischemic stroke

Limb claudicat ion/ischemia

Deep venous thrombosis

Pulmonary embolism

Composition Mainly platelets Mainly fibrin

Treatment Mainlyantiplatelet 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. Hypercoagulability

2. Stasis

3. Endothelial damage
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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

HypercoagulabilityChanges in bloodcoagulationpathway, shifting

balance towardcoagulation

Hereditary factors (inherited thrombophilia)

Factor V Leiden*: Activated factor V (FVa) is a cofactor for activated factor X, andtogether, they lead to thrombin generation from its zymogen, prothrombin. Thrombin

is a serine protease that cleaves soluble fibrinogeninto insoluble fibrinand activatesother factors that amplify the coagulation cascade. To regulate coagulation andprotect against clot formation, activated protein C (aPC)cleaves and inactivates FVa.Factor V Leidenis a mutation at one of the aPC cleavage sites, rendering factorVa resistant to inactivation, thus p redisposing to clot formation and VTE. Individualswith this mutation are at a 5-fold increased risk for developing a first VTE.


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Prothrombin G20210A*: Mutation at nucleotide 20210 from guanine to adenine. Themutation is in the 3 untranslated region of the prothrombin and therefore does notalter the structure of the protein, but causes increased production ofprothrombin(factor II). Individuals with this mutation are at a 2- 4 fold increased risk for developinga first VTE.

Def iciencies in ant ithrombin (AT), protein C (PC) and protein S (PS),plasminogen (Pg):

AT, PS and PC are the major anticoagulation proteins and genetic defectscan lead to qualitative or quantitative defects in their structure predisposingpatients 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 ofmicroparticles (soluble fragments of tumour cell membranes) leading to a systemichypercoagulable state. Two common procoagulant proteins are tissue fact or,which indirectly activates factor X by complexing with factor VII, and cancerprocoagulant , which directly activates factor X. Tumour-induced hypoxia andrelease of inflammatory cytokines have also been speculated to cause a

prothrombotic state.Pathophysiol Haemost Thromb.2006;35(1-2):103-10.Best Pract Res Clin Haematol.2009 Mar;22(1):49-60.

Chemotherapy: Chemotherapy drugs have been shown to induce TF in tumor cellsas well as monocytes, downregulation of protein C and S (natural anticoagulationmechanism), direct damage to the vascular endothelium, and platelet activation.Anti-angiogenic agents (bevacizumab)have platelet and endothelial activationproperties leading to a prothrombotic state.Arterioscler Thromb Vasc Biol.2009 Mar;29(3):316-20.

Oral contracept ives and hormone replacement therapy:Hyperestrogenemiacauses increased hepatic synthesis of procoagulant proteins and decreasedsynthesis of anticoagulant and fibrinolytic proteins.

Thromb Res.2010 Jul;126(1):5-11.Pregnancy and post partum period:High estrogen like OCP/HRT and stasis dueto obstruction of inferior vena cava by fetus.

Central obesity: Mechanisms include procoagulant effects of adipocytokines(leptin and adiponectin), increased activity of coagulation cascade, increasedinflammation, oxidative stress, and endothelial dysfunction.Eur J Vasc Endovasc Surg.2007 Feb;33(2):223-33.

Heparin-induced t hrombocytopenia (HIT): Heparin binds platelet factor 4 (PF4)and exposes a previously masked epitope, leading to the production of IgGantibody in some heparin treated patients. IgG binds to the heparin-PF4 complex,forming immune complexes that bind and activate platelets. This leads to ahypercoagulable state and thrombocytopenia. Platelet activation also induces

endothelial cell injury.Blood.2007 Dec 15;110(13):4253-60.

StasisThe slowing o rstopping of bloodflow

Reduced mobility: Increases length of contact of coagulation factors withendothelium.

Examples: Long-haul air travel, hospitalization

Polycythemia : Hyperviscosity, due to excessive overproduction of red blood cells,leads to stasis of blood in the veins.

Endot helial injury: Stasis directly damages the endothelium as well as reduces

the natural fibrinolysis.

Congestive heart failure:Failure to pump blood forward results in venous stasisand elevated central venous pressure.

Endothelial Endothelial dysfunct ion: Shifts the balance between clot generation and breakdown
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damageNormal endotheliumis antithrombotic.

towards thrombosis due to decreased synthesis of nitric oxide and prostacyclin andincreased endothelin-1.

Hypertension

Cigarette smoking

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

Chronic indwelling central venous catheter (catheters a lso directly activate the

intrinsic pathway)

Major surgery

Trauma

Pathophysiology of DVT

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 ext remities. Most DVTs form in the calf veins, particularly in

the soleus sinusoids and cusps of the valves.

Venous valvesare 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 f actorto the endothelium, which can

complex with activated factor VIIto 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. Plateletsalso contribute, but to a lesser extent.

The skeletal muscle pumphelps prevent DVT by moving blood past the valves (i.e. reducing venous

stasis), which washes away activated clo tting factors that can otherwise propagate the initial thrombus.

If a clot forms and does not resolve (see below), it will extend proximally into the poplit eal and f emoral

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 ext remities; 4% arise in the upper ext remit ies.

Chest.2008 Jan;133(1):143-8.

Of symptomaticlower-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 -t hrombot ic syndromeafter 5 years.

Resolution and consequences

The initial thrombus can lead to complete resolution, clot extension/embolization, or organization.

Complete resolution: Fibrinolysisis a dynamic process whereplasminogenis 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 embolizat ion: Proximal flow of the venous blood sweeps the thrombus in the same
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direction, extending it into the proximal veins.

Organization: Thrombi that do not resolve begin to retractwithin 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 (re-endothelialization). 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 -t hrombot ic syndrome.

Post- thrombotic syndromeis 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 obstructionby residual clots or venous scarring and venous refluxdue to

valve destruction. Prevention of this sequela includes adequate anticoagulationto prevent VTE

recurrence and compression stockingsto improve venous return.

Pathophysiology of PE

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

Circulation.2003 Dec 2;108(22):2726-9.

Effects of mechanical occlusion

Increased a lveolar (physiologic) dead space : decreased perfusion of alveoli distal to thrombus causesthe alveoli to be ventilated but not perfused, resulting in V/Q mismatch (high V/Q) and increased dead space

Increased minute ventilat ion: patient compensates for dead space and responds to chemical

irritation by hyperventilation.

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 surfact ant and at electasis: vascular compromise beyond thrombus reduces surfactant

production and thus predisposes distal region to atelectasis

Eff ects of chemical mediators

Platelets from the thrombus secrete chemical mediators such as histamineand serotonin, which causes

pulmonary vasoconstrict ionand bronchoconstriction.

Bronchoconstriction leads to alveolar hypoxemia, which in turn causes more vasoconstriction and increased

vascular resistance.

Hemodynamic consequences

Increased right ventricular af terload: from increased pulmonary vascular resistance.

Right ventricular dilat at ion and hypertrophy: parasternal heave, loud P2

RV ischemia

Right-sided (backward) heart failure: increased jugular venous pressure (JVP)

Decreased lef t ventricular filling: because of bowing of interventricular septum to left side from RV

hypertrophy

Left- sided (f orward) 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 filt er(if anticoagulation is contraindicated).
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See Treatment section for details.

Untreated large PE causes deathby acute increase in right ventricular pressure, leading to RV failure.


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Clinical feat ures of DVT

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 a lso present with features of pulmonary embolism.

Symptoms Signs Mechanism

Asymmetricleg/calfswelling

Pitting edemaon affect side

Swelling and pitting edema are caused by venous obstruction. Calf circumference ismeasured 10cm below the tibial tuberosity. Normal difference between the two legsshould be less than 1cm; greater than 3cm difference is considered significant.

Pain,

erythema

Localized

tendernessalong deepvenoussystem

Pain, erythema, and tenderness are caused by vascular inflammation. Recruitment

of inflammatory cells to thrombus and venous stasis causes phlebitis.

Homans sign First observed by surgeon Dr. John Homans, the sign is elicited by passive
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dorsiflexion of the ankle. Positive findings include increased resistance todorsiflexion or knee flexion, both in response to irritation of the posterior calfmuscles. This sign is neither sensitive nor specific.

N Engl J Med.1946 Aug 1;235(5):163-7.

Dilatedsuperficialveins (non-varicose)

Palpablecord

Dilated superficial veins are caused by obstruction of the deep venous system.Palpable cord refers to palpable superficial veins, which is a sign of superficialphlebitis.

Clinical feat ures of PE

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.

Symptoms Correspondingsign(s)

Mechanism

Dyspnea* Tachypnea*,decreased air entry,localized rales,wheezing

Hyperventilation to compensate for increased dead space and in responseto chemical mediators from platelets.Dyspnea is a symptom of central,which causes more severe hemodynamic consequences because ofocclusion of larger vessels. *Most common symptom and sign, respectively.

Parasternal heave,loud P2, increasedJVP

Increased pulmonary pressure (from vasoconstriction) causes rightventricular overload (loud P2) and right ventricular dilatation (parasternalheave). Right-sided backward heart failure causes increased JVP,andeventually left-sided heart failure (tachycardia).

Palpitations Hemodynamicsigns: Tachycardia

See above. Tachycardia is a sympathetic response to decreased cardiacoutput.

Pleuriticchest pain

Pleural friction rub,signs of pleuraleffusion (stonydullness onpercussion,decreased fremitus)

PE near the pleura (peripheral PE) causes ischemia to the region,resulting in inflammation. Since the pleura is innervated, inflammation willproduce localized pleuritic chest pain. Inflammation also increases thepermeability of the pleural surface, leading to accumulation of exudativepleural fluid (pleural effusion).

Hemoptysisand cough

PE causes damage to the pulmonary vasculature, which leads to bleedinginto the airways. Cough is usually nonproductive, and may be triggered byirritation of the pleura or the airways.Am J Med.2007 Oct;120(10):871-9.

Syncope Hypotension,

cyanosis

Decreased left ventricular filling, causing forward heart failure.

Diagnosis of DVT

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 predict ion 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-dimerlevel can be done to rule-out DVT in individuals with low pretest probability (see discussion in

Diagnosis of PE).
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Contrast venographyis 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.

Diagnosis of PE

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

Diagnosis is based o n 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 Points

1 Clinical signs/symptoms of DVT 3

2 No other diagnosis more likely than PE 3

3 Tachycardia: heart rate > 100 1.5

4 Immobilizationfor > 3 days (e.g. strict bed rest)

OR

Surgeryin the previous 4 weeks

1.5

5 Previous DVT or PE 1.5

6 Hemoptysis 1

7 Malignancy 1

Low risk (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 D-dimer. 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) anticoagulationto prevent further clot generation and (ii) thrombolysisif

the thrombus is large enough to cause hemodynamic compromise.

Anticoagulation: Reduces f urther clot f ormation

Anticoagulation with parenteral(intravenous or subcutaneous) and oralanticoagulants 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 bridg ing of AT with Xa only, and not thrombin.
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Fondaparinux: A pentasaccharide sequence that directly binds to AT (at an allosteric site) and induces a

conformational change a llowing it to b ind and inhibit factor Xa only.

Rivaroxaban:A new oral anticoagulant that inhibits factor Xa by b inding 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 drugsare the mainstay for outpatient

anticoagulation. Vitamin K antago nists (e.g. warfarin)were traditionally used, but newer agents, such asdabigatranand rivaroxaban, can also be used. In addition, aspirinis an antiplatelet agent that has been shown

to reduce VTE events in recent trials.

Vitamin K antago nists (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).

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 a re 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.

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 b leeding 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 s ite.

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 pa tients, 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 classica lly 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 act ivator (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 removedor by interventional radiology.

Inferior vena cava (IVC) f ilter: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.
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