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Venous thromboembolism (VTE)

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Def init ion


Deep vein t hrombosis (DVT) and pulmonary embolism (PE) are manifestations of the same pathological entity, called venous t hromboembolism (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 (t hrombus) , fat, air, amniotic fluid, or tumour, a PE is usually caused by a thrombus originating from the deep veins in the legs (deep venous t hrombosis, 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 art eries and veins , but they have different pathophysiology and lead to different outcomes. This chapter is about venous t hrombosis . Art erial t hrombosis Mechanism Location Diseases Typically from rupture of atherosclerotic plaques. Left heart chambers, arteries Acut e coronary syndrome Ischemic st roke Limb claudicat ion/ischemia Composition Mainly platelets Treatment Mainly antiplatelet agents (ASA, clopidogrel) Mainly fibrin Mainly anticoagulants (heparins, warfarin) Venous t hrombosis (VTE) Typically from a combination of factors from Virchows triad. Venous sinusoids of muscles and valves in veins Deep venous t hrombosis Pulmonary embolism

Et iology
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 t riad : three conditions that predispose to thrombus formation. 1. Hypercoagulability 2. Stasis 3. 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 Associat ed risk f act ors

Hypercoagulabilit y Heredit ary f act ors ( inherited thrombophilia) Changes in blood Fact or V Leiden*: Activated factor V (FVa) is a cofactor for activated factor X, and coagulation together, they lead to thrombin generation from its z ymogen, prothrombin. Thrombin pathway, shifting is a serine protease that cleaves soluble fibrinogen into insoluble fibrin and activates balance toward other factors that amplify the coagulation cascade. To regulate coagulation and coagulation protect against clot formation, activated protein C (aPC) cleaves and inactivates FVa. Fact or 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.

Prot hrombin 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. Def iciencies in ant it hrombin (AT), prot ein C (PC) and prot ein S (PS), plasminogen (Pg): 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; aut osomal dominant risk inheritance Acquired f act ors 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 are t issue f act or, 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):103- 10. Best Pract Res Clin Haematol. 2009 Mar;22(1):49- 60. Chemot herapy: 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):316- 20. Oral cont racept ives and hormone replacement t herapy: 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 post part um period: High estrogen like OCP/HRT and stasis due to obstruction of inferior vena cava by fetus. Cent ral obesit y: 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 t hrombocyt openia (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. St asis The slowing or stopping of blood flow

Reduced mobilit y: Increases length of contact of coagulation factors with endothelium. Examples : Long- haul air travel, hospitaliz ation Polycyt hemia : 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. Congest ive heart f ailure: Failure to pump blood forward results in venous stasis and elevated central venous pressure.

Endot helial

Endot helial dysf unct ion: Shifts the balance between clot generation and breakdown

damage Normal endothelium is antithrombotic.

towards thrombosis due to decreased synthesis of nitric oxide and prostacyclin and increased endothelin- 1. Hypertension Cigarette smoking Endot helial 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

Pat hophysiology 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 remit ies . 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 t issue f act or to the endothelium, which can complex with act ivat ed f act or VII to begin the coagulation cascade via the extrinsic pathway. The main component of these venous thrombi is f ibrin (as product of coagulation cascade) and red blood cells , which get trapped in the clot. Platelets also contribute, but to a lesser extent. The skelet al 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 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 emboliz e to form dangerous PEs.

By the numbers
96% arise in the lower ext remit ies ; 4% arise in the upper ext remit ies . Chest. 2008 Jan;133(1):143- 8. Of sympt omat ic 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 asympt omat ic PEs . 70% of PEs have asympt omat ic DVTs . 28% of symptomatic DVTs will have post - t hrombot ic syndrome after 5 years.

Resolution and consequences


The initial thrombus can lead to complete resolution, clot extension/emboliz ation, or organiz ation. Complet e resolut ion: Fibrinolysis is a dynamic process where plasminogen is converted into plasmin, an enz yme 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 ext ension and emboliz at ion: Proximal flow of the venous blood sweeps the thrombus in the same

direction, extending it into the proximal veins. Organiz at ion: 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 (re- endothelializ ation). This process, called organiz at ion, 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 - t hrombot ic 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 anticoagulation to prevent VTE recurrence and compression stockings to improve venous return.

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

Ef f ects of mechanical occlusion


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 Increased minut e vent ilat 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 resist ance : due to vascular obstruction by thrombus and chemical mediators from platelets (see below) Decreased surf act ant and at elect asis : vascular compromise beyond thrombus reduces surfactant production and thus predisposes distal region to atelectasis

Ef f ects of chemical mediators


Platelets from the thrombus secrete chemical mediators such as histamine and serotonin, which causes pulmonary vasoconst rict ion and bronchoconst rict ion. Bronchoconstriction leads to alveolar hypoxemia , which in turn causes more vasoconstriction and increased vascular resistance.

Hemodynamic consequences
Increased right vent ricular af t erload : from increased pulmonary vascular resistance. Right vent ricular dilat at ion and hypert rophy: parasternal heave, loud P2 RV ischemia Right - sided (backward) heart f ailure : increased jugular venous pressure (JVP) Decreased lef t vent ricular f illing : because of bowing of interventricular septum to left side from RV hypertrophy Lef t - sided (f orward) heart f ailure : 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 ant icoagulat ion t herapy (oral or parenteral), t hrombolyt ic t herapy (for massive PE causing cardiogenic shock), or inf erior vena cava f ilt er (if anticoagulation is contraindicated).

See Treatment section for details. Untreated large PE causes deat h by acute increase in right ventricular pressure, leading to RV failure.

Clinical f eat 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 obst ruct ion and (ii) inf lammat ion of t he veins . Patients may also present with features of pulmonary embolism. Sympt oms Asymmetric leg/calf swelling Pain, erythema Signs Pitting edema on affect side Localiz ed tenderness along deep venous system Homans sign Mechanism Swelling and pitting edema are caused by 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, erythema, and tenderness are caused by vascular inflammation. Recruitment of inflammatory cells to thrombus and venous stasis causes phlebitis.

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

Clinical f eat 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. Sympt oms Dyspnea * Corresponding sign(s) Tachypnea *, decreased air entry, localiz ed rales, wheez ing Parasternal heave, loud P2, increased JVP Palpitations Pleuritic chest pain Hemodynamic signs: Tachycardia Pleural friction rub, signs of pleural effusion (stony dullness on percussion, decreased fremitus) Mechanism Hyperventilation to compensate for increased dead space and in response to chemical mediators from platelets.Dyspnea is a symptom of cent ral , which causes more severe hemodynamic consequences because of occlusion of larger vessels. *Most common symptom and sign, respectively. Increased pulmonary pressure (from vasoconstriction) causes right ventricular overload (loud P2) and right ventricular dilatation (parast ernal heave ). Right- sided backward heart failure causes increased JVP, and eventually left- sided heart failure (t achycardia ). See above. Tachycardia is a sympathetic response to decreased cardiac output. PE near the pleura (peripheral PE ) causes ischemia to the region, resulting in inflammation. Since the pleura is innervated, inflammation will produce localiz ed pleuritic chest pain. Inflammation also increases the permeability of the pleural surface, leading to accumulation of exudative pleural fluid (pleural effusion). PE causes damage to the pulmonary 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. Hypotension, cyanosis Decreased left ventricular filling, causing forward heart failure.

Hemoptysis and cough

Syncope

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 hist ory (risk f act ors) 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 ult rasonography, 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 ).

Cont rast 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.

Diagnosis of PE
JAMA. 2003 Dec 3;290(21):2849- 58. Diagnosis is based on hist ory and physical, and conf irmed wit h CT or V:Q scan if t he clinical suspicion is high. The Wells crit eria can be used to determine risk (pretest probability) of PE. Crit eria 1 Clinical signs/symptoms of DVT 2 No other diagnosis more likely than PE 3 Tachycardia : heart rate > 100 4 Immobiliz at ion for > 3 days (e.g. strict bed rest) OR Surgery in the previous 4 weeks 5 Previous DVT or PE 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. Not e 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. 1.5 1 1 Point s 3 3 1.5 1.5

Treat ment
Chest. 2012 Feb;141(2 Suppl):e419S- 94S. The goals of treatment for VTE are (i) ant icoagulat ion to prevent further clot generation and (ii) t hrombolysis if the thrombus is large enough to cause hemodynamic compromise.

Anticoagulation: Reduces f urther clot f ormation


Anticoagulation with parent eral (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. Unf ract ionat ed heparin (UFH) : Inhibits the function of thrombin as well as Xa by inducing conformational changes in ant it hrombin, allowing it to bind the enz ymes 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 f uture VT E


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 ant icoagulat ion drugs are the mainstay for outpatient anticoagulation. Vit amin K ant agonist s (e.g. warf arin) were traditionally used, but newer agents, such as dabigat ran and rivaroxaban, can also be used. In addition, aspirin is an antiplatelet agent that has been shown to reduce VTE events in recent trials. Vit amin K ant agonist s (e.g. warf arin) : 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 normaliz ed ratio (INR) is therapeutic (23), 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. Direct t hrombin inhibit ors (e.g. dabigat ran): 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 (RECOVER trial). N Engl J Med. 2009 Dec 10;361(24):2342- 52. Direct Xa inhibit ors (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 art erial t hrombosis , 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.

T hrombolysis: Breaks down the thrombus


Tissue plasminogen act ivat or (t PA): activates plasminogen (Pg) to plasmin (Pn), which cleaves the thrombus, generating soluble D- dimer products.

Contraindications to anticoagulation
Thrombect omy: If a large thrombus creates hemodynamic compromise, and there are contraindications to thrombolysis, the clot can be surgically removed or by interventional radiology. Inf erior vena cava (IVC) f ilt er: 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.