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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
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
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.
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.
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.
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.
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.
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.
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.