VTE : Facts / Pathophysiology / Pharmacology

  • Facts about VTE 
  • What are the 3 natural anti-coagulant system?
  • What are the 4 pharmacological anticoagulation mechanism?
  • Fibrinolytic Drugs (tPA, Streptokinase, Urokinase) act by fibrin lysis by activating plasminogen
  • Mechanism of Loss of Natural Anti-coagulant 
  • VTE pathophysiology
  • Some Clinical Questions to understand PATHOPHYSIOLOGY 

Facts about VTE

50-70 % of VTE occur in non-surgical patient
VTE is a major cause of in hospital mortality 
Most VTE occur out side of hospital, despite huge emphasis on in hospital prophylaxis. May be related to hospital admission. Mostly occur in first 30 days

What are the 3 natural anti-coagulant system?
  • 1. Protein C Anti-couagulant system. APC leads to degradation of Factor Va, and VIIIa. 
Figure 1 c of 
NEJM 2015 
    • What are the defects associated with defects in Protein C Anti-coagulant system?
      • Protein C deficiency
      • Factor V leidein 
      • Protein S deficiency 
      • APC also inhibits inhibitor of tPA (tissue plasminogen activator), thus activating plasminogen to plasmin conversion. Plasmin causes fibrinolysis. 
  • 2. Anti-thrombin (or AT- III or Heparin cofactor) complex / Heparin System (catalyzed by endothelial or circulating heparin sulphate) (see above Figure 1 c of NEJM 2015 ) 
    • Inactivates Thrombin, VIIa, IXa, Xa, XIa, XIIa
    • This system acts on Thrombin that is carried from the site of clot by blood  and prevents the dissemination of coagulation cascade, and makes it localized to the site of tissue injury. Pathophysiology of Blood Disorder
      • What are the components of this system?
        • AT-III - Thrombin / Heparin (Note: Heparin has to bind with both AT and T)
        • AT -III - Factor Xa or XIa or IXa (Note: LMWH, and Fondaparinaux bind to AT and not to Thrombin, and then inactivates Xa) 
  • 3. Tissue factor pathway Inhibition
    • Synthesized in endothelial cells and stored in platelets and in plasma. 
    • TFPI forms complex with Xa. TFPI/Xa complex then inhibits TF/VIIa. Thus, it shuts down extrinsic pathway. 
What are the 4 pharmacological anticoagulation mechanism?
  • Vitamin K antagonist (Warfarin) 
    • Blocks vitamin K dependent post translational modification of Protein C,S, Factor II, VII, IX, X. 
  • Indirect Thrombin Inhibitors (Note: These are also indirect Xa inhibitors):
    • Heparin and its derivatives i.e Heparin, LMWH, Fondaparinux (See above Figure 1 c of NEJM 2015 ) 
      • Thrombin-Anti-thrombin complex is activated by heparin or its derivatives   and this in turn inhibits the thrombin generation by inhibiting various coagulation proteases i.e Thrombin, VIIa, IXa, Xa, XIa, XIIa
      • Note: 
        • LMWH and Fondaparinux are an Indirect Xa inhibitor acting via Anti-thrombin.
        • Also, LMWH and Fondaparinux does not have binding site with thrombin (contrast to heparin)  
  • DTI (Direct Thrombin Inhibitors) :
    • Parenteral agent: Argatroban, Lepirudin, Bivalirudin (Angiomax).  
    • Only oral DTI is Dabigatran (Pradaxa) 
    • Binds with high affinity, and specificity with thrombin's active site, thus inhibiting the fibrinogen to fibrin formation.
    • Knowledge of the 3D structure of the thrombin lead to the discovery of this class of drugs
  • Direct Xa Inhibitors: Rivaroxaban (Xarelto), Epixaban (Eliquis), Endoxaban (Lixiana) 
    • Immediate upstream of Thrombin
    • Convergence point of Intrinsic and Extrinsic pathway 
Fibrinolytic Drugs (tPA, Streptokinase, Urokinase) act by fibrin lysis by activating plasminogen

Mechanism of Loss of Natural Anti-coagulant 
    • 1. DIC (in both Venous limb gangrene and Symmetrical Peripheral Gangrene) causing increased consumption and thus deficiency of Protein C, and Anti-thrombin
    • 2. Protein C Deficiency (in DVT after use of Coumadin)
    • 3. Decreased synthesis of both Protein C, and Anti-thrombic factors due to shock liver in Symmetrical Peripheral gangrene 
  • Important Clinical Findings to look for 
    • 1. Pulses
    • 2. Purpura fulminates (non-acral skin necrosis) 
    • 3. Phlegmesia Cerula Dolens 

VTE Pathophysiology

Clinical Questions to understand PATHOPHYSIOLOGY 
  • Does warfarin help in cancer associated thrombosis?
    • Probably it does not help. 
      • Phelgmesia or gangrene may happen soon after the over lap of heparin - warfarin is over. 
        • While heparin is used, it activates thrombin - antithrombin complex (T-AT Complex) inhibiting the thrombin generation. So, platelet count is also high. Soon after heparin bridge is over, T-AT Complex does not work any more leading to more clot formation. This is reflected by decreasing platelet count after heparin is stopped. Coumadin has no role in this pathophysiology. 
    • Rather Coumadin makes it worse!
      • Warfarin use causes severe protein C deficiency. This promotes micro thrombosis. This is reflected by supra therapeutic INR. 
  • Mechanism of gangrene in HIT?
    • 2 Mechanism
      • 1. Arterial occlusion due to white clot or platelet rich clot
      • 2. Venous limb gangrene associated with protein C deficiency either due to warfarin use or DIC. Note: DIC causes loss of both protein C and anti-thromobin. 
  • Elevated INR is a proxy of protein c deficiency in 
    • Warfarin use with supra therapeutic INR
    • DIC 
      • Of note: there is a parallel severe reduction of Factor VII 
      • Also, since there are other coagulant factor (i.e Factor II (prothrombin), Factor, IX, Factor X)  in relative excess, thrombin generation persists despite supra therapeutic INR, and micro thrombosis continues. 
  • How to differentiate HIT associated gangrene from Cancer associated gangrene? 
    • Why is this question important?
      • In HIT, you have to stop Heparin to prevent further clot formation. In Cancer associated gangrene, you have to use Heparin to prevent clot formation. 
      • Answer: Look for INR and platelet changes in Figure 2 of NEJM 2015
  • Name 2 situations where warfarin actually predisposes to clot formation? NEJM 2015
    • Warfarin Induced Venous Limb Gangrene. 
    • Warfarin Induced Skin Necrosis. 
      • What is the difference between these two conditions?
        • Skin necrosis is limited to skin, venous limb gangrene is associated with clot formation in deeper tissues
        • Both conditions are due to severe depletion of protein C. 
          • Skin Necrosis occurs in patient with defective Protein C Anti-coagulant system (Protein C deficiency or Factor V leiden). 
  • PEARL: 
    • Decreased Platelet count associated with increased INR is a marker of consumptive process going on
      • DIC: Increased INR due to Protein C deficiency; Decreased Platelet count due to consumption
      • HIT: Increased INR due to Protein C deficiency; Decreased Platelet count due to consumption
      • Shock: Decreased Protein C and Anti-thrombin shifts towards pro-coagulant state. Because of Decreased Protein C, INR is high. Yet, due to procoagulant state, consumptive process occurs. This leads to thrombocytopenia. 
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