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Flashcards in Thrombosis Deck (16)
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Why does coagulation occur (as in, what is its purpose)?

  • Coagulation prevents blood loss.
  • Inflammation activates coagulation and coagulation promotes inflammation.
  • Coagulation is an immunological response.


What is the response to tissue damage inflammation?

  • Primary haemostasis is the aggregation of platelets
  • Secondary haemostasis is the conversion of fibrinogen to fibrin mesh by thrombin which is a protease.
  • Thrombin is itself converted from prothrombin which is the culmination (end point) of a cascade of similar activation step.
  • Anticoagulants prevent thrombosis.
  • Fibrinolysis reverses thrombosis.


Describe both arterial and venous thrombosis.

    • they mostly result from an atheroma rupture or damage to the endothelium (eg. MI, stroke)
    • it is a platelet-rich, 'white' thrombosis; it's mostly primary haemostasis
    • it may block downstream arteries
    • it often results from stasis (period of inactivity) or a hyper-coagulant state (eg. DVT/ deep vein thrombosis)
    • it is a platelet-poor, 'red' thrombus; it is mostly secondary haemostasis
    • it may move to the lungs


What is the coagulation vs fibrinolysis balance?

  • If there is damage to endothelium, things such as tissue factor (TF) are exposed to the blood and can start coagulation.
    • Tissue factor will initiate clotting
    • Von Willebrand factor (VWF) activates platelets
  • Mechanisms to stop clot formation
    • Anti thrombin and heparan inhibit clotting
    • Prostaglandins inhibit platelets
    • Nitric oxide inhibits platelets
  • When a clot forms there are also mechanisms
    • we have a tPA (tissue Plasminogen Activator) that converts plasminogen into plasmin which caused fibrinolysis to create D dimers


What is Virchow's Triad, and what are its three components?

  • It describes the three categories that are thought to contribute to thrombosis.
  • These three categories are: -
    1. STASIS: static blood lacks kinetic energy and tends to clot
    2. HYPER-COAGULANT STATE: eg. infection, hereditary, drugs (eg. HRT/hormone replacement therapy)
    3. ENDOTHELIAL DAMAGE: eg. surgery or cannula


How are the valves involves in stasis?

Blood tends to eddy (a circular movement of water causing a small whirlpool) around the valves, increasing the risk of stasis.


What are the four possible fates of a thrombus?

  1. RESOLUTION: where the fibrinolytic system destroys the whole clot over time
  2. EMBOLISM: where the thrombus dislodges and goes to the heart/lungs, causing death
  3. ORGANISED: where the endothelial cells just grow over the clot; this makes the person more prone to having another one due to the narrower vein
  4. RECANALISED AND ORGANISED: where the thrombus is so big you can't grow over it, but you can grow through it


What is the difference between a proximal DVT and a distal DVT?

  • With a proximal DVT (above the knee), there is a higher risk of a pulmonary embolism and post-thrombotic syndrome (When its blocking the vessel and not dislodging causing pain, swelling, and sometimes ulcers) as the vessels are relatively larger.
  • With a distal DVT (lower leg), it rarely causes a pulmonary embolism or post-thrombotic syndrome as the vessels are relatively small.


What is the fate of venous thrombosis?

  • Small venous thrombolus- may be asymptomatic
    • Slight VQ mismatch/small infarct zone
  • Large venous thrombolus- can cause rapid death
    • Saddle embolism can block both pulmonary arteries
      • Saddle pulmonary embolism commonly refers to a large pulmonary embolism that straddles the bifurcation of the pulmonary trunk, extending into the left and right pulmonary arteries.


What does a platelet release when it has been activated?

  1. Upon exposure of the sub endothelial cells, the von Williebrand factor on the sub endothelial cells will bind the platelets and cause the platelets to become activated.
  2. The circulating von Williwbrand factors may bind to exposed subendothelial cells.
  3. So there will be a whole lot of activated platelets with von Williebrand factor all at the site of tissue damage.
  4. The activated platelet releases thromboxane A2 (TxA2) and adenosine diphosphate (ADP); these induce receptors (GPIIb/IIIa) for fibrinogen.
  5. These bind to receptors on adjacent platelets and increase expression of the glycoprotein complex GPIIb/IIIa.
  6. These factors behave in a paracrine (relating to or denoting a hormone which has effect only in the vicinity of the gland secreting it) and autocrine (denoting or relating to a cell-produced substance that has an effect on the cell by which it is secreted) fashion.
  7. Fibrinogen acts as a tether, holding platelets together  (this is not blood coagulation).
  8. Once you have a clump of platelets they form a negatively charged phospholipid surface which is required for coagulation.
  9. Coagulation involves the conversion of fibrinogen to fibrin and then crosslinking of the fibrin clot.


What are the three coagulation pathways?

  1. Common pathway 
  2. Extrainsic pathway - the most important in vivo.
  3. Intrinsic pathway - forms the basis of laboratory tests of coagulation.


Describe the common pathway.

The common pathway pathway reactions run at a trickle and are easily overpowered by inihibitors.

  1. Factor IXa activates Factor X by proteolysis to create Factor Xa.
  2. Factor Xa (FXa) cleaves prothrombin to form thrombin (FIIa).
  3. Thrombin (FIIa) is a protease that cleaves fibrinogen into fibrin. Fibrinogen is a large molecule that's present in plasma - once cleaved, it becomes insoluble fibrin.
  4. Fibrinogen also promotes blood clotting by forming bridges between, and activating, blood platelets through binding to their GpIIb/IIIa surface membrane fibrinogen receptor.
  5. Thrombin cleaves Factors V and VIII to give FVa and FVIIIa. This is known as amplification, as FVIIIa and FVa amplify the existing reactions, making them harder to overpower.
  6. FVa and FVIIIa together with the plasma Ca2+ form the: -
    • Tenase complex - FVIIIa + FIXa = FXa 
    • Prothrombinase complex - FVa + FXa = thrombin
  7. These complexes assemble on the charged phospholipid surfaces in the activated platelets. 
  8. Once enough thrombin has been generated, XIII is activated, which crosslinks the fibrin fibres into a solid clot.


Describe the prothrombinase complex.

  • The negative surface of the activated platelet causes Ca2+, prothrombin and Factor Xa and Va to bind.
  • This makes the prothrombinase complex.
  • Factor Xa is bound to negatively charged phospholipids via GLA domain. In order to make GLA domain you need vitamin K. Activating factor X leads to cleavage of prothrombin to thrombin. 
  • Forming these GLA domains is Vitamin K dependent and can be inhibited by warfarin (rat poison).


Describe the extrinsic pathway.

  1. Trauma can lead to blood being exposed to tissue factor (TF) which is under the endothelial cells. TF is a receptor for factor VIIa, also bound to a negatively charged surface of platelet phospholipids along with calcium.
  2. Once activated, VIIa activates Xa and the common pathways begins.
  3. Major one happening in vivo.


Describe the intrinsic pathway.

  1. Activated when you put blood on a charged surface such as glass
  2. Defects in the factors of the extrinsic pathway have for larger physiological effects than mutations in the enzymes of the intrinsic pathway.


How do you get rid of a clot once you heal?

  1. Fibrinolysis by tissue plasminogen activator (tPA)
    • Thrombolytic agents can be used to treat strokes and myocardial infarctions
    • tPA converts plasminogen into plasmin. Plasmin causes fibrinolysis of the clot into D dimers.
  2. Fibrinolysis by antithrombin
    • Expressed by endothelial cells
      • Inhibits a lot of enzymes in the coagulation cascade such as Thrombin and factor VII.
    • Heparan binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in its activation. Activated AT, inactivates thrombin, factor Xa and other proteases.

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