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50 Cards in this Set
- Front
- Back
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What is hemostasis?
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Physiological blood clotting (in response to injury or vascular leak)
"keeping blood where it belongs" |
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What is thrombosis?
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Pathological blood clotting
"an undesirable blockage of blood flow" |
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What are the main components of hemostasis?
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Vasoconstriction
- vessel constricts in response to injury Platelet deposition - forms the initial plug Fibrin deposition - provides the scaffold to stabilize the platelet-rich clot and get the repair underway Fibrinolysis - restores tissue blood flow after repair of the injury |
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What do platelets do?
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Stick to holes and cracks-- adhesion to sub-endothelium
Recruit more platelets-- aggregation Promote clotting-- phospholipid surface |
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How do platelets recruit more platelets?
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Release of ADP (adenosine diphosphate) and TXA2 (thromboxane A2)
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What are the tests of primary hemostasis?
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Ivy Template Bleeding Time
Platelet function screening: PFA-100 (Platelet Function Analyzer) |
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What are the limitations of the Ivy Template Bleeding Time?
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invasive (need to make cuts in skin); time-consuming; low sensitivity; poorly reproducible (operator-dependent); does not correlate with surgical blood loss or transfusion needs when used as a pre-operative screening tool
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How does the PFA-100 work?
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Whole blood flows through... eventually platelets plug up the grid; 'Closure time' refers to how long it takes for flow to stop-- gives diagnostic information
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How do you interpret the PFA-100 test results?
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If closure time is prolonged only in collagen/epinephrine channel, it is likely to be an aspirin/NSAID effect
If closure time is prolonged in both the collagen/epinephrine and collagen/ADP channels, it is more likely to be von Willebrand disease or another platelet function defect |
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What are the advantages of PFA-100?
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Quick, easy, non-invasive, good reproducibility, performs platelet function analysis under flow using physiological shear conditions
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What does the formation of a stable plug require?
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Secondary hemostasis: Fibrin formation
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How is a stable clot formed?
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Insoluble fibrin is generated from circulating fibrinogen by thrombin clot
Coagulation... A series of inter-dependent enzyme-mediated reactions that ultimately leads to thrombin generation |
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Where are coagulation proteins primarily made?
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In the liver
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In what form do coagulation proteins circulate in plasma?
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In an inactive form
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What leads to generation of the active coagulation protein?
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Activation by a clotting enzyme complex on a phospholipid surface in the presence of calcium
e.g. prothrombin circulates in plasma but must be converted to thrombin to be active in coagulation |
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What makes up the prothrombinase complex, aka "the final common pathway"? What is its function?
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Ca++, P-Lip, Va*, Xa
Converts prothrombin to thrombin (to clot fibrinogen) |
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What is the significance of the coagulation factor nomenclature?
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LITTLE relation to sequence of reactions; roman numerals were assign in the order of discovery
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What are most factors before activation? What do they become upon activation?
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Pro-enzymes ("zymogens")
Become active serine proteases upon activation |
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What two factors are not pro-enzymes? What are they instead?
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V, VIII are pro-cofactors and must be activated by thrombin to become active cofactors (Va, VIIIa)
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What are the common names for factors I, II and IIa?
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Factor I: fibrinogen
Factor II: prothrombin Factor IIa: thrombin |
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How is Factor X activated? (Two ways)
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FVIIIa* x FIXa => activation of FX to Xa
FVIIa x TF => activation of FX to Xa (TF= Tissue Factor; TF also can activate FIX to IXa) |
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What does the "Contact Activation" system involved? What triggers it?
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Triggered by negatively-charged surface
FXII + HMW Kininogen + Prekallikrein + FXIa => Activation of FIX to IXa *not very important to hemostasis in vivo *important for understanding aPTT test |
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REVIEW the intrinsic pathway and extrinsic pathway for coagulation -> cross-linked fibrin clot
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Using slide with all the enzymes and cofactors
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What is the most important initiator of coagulation in vivo?
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Tissue Factor
*blood only comes into contact with TF in the event of injury because it is expressed by cells in the adventitia and not by luminal endothelial cells |
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How is coagulation initiated in vivo?
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Sub-endothelial tissue factor (cell-bound protein, not soluble) is exposed at sites of endothelial injury, binds to activationed factor VII, and initiates the coagulation cascade
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What are the routine coagulation tests?
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PT: Prothrombin Time (measure of extrinsic pathway)
aPTT: activated Partial Thromboplastin Time (measure of intrinsic pathway) TT/TCT: Thrombin [clotting] time |
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If TF/VIIa can also activate FIX, how come the PT is not sensitive to FVIII/FIX deficiency?
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Because TF in vast excess (as in thromboplastin reagents IN LAB) drives the pathway toward X activation
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What makes the PT long?
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Anything that makes the TT long
Something wrong with the Vitamin-K-related factors: II, VII, IX, X Something wrong with factor V or FV deficiency (very rare) |
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What causes problems with the Vit-K-related factors (II, VII, IX, X)?
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Vit K deficiency, Warfarin, liver disease, DIC
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What differentiates PT and TT?
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Protime is much less sensitive than TT for heparin and fibrin degradation products (FDPs)
PT is long when there is something wrong with Vit-K-related factors (II, VII, IX, X) |
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Where does the body get Vitamin K?
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*Diet* green vegetables
Gut flora (Vit K deficiency can be caused by dietary deficiency, antibiotics, or malabsorption of fat) |
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Vitamin K is required for synthesis of which factors?
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II (prothrombin); VII (the Tissue Factor partner); IX (missing in Hemophilia B); X (in final common pathway)
Protein C (Coag regulatory protein); Protein S (Protein C's cofactor); some bone homeostatic enzymes |
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Why do you need Vitamin K?
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It acts as a cofactor for a carboxylase enzyme (gamma-carboxylase) to glutamic acid residues on the K-dependent factors ---> Creates the binding pocket for calcium-dependent phospholipid binding -- to assemble those complexes
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What is INR? How is it calculated?
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International Normalized Ratio
(Patient PT/ Mean Nl PT)^Exp Exp reflects strength of reagent thromboplastin used |
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What is the purpose of INR?
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To allow PT results to be more comparable from one lab to another
(especially helpful in managing warfarin anticoagulation) |
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What is the normal value for INR? What is the usual target range for warfarin?
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Normal: 1.0 +/- 0.12
For warfarin = 2.0--3.0 |
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What does Partial Thromboplastin provide (for PTT test)?
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Phospholipid but no TF
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What makes PTT long?
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Anything that makes TT long
Something wrong with V, II, or X (final common pathway) Something wrong with the contact activation factors (XII, XI...) -- only XI deficiency is associated with some (milder) bleeding risk Something wrong with VIII (deficiency= hemophilia A/classical hemophilia) Something wrong with IX (deficiency= hemophilia B) Vit K deficiency or warfarin can prolong PTT, but PTT is not as sensitive as PT |
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What inhibitors make PTT long?
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Heparin
-- PTT is between the PT and TT in sensitivity to heparin Lupus inhibitors |
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What are lupus inhibitors?
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Autoantibodies against phospholipid complexed with a carrier protein; tend to interfere with PTT > PT
Not associated with bleeding, but may paradoxically be associated with thrombosis |
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What is a handy trick to figure out whether PTT is long due to something missing or an inhibitor?
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The 1:1 mix (Equal mix of normal plasma and patient's plasma)
If something is missing--- test should be normal If an inhibitor is present--- test will still be abnormal (PTT will still be long) |
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What is deficient if PT and PTT are both elevated?
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Intrinsic + Extrinsic Pathway
Intrinsic + Common Pathway Extrinsic + Common Pathway Extrinsic + Intrinsic + Common Pathway Common Pathway Only (FX, FV, FII, fibrinogen) |
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What causes other than factor deficiencies can elevate both PT and PTT?
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Supertherapeutic Warfarin or Heparin
Direct Thrombin Inhibitors Liver Disease DIC Afibrinogenemia or Hypofibrinogenemia Congenital Dysfibrinogenemia |
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Why don't we clot to death with every minor injury?
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Regulatory Proteins!
Protein C/ Protein S Antithrombin (III) |
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What is the Protein C/ Protein S Pathway?
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FIIa binds to TM; PC activated by FIIA bound to TM --> APC
APC and PS bind to phospholipid membrane and calcium ==> go after Va and VIIIa to turn off coagulation |
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What is the mechanism of action for Antithrombin (III)?
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AT-III is a serine protease inhibitor
Once AT-III is bound to heparan (natural) or heparin (pharma), it will inactivate XIa, IXa, Xa, or IIA |
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With what are deficiencies of Proteins C, S, and Antithrombin associated?
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Thrombotic Propensity
*do not cause PT/PTT/TT abnormalities |
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What is the goal of the fibrinolytic system? What is the function?
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To generate plasmin
To remove/remodel fibrin clot |
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What are the components of the fibrinolytic system?
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Plasminogen (in plasma)
Plasminogen activator (tissue plasminogen activator or urokinase -- in plasma) Fibrin (in clot) --> a co-factor for its own destruction |
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What are the principal inhibitors of fibronlysis?
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Plasminogen activator inhibitor-1 (PAI-1) --> inhibits t-Pa and urokinase
Alpha2-antiplasmin --> inhibits plasmin |
