Coagulation (Exam IV) Flashcards
What two factors are exposed by injury leading to platelet adherence & activation?
-Exposed Collagen
- Von Willebrand Factor
What type of thrombus is associated with a high pressure vessel (i.e. artery)?
White Thrombus (No RBCs, just fibrin)
What type of thrombus is associated with a low pressure vessel (i.e. vein)?
Red Thrombus (RBC + fibrin)
What do platelets release that. causes local vasoconstriction?
Serotonin
What type of thrombus would you expect to see associated with Coronary Artery Disease? Why?
White Thrombus (high pressure vessel, no RBCs)
Detachment of Red thrombi typically leads to what complication?
- Pulmonary Embolism
DVT risk factors can be _________ and/or _________.
- Inherited; acquired
What are some examples of inherited DVT risk factors?
- Antithrombin III deficiency
- Protein C or S deficiency
- Sickle Cell Anemia
- Activated Protein C resistance
What are some examples of acquired DVT risk factors?
- Bedbound
- Surgery/trauma
- Obesity
- Estrogen use (birth control typical)
- Malignancies
What common form of transportation is a risk factor for DVT formation? How is this prevented?
- Airplane flights
- Getting up, stretching, flexing lower extremities.
What is DIC? Why does this occur?
What results from this condition?
- Disseminated Intravascular Coagulation
- Completely used up blood clotting factors
- Excessive spontaneous bleeding is the result.
What are four common causes of DIC?
What are the treatments?
- Massive tissue injury
- Malignancy
- Bacterial Sepsis
- Abruptio Placentae
Plasma transfusion & treatment of underlying cause.
What is the mortality of DIC?
- 10-50%
How is overcoagulation avoided by our body’s internal mechanisms?
Regulation of Coagulation via:
- Fibrin Inhibition
- Fibrinolysis
What 4 protease inhibitors rapidly inactivate coagulation proteins?
- α1 antiprotease
- α2 macroglobulin
- α2 antiplasmin
- Antithrombin
What enzyme converts plasminogen to plasmin?
What is the purpose of this conversion?
- tPA (tissue Plasminogen Activator)
- Plasmin actually breaks down the clot itself
What drug protects a clot from lysis via plasmin?
- Aminocaproic acid
Which three enzymes potentiate the fibrinolytic process?
How do they accomplish this?
- t-PA
- Urokinase (produced in kidneys)
- Streptokinase
Conversion of plasminogen to plasmin.
What are the four groups of coagulation modifying drugs?
- Anticoagulants
- Antiplatelets
- Thrombolytic (Fibrinolytics)
- Hemostatic/Antifibrinolytics
Differentiate anticoagulants & antiplatelets.
- Anticoagulants - Inhibit action or formation of clotting factors thus preventing clot formation.
- Antiplatelets - Inhibit platelet aggregation thus preventing platelet plugs.
What is the prototypical parenteral anticoagulant drug & its general MOA?
What is the goal of therapy with this drug?
- Heparin = inactivation of clotting factors
- Goal = ↓ venous thrombosis
What is the prototypical oral anticoagulant drug & its general MOA?
What is the goal of therapy with this drug?
- Warfarin = ↓ synthesis of clotting factors
- Goal = ↓ venous thrombosis
What is the prototypical oral antiplatelet drug & its generalized MOA?
What is the goal of therapy with this drug?
- Aspirin - ↓ platelet aggregation
- Goal = ↓ arterial thrombosis
What is the prototypical thrombolytic drug?
Streptokinase
What drugs are indirect thrombin inhibitors?
What is their MOA?
- Unfractionated & fractionated forms of heparin
- Enhances anti-thrombin activity, inactivation of factor Xa, & inhibition of thrombin.
Differentiate unfractionated heparin, LMW heparin, & Fondaparinux.
- Unfractionated Heparin = ↑ Antithrombin III activity, binds to ATIII, Xa, & Thrombin.
- LMW Heparin = Binds to Xa, & ATIII
- Fondaparinux = binds to ATIII only (via pentasaccharide sequence)
What enzyme does heparin activate?
How much does heparin enhance this enzyme’s activity?
At what rate is the heparin consumed through this process?
- Antithrombin III (via conformational change)
- 1000x enhancement
- Heparin is not consumed by this process, only acts as a catalyst.
What molecular weight (MW) would you expect of unfractionated heparin?
- 5000 to 30,000
Where is unfractionated heparin derived from?
- Pig (porcine) intestine and/or cow (bovine) lung
Which heparin is more specific for factor Xa?
What does this mean for its efficacy?
- LMW heparin (enoxaparin)
- Less anticoagulative efficacy due to no binding on thrombin itself.
When would a LMW heparin be chosen over an unfractionated heparin?
- If an allergy to unfractionated heparin is present.
What are the two possible complications associated with heparin toxicity?
- Bleeding
- Transient thrombocytopenia (HIT)
With what heparin is the risk of HIT (heparin-induced thrombocytopenia) higher?
What is the basic pathophysiology of HIT?
- Unfractionated.
- Transient ↓PLTs (platelets) due to antibodies binding to heparin-PLT complex and immune system destruction of PLTs.
Who is more prone to hemmorrhage associated with heparin toxicity?
- Elderly women & renal failure patients
What lab value is utilized to monitor proper anticoagulation levels when utilizing heparin?
aPTT (activated Partial Thromboplastin Time)
Which lab test evaluates the extrinsic system of the coagulation cascade?
- Prothrombin time (PT/INR)
Describe a PT/INR test.
What is a normal INR?
- Tissue Factor III is added to the blood. The time to clot (PT) is measured & compared to a control (INR).
- Normal INR is 1
What does aPTT measure?
What is added to this test to get this measurement?
What is a normal aPTT?
- Activity of intrinsic system & common pathway
- Phospholipids are added.
- 35 - 45s
What drug is given to reverse heparin?
What is this drugs MOA?
What is this drug’s effects on enoxaparin & fondaparinux?
- Protamine Sulfate
- very + charge and binds to - charge heparin
- Small effect on LMW heparin & no effect on fondaparinux
What is Fondaparinux?
What is it selective for?
When is this drug useful?
- Pentasaccharide molecule of heparin.
- Selective for Antithrombin & factor X.
- Useful for HIT
Which direct thrombin inhibitors bind to both active & substrate sites of thrombin?
Which direct thrombin inhibitors bind only to thrombin active sites?
What animal do we derive these drugs from?
- Hirudin & Bivalirudin
- Argatroban, Melagatran, & Dabigatran
- Direct thrombin inhibitors derived from leeches.
What is the bioavailability of warfarin?
Protein binding?
T½?
- 100% bioavailable
- 99% protein bound?
- T½ = 36 hours
What is warfarin’s mechanism of action?
Blocks Vitamin K reductase from converting prefactors into factors.
needs verification & better explanation
What is the delay in onset of action of warfarin?
What does this mean clinically?
- 8-12 hours till effect is seen
- Wean off of heparin & on to warfarin slowly.
What toxicity is seen with warfarin overdosing?
- Bleeding
- Hemmorhagic disorder of fetus & birth defects
- Cutaneous necrosis
What is a normal INR?
What is the target INR with warfarin therapy?
- 0.8 - 1.2
- Target: 2-3
The goal of warfarin therapy is reduction of prothrombin activity by ______ %.
25%
What is the consequence of warfarin’s rate of protein binding?
- Warfarin protein binding rate (99%) can antagonize binding of other drugs.
ex. Phenytoin can be displaced by warfarin thus causing phenytoin toxicity.
What would be given to reverse warfarin?
- Stopping warfarin
- Large dose of Vitamin K
- FFP or Factor concentrates
What reversal is available for all the -aban drugs? (apixaban, rivaroxaban, etc.)
How do these drugs work?
- No reversal is available.
- Inhibition of Factor Xa & Thrombin
How do virtually all fibrinolytic drugs work?
- Catalyze the formation of Plasminogen into plasmin.
Differentiate streptokinase & urokinase.
- Urokinase is synthesized by the kidneys & streptokinase is synthesized by streptococci. Both break down clots directly via catalyzation of plasminogen into plasmin
How does t-PA differ from other fibrinolytics?
- t-PA preferentially activates plasminogen that is bound to fibrin avoiding systemic fibrinolysis and focusing on formed thrombus.
What is aspirin’s mechanism of action?
Inhbition of TXA₂ via inhibition of COX pathway.
What is the mechanism of action of clopidogrel & Ticlopidine?
Which of these two is associated with thrombocytopenic purpura?
- Irreversible inhibition of ADP receptor on platelets. This prevents eventual platelet interbinding using GP IIb/IIIa receptors.
- TTP associated with Ticlopidine.
How does Plavix (clopidogrel) compare in efficacy to aspirin?
- Well. 8.7% reduction in ischemic events vs aspirin only.
Where do Monoclonal antibody anti-platelet
drugs work?
Name the prototypical drug of this class.
- Targeting of IIb/IIIa receptors on platelet, thus preventin platelets from adhering to each other using fibrin.
- Abciximab
What phosphodiesterase inhibitor prevents platelet aggregation?
Cilostazol
What antiplatelet drug inhibits adenosine uptake & cGMP phosphodiesterase activity & is used as an adjunct with other therapies?
Dipyridamole
Where does Vitamin K confer its effects to upregulate blood coagulation?
- Prothrombin
- Factors VII, IX, & X
What does Desmopressin Acetate treat?
How does it work?
- Hemophilia A & von Willebrand Disease
- ↑ Factor VIII activity
Which drugs inhibit fibrinolytic activity? How?
- Aminocaproic & Tranexamic Acid inhibit fibrinolysis by preventing the conversion of plasminogen to plasmin.
What is Tranexamic acid used for?
- Decreasing bleeding in Trauma, heavy menstruation, & epistaxis.
What links platelets together to form the platelet plug?
What receptors are used to accomplish this?
- Fibrinogen
- GP IIb/IIIa receptors on the platelet.
What drug class is Abciximab?
Monoclonal Antibody GP IIb/IIIa Inhibitor
What is Virchow’s Triad?
- Endothelial Injury
- Stasis
- Hypercoagulability
What two things are exposed by an endothelial cell injury?
Collagen & vWF
What do Collagen and vonWillebrand factor interact with once exposed by injury?
- GP 1a & 1b receptors on the Platelet.
What occurs with platelet GP 1a & 1b receptor activation?
- ADP, Thromboxane, & Serotonin are released & cause platelets to use GP IIb/IIIa receptors & fibrin to stick together.
