Hematologic Agents Flashcards by Jon Pickos

Hemostasis Systems (5)

Vascular
Platelet
Coagulation
Anti-Coagulation
Fibrinolytic

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Initial binding to begin platelet activation (receptor and binding ligand)

GpIb binds von Willebrand Factor

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Platelets secrete 3 main things after being activated

ADP, TXA2, 5-HT

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Linking of platelets together is due to activation of which receptor? What ligand stabilizes binding

GpIIb/IIIa

Fibrin

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Intrinsic system

XII, XI, IX, VIII

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Common Pathway

X, V, III, II

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Extrinsic System

VII + Tissue Factor (III)

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What factor stabilizes fibrin crosslinks?

XIIIa

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What to factors inhibit the clotting cascade?

What factors do they inhibit/inactivate?

Protein C and S

Factor VIIIa and Va

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What factor blocks Xa?

What speeds up its activity?

Antithrombin

Heparin

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Where does fibrinogen bind to be converted to fibrin?

active site of thrombin

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What is the E1 site on thrombin for?

binding fibrin

limits the diffusion of thrombin away from the clot

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What is the significance of the thrombin already bound to fibrin?

It isn’t inhibited by antithrombin/heparin

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What are the characteristics of venous thrombosis?

What is the significance for treatment?

platelet poor

often occur at valve cusps (slow moving/sluggish blood)

can lead to VTE or PE

Typically won’t use anti-platelet therapies

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What are the characteristics of arterial thrombosis?

Most common cause of what?

often occur on top of ruptured atherosclerotic plauqes

rich in platelets

MI and Ischemic Strokes

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Aspirin MOA

irreversibly blocks cyclooxygenase-1

reduces TXA2 synthesis - leads to decreased platelet activation

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Dipyridamole MOA

elevated cAMP decreases Ca levels intracellularly

reduces activation of platelets

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P2Y12 antagonists

Clopidogrel
Prasugrel
Ticagrelor
Cangrelor

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Ticagrelor and Cangrelor don’t need what?

to be activated

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Clopidogrel and Prasugrel need what?

to be activated through metabolism in the liver

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P2Y12 antagonists Ultimate MOA

decrease activation of GpIIb/IIIa and decrease calcium mobilization

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GpIIb/IIIa Antagonists General MOA

Inhibit cross linking of GpIIb/IIIa receptors

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GpIIb/IIIa Antagonists

Abciximab
Eptifibatide
Tirofiban

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Abciximab MOA

Fab fragment that binds to GpIIb/IIIa

also binds to receptor on leukocytes - may explain anti-inflammatory effects

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Eptifibatide MOA

peptide that binds to GpIIb/IIIa

Tirofiban MOA

nonpeptide that binds and inhibits GpIIb/IIIa

Dual Antiplatelet Therapy

Aspirin + P2Y12 Antagonist

Triple Antiplatelet Therapy

Aspirin, Warfarin, Clopidogrel

Indirect Inhibitors of Thrombin or Factor Xa

Heparin Enoxaparin Fondaparinux

Direct Thrombin Inhibitors

Lepirudin Bivalirudin Argatroban Dabigatran

Direct Xa Inhibitors

Rivaroxaban | Apixaban

Vitamin K Antagonist

Warfarin

Heparin MOA

specific sequence binds to antithrombin changes conformation to increase affinity for factor Xa can also increase AT-induced inhibition of thrombin (w/long enough molecules)

Heparin administration

Intravenously most common

Heparin characteristics

short half life can bind to other plasma proteins and endothelium of vessels Dosing is unpredictable because binding differs from person to person

Heparin Pharmacokinetics Special Considerations

Cleared by 2 mechanisms Clearance decreases as dose increases, therefore half life increases as dose increases

Heparin most common complication Heparin overdose treatment

Bleeding Protamine Sulfate

Long term heparin use associated with?

osteoporosis

Type 1 Heparin-Induced Thrombocytopenia

25% of patients develop thrombocytopenia within first 2-5 days fo tx Not though to be caused by immune system

Explain Type 2 Heparin-Induced Thrombocytopenia

Uncommon Heparin can bind platelet factor 4 Antibodies are generated toward hep/PF4 complex Can bind platelets and activate them Leads to venous and arterial thrombosis

Low molecular weight heparin (enoxaparin) MOA Advantages Disadvantage

primarily acts by inhibiting factor Xa easier to dose, given subcutaneously, longer half life, predictable clearance, lower osteoporosis risk Protamine only partially reverses

Fondaparinux MOA Cannot be inhibited by?

analog of AT-binding pentasaccharide sequence inhibits factor Xa but CANNOT bind antithrombin Protamine sulfate

What test is used to monitor LMWH and Fondaparinux?

Anti-factor Xa assay

LMWH and Fondaparinux contraindicated in?

patients with severe renal insufficiency

Bivalirudin and Lepirudin MOA

bind to fibrin binding site and active site of thrombin

Argatroban and Dabigatran MOA

bind only the active site of thrombin

Parenteral Direct thrombin inhibitors

Bivalirudin, Lepirudin, Argatroban

Oral direct thrombin inhibitor

Dabigatran

Major advantage of DTI's over Heparin?

DTI's can inhibit thrombin bound to fibrin

DTI's used in (3)

heparin induced thrombocytopenia percutaneous coronary intervention Dabigatran also used in stroke prevention

Warfarin MOA

competes with vitamin K for vitamin K reductase reduces activation of factors 10, 9, 7, 2, Protein C, and Protein S (coumadin)

Warfarin Important Characteristics

close 100% bioavailability small Vd full effect takes about 3-5 days

Warfarin is metabolized by

CYP2C9 and other CYP's

Drugs that potentiate Warfarins effect _____ INR

increase

Drugs that inhibit warfarins effect _____ INR

decrease

Drugs that increase Warfarins function

Broad-spectrum ABX NSAID's Some SSRI's Some Statins

Drugs that decrease Warfarins function

rifampin barbiturates carbamazepine

Diseases that affect warfarin function

Hepatic function - increases INR - d/t decreased clearance Intestinal diseases - increase INR - d/t decreased vit K absorption Renal insufficiency - increases INR - d/t decreased albumin

Warfarin Adverse Effects

Hemorrhage (stroke) Placental Transfer Birth defects Necrosis (rare) - d/t protein C levels decrease

Rivaroxaban MOA

direct factor Xa inhibitor

Dabigatran MOA Used for Contraindicated in?

oral thrombin inhibitor stroke prevention in a-fib and DVT/PE tx patients with mechanical heart valves

Main enzyme that breaks down fibrin?

plasmin

Fibrinolytic Drugs (3)

Streptokinase Urokinase plasminogen activator Tissue plasminogen activator

Alteplase MOA

activates plasminogen to form plasmin

Main use of tPA's

acute myocardial infarction, with ST segment elevation w/oin 12 hrs of onset

Fibrinolysis Inhibitors

Aminocaproic acid | Tranexamic acid

Fibrinolysis Inhibitors MOA

block interaction of plasmin with fibrin