1.02 DRUGS USED IN DISORDERS OF COAGULATION

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Which natural anticoagulant inactivates the serine protease IIa?

Protein S

Antithrombin (AT) (correct)

Protein C

Plasmin

Which factor is responsible for the initial activation of factor X to Xa?

Factor V Leiden

Factor IX

Factor VIIa (correct)

Factor VIII

In what condition is a systemic lytic state created with an attendant increase in bleeding risk?

Hemophilia A

Protein C deficiency

Disseminated intravascular coagulation (DIC) (correct)

Thrombotic disease

What causes resistance to inactivation by the protein C, protein S mechanism?

Mutation in factor V (factor V Leiden) Signup and view all the answers

Which regulatory system is overwhelmed by therapeutic doses of plasminogen activators?

Inhibition by plasminogen activator inhibitor (PAI) Signup and view all the answers

What is a clinically useful inhibitor of fibrinolysis?

Aminocaproic acid Signup and view all the answers

What is the ideal goal of anticoagulant drugs?

Limit bleeding Signup and view all the answers

How do indirect thrombin inhibitors exert their antithrombotic effect?

By binding to antithrombin and enhancing its inactivation of thrombin Signup and view all the answers

Which drug binds to antithrombin and enhances its inactivation of factor Xa?

Low-molecular-weight heparin (LMW) Signup and view all the answers

What is the principle toxicity of anticoagulants and fibrinolytic drugs?

Increased bleeding risk Signup and view all the answers

Which phase of the clotting mechanism does unfractionated heparin (UFH) enhance?

Initiation phase Signup and view all the answers

What is the main interaction of indirect thrombin inhibitors for exerting their antithrombotic effect?

Interaction with thrombin Signup and view all the answers

What is the effect of unfractionated heparin and to a lesser extent LMW heparin on antithrombin?

Enhancement of antithrombin's inactivation of factor Xa Signup and view all the answers

What is the role of thromboxane A2 (TXA2) in platelet function?

It is a platelet activator and potent vasoconstrictor Signup and view all the answers

Which of the following substances is released from platelet granules and is a powerful inducer of platelet aggregation?

Adenosine Diphosphate (ADP) Signup and view all the answers

What is the main initiator of blood coagulation in vivo?

Tissue factor (TF) Signup and view all the answers

What is the function of the glycoprotein (GP) IIb/IIIa receptor on platelets?

It enables platelets to bind fibrinogen and other macromolecules Signup and view all the answers

In paVents with defects in primary hemostasis, such as von Willebrand disease, where do they typically bleed from?

Surface sites (gingiva, skin, heavy menses) Signup and view all the answers

What regulates the TF-factor VIIa-catalyzed activation of factor Xa in blood coagulation cascade?

Tissue factor pathway inhibitor (TFPI) Signup and view all the answers

What is the primary function of hemostasis?

Limiting blood loss Signup and view all the answers

What are common causes of dysregulated hemostasis?

Hereditary or acquired defects in the clotting mechanism Signup and view all the answers

What is atrial fibrillation associated with?

Stasis of blood in the atria and increased risk of occlusive stroke Signup and view all the answers

What is the normal relationship between the vascular endothelial cell layer and circulating blood platelets and clotting factors?

Do not adhere to it at all Signup and view all the answers

What are the risk factors considered in the CHA2DS2-VASC score for the use of oral anticoagulants?

Congestive heart failure, hypertension, age, diabetes, history of stroke, vascular disease, and sex Signup and view all the answers

Which condition represents a breakdown of the hemostatic mechanism?

Thrombosis Signup and view all the answers

What is the peak therapeutic level of enoxaparin for twice-daily dosing?

0.5–1 unit/mL Signup and view all the answers

What is the primary risk associated with long-term heparin therapy?

Osteoporosis and spontaneous fractures Signup and view all the answers

What is a major adverse effect of heparin?

Bleeding risk Signup and view all the answers

How are patients who develop HIT (heparin-induced thrombocytopenia) treated?

Direct thrombin inhibitor administration Signup and view all the answers

What is the therapeutic range for treatment of venous thromboembolic disease with heparin?

$0.2–0.4$ unit/mL (by protamine titration) Signup and view all the answers

How is low-dose prophylaxis of heparin achieved?

Subcutaneous administration Signup and view all the answers

What is the molecular weight range of unfractionated heparin (UFH)?

5000–30,000 Signup and view all the answers

How do LMW heparins such as ENOXAPARIN, DALTEPARIN, and TINZAPARIN compare with UFH in terms of dosing requirements?

They have less frequent dosing requirements Signup and view all the answers

Which factor does unfractionated heparin (UFH) inhibit to a greater extent than thrombin?

Activated factor X Signup and view all the answers

How is the biologic activity of heparin dependent upon antithrombin?

By forming stable complexes with clotting factor proteases Signup and view all the answers

In patients receiving UFH, which monitoring test is necessary for close monitoring of its effect?

Activated partial thromboplastin time (aPTT) Signup and view all the answers

How does heparin function as a cofactor for the antithrombin-protease reaction without being consumed?

It forms equimolar stable complexes with clotting factor proteases Signup and view all the answers

What is the mechanism of action of fondaparinux?

It binds to factor Xa and inhibits its activity Signup and view all the answers

How is excessive anticoagulant action of heparin treated?

By administering protamine sulfate Signup and view all the answers

What is the role of protamine sulfate in neutralizing heparin's anticoagulant activity?

It forms a stable complex with negatively charged heparin Signup and view all the answers

Why must excess protamine be avoided when used to neutralize heparin?

Because it has an anticoagulant effect Signup and view all the answers

What effect does protamine have on LMW heparin?

It partially neutralizes the anticoagulant effect Signup and view all the answers

What is the effect of protamine on fondaparinux?

It reverses the activity of fondaparinux Signup and view all the answers

What is the advantage of fondaparinux's long half-life of 15 hours?

It allows for once-daily dosing by subcutaneous administration Signup and view all the answers

In what situation is administration of protamine sulfate indicated?

In case of bleeding due to heparin overdose Signup and view all the answers

What is the mechanism of action of warfarin in preventing blood clot formation?

Reduction of prothrombin activity Signup and view all the answers

Which drug interaction mechanism causes an increased anticoagulant effect and risk of bleeding when combined with warfarin?

Synergism (impaired hemostasis) Signup and view all the answers

How does warfarin affect the fetal proteins with γ-carboxyglutamate residues found in bone and blood?

It can cause abnormal bone formation Signup and view all the answers

Which drug inhibits the metabolic transformation of S-warfarin, leading to an increased anticoagulant effect?

Trimethoprim sulfamethoxazole Signup and view all the answers

What is the recommended international normalized ratio (INR) range for prophylaxis and treatment of thrombotic disease?

2–3 Signup and view all the answers

How does cholestyramine affect warfarin's absorption and bioavailability?

Reduces absorption Signup and view all the answers

What is the main adverse effect associated with cutaneous necrosis during the first weeks of warfarin therapy in patients with inherited deficiency of protein C?

Venous thrombosis Signup and view all the answers

What was the initial use of warfarin and its congeners?

As a rodenticide Signup and view all the answers

What is the main mechanism of action of coumarin anticoagulants?

Blocking the γ-carboxylation of certain clotting factors Signup and view all the answers

How does warfarin's binding to plasma albumin contribute to its characteristics?

It increases its volume of distribution Signup and view all the answers

What is the specific function of vitamin K in the context of coumarin anticoagulants?

It promotes the γ-carboxylation of clotting factors Signup and view all the answers

What is the oral bioavailability of racemic warfarin?

100% Signup and view all the answers

How do coumarin anticoagulants affect coagulation factor molecules?

They inactivate coagulation factor molecules Signup and view all the answers

What contributes to the long half-life of racemic warfarin in plasma?

Its binding to plasma albumin Signup and view all the answers

How can the excessive anticoagulant effect and bleeding from warfarin be reversed?

By administering oral or parenteral vitamin K1 Signup and view all the answers

What is the mechanism of action of rivaroxaban, apixaban, and edoxaban?

Inhibiting factor Xa, in the final common pathway of clotting Signup and view all the answers

What is the recommended prophylactic dosage of rivaroxaban for prevention of venous thromboembolism following hip replacement?

10 mg orally per day for 35 days Signup and view all the answers

Why do rivaroxaban, apixaban, and edoxaban not require monitoring?

They have fixed doses Signup and view all the answers

Which factor influences the drug half-life of rivaroxaban?

Age of the patient Signup and view all the answers

What is the recommended dosage of apixaban for prevention of venous thromboembolism following hip or knee surgery?

2.5 mg twice a day for VTE prevention Signup and view all the answers

What makes edoxaban a once-daily Xa inhibitor with a 62% oral bioavailability?

It does not induce CYP450 enzymes Signup and view all the answers

Which oral direct thrombin inhibitor is approved for the reduction of risk of stroke and systemic embolism with nonvalvular atrial fibrillation?

Dabigatran etexilate mesylate Signup and view all the answers

What is the primary toxicity of dabigatran, the only oral direct thrombin inhibitor approved by the FDA?

Bleeding Signup and view all the answers

Which direct thrombin inhibitor has a short half-life with clearance that is 20% renal and the remainder metabolic, and has been FDA-approved for use in percutaneous coronary angioplasty?

Bivalirudin Signup and view all the answers

Which direct thrombin inhibitor is a small molecule thrombin inhibitor FDA-approved for use in patients with heparin-induced thrombocytopenia (HIT) with or without thrombosis?

Argatroban Signup and view all the answers

Which direct thrombin inhibitor requires no monitoring due to its predictable pharmacokinetics and bioavailability, allowing for fixed dosing and predictable anticoagulant response?

Dabigatran etexilate mesylate Signup and view all the answers

Which direct thrombin inhibitor is excreted by the kidney and should be used with great caution in patients with renal insufficiency as no antidote exists?

Lepirudin Signup and view all the answers

Which direct thrombin inhibitor inhibits platelet activation and has been FDA-approved for use in percutaneous coronary angioplasty?

Bivalirudin Signup and view all the answers

For which condition is Idarucizumab, a humanized monoclonal antibody Fab fragment that binds to dabigatran and reverses its anticoagulant effect, approved for use?

Life-threatening bleeding or emergent surgery Signup and view all the answers

What is the action of lepirudin, a specific, irreversible thrombin inhibitor from leech saliva?

It has little effect on platelets or bleeding time. Signup and view all the answers

Which drug is synthesized by streptococci and combines with the proactivator plasminogen?

Urokinase Signup and view all the answers

What permits the clinical use of urokinase and the streptokinase-proactivator complex?

Absence of inhibitors for urokinase and the streptokinase-proactivator complex Signup and view all the answers

What is the preferred target of tissue plasminogen activators (t-PAs) for activation of plasminogen?

Fibrin Signup and view all the answers

How is recombinant human t-PA manufactured?

Alteplase Signup and view all the answers

What prevents the effects of naturally occurring inhibitors (antiplasmins) on urokinase and the streptokinase-proactivator complex?

Binding to thrombus Signup and view all the answers

What is the primary source of streptokinase?

Streptococci Signup and view all the answers

What converts plasminogen to active plasmin in the absence of inhibitors?

Urokinase Signup and view all the answers

What does recombinant human t-PA preferentially activate if bound?

Fibrin Signup and view all the answers

What is the primary clinical use of recombinant factor VIIa?

Treatment of bleeding associated with invasive procedures in hemophilia patients Signup and view all the answers

What is the recommended dosage of tranexamic acid for congenital factor VII deficiency?

15–30 mg/kg every 4–6 hours Signup and view all the answers

What is the main clinical use of aminocaproic acid?

Adjunctive therapy in hemophilia Signup and view all the answers

What is the mechanism of action of aminocaproic acid?

Competitively inhibits plasminogen activation Signup and view all the answers

For which condition is recombinant factor VIIa not indicated?

Venous thromboembolic disease Signup and view all the answers

What is the mechanism of action of tranexamic acid?

Competitively inhibits fibrinolysis Signup and view all the answers

What is the primary clinical use of fresh frozen plasma?

Treatment of bleeding associated with invasive procedures in hemophilia patients Signup and view all the answers

What is the role of a four-factor plasma replacement preparation containing vitamin K– dependent factors II, VII, IX, and X (4F PCC, Kcentra)?

Rapid reversal of warfarin in bleeding patients Signup and view all the answers

What adverse effect is most seriously associated with ticlopidine?

Leukopenia Signup and view all the answers

Which drug is contraindicated in patients with a history of TIA or stroke due to increased bleeding risk?

Prasugrel Signup and view all the answers

Which drug is rarely associated with neutropenia and is frequently preferred over ticlopidine due to its superior adverse effect profile?

Clopidogrel Signup and view all the answers

Which drug achieves maximum platelet inhibition with a maintenance dosage of 75 mg/d?

Clopidogrel Signup and view all the answers

Which drug is a peptidomimetic inhibitor with the RGD sequence motif?

Tirofiban Signup and view all the answers

Which P2Y12 inhibitor is approved for IV use in coronary interventions in patients without previous ADP P2Y12 inhibitor therapy?

Ticagrelor Signup and view all the answers

What is the primary function of the platelet GP IIb/IIIa (integrin αIIbβ3) receptor?

Initiation of platelet aggregation Signup and view all the answers

Which drug is a vasodilator that inhibits platelet function by inhibiting adenosine uptake and cGMP phosphodiesterase activity?

Dipyridamole Signup and view all the answers

Which vitamin confers biologic activity upon prothrombin and factors VII, IX, and X?

Vitamin K1 Signup and view all the answers

What are the two natural forms of vitamin K?

Vitamin K1 and Vitamin K2 Signup and view all the answers

Which factor deficiency accounts for classic hemophilia, or hemophilia A?

Factor VIII deficiency Signup and view all the answers

Which factor is Eloctate, a factor VIII-Fc domain conjugate, designed to treat?

Factor VIII deficiency Signup and view all the answers

Which drug is used primarily to treat intermittent claudication?

Cilostazol Signup and view all the answers

How is Alteplase (t-PA) administered?

As a loading dose of 300,000 units given over 10 minutes and a maintenance dose of 300,000 units/h for 12 hours Signup and view all the answers

What is the recommended dose of recombinant t-PA for acute ischemic stroke?

0.9 mg/kg, not to exceed 90 mg, with 10% given as a bolus and the remainder during a 1-hour infusion Signup and view all the answers

What is the dosing scheme for Reteplase?

As two 10-unit bolus injections, the second administered 30 minutes after the first injection Signup and view all the answers

How does Aspirin inhibit platelet aggregation?

By irreversible acetylation of the enzyme cyclooxygenase Signup and view all the answers

How do Thienopyridines such as Ticlopidine, Clopidogrel, & Prasugrel reduce platelet aggregation?

By inhibiting the ADP pathway of platelets Signup and view all the answers

What is the main target for antiplatelet drugs that block GP IIb/IIIa receptors on platelets?

Blockade of glycoprotein IIb/IIIa (GP IIb/IIIa) receptors on platelets Signup and view all the answers

What is the mechanism of action of Dipyridamole and Cilostazol as antiplatelet drugs?

Interacting with substances generated within the platelet that act within the platelet Signup and view all the answers

How do recombinant T-PA drugs differ from Reteplase and Tenecteplase in terms of dosing schemes?

They require a loading dose followed by a maintenance dose over a period of time Signup and view all the answers

Match the fibrinolytic drug with its mechanism of action:

Streptokinase = Combines with the proactivator plasminogen to catalyze its conversion to active plasmin Urokinase = Directly converts plasminogen to active plasmin Signup and view all the answers

Match the drug characteristic with the corresponding effect:

Plasmin formed inside a thrombus by activators like streptokinase and urokinase = Protected from plasma antiplasmins, allowing it to lyse the thrombus from within Recombinant human tissue plasminogen activator (t-PA) = Manufactured as alteplase Signup and view all the answers

Match the drug dosing scheme with the corresponding drug:

Streptokinase = Administered by intravenous infusion of a loading dose of 250,000 units, followed by 100,000 units/h for 24–72 hours Reteplase = Dosing scheme not provided in the given text Signup and view all the answers

Match the drug's inhibitor with the corresponding protection mechanism:

Urokinase and streptokinase-proactivator complex = Protected from naturally occurring inhibitors (antiplasmins) in plasma Signup and view all the answers

Match the antiplatelet drug with its recommended dosage for patients with acute coronary syndromes:

Ticlopidine = 250 mg twice daily orally Clopidogrel = 300-mg loading dose orally followed by 75 mg daily Prasugrel = 60-mg loading dose and then 10 mg/d Ticagrelor = Oral use in combination with aspirin Signup and view all the answers

Match the antiplatelet drug with its adverse effects:

Ticlopidine = Nausea, dyspepsia, diarrhea, hemorrhage, leukopenia Clopidogrel = Neutropenia, increased bleeding risk Prasugrel = Increased major and minor bleeding risk Ticagrelor = Superior adverse effect profile Signup and view all the answers

Match the antiplatelet drug with its primary clinical use:

Ticlopidine = Prevention of stroke in patients with a history of TIA or thrombotic stroke Clopidogrel = Unstable angina, recent myocardial infarction, stroke, or established peripheral arterial disease Prasugrel = Acute coronary syndromes Ticagrelor = Treatment of STEMI/NSTEMI Signup and view all the answers

Match the antiplatelet drug with its unique pharmacological characteristic:

Ticlopidine = Associated with thrombotic thrombocytopenic purpura Clopidogrel = Cytochrome P450 genotype status is an important factor in pharmacology Prasugrel = Not influenced by cytochrome P450 genotype status Ticagrelor = Newer type of ADP inhibitor Signup and view all the answers

Match the following drugs with their primary mechanism of action:

Abciximab = Chimeric monoclonal antibody directed against the IIb/IIIa complex Eptifibatide = Cyclic peptide derived from rattlesnake venom that contains a variation of the RGD motif Tirofiban = Peptidomimetic inhibitor with the RGD sequence motif Dipyridamole = Vasodilator that inhibits platelet function by inhibiting adenosine uptake and cGMP phosphodiesterase activity Signup and view all the answers

Match the following drugs with their clinical use:

Dipyridamole = Used primarily in combination with aspirin to prevent cerebrovascular ischemia Cilostazol = Primarily used to treat intermittent claudication Eloctate = Factor VIII-Fc domain conjugate that prolongs the factor VIII half-life Idelvion = Factor IX-albumin conjugate with a prolonged half-life, FDA-approved for treatment of bleeding in hemophilia B patients Signup and view all the answers

Match the following vitamin K forms with their characteristics:

Vitamin K1 (phytonadione) = Found in food and available clinically in oral and parenteral forms Vitamin K2 (menaquinone) = Found in human tissues, synthesized by intestinal bacteria, and requires bile salts for absorption Vitamin K1 and K2 = Confer biologic activity upon prothrombin and factors VII, IX, and X by participating in their post ribosomal modification Vitamin K repletion = Best achieved with intravenous or oral administration due to erratic bioavailability after subcutaneous administration Signup and view all the answers

Match the following plasma coagulation factor products with their characteristics:

Eloctate = Factor VIII-Fc domain conjugate that prolongs the factor VIII half-life and allows twice-weekly dosing in many cases Idelvion = Factor IX-albumin conjugate with a half-life of 100 hours, FDA-approved for prophylaxis or treatment of bleeding in hemophilia B patients Vonicog alfa = Recombinant von Willebrand factor product approved for treatment and control of bleeding in adults with von Willebrand disease Plasma fractions and recombinant protein preparations = Available for the treatment of deficiencies such as factor VIII deficiency and factor IX deficiency Signup and view all the answers

Match the thrombolytic agent with its dosing scheme for administration:

Alteplase (t-PA) = 15-mg bolus followed by 0.75 mg/kg over 30 minutes and then 0.5 mg/kg over 60 minutes Reteplase = Two 10-unit bolus injections, the second administered 30 minutes after the first injection Tenecteplase = Single intravenous bolus ranging from 30 to 50 mg depending on body weight Reptilase = Loading dose of 300,000 units given over 10 minutes and a maintenance dose of 300,000 units/h for 12 hours Signup and view all the answers

Match the antiplatelet drug with its mechanism of action:

Aspirin = Inhibits the synthesis of thromboxane A2 by irreversible acetylation of the enzyme cyclooxygenase Ticlopidine, Clopidogrel, & Prasugrel = Irreversibly block the ADP P2Y12 receptor on platelets, reducing platelet aggregation Dipyridamole and Cilostazol = Act as additional antiplatelet drugs Abciximab, Tirofiban, and Eptifibatide = Blockade of glycoprotein IIb/IIIa (GP IIb/IIIa) receptors on platelets Signup and view all the answers

Match the factor with its association in the context of anticoagulant drugs:

Thrombin = Inhibited to a greater extent than thrombin by unfractionated heparin (UFH) Factor Xa = Directly inhibited by certain antiplatelet agents Factor IIa (thrombin) = Binds to antithrombin and enhances its inactivation by certain drugs Factor VIIa = Used for specific clinical purposes and not indicated for other conditions Signup and view all the answers

Match the drug with its clinical indication for use:

Alteplase (t-PA) = Management of acute ischemic stroke within 3 hours of symptom onset Streptokinase = Associated with increased bleeding risk in acute ischemic stroke when given at a specific dose Idarucizumab = Approved for use in reversing the anticoagulant effect of dabigatran Eloctate = Designed to treat a specific factor deficiency Signup and view all the answers

Match the following inhibitors of fibrinolysis with their clinical uses:

Aminocaproic Acid (EACA) = Prophylaxis for rebleeding from intracranial aneurysms Tranexamic Acid = Administered orally with a loading dose followed by maintenance dosage Signup and view all the answers

Match the following recombinant coagulation factors with their clinical uses:

Recombinant Factor VIIa = Factor VII deficiency Eloctate (Factor VIII-Fc domain conjugate) = Designed to treat Signup and view all the answers

Match the following anticoagulants with their respective dosing schemes:

Warfarin = Rapid reversal in bleeding patients Recombinant T-PA = Dosage of 90 mg/kg every 2 hours until hemostasis is achieved Rivaroxaban, Apixaban, Edoxaban = No monitoring required Reteplase = Dosing scheme Signup and view all the answers