question

HEPARIN: CLASS

answer

*Anticoagulant

question

HEPARIN: DOSE

answer

*Heart surgery with CPB: 400 U/kg Bolus to ACT >400 *Neuro/vascular procedures: 3000-5000 U→goal to double ACT. *Low dose thrombosis prophylaxis: SC 5000 units 2 hrs prior to surgery, then every 12 hrs *Treatment of venous thromboembolism: 5000 U IV followed by a continuous infusion of 30,000 U q24 hrs *Tx unstable angina/MI: 5000 U IV followed by infusion of 24,000 U q24 hrs *Intermittent IV: 10,000 U, then 50-70 U/kg q4 hrs *Do not inject IM

question

HEPARIN: ONSET/PEAK/DOA/HL (IV)

answer

*Onset: Immediate *Peak: *HL: 1-3 Hr (Dose dependent)

question

HEPARIN: INDICATIONS

answer

*Acute coronary syndrome *NSTEMI *Atrial fibrillation *DVT & PE *Cardiopulmonary bypass for heart surgery *ECMO circuit for extracorporeal life support *Hemofiltration *Indwelling central or peripheral venous catheters

question

HEPARIN: MOA

answer

*Inhibition of the coagulation factors thrombin (factor IIa) and factor Xa by heparin bound to AT. *Has a polycomponent anticoagulant mechanism inhibiting numerous coagulation factors, inhibiting platelet function, and enhancing theantithrombotic functions of vascular endothelium as well as fibrinolysis. *By inhibiting thrombin, heparin affects thrombin-mediated coagulation mechanisms involving: -Factor V -Factor VIII -Protein C -Thrombin Activatable Fibrinolytic Inhibitor (TAFI) *Releases tissue factor pathway inhibitor (TFPI) *Inhibits the release of P-selectin *Impairs vascular barrier properties *Attenuates nitric oxide-mediated vasodilatation during dynamic changes in blood flow. *Negatively charged *Molecular weights ranging from 3,000 to 30,000 daltons

question

HEPARIN: METABOLISM

answer

*Hepatic *Renal excretion

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HEPARIN:

answer

...

question

HEPARIN:

answer

...

question

HEPARIN: MONITORING

answer

*aPTT *ACT *TEG

question

HEPARIN: REVERSAL

answer

*Protamine IV -1 mg for every 100 U of Heparin administered over the last 4 hours (give slowly)

question

PROTAMINE SULFATE: CLASS

answer

*Heparin Antagonist

question

PROTAMINE SULFATE: DOSE

answer

*1 mg for every 100 U of Heparin administered over the last 4 hours (give slowly) **Maximum infusion rate should not exceed 5 mg/min and the total dose should not exceed 50 mg.

question

PROTAMINE SULFATE: ONSET/PEAK/DOA/HL

answer

*Onset: <1 Min *Peak: 5 Min *DOA: 2 Hrs (dependent on body temp)

question

PROTAMINE SULFATE: INDICATIONS

answer

*Reversal of effects of heparin and limited ability to reverse LMWH *Preferential reversal of Factor IIa Inhibition, therefore it's more effective at reversing heparin.

question

PROTAMINE SULFATE: MOA

answer

*The positively charged alkaline protamine combines electrostatically with the negatively charged acidic heparin to form a stable complex that is devoid of anticoagulant activity → a neutralization reaction.

question

PROTAMINE SULFATE: METABOLISM

answer

*Removed and broken down by the reticuloendothelial system after binding to heparin complexes

question

PROTAMINE SULFATE: Precautions

answer

*HOTN: d/t rapid injection from the histamine release; administer a test dose 1-5 mg 1st then administer SLOWLY over 5 minutes. *Pulmonary HTN: in in rare cases, the neutralization of heparin → thromboxane and serotonin secretion manifesting as pulmonary vasoconstriction, pulm HTN, and pulm edema. Pretreat with COX inhibitors (i.e. ASA) blunts the increase in PVR *These multiple cardiovascular effects are mediated via complement activation, histamine release, thromboxane and nitric oxide production, and antibody formation

question

PROTAMINE SULFATE: Heparin Rebound

answer

*Clearance of protamine is more rapid than heparin, make sure to confirm the adequacy of heparin reversal.

question

PROTAMINE SULFATE: Anticoagulation Effects

answer

*If excess protamine given; protamine in the absence of heparin interacts with platelets and proteins → anticoagulation

question

PROTAMINE SULFATE: Allergic Reaction

answer

*Both IgE and IgG mediated anaphylaxis; more common in pts who have received protamine in the past, pts who have received protamine-based insuln (NPH), pts with fish allergies, and vasectomized pts

question

COUMADIN (Warfarin): CLASS

answer

*Vitamin K Antagonist

question

COUMADIN (Warfarin): DOSE

answer

*Initial dose: PO 10-15 mg *Daily dose: PO 2-10 mg *Adjust to INR of 2-3 for low intensity anticoagulation and 4-5 for high intensity therapy.

question

COUMADIN (Warfarin): ONSET/PEAK/DOA/HL

answer

*Onset: 8-12 Hrs *Peak: 1-5 Days *DOA: 2-10 Days *HL: 35 hrs

question

COUMADIN (Warfarin): INDICATIONS

answer

*Prophylaxis and Tx of thromboembolic disorders (venous, pulmonary) and embolic complications arising from atrial fibrillation or cardiac valve replacement *Adjunct to reduce risk of systemic embolism (eg, recurrent MI, stroke) after MI

question

COUMADIN (Warfarin): MOA

answer

*Warfarin inhibits vitamin K- dependent synthesis of biologically active forms of clotting factors II, VII, IX & X, as well as the regulatory factors protein C and protein S. *Inhibits vitamin K epoxide reductase → blocks conversion of vitamin K epoxide to vitamin K → subsequent depletion of vitamin K results in the production of ehmostatically defective viamin K-dependent coagulation proteins = DECLINE OF THE CARBOXYLATED CLOTTING FACTORS.

question

COUMADIN (Warfarin): METABOLISM

answer

*R enantiomer is metabolized primarily by two microsomal cytochrome enzymes (CYP1A2 and CYP3A4) to 6- and 8-hydroxywarfarin *S enantiomer is metabolized primarily by the CYP2C9 enzyme of the P450 system to 7-hydroxywarfarin *The inactive hydroxywarfarins are excreted renally

question

COUMADIN (Warfarin): REGIONAL CONSIDERATIONS

answer

*Caution should be used when performing neuraxial techniques in patients recently discontinued from chronic warfarin therapy. *The anticoagulant therapy must be stopped, (ideally 4-5 days prior to the planned procedure) and the PT/INR measured prior to initiation of neuraxial block. *Early after discontinuation of warfarin therapy, the PT/INR reflect predominantly factor VII levels, and in spite of acceptable factor VII levels, factors II and X levels may not be adequate for normal hemostasis. *Adequate levels of II, VII, IX, and X may not be present until the PT/INT is within normal limits. *As thromboprophylaxis with warfarin is initiated, neuraxial catheters should be removed when the INR is 3 should prompt the physician to withhold or reduce the warfarin dose in patients with indwelling neuraxial catheters.

question

COUMADIN (Warfarin): SURGICAL CONSIDERATIONS

answer

*Stop 4-5 days prior to surgery

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COUMADIN (Warfarin): MONITORING

answer

*PT *INR

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COUMADIN (Warfarin): REVERSAL

answer

*Vit K: Po 2.5-10 mg (no bleeding) *IV 5-50mg for bleeding *FFP: 15 mL/kg *rFVII: 15 - 90 mcg/kg *PCC: prothrombin complex concentrate (PCC)

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RIVAROXABAN (Xarelto): CLASS

answer

*Direct Factor Xa inhibitor

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RIVAROXABAN (Xarelto): ROUTE

answer

*PO

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RIVAROXABAN (Xarelto): HL

answer

*5-11 hrs

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RIVAROXABAN (Xarelto): INDICATIONS

answer

*Prevention of VTE, PE & Stroke

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RIVAROXABAN (Xarelto): MOA

answer

*Direct factor Xa inhibitors bind directly to the active site of Xa and block its interaction with substrates, thereby inhibiting both free and platelet-bound (bound in the prothrominase complex) factor Xa

question

RIVAROXABAN (Xarelto): METABOLISM

answer

*Hepatic; CYP450 (CYP3A4) drug interactions *Renal/GI Excretion

question

RIVAROXABAN (Xarelto): REGIONAL CONSIDERATIONS

answer

*24 hrs after last dose before puncture/catheter removal *Start 6 hrs after puncture/catheter removal *Contraindicated in patients with severe liver disease.

question

RIVAROXABAN (Xarelto): MONITORING

answer

*Rivaroxaban-calibrated PT *aPTT *Anti-Xa assay *Heptest

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RIVAROXABAN (Xarelto): REVERSAL

answer

*None *Because of the high plasma protein binding, dialysis may not remove *Use of procoagulant reversal agents such as prothrombin complex concentrate, activated prothrombin complex concentrate, or rFVIIa may be considered, but has not been evaluated in clinical trials. *Activated oral charcoal reduces absorption of apixaban

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TICAGRELOR (Brilinta): CLASS

answer

*ADP receptor/Direct Reversible P2Y12 inhibitor -Nonthienopyridine -(nucleotide/nucleoside analog) -antiplatelet

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TICAGRELOR (Brilinta): ROUTE

answer

*PO

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TICAGRELOR (Brilinta): HL

answer

*7 hrs for Ticagrelor *9 hrs for active metabolite **Ticagrelor is a reversible inhibitor, so platelet function normalizes after drug clearance.

question

TICAGRELOR (Brilinta): INDICATIONS

answer

*Reduce risk of thrombotic events in patients with ACS

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TICAGRELOR (Brilinta): MOA

answer

*G-Protein Coupled Receptor *"Not" a Prodrug *Directly blocks the P2Y12 receptor and inhibits platelet aggregation

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TICAGRELOR (Brilinta): METABOLISM

answer

*Hepatic; CYP3A4/5 drug interactions *Hepatic metabolism *Mainly Fecal excretion, some renal

question

TICAGRELOR (Brilinta): REGIONAL CONSIDERATIONS

answer

*Stop >5 days before surgery

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TICAGRELOR (Brilinta): MONITORING

answer

*None

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TICAGRELOR (Brilinta): REVERSAL

answer

*None

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DABIGATRAN (Pradaxa): CLASS

answer

*Direct Thrombin (Factor IIa) Inhibitor *Univalent

question

DABIGATRAN (Pradaxa): ROUTE

answer

*PO *Only FDA approved DTI in oral form

question

DABIGATRAN (Pradaxa): HL

answer

*12-17 Hrs

question

DABIGATRAN (Pradaxa): INDICATIONS

answer

*Prevention of VTE and Stroke

question

DABIGATRAN (Pradaxa): MOA

answer

*A competitive and reversible direct thrombin inhibitor. *Inactivates both fibrin-bound and free thrombin through binding to the active site

question

DABIGATRAN (Pradaxa): METABOLISM

answer

*Primarily renal, remainder is conjugated with glucuronic acid in liver *Undergoes conjugation with glucuronic acid to form pharmacologically active conjugates that account for approximately 20% of total dabigatran in plasma. *Renal excretion

question

DABIGATRAN (Pradaxa): CONSIDERATIONS

answer

*Rapid onset of action, lack of interaction with CYP450, food or drugs, broad TI, fixed dose administration and good safety profile, not associated with hepatotoxicity for long-term use.

question

DABIGATRAN (Pradaxa): REGIONAL CONSIDERATIONS

answer

*72 hrs after last dose before puncture/catheter removal *Start 6 hrs after puncture/catheter removal

question

DABIGATRAN (Pradaxa): MONITORING

answer

*ECT *aPTT and Thrombin Time can provide qualitative information *Bleeding risk can be assessed by the ecarin clotting time (ECT), a laboratory test used to monitor anticoagulation during treatment with hirudin, which is a better marker of the anticoagulant activity of dabigatran than aPTT, PT/ INR, or TT. If ECT is not available, the aPTT provides the next best approximation of dabigatran anticoagulant activity.

question

DABIGATRAN (Pradaxa): REVERSAL

answer

*None *Dialysis my remove up to 65% *Use of procoagulant reversal agents such as prothrombin complex concentrate, activated prothrombin complex concentrate, or rFVIIa may be considered, but has not been evaluated in clinical trials.

question

PRASUGREL (Effient): CLASS

answer

*ADP receptor Antagonist *Irreversible P2Y12 Inhibitor -(Thienopyridine) -antiplatelet

question

PRASUGREL (Effient): ROUTE

answer

*PO

question

PRASUGREL (Effient): HL

answer

*7 hrs *Inhibit platelet function for lifetime of platelet. Inhibition takes 7 10 days to resolve as new platelets are generated.

question

PRASUGREL (Effient): INDICATIONS

answer

*Reduce risk of thrombotic events in patients with ACS managed by PCI

question

PRASUGREL (Effient): MOA

answer

*G-Protein Coupled Receptor *Prodrug *ADP Antagonist *P2Y12 Inhibitor *Indirect acting *The P2Y12 receptor couples to Gi and, when activated by ADP, inhibits adenylyl cyclase, resulting in lower levels of cyclic AMP and thereby less cyclic AMP- dependent inhibition of platelet activation.

question

PRASUGREL (Effient): METABOLISM

answer

*Hepatic *Renal/GI Excretion

question

PRASUGREL (Effient): CONSIDERATIONS

answer

*As opposed to clopidogrel, proton pump inhibitors do not reduce the antiplatelet effects of prasugrel and hence it is relatively safe to use these medications together.

question

PRASUGREL (Effient): REGIONAL CONSIDERATIONS

answer

*5-7 days after last dose before puncture/catheter removal *Start 6 hrs after puncture/catheter removal

question

PRASUGREL (Effient): SURGICAL CONSIDERATIONS

answer

*Stop 7-10 days before surgery

question

PRASUGREL (Effient): REVERSAL

answer

*HASHTI *Platelet transfusion **Circulating drug or active metabolites can inhibit transfused platelets. *DDAVP

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DESIRUDIN (Iprivask): CLASS

answer

*Direct Thrombin (Factor IIa) Inhibitor *Bivalent

question

DESIRUDIN (Iprivask): ROUTE

answer

*SQ

question

DESIRUDIN (Iprivask): HL

answer

*2 hrs

question

DESIRUDIN (Iprivask): INDICATIONS

answer

*VTE/PE prophylaxis in pts undergoing hip arthroplasty

question

DESIRUDIN (Iprivask): MOA

answer

*A competitive and reversible direct thrombin inhibitor. *Inactivates both fibrin-bound and free thrombin through binding to both the active site and exosite 1

question

DESIRUDIN (Iprivask): METABOLISM

answer

*Renal Metabolism & Excretion

question

DESIRUDIN (Iprivask): REGIONAL CONSIDERATIONS

answer

*Initiate after regional anesthesia *Typically wait 2-3 half-lives prior to pulling catheter *Confirm aPTT

question

DESIRUDIN (Iprivask): MONITORING

answer

*aPTT

question

DESIRUDIN (Iprivask): REVERSAL

answer

*None *Blood transfusions are appropriate *Thrombin rich plasma concentrates *DDAVP may be helpful

question

FONDAPARINUX (Arixtra): CLASS

answer

*Indirect Factor Xa Inhibitor

question

FONDAPARINUX (Arixtra): ROUTE

answer

*SQ

question

FONDAPARINUX (Arixtra): HL

answer

*17-21 hrs

question

FONDAPARINUX (Arixtra): INDICATIONS

answer

*Prevention and treatment of VTE

question

FONDAPARINUX (Arixtra): MOA

answer

*An indirect factor Xa inhibitor that selectively binds to antithrombin III, potentiating factor Xa neutralization and inhibiting thrombin formation.

question

FONDAPARINUX (Arixtra): METABOLISM

answer

*Metabolized Minimally *Renal excretion

question

FONDAPARINUX (Arixtra): CONSIDERATIONS

answer

*

question

FONDAPARINUX (Arixtra): REGIONAL CONSIDERATIONS

answer

*36 hrs after last dose before puncture/catheter removal *Start 12 hrs after puncture/catheter removal

question

FONDAPARINUX (Arixtra): MONITORING

answer

*Anti-Xa assay

question

FONDAPARINUX (Arixtra): REVERSAL

answer

*None officially *Hemodialysis can reduce levels by 20% *Possible value of rFVIIa (with transexamic acid)

question

TINZAPARIN (Innohep): CLASS

answer

*LMHW

question

TINZAPARIN (Innohep): ROUTE

answer

*SQ

question

TINZAPARIN (Innohep): HL

answer

*3-4 hrs

question

TINZAPARIN (Innohep): INDICATIONS

answer

*Treatment of VTE

question

TINZAPARIN (Innohep): MOA

answer

*Inhibits thrombosis by inactivating both factor Xa and factor IIa (ratio 2:1 vs. unfractionated heparin 1:1) *To a lesser degree than heparin, it also inhibits factor IX, X, XI, XII, thrombin, and fibrin stabilizing factor. *To a lesser degree it also stimulates ATIII *Binds and inactivates Xa complex and indirectly inhibits thrombin production

question

TINZAPARIN (Innohep): METABOLISM

answer

*Desulphation and depolymerization *Renal Excretion

question

TINZAPARIN (Innohep): CONSIDERATIONS

answer

*The only low molecular weight heparin shown to be safe in pregnancy and in critically ill people with renal failure at both treatment and prophylaxis dose levels. *Contraindicated with pts with cr clearance <30 ml/min

question

TINZAPARIN (Innohep): REGIONAL CONSIDERATIONS

answer

Preoperative LMWH a. Patients on preoperative LMWH thromboprophylaxis can be assumed to have altered coagulation. In these patients needle placement should occur at least 10-12 hours after the LMWH dose. b. Patients receiving higher (treatment) doses of LMWH will require delays of at least 24 hours to assure normal hemostasis at the time of needle insertion. c. Neuraxial techniques should be avoided in patients administered a dose of LMWH two hours preoperatively (general surgery patients), because needle placement would occur during peak anticoagulant activity.

question

TINZAPARIN (Innohep): MONITORING

answer

*None

question

TINZAPARIN (Innohep): REVERSAL

answer

*Urgent (Not bleeding) • Wait 12-24 hours if possible • Consider protamine sulfate (will reverse 85%) if delay not possible for high bleeding risk procedure *Urgent (Bleeding) • HASHTI • Protamine sulfate (will reverse 85%) • Consider rVIIa

question

LEPIRUDIN (Refludan): CLASS

answer

*Direct Thrombin (Factor IIa) Inhibitor *Bivalent

question

LEPIRUDIN (Refludan): ROUTE

answer

*IV Infusion

question

LEPIRUDIN (Refludan): HL

answer

*1-2 hrs

question

LEPIRUDIN (Refludan): INDICATIONS

answer

*Prophylaxis for VTE in patients with HIT

question

LEPIRUDIN (Refludan): MOA

answer

*A competitive and reversible direct thrombin inhibitor. *Inactivates both fibrin-bound and free thrombin through binding to both the active site and exosite 1

question

LEPIRUDIN (Refludan): METABOLISM

answer

*Catabolic hydrolysis *Renal Excretion

question

LEPIRUDIN (Refludan): REGIONAL CONSIDERATIONS

answer

*Initiate after regional anesthesia *Typically wait 2-3 half-lives prior to pulling catheter *Confirm aPTT

question

LEPIRUDIN (Refludan): MONITORING

answer

*aPTT

question

LEPIRUDIN (Refludan): REVERSAL

answer

*Modified ultrafiltration can eliminate a limited amount depending on the filter type. *Hemodialysis is ineffective *rFVIIa) has been used, success has been marginal. *FFP or cryoprecipitate can be given to work as a competitor to displace bivalirudin from thrombin. *Antifibrinolytic drugs such as Amicar can be used. *Hemodialysis may help

question

ANAGRELIDE (Agrylin): CLASS

answer

*Platelet reducing agent/Phosphodiesterase III Inhibitor -Imidazoquinazolin derivative

question

ANAGRELIDE (Agrylin): ROUTE

answer

*PO

question

ANAGRELIDE (Agrylin): HL

answer

*1.5 hrs

question

ANAGRELIDE (Agrylin): INDICATIONS

answer

*Thrombocythemia, reduce risk of thrombosis *Essential thrombocytosis *Patients who are suitable for anagrelide often meet one or more of the following factors: -age >60 yrs -platelet count over 1.5×10^6/L -Hx of thrombosis *Has been used in the treatment of Chronic Myeloid Leukemia

question

ANAGRELIDE (Agrylin): MOA

answer

*Interferes with megakaryocyte maturation, possibly through the action of a metabolite, an effect that makes it useful for treating thrombocythemia in patients with myeloproliferative conditions. *It is a potent inhibitor of PDE-3 and Phospholipase A2

question

ANAGRELIDE (Agrylin): METABOLISM

answer

*Hepatic; CYP1A2 *Renal Excretion

question

ANAGRELIDE (Agrylin): REGIONAL CONSIDERATIONS

answer

*Increased Platelet count in 4 days; check Platelet count before procedure

question

ANAGRELIDE (Agrylin): MONITORING

answer

*Platelet Count

question

ANAGRELIDE (Agrylin): REVERSAL

answer

*Platelets

question

TICLOPIDINE (Ticlid): CLASS

answer

*ADP receptor Antagonist *Irreversible P2Y12 Inhibitor -(Thienopyridine) -antiplatelet

question

TICLOPIDINE (Ticlid): ROUTE

answer

*PO

question

TICLOPIDINE (Ticlid): HL

answer

*12 Hrs *Inhibit platelet function for lifetime of platelet. Inhibition takes 7 10 days to resolve as new platelets are generated.

question

TICLOPIDINE (Ticlid): INDICATIONS

answer

*Prevent cerebrovascular events in secondary prevention of stroke

question

TICLOPIDINE (Ticlid): MOA

answer

*G-Protein Coupled Receptor *Prodrug *ADP Antagonist *P2Y12 Inhibitor *Indirect acting *The P2Y12 receptor couples to Gi and, when activated by ADP, inhibits adenylyl cyclase, resulting in lower levels of cyclic AMP and thereby less cyclic AMP- dependent inhibition of platelet activation.

question

TICLOPIDINE (Ticlid): METABOLISM

answer

*Hepatic *Renal/Fecal excretion

question

TICLOPIDINE (Ticlid): REGIONAL CONSIDERATIONS

answer

*Stop 14 days prior to neuraxial blockade

question

TICLOPIDINE (Ticlid): MONITORING

answer

*None

question

TICLOPIDINE (Ticlid): REVERSAL

answer

*HASHTI *Platelet transfusion **Circulating drug or active metabolites can inhibit transfused platelets.

question

CLOPIDOGREL (Plavix): CLASS

answer

*ADP receptor Antagonist *Irreversible P2Y12 Inhibitor -(Thienopyridine) -antiplatelet

question

CLOPIDOGREL (Plavix): ROUTE

answer

*PO

question

CLOPIDOGREL (Plavix): HL

answer

*8 Hrs ** Platelet inhibition can be demonstrated two hours after a single dose, but OOA is slow, thus 300mg loading dose normally given *Inhibit platelet function for lifetime of platelet. Inhibition takes 7 10 days to resolve as new platelets are generated.

question

CLOPIDOGREL (Plavix): INDICATIONS

answer

*Prevention of vascular ischemic events in people with symptomatic atherosclerosis *ACS without ST-segment elevation (NSTEMI) *ST elevation MI (STEMI)

question

CLOPIDOGREL (Plavix): MOA

answer

*G-Protein Coupled Receptor *A Prodrug, which requires by cytochrome P450 enzymes, including CYP2C19 for its activation *ADP Antagonist *Irreversible P2Y12 Inhibitor *Indirect acting *The P2Y12 receptor couples to Gi and, when activated by ADP, inhibits adenylyl cyclase, resulting in lower levels of cyclic AMP and thereby less cyclic AMP- dependent inhibition of platelet activation.

question

CLOPIDOGREL (Plavix): METABOLISM

answer

*Hepatic metabolism *Clopidogrel is metabolized into 2-oxo-clopidogrel through a CYP-dependent pathway. *Renal/Biliary(fecal) excretion

question

CLOPIDOGREL (Plavix): PRECAUTIONS

answer

*Should be used with caution in patients on proton pump inhibitors (because they are inhibitors of CYP2C19, required for the activation of clopidogrel) *40-100 times more potent than Ticlid

question

CLOPIDOGREL (Plavix): REGIONAL CONSIDERATIONS

answer

*5-7 days after last dose before puncture/catheter removal *Start after puncture/catheter removal

question

CLOPIDOGREL (Plavix): SURGICAL CONSIDERATIONS

answer

*Stop 5-7 days prior to surgery

question

CLOPIDOGREL (Plavix): REVERSAL

answer

*HASHTI *Platelet transfusion **Circulating drug or active metabolites can inhibit transfused platelets. *DDAVP

question

ABCIXIMAB (ReoPro): CLASS

answer

*Glycoprotein IIb/IIIa Inhibitor -Noncompetitive (monoclonal antibody) -antiplatelet

question

ABCIXIMAB (ReoPro): ROUTE

answer

*Infusion

question

ABCIXIMAB (ReoPro): HL

answer

*15-30 min *Requires 24 to 48 hours for return of normal platelet aggregation *Despite its short half-life of 15 to 30 minutes, abciximab has a prolonged biologic half-life with 50% inhibition of platelet function still present 48 hours after drug discontinuation.

question

ABCIXIMAB (ReoPro): INDICATIONS

answer

*Preventing thrombotic complications after PCI and in patients with ACS

question

ABCIXIMAB (ReoPro): MOA

answer

*The GPIIb/IIIa receptor on the platelet surface serves as a base for fibrin cross-linking responsible for platelet aggregation. *Directly block the fibrinogen receptor on platelets, thereby preventing ligand binding and aggregation

question

ABCIXIMAB (ReoPro): METABOLISM

answer

*It is taken up by the reticular endothelial system where it is degraded by proteolysis.

question

ABCIXIMAB (ReoPro): CONSIDERATIONS

answer

*Contraindicated within 4 weeks of surgery

question

ABCIXIMAB (ReoPro): REGIONAL CONSIDERATIONS

answer

*Following administration, the time to normal platelet aggregation is 24-48. Neuraxial techniques should be avoided until platelet function has recovered.

question

ABCIXIMAB (ReoPro): MONITORING

answer

*Platelet aggregometry

question

ABCIXIMAB (ReoPro): REVERSAL

answer

*HASHTI *Platelet transfusion **Circulating drug or active metabolites can inhibit transfused platelets.

question

EPTIFIBATIDE (Integrilin): CLASS

answer

*Glycoprotein IIb/IIIa Inhibitor -Competitive (polypeptide) -antiplatelet

question

EPTIFIBATIDE (Integrilin): ROUTE

answer

*Infusion

question

EPTIFIBATIDE (Integrilin): HL

answer

*2.5 Hrs *Requires 4 to 8 hours for return of normal platelet aggregation

question

EPTIFIBATIDE (Integrilin): INDICATIONS

answer

*Preventing thrombotic complications after PCI and in patients with ACS

question

EPTIFIBATIDE (Integrilin): MOA

answer

*The GPIIb/IIIa receptor on the platelet surface serves as a base for fibrin cross-linking responsible for platelet aggregation. *Directly block the fibrinogen receptor on platelets, thereby preventing ligand binding and aggregation

question

EPTIFIBATIDE (Integrilin): METABOLISM

answer

*In healthy subjects, renal clearance accounts for approximately 50% of total body clearance, with the majority of the drug excreted in the urine as eptifibatide, deaminated eptifibatide, and other, more polar metabolites. No major metabolites have been detected in human plasma. *Reduce dose in renal pts

question

EPTIFIBATIDE (Integrilin): CONSIDERATIONS

answer

*Contraindicated within 4 weeks of surgery

question

EPTIFIBATIDE (Integrilin): REGIONAL CONSIDERATIONS

answer

*Following administration, the time to normal platelet aggregation is 4-8. Neuraxial techniques should be avoided until platelet function has recovered.

question

EPTIFIBATIDE (Integrilin): MONITORING

answer

*Platelet aggregometry

question

EPTIFIBATIDE (Integrilin): REVERSAL

answer

*HASHTI *Platelet transfusion **Circulating drug or active metabolites can inhibit transfused platelets.

question

TIROFIBAN (Aggrastat): CLASS

answer

*Glycoprotein IIb/IIIa Inhibitor -Competitive (peptidomimetic) -antiplatelet

question

TIROFIBAN (Aggrastat): ROUTE

answer

*Infusion

question

TIROFIBAN (Aggrastat): HL

answer

*2 Hrs *Requires 4 to 8 hours for return of normal platelet aggregation

question

TIROFIBAN (Aggrastat): INDICATIONS

answer

*Preventing thrombotic complications after PCI and in patients with ACS

question

TIROFIBAN (Aggrastat): MOA

answer

*The GPIIb/IIIa receptor on the platelet surface serves as a base for fibrin cross-linking responsible for platelet aggregation. *Directly block the fibrinogen receptor on platelets, thereby preventing ligand binding and aggregation

question

TIROFIBAN (Aggrastat): METABOLISM

answer

*Cleared from the plasma largely by renal excretion, with about 65% of an administered dose appearing in urine and about 25% in feces, both largely as unchanged tirofiban. *Reduce dose in renal pts

question

TIROFIBAN (Aggrastat): CONSIDERATIONS

answer

*Contraindicated within 4 weeks of surgery

question

TIROFIBAN (Aggrastat): REGIONAL CONSIDERATIONS

answer

*Following administration, the time to normal platelet aggregation is 4-8. Neuraxial techniques should be avoided until platelet function has recovered.

question

TIROFIBAN (Aggrastat): MONITORING

answer

*Platelet aggregometry

question

TIROFIBAN (Aggrastat): REVERSAL

answer

*HASHTI *Platelet transfusion **Circulating drug or active metabolites can inhibit transfused platelets.

question

LOVENOX (Enoxaparin): CLASS

answer

*LMWH

question

LOVENOX (Enoxaparin): ROUTE

answer

*SQ

question

LOVENOX (Enoxaparin): ONSET/PEAK/DOA/HL

answer

*Onset: 20-30 min *Peak: 3-5 hrs *DOA: ~12 hrs *HL: 4.5 hrs

question

LOVENOX (Enoxaparin): INDICATIONS

answer

*Tx of unstable angina and non-Q-wave MI (NQMI), administered concurrently with aspirin *Prophylaxis of DVT *Total hip and knee replacement *Abdominal surgery *Tx of DVT with or without PE *Tx of DVT inpatient, with ACS, including STEMI

question

LOVENOX (Enoxaparin): MOA

answer

*Compared with heparin, which has an antiactivated factor X to antiactivated factor II activity of about 1:1, enoxaparin has a corresponding ratio of 4:1 *To a lesser degree than heparin, it also inhibits factor IX, X, XI, XII, thrombin, and fibrin stabilizing factor. *To a lesser degree it also stimulates ATIII *Binds and inactivates Xa complex and indirectly inhibits thrombin production *Mean molecular weight of 4,000 to 5,000 daltons

question

LOVENOX (Enoxaparin): METABOLISM

answer

*Hepatic *Renal excretion

question

LOVENOX (Enoxaparin): Protamine Reversal Dose

answer

*1 mg per 1 mg Enoxaparin in previous 8 hours

question

LOVENOX (Enoxaparin): REGIONAL CONSIDERATIONS

answer

Preoperative LMWH a. Patients on preoperative LMWH thromboprophylaxis can be assumed to have altered coagulation. In these patients needle placement should occur at least 10-12 hours after the LMWH dose. b. Patients receiving higher (treatment) doses of LMWH will require delays of at least 24 hours to assure normal hemostasis at the time of needle insertion. c. Neuraxial techniques should be avoided in patients administered a dose of LMWH two hours preoperatively (general surgery patients), because needle placement would occur during peak anticoagulant activity.

question

LOVENOX (Enoxaparin): MONITORING

answer

*None

question

LOVENOX (Enoxaparin): REVERSAL

answer

*Urgent (Not bleeding) • Wait 12-24 hours if possible • Consider protamine sulfate if delay not possible for high bleeding risk procedure *Urgent (Bleeding) • HASHTI • Protamine sulfate • Consider rVIIa

question

APIXABAN (Eliquis): CLASS

answer

*Direct Factor Xa inhibitor

question

APIXABAN (Eliquis): ROUTE

answer

*PO

question

APIXABAN (Eliquis): HL

answer

*9-14 Hrs

question

APIXABAN (Eliquis): INDICATIONS

answer

*Prevention of VTE, PE & Stroke

question

APIXABAN (Eliquis): MOA

answer

*Direct factor Xa inhibitors bind directly to the active site of Xa and block its interaction with substrates, thereby inhibiting both free and platelet-bound (bound in the prothrominase complex) factor Xa

question

APIXABAN (Eliquis): METABOLISM

answer

*Hepatic; CYP450 (CYP3A4) drug interactions *Renal/Fecal excretion

question

APIXABAN (Eliquis): SURGICAL CONSIDERATIONS

answer

*Discontinue at least 48 hours prior to procedure with moderate or high risk of significant bleeding. *Discontinue at least 24 hours prior to procedure with low risk of bleeding or where the bleeding would be in non-critical location and easily controlled.

question

APIXABAN (Eliquis): MONITORING

answer

*Anti-Xa assay

question

APIXABAN (Eliquis): REVERSAL

answer

*None *Because of the high plasma protein binding, dialysis may not remove apixaban. *Use of procoagulant reversal agents such as prothrombin complex concentrate, activated prothrombin complex concentrate, or rFVIIa may be considered, but has not been evaluated in clinical trials. *Activated oral charcoal reduces absorption of apixaban

question

BIVALIRUDIN (Angiomax): CLASS

answer

*Direct Thrombin (Factor IIa) Inhibitor *Bivalent

question

BIVALIRUDIN (Angiomax): ROUTE

answer

*Infusion

question

BIVALIRUDIN (Angiomax): HL

answer

*25 mins *Coagulation tests WNL after 2 hrs of discontinuation

question

BIVALIRUDIN (Angiomax): INDICATIONS

answer

*Used as an alternative to heparin in patients undergoing coronary angioplasty or cardiopulmonary bypass surgery. *Patients with heparin-induced thrombocytopenia (HIT) or a history of this disorder also can be given bivalirudin instead of heparin during coronary angioplasty.

question

BIVALIRUDIN (Angiomax): MOA

answer

*A competitive and reversible direct thrombin inhibitor. *Inactivates both fibrin-bound and free thrombin through binding to both the active site and exosite 1

question

BIVALIRUDIN (Angiomax): METABOLISM

answer

Bivalirudin has renal excretion but also a unique metabolic elimination process. Thrombin can cleave the Pro-Arg bond of the active site binding moiety to metabolize bivalirudin *Reduce dosage in pts with renal failure

question

BIVALIRUDIN (Angiomax): MONITORING

answer

*aPTT *ACT

question

BIVALIRUDIN (Angiomax): REVERSAL

answer

*Modified ultrafiltration can eliminate 45 to 69% of bivalirudin, depending on the filter type. *Hemodialysis decreases the plasma concentration of bivalirudin by only 25%. *rFVIIa) has been used, success has been marginal. *FFP or cryoprecipitate can be given to work as a competitor to displace bivalirudin from thrombin. *Antifibrinolytic drugs such as Amicar can be used.

question

ARGATROBAN (Acova): CLASS

answer

*Direct Thrombin (Factor IIa) Inhibitor *Univalent

question

ARGATROBAN (Acova): ROUTE

answer

*Infusion

question

ARGATROBAN (Acova): HL

answer

*45 Mins *Coagulation tests WNL after 4 hrs of discontinuation

question

ARGATROBAN (Acova): INDICATIONS

answer

*Heparin Induced Thrombocytopenia (HIT)

question

ARGATROBAN (Acova): MOA

answer

*A competitive and reversible direct thrombin inhibitor. *Inactivates both fibrin-bound and free thrombin through binding to the active site

question

ARGATROBAN (Acova): METABOLISM

answer

*Metabolized by Hepatic CYPs and is excreted in the bile; therefore, dosage reduction is required for patients with hepatic insufficiency. *May be given to pts with renal failure

question

ARGATROBAN (Acova): MONITORING

answer

*aPTT *ACT *Also prolongs the PT in a dose-dependent manner. This has implications when transferring pts to Coumadin

question

ARGATROBAN (Acova): REVERSAL

answer

*Modified ultrafiltration can eliminate a limited amount depending on the filter type. *Hemodialysis is ineffective *rFVIIa) has been used, success has been marginal. *FFP or cryoprecipitate can be given to work as a competitor to displace bivalirudin from thrombin. *Antifibrinolytic drugs such as Amicar can be used.

question

AMINOCAPROIC ACID (Amicar): CLASS

answer

*Antifibrinolytic -Lysine analog

question

AMINOCAPROIC ACID (Amicar): ROUTE

answer

*IV *PO

question

AMINOCAPROIC ACID (Amicar): HL

answer

*2 Hrs

question

AMINOCAPROIC ACID (Amicar): INDICATIONS

answer

*Frequently used in surgeries with high risk of blood loss such as cardiac, liver, vascular and large orthopedic procedures. *Overdose and/or toxic effects of the thrombolytic pharmacologic agents tissue plasminogen activator (commonly known as tPA) and streptokinase

question

AMINOCAPROIC ACID (Amicar): MOA

answer

*Competes for lysine binding sites on plasminogen and plasmin, blocking the interaction of plasmin with fibrin. Is thereby a potent inhibitor of fibrinolysis and can reverse states that are associated with excessive fibrinolysis.

question

AMINOCAPROIC ACID (Amicar): METABOLISM

answer

*Renal *Excreted in the urine and dose reductions are necessary in patients with renal impairment.

question

TRANEXAMIC ACID (Lysteda, Cyklokapron): CLASS

answer

*Antifibrinolytic -Lysine analog

question

TRANEXAMIC ACID (Lysteda, Cyklokapron): ROUTE

answer

*IV *PO

question

TRANEXAMIC ACID (Lysteda, Cyklokapron): HL

answer

*3 Hrs

question

TRANEXAMIC ACID (Lysteda, Cyklokapron): INDICATIONS

answer

*Frequently used in surgeries with high risk of blood loss such as cardiac, liver, vascular and large orthopedic procedures. *Heavy menstrual bleeding *Overdose and/or toxic effects of the thrombolytic pharmacologic agents tissue plasminogen activator (commonly known as tPA) and streptokinase *Has roughly eight times the antifibrinolytic activity of an older analogue, ε-aminocaproic acid.

question

TRANEXAMIC ACID (Lysteda, Cyklokapron): MOA

answer

*Competes for lysine binding sites on plasminogen and plasmin, blocking the interaction of plasmin with fibrin. Is thereby a potent inhibitor of fibrinolysis and can reverse states that are associated with excessive fibrinolysis.

question

TRANEXAMIC ACID (Lysteda, Cyklokapron): METABOLISM

answer

*Renal *Excreted in the urine and dose reductions are necessary in patients with renal impairment.

question

DIPYRIDAMOLE (Persantine): CLASS

answer

*Phosphodiesterase Inhibitor

question

DIPYRIDAMOLE (Persantine): ROUTE

answer

*PO

question

DIPYRIDAMOLE (Persantine): HL

answer

*The decline in plasma concentration fits a two-compartment model with an α half-life (initial decline following peak concentration) of 40 minutes and a β half-life of 10 hours. This is consistent with the twice-daily regimen used in recent clinical studies.

question

DIPYRIDAMOLE (Persantine): INDICATIONS

answer

*A vasodilator that, in combination with warfarin, inhibits embolization from prosthetic heart valves.

question

DIPYRIDAMOLE (Persantine): MOA

answer

*Interferes with platelet function by increasing the cellular concentration of cyclic AMP. This effect is mediated by inhibition of cyclic nucleotide phosphodiesterases and/ or by blockade of uptake of adenosine, which acts at adenosine A2 receptors to stimulate platelet adenylyl cyclase and thence cellular cyclic AMP.

question

DIPYRIDAMOLE (Persantine): METABOLISM

answer

*Metabolized in the liver where it is conjugated to a glucuronide *Excreted in the bile *It is subject to enterohepatic recirculation

question

DIPYRIDAMOLE (Persantine): OVERDOSE

answer

*Dipyridamole overdose can be treated with aminophylline which reverses its hemodynamic effects (vasodilation). *Symptomatic treatment is recommended, possibly including a vasopressor drug. *Since dipyridamole is highly protein bound, dialysis is not likely to be of benefit.

question

ASPIRIN (acetylsalicylic acid): CLASS

answer

*COX Inhibiter -antiplatelet

question

ASPIRIN (acetylsalicylic acid): DOSE

answer

*PO: 81-324mg

question

ASPIRIN (acetylsalicylic acid): HL

answer

*20 mins **Inhibit platelet function for lifetime of platelet. Inhibition takes 7 10 days to resolve as new platelets are generated.

question

ASPIRIN (acetylsalicylic acid): INDICATIONS

answer

*Aspirin is used in the treatment of a number of conditions, including: *ACS *Fever *Pain *Rheumatic fever *Inflammatory diseases such as rheumatoid arthritis *Pericarditis *Kawasaki disease.

question

ASPIRIN (acetylsalicylic acid): MOA

answer

*Blocks production of TxA2 (thromboxane A2) by acetylating a serine residue near the active site of platelet cyclooxygenase-1 (COX-1), the enzyme that produces the cyclic endoperoxide precursor of TxA2.

question

ASPIRIN (acetylsalicylic acid): METABOLISM

answer

*Hepatic *Renal excretion

question

ASPIRIN (acetylsalicylic acid): CONSIDERATIONS

answer

*Asthma (occurs in 8% to 20% of all asthmatic adults)- Samter's *Samter's Triad is a medical condition consisting of asthma, aspirin and NSAID sensitivity, and nasal/ethmoidal polyposis *Allergic reactions to aspirin, although rare, can be life-threatening. Clinical manifestations may appear within minutes of ingestion and can include vasomotor rhinitis, laryngeal edema, bronchoconstriction, and cardiovascular collapse. *Reye's Syndrome *Glucose-6-phosphate dehydrogenase deficiency

question

ASPIRIN (acetylsalicylic acid): OVERDOSE

answer

*Excessive doses of aspirin may produce stimulation of the CNS manifesting as hyperventilation and seizures. *Hyperventilation is due to direct stimulation of the medullary ventilatory center. Initially, these changes result in respiratory alkalosis, which is promptly compensated for by renal excretion of bicarbonate, sodium, and potassium ions with return of the pH toward normal. Ultimately, however, salicylate overdose is likely to progress to metabolic and respiratory acidosis. *Metabolic acidosis reflects depression of renal function with accumulation of strong metabolic acids in addition to derangement of carbohydrate metabolism, leading to an increased formation of pyruvic, lactic, and acetoacetic acids.

question

ASPIRIN (acetylsalicylic acid): MONITORING

answer

*None *Bleeding Time will be prolonged

question

ASPIRIN (acetylsalicylic acid): REVERSAL

answer

*HASHTI *Platelet transfusion **Circulating drug or active metabolites can inhibit transfused platelets. *DDAVP

question

Antifibrinolytics (Lysine analogs): Name 2

answer

*AMINOCAPROIC ACID (Amicar) *TRANEXAMIC ACID (Lysteda, Cyklokapron)

question

Factor Xa inhibitors:

answer

* *RIVAROXABAN (Xarelto)- direct *APIXABAN (Eliquis)- direct *FONDAPARINUX (Arixtra)- indirect

question

*ADP receptor/P2Y12 inhibitors:

answer

* *TICAGRELOR (Brilinta) *PRASUGREL (Effient) *TICLOPIDINE (Ticlid) *CLOPIDOGREL (Plavix)

question

*Direct Thrombin (Factor IIa) Inhibitors:

answer

*DABIGATRAN (Pradaxa)- Univalent *ARGATROBAN (Acova)- Univalent *DESIRUDIN (Iprivask)- Bivalent *LEPIRUDIN (Refludan)- Bivalent *BIVALIRUDIN (Angiomax)- Bivalent

question

LMHW

answer

*LOVENOX (Enoxaparin) *TINZAPARIN (Innohep)

question

Glycoprotein IIb/IIIa Inhibitors:

answer

*ABCIXIMAB (ReoPro) *EPTIFIBATIDE (Integrilin) *TIROFIBAN (Aggrastat)

question

*HASHTI: Acronym

answer

*Hold further doses of anticoagulant *Antidote *Supportive treatment: volume resuscitation, inotropes as needed *Hemostatic measures: topical agents (aminocaproic acid, tranexamic acid) *Transfusion (red cells, platelets, FFP as indicated) *Investigate for bleeding source

question

Aspirin is known to cause hemolytic anemia in people who have the genetic disease...

answer

glucose-6-phosphate dehydrogenase deficiency, particularly in large doses and depending on the severity of the disease.

question

People with kidney disease, hyperuricemia, or gout should not take..

answer

aspirin because it inhibits the kidneys' ability to excrete uric acid, and thus may exacerbate these conditions.

question

Hemostasis is regulated by a number of factors, including (5):

answer

(1) Vascular extracellular matrix and alterations in endothelial reactivity (2) Platelets (3) Coagulation proteins (4) Inhibitors of coagulation (5) fibrinolysis

question

Heparin-induced thrombocytopenia (HIT) is an important antibody-mediated prothrombotic complication of...

answer

heparin therapy that occurs in 0.5% to 5% of patients treated with heparin for at least 5 days.

question

HIT is characterized by an otherwise unexplained drop in platelet count by...

answer

50% or more, often to less than 150,000/ µL and frequently accompanied by thrombosis, plus the presence of HIT antibodies. *When HIT is suspected, treatment should be initiated even before laboratory confirmation.

question

Cardiac transplant and neurosurgery patients (11% and 15%, respectively), as well as orthopedic patients, are at increased risk of...

answer

HIT. HIT increases the risk of thrombosis including deep VTE, pulmonary embolism, myocardial infarction, stroke, and limb artery occlusion requiring amputation..

question

The overall risk for thrombosis in patients with HIT is 38% to 76%. Other risk factors for HIT-related thrombosis include...

answer

*Female gender *Malignancy *Higher titer heparin-PF4 antibodies *More severe thrombocytopenia ***Other complications include skin lesions at heparin injection sites, DIC, warfarin-associated venous limb ischemia, and acute systemic reactions following heparin bolus.

question

Although counterintuitive, bleeding in pts with HIT is...

answer

rare even in the presence of severe thrombocytopenia.

question

HIT should be suspected whenever the...

answer

platelet count drops by 50%, or new thrombosis occurs in a patient 5 to 14 days after the start of heparin therapy. Other causes of thrombocytopenia (e.g., sepsis, mechanical destruction with an intraaortic balloon pump, or another drug-induced thrombocytopenia) should be excluded.

question

In "rapid onset" HIT, the platelet count begins to drop...

answer

minutes to hours after heparin exposure, usually due to heparin-PF4 antibodies from a previous heparin exposure, within the prior 3 months.

question

HIT should also be suspected if acute systemic reactions, such as hypotension, pulmonary hypertension, and/ or tachycardia, occur...

answer

2 to 30 minutes after intravenous heparin bolus. This can be observed intraoperatively and can present as anaphylaxis, usually accompanied by acute thrombocytopenia.

question

HIT can also occur days to weeks after...

answer

stopping heparin (" delayed onset HIT"), and should be considered if a recently hospitalized, heparin-treated patient presents with thrombosis.

question

The recommended treatment for strongly suspected or confirmed HIT, with or without complicating thrombosis, is...

answer

*Stopping heparin *Initiating a nonheparin alternative anticoagulant such as a direct thrombin inhibitor (e.g., lepirudin, argatroban, desirudin, or bivalirudin) *Other heparin sources such as catheter flushes and heparin-coated devices should be eliminated *A sign on the patient's bed and/or chart stating "No heparin: HIT" helps prevent inadvertent heparin exposure

question

Different direct thrombin inhibitors are approved in the United States for use in HIT patients...

answer

*Without initial thrombosis (argatroban) *In HIT patients with thrombosis (lepirudin, argatroban) *In patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI) (argatroban, bivalirudin) *Desirudin is another agent available for thromboembolism prophylaxis.

question

Important indicators of high-risk for bleeding and transfusion requirements include (6):

answer

(1) Advanced age (2) Low preoperative RBC volume (preoperative anemia or small body size) (3) Preoperative antiplatelet or antithrombotic treatment (4) Reoperation or complex procedures (5) Emergency operations (6) Noncardiac patient comorbidities

question

PT (Prothrombin Time): Normal Range

answer

*11-13 seconds

question

PT (Prothrombin Time): Overview

answer

*Assesses the extrinsic and common coagulation pathways *Primarily used to monitor long-term use of anticoagulant therapy through the INR, evaluate liver function, evaluate coagulation disorders

question

PT (Prothrombin Time): Test

answer

*The time it takes for clot to form after recalcification and thromboplastin is added to citrated plasma

question

aPTT (Activated Partial Thromboplastin Time): Normal Range

answer

*25-38 seconds

question

aPTT (Activated Partial Thromboplastin Time): Overview

answer

*Assesses the intrinsic and common coagulation pathways *The best single screening test for coagulation disorders; when properly performed, activated partial thromboplastin time (aPTT) is abnormal in 90% of patients with coagulation disorders *Used to monitor heparin therapy, screen for hemophilia A and B, detect clotting inhibitors

question

aPTT (Activated Partial Thromboplastin Time): Test

answer

*The time it takes for clot to form after recalcification and addition of phospholipid and an activator of the intrinsic coagulation system to citrated plasma *Tests Thrombin and Factors IXa and Xa

question

Fibrinogen: Normal Range

answer

*2-4 g/L

question

Fibrinogen: Overview

answer

*Fibrinogen, or factor I, is a glycoprotein synthesized in the liver. It is cleaved by thrombin to produce fibrin monomer, the basis of clot formation *Decreased levels of fibrinogen can indicate Disseminated Intravascular Coagulation, liver disease, or dilutional coagulopathy

question

Fibrinogen: Test

answer

*Fibrinogen can be assessed both quantitatively, using immunologic methods, and qualitatively, with clotting assays similar to one-stage assay methods used for other clotting factors.

question

Platelet Aggregation Studies: Normal Range

answer

*>65% aggregation in response to the platelet activators adenosine diphosphate, epinephrine, collagen, ristocetin, and arachidonic acid

question

Platelet Aggregation Studies: Overview

answer

*Platelet aggregation studies are used to classify qualitative platelet abnormalities *Abnormalities can be in adhesion, release, or aggregation

question

Platelet Aggregation Studies: Test

answer

*Platelet aggregation is stimulated by introducing activators in vitro *Aggregation is measured using a turbidimeter and expressed graphically by wave patterns

question

One unit of RBCs collected in anticoagulant-preservative solution is about...

answer

300mL with a hematocrit of 50% to 70%. Dextrose is added to maintain glucose metabolism, and adenine and phosphate allow synthesis of adenosine triphosphate. Additive solutions (adenine, glucose, mannitol, sodium chloride) are also used to extend shelf life up to 42 days.

question

Depending on the storage solution, RBCs have a shelf life of...

answer

28 to 42 days at 1°C to 6°C.

question

During storage of PRBCs, intracellular 2,3-DPG is reduced to less than...

answer

10% of normal at 5 weeks such that release of oxygen from hemoglobin is significantly impaired.

question

According to the American Society of Anesthesiologists (ASA) guidelines for blood component therapy, transfusion of RBCs is almost always indicated for hemoglobin less than...

answer

6 g/dL, whereas it is rarely indicated for hemoglobin greater than 10 g/dL. For hemoglobin between 6 g/dL and 10 g/dL, transfusion should be considered if complications due to inadequate oxygenation are anticipated.

question

Acute hemolytic transfusion reactions are usually caused by...

answer

ABO incompatibility. This potentially fatal complication occurs in about 1 in 30,000 transfusions. As little as 20 to 30 mL of incompatible RBCs can cause agitation, nausea and vomiting, dyspnea, fever, flushing, hypotension, tachycardia, and hemoglobinuria.

question

Two major complications of intravascular hemolysis include...

answer

renal failure from acute tubular necrosis and disseminated intravascular coagulation (DIC).

question

At the injury site, platelets adhere to subendothelial collagen via interactions between...

answer

von Willebrand factor (vWF) and the platelet-surface glycoprotein (GP) receptor GPIb/IX. Platelet integrin receptor α2β1 reinforces binding to collagen.

question

Trace amounts of thrombin are generated during the initiation phase of coagulation by...

answer

factor Xa (FXa) via interactions between circulating FVIIa and tissue factor (TF) expressed on subendothelial pericytes and fibroblasts

question

Platelets activated by collagen and thrombin release...

answer

adenosine-5′-diphosphate (ADP) and thromboxane A2 (TXA2), which activate platelets in the vicinity

question

Activated platelets express...

answer

GPIIb/IIIa and capture fibrinogen (F).

question

Each unit of platelets, referred to as "random-donor platelets," contains...

answer

5.5 × 10^10 platelets in 50 to 70 mL of plasma. Four to eight random-donor units are pooled to increase platelet count by 15 to 30 × 10^9/ L in the adult.

question

In order to decrease multiple donor exposures, single donor platelet apheresis is increasingly used. During the apheresis procedure, donor blood is placed in the extracorporeal circuit and centrifuged to separate platelets. One platelet apheresis unit contains...

answer

30 to 50 × 10^10 platelets in 250 to 300 mL of plasma. Platelet concentrates are agitated and stored at room temperature (20 ° C to 24 ° C) for up to 5 days

question

A platelet count of 50 × 10^9/L is reached after loss of...

answer

twice the blood volume in an average sized adult.

question

Plasma transfusion is used to treat bleeding conditions when prothrombin time (PT) is greater than...

answer

1.5 times the midpoint of the normal range, or activated partial thromboplastin time (aPTT) is greater than 1.5 times the upper limit of normal. The usual dose is 5 to 8 mL/kg, but up to 10 to 30 mL/kg might be necessary to keep coagulation factors above 50% of normal.

question

Half-life clotting factor VII:

answer

*3-6 hrs *Shortest HL of all clotting factors

question

Cryoprecipitate is prepared from thawing FFP at 1° C to 6° C. The cold-insoluble precipitate contains...

answer

FVIII, vWF, FXIII, fibrinogen, and fibronectin. The precipitate is resuspended in a small amount of plasma (~15 mL) and is stored at −18° C up to 12 months.

question

Plasma-derived or recombinant factor concentrate has largely replaced the use of...

answer

cryoprecipitate in congenital deficiency of FVIII, vWF, FXIII, or fibrinogen.

question

Cryoprecipitate is used to manage bleeding due to...

answer

acquired hypofibrinogenemia (<100-150 mg/dL). Each unit contains 150 to 250 mg of fibrinogen; 5 to 10 units are thawed and pooled before infusion.

question

Each unit of cryoprecipitate increases plasma fibrinogen by approximately...

answer

100 mg/dL per 5kg body weight.

question

The recommended initial dose of rFVIIa for hemophiliacs with inhibitors is...

answer

90 to 120 µg/kg, but higher doses of 200 to 400 µg/kg have been used without major thrombosis.

question

In nonhemophiliacs, the initial dose of rFVIIa is...

answer

20-70 µg/kg

question

PCC (Prothrombin Complex Concentrate) is a sterile, lyophilized concentrate of factors...

answer

II, VII, IX, and X and protein C and S. (Vit K dependent factors)

question

Advantages of PCC include...

answer

rapid availability, small volume of infusion, and avoidance of complications such as ABO incompatibility and TRALI associated with FFP.

question

PCC Dose: Life-threatening bleeding associated with anticoagulation including intracranial hemorrhage and retroperitoneal bleeding

answer

30-50 IU/kg (maximum, 5000 IU)

question

PCC Dose: Soft tissue bleeding, epistaxis, and hematuria

answer

20-25 IU/kg

question

In acute bleeding, the major advantage of PCC is that procoagulant FII, FVII, FIX, and FX can be rapidly (<30 min) increased by...

answer

40% to 80% without dilution of RBCs and platelets.

question

The lysine analogues ε-aminocaproic acid (EACA) and tranexamic acid (TXA) prevent plasminogen from binding to fibrin by occupying the...

answer

plasminogen lysine-binding site. By preventing colocalization of tissue plasminogen activator and plasminogen on fibrin, plasmin activation, and subsequent fibrin degradation are inhibited.

question

Fibrinogen can be replaced more efficiently by...

answer

cryoprecipitate (or plasma-derived fibrinogen) than by FFP.

question

The initial response of the hemostatic system to tissue or endothelial injury is to...

answer

produce a platelet plug (primary hemostasis).

question

Platelets have multiple surface receptors, which when stimulated produce a shape change involving the energy-dependent actin-myosin system. Principal among these receptors are the glycoprotein Ib (GpIb) receptor, which binds to...

answer

von Willebrand factor (vWF). This factor is expressed on the abluminal side of endothelial cells and is thus exposed if there is endothelial injury. The GpIb receptor is expressed at all times. There are also receptors for adenosine diphosphate (ADP), thrombin, and thromboxane A2. These receptors principally allow a feedback amplification pathway to enhance the generation of the primary hemostatic plug.

question

With the shape change, the surface of the platelet also changes with expression of a second binding site, the...

answer

glycoprotein IIb/IIIa (GpIIb/ IIIa) receptor. GpIIb/ IIIa receptors bind fibrinogen to provide bridging between adjacent platelets. In addition, the surface of the platelet becomes electronegatively charged and expresses binding sites for factor V, an essential cofactor in the generation of thrombin.

question

The coagulation phase of hemostasis involves generation by thrombin of...

answer

fibrin, which binds and stabilizes the weak platelet hemostatic plug.

question

Historically the blood coagulation system is divided into two initiating pathways:

answer

*The tissue factor (extrinsic) pathway *The contact factor (intrinsic) pathway *These pathways meet in a final common pathway whereby factor Xa converts prothrombin to thrombin, which then cleaves fibrinogen to fibrin.

question

The prothrombin time (PT) is a plasma and test tube test of the integrity of the...

answer

extrinsic pathway

question

The activated clotting time (ACT) or activated partial thromboplastin time (aPTT) are tests of the...

answer

intrinsic system for blood and plasma, respectively.

question

UFH is a naturally occurring glycosaminoglycan. It is a ...

answer

negatively charged sulfated polysaccharide formed from alternating residues of D-glucosamine and L-iduronic acid.

question

Heparin is mostly located in lung, intestine, and liver in mammals. Standard preparations are derived from...

answer

either porcine intestine or bovine lung and prepared as calcium or sodium salts.

question

Heparin alone has no anticoagulant activity but requires a plasma cofactor, originally designated...

answer

antithrombin III, and now simply called antithrombin or AT.

question

The binding of AT to thrombin is suicidal to the thrombin-antithrombin (T-AT) complex. Inhibition of thrombin activation prevents...

answer

feedback by thrombin on factors V and VIII, which normally amplifies the clotting cascade.

question

Heparin also impairs platelet aggregation mediated by vWF and collagen, and inhibits platelet function by...

answer

direct binding to platelets. The higher molecular weight heparins interfere most with platelet function.

question

Inhibition of factors IXa, Xa, and XIIa requires only that heparin bind...

answer

AT to form the heparin-AT complex. This explains why LMWHs and the synthetic pentasaccharide fondaparinux act as inhibitors of factor Xa but not necessarily of thrombin.

question

Heparin also stimulates release of tissue factor plasma inhibitor (TFPI), which...

answer

binds and neutralizes the tissue factor- VIIa complex, reducing prothrombinase production via the extrinsic pathway.

question

Elimination of heparin is nonlinear and occurs by two separate processes:

answer

*The rapid saturable phase of heparin clearance is thought to be due to cellular degradation. *The slower phase of heparin elimination is due to renal excretion. *There are no consistent reports of the effects of renal or hepatic dysfunction on the pharmacokinetics of heparin.

question

As the dose of heparin is increased, elimination half-life increases and...

answer

the anticoagulant response is exaggerated. At a dose of 25 U/kg the half-life is about 30 minutes, increasing to about 150 minutes with a bolus dose of 400 U/kg.

question

There is great variability in plasma concentration of heparin in relation to dose. After intravenous injection, more than 50% of heparin circulates bound to plasma proteins, including...

answer

*Platelet factor 4 *Histidine-rich glycoprotein *Vitronectin *Fibronectin *vWF. *The first three of these neutralize heparin activity and its bioavailability. *Increased levels of these proteins might account for heparin resistance sometimes seen in malignancy and inflammatory disorders. *Plasma levels also decline rapidly due to redistribution and uptake by endothelial cells and macrophages.

question

For thromboembolic prophylaxis, UFH is administered either as...

answer

"low dose" (5000 U SQ q8 or q12 hrs) or "adjusted dose" (3500 U q8 or q12 hrs adjusted to maintain aPTT about 3 to 5 seconds above control).

question

Type I HIT involves mild thrombocytopenia with platelet count rarely less than...

answer

100 × 10^9/ L that occurs during the first few days of treatment and usually recovers rapidly even if heparin is continued. *Patients are normally asymptomatic and no specific treatment is required. *The underlying mechanism probably involves the action of heparin as a mild platelet aggregator.

question

Type II HIT is characterized by a delayed onset of severe, progressive thrombocytopenia with platelet counts less than...

answer

100 × 10^9/ L and often < 50 × 10^9/ L. *Platelet count does not recover unless heparin therapy is stopped and recurs promptly if heparin is restarted. *Recovery of platelet count usually occurs within a week but can occasionally be prolonged. *An immune mechanism has been suggested in which heparin binds to platelet factor 4 to stimulate production of an IgG antibody.

question

The antithrombotic activity of fondaparinux is the result of...

answer

AT-mediated selective inhibition of factor Xa.

question

By selectively binding to AT, fondaparinux potentiates (about 300 times) the innate neutralization of...

answer

factor Xa by AT. Fondaparinux does not interact with AT to inactivate thrombin and has no known effect on platelet function.

question

In healthy individuals with normal kidney function up to 75 years of age, about 80% of a single subcutaneous dose is...

answer

eliminated in urine as unchanged drug in 72 hours with an elimination half-life of 17 to 21 hours.

question

Fondaparinux elimination is prolonged in patients with...

answer

renal impairment in that the major route of elimination is urinary excretion of unchanged drug.

question

Fondaparinux elimination is prolonged in patients older than...

answer

75 years with total clearance 25% lower compared to patients younger than 65 years. Total clearance is also decreased by 30% in patients weighing less than 50 kg.

question

Warfarin inhibits epoxide reductase (specifically the VKORC1 subunit), thereby diminishing available...

answer

vitamin K and vitamin K hydroquinone, which inhibits carboxylation activity of glutamyl carboxylase. Coagulation factors not carboxylated are incapable of binding to surface phospholipids and are thus biologically inactive.

question

Loading doses of warfarin of more than 5 mg produce a rapid decline in...

answer

carboxyglutamyl factor VII (half-life 5-7 hours), resulting in an initial prolongation of the INR, but full antithrombotic effect does not occur until a significant reduction in prothrombin activity occurs (half-life about 60 hours) days later.

question

Initiation of warfarin therapy can promote clot formation temporarily because...

answer

anticoagulant protein C and protein S are also dependent on vitamin K activity. Warfarin causes reduced protein C levels. In addition, reduced levels of protein S lead to a reduction in activity of protein C (for which it is the cofactor) and therefore reduced inactivation of factor Va and factor VIIIa. The hemostasis system then becomes temporarily biased toward thrombus formation. Thus it is beneficial to coadminister heparin with initiation of warfarin therapy for 4 to 5 days until the full effect of warfarin has been achieved.

question

A rare but serious complication is warfarin necrosis, which occurs more frequently shortly after commencing treatment in patients with a deficiency of...

answer

protein C. Protein C requires vitamin K- dependent carboxylation for its activity. Because warfarin initially decreases protein C levels faster than the coagulation factors, it can paradoxically increase coagulation when treatment is first begun, leading to thrombosis typically manifesting as skin necrosis and peripheral gangrene.

question

Drugs that impair platelet function, especially acetylsalicylic acid (aspirin) and clopidogrel, increase the risk of major hemorrhage in patients taking...

answer

warfarin without elevating the INR.

question

Selective serotonin reuptake inhibitors can inhibit platelet aggregation by...

answer

depleting platelet serotonin. They also inhibit CYP2C9 and coadministration with warfarin increases the risk of major bleeding.

question

Warfarin is contraindicated in pregnancy because it...

answer

crosses the placenta and can cause bleeding in the fetus. Coumarin (e.g., warfarin) is also teratogenic.

question

Argatroban is also a synthetic compound derived from arginine but is attached only to the...

answer

active enzymatic site of thrombin and is termed a monovalent inhibitor.

question

All DTI compounds inhibit both...

answer

free and bound thrombin, and none are affected by platelet factor 4.

question

The excretion of the recombinant hirudins is affected by renal function, whereas argatroban is...

answer

entirely metabolized by the liver.

question

While impaired liver function is not a contraindication to the use of argatroban, the dose should be...

answer

lowered and full reversal of anticoagulant effects might require more than 4 hours.

question

Bivalirudin has renal excretion but also a unique...

answer

metabolic elimination process. Thrombin can cleave the Pro-Arg bond of the active site binding moiety to metabolize bivalirudin. This improves the safety of use of bivalirudin in patients with impaired renal function such as the elderly.

question

The anticoagulant effect of thrombin inhibitors is monitored by the...

answer

aPTT or ACT; coagulation time increases in a dose-dependent dose-dependent manner. Argatroban also prolongs the PT in a dose-dependent manner. This has implications for assessing anticoagulation when transferring patients to long-term anticoagulation with vitamin K antagonists. The manufacturers recommend no loading dose of warfarin, but starting with a dose near the anticipated maintenance dose.

question

Argatroban also prolongs the PT in a dose-dependent manner. This has implications for assessing anticoagulation when transferring patients to long-term anticoagulation with...

answer

vitamin K antagonists. The manufacturers recommend no loading dose of warfarin, but starting with a dose near the anticipated maintenance dose.

question

The only oral direct thrombin inhibitor currently available is...

answer

dabigatran.

question

Dabigatran is a competitive direct thrombin inhibitor. It is orally administered as the prodrug...

answer

dabigatran etexilate. The active drug inhibits both free and clot-bound thrombin and thrombin-induced platelet activation.

question

Dabigatran is not metabolized by...

answer

CYP isoenzymes. Concomitant use with P-glycoprotein inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided.

question

Due to shortcomings of vitamin K antagonists as the only form of oral anticoagulant and the critical role of factor...

answer

Xa in the coagulation cascade, factor Xa has become an important target for anticoagulant development.

question

Direct Factor Xa inhibitors bind to and inhibit factor Xa directly without a requirement for...

answer

AT. The major advantage of direct factor Xa inhibitors is their small size and resultant ability to inactivate circulating, as well as bound, forms of factor Xa.

question

Inhibition of one factor Xa moiety can lead to a...

answer

50-fold reduction in thrombin production.

question

Rivaroxaban is an oral, direct, reversible, competitive, rapid, and dose-dependent inhibitor of...

answer

factor Xa. Rivaroxaban inhibits factor Xa with more than 10,000-fold greater selectivity than other biologically relevant serine proteases, such as thrombin, trypsin, plasmin, factor VIIa, factor IXa, urokinase, and activated protein C.

question

Apixaban is a highly selective and potent inhibitor of...

answer

both free and prothrombinase bound factor Xa.

question

Direct Factor Xa inhibitors induce a prolongation of ...

answer

coagulation time by 2 to 3 hours following ingestion, with increases in PT and aPTT by approximately 20%.

question

Platelets can be activated in a number of ways. The major targets for pharmacologic intervention have been inhibition of...

answer

cyclooxygenase with aspirin and phosphodiesterase with dipyridamole. More recent pharmacologic interventions have been to inhibit receptors at the platelet surface. In particular there is considerable interest in inhibition of purinergic receptors and those binding fibrinogen (the GpIIb/ IIIa receptor).

question

Acetylsalicylic acid (ASA) is a derivative of salicylic acid that works by...

answer

inhibiting the enzyme prostaglandin H-synthase also known as cyclooxygenase (COX).

question

Prostaglandin H-synthase 1 and 2 (also known as COX 1 and 2) catalyze the conversion of arachidonic acid to...

answer

prostaglandin H2 (PGH2). Human platelets and vascular endothelial cells convert PGH2 primarily to thromboxane A2 (TXA2) and prostaglandin I2 (PGI2). TXA2 induces platelet aggregation and vasoconstriction, whereas PGI2 inhibits platelet aggregation and induces vasodilatation.

question

Human platelets and vascular endothelial cells convert PGH2 primarily to...

answer

thromboxane A2 (TXA2) and prostaglandin I2 (PGI2). TXA2 induces platelet aggregation and vasoconstriction, whereas PGI2 inhibits platelet aggregation and induces vasodilatation.

question

TXA2 induces platelet aggregation and vasoconstriction, whereas PGI2...

answer

inhibits platelet aggregation and induces vasodilatation.

question

Whereas TXA2 is largely a COX-1- derived product (mostly from platelets) and thus highly sensitive to aspirin inhibition, vascular PGI2 can...

answer

derive both from COX-1 and, to a greater extent even under physiologic conditions, from COX-2. COX-2- mediated PGI2 production occurs mainly in response to shear stress and is insensitive to aspirin inhibition at conventional antiplatelet doses.

question

COX-2- mediated PGI2 production occurs mainly in response to shear stress and is insensitive to...

answer

aspirin inhibition at conventional antiplatelet doses.

question

The molecular mechanism of permanent inactivation of COX activity by aspirin is as a consequence of...

answer

acetylation of a serine residue that results in a lack of access of the substrate to the catalytic site.

question

Inhibition of COX-1- dependent platelet function can be achieved with low doses of...

answer

ASA given once daily. Inhibition of COX-2- dependent inflammatory processes requires larger doses of aspirin and a much shorter dosing interval. Thus there is an approximately 100-fold variation in daily doses of aspirin when used as an antiinflammatory rather than as an antiplatelet agent.

question

ASA is rapidly absorbed in the stomach and upper intestine. Peak plasma levels occur 30 to 40 minutes after ingestion, and inhibition of platelet function is evident by...

answer

1 hour. In contrast, it can take 3 to 4 hours to reach peak plasma levels after administration of enteric-coated aspirin.

question

The plasma concentration of ASA decays with a half-life of...

answer

15 to 20 minutes. Despite rapid clearance from the circulation, its platelet-inhibitory effect lasts for the life span of the platelet because it irreversibly inactivates platelet COX-1. Aspirin also acetylates the enzyme in megakaryocytes before new platelets are released into the circulation.

question

The mean life span of human platelets is 5 to 10 days, so 10% to 20% of circulating platelets are replaced daily. Bleeding times, implying normal primary hemostasis, require about...

answer

20% to 30% of normal platelet numbers/ function. This suggests that cessation of ASA ingestion for 48 hours will result in a return to normal hemostatic activity.

question

Dipyridamole is a pyrimidopyrimidine derivative with vasodilator and antiplatelet properties. The mechanism of action of dipyridamole as an antiplatelet agent involves...

answer

increased intracellular cyclic adenosine monophosphate (cAMP), which inhibits the platelet shape change. Increased cAMP concentration is due to one or both of two mechanisms: inhibition of phosphodiesterase and blockade of uptake of adenosine (which acts at adenosine A2 receptors to stimulate platelet adenylyl cyclase and thus increase cAMP).

question

Increased cAMP concentration with dipyridamole is due to one or both of two mechanisms:

answer

*Inhibition of phosphodiesterase *Blockade of uptake of adenosine (which acts at adenosine A2 receptors to stimulate platelet adenylyl cyclase and thus increase cAMP).

question

Following an oral dose of dipyridamole tablets, the average time to peak concentration is about...

answer

75 minutes. The decline in plasma concentration fits a two-compartment model with an α half-life (initial decline following peak concentration) of 40 minutes and a β half-life of 10 hours. This is consistent with the twice-daily regimen used in recent clinical studies.

question

Dipyridamole is highly bound to plasma proteins, and is metabolized in the...

answer

liver where it is conjugated to a glucuronide and excreted in the bile. It is subject to enterohepatic recirculation.

question

There are three known subtypes of ADP receptors on platelets:

answer

*P2X1 *P2Y1 *P2Y12

question

The P2Y12 receptor is abundantly expressed on...

answer

human platelets and on smooth muscle. ADP is released from damaged vessels, red blood cells, and platelets stimulated by other agonists.

question

ADP binds to the P2Y1 receptor to initiate platelet aggregation and to the P2Y12 receptor, which...

answer

amplifies platelet aggregation.

question

Sustained ADP-induced platelet aggregation requires coactivation of...

answer

P2Y1 and P2Y12 receptors.

question

The P2Y12 receptor acts by inhibiting...

answer

adenylyl cyclase via a Gi protein and potentiates dense granule secretion, procoagulant activity, and platelet aggregation. Without continued P2Y12 activation, aggregated platelets disaggregate.

question

The P2Y1 receptor initiates...

answer

platelet aggregation and the P2Y12 receptor amplifies and completes the aggregation process. Continued stimulation of P2Y12 receptors is needed to prevent platelet disaggregation.

question

Thienopyridines selectively inhibit...

answer

ADP-induced platelet aggregation with no direct effects on arachidonic acid metabolism.

question

The thienopyridines do not act...

answer

directly, but are administered as prodrugs requiring hepatic transformation.

question

Clopidogrel is metabolized into...

answer

2-oxo-clopidogrel through a CYP-dependent pathway.

question

Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed by...

answer

esterase in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP 3A4 and CYP 2B6, and to a lesser extent by CYP 2C9 and CYP 2C19. The active metabolite of prasugrel is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to plasma proteins.

question

The active metabolite of prasugrel is metabolized to two inactive compounds by...

answer

S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to plasma proteins.

question

Clopidogrel is also metabolized by...

answer

esterases to produce an inactive carboxylic acid derivative designated as SR 26334, which is thought to represent more than 80% of circulating metabolites.

question

The active metabolites of both clopidogrel and prasugrel couple through a covalent disulfide bond to...

answer

P2Y12 receptors rendering the receptor unresponsive to ADP. Because the bond is covalent it is essentially irreversible; thus platelets exposed to the active thiol are affected for the remainder of their lifespan (about 7-10 days).

question

Thienopyridines produce dose-dependent inhibition of platelet aggregation occuring about...

answer

2 hours following ingestion.

question

The major interactions with clopidogrel involve drugs that modify the CYP 2C19 and CYP 3A4 isoenzymes. An example of the former is the...

answer

proton pump inhibitor omeprazole, which reduces platelet ADP response.

question

The CYP 3A4 and 3A5 isozymes metabolize clopidogrel more rapidly than other CYP enzymes and are most abundant in the liver. Atorvastatin and other CYP 3A4 inhibitors...

answer

reduce platelet inhibition and a CYP 3A4 activator enhances this inhibition when coadministered with clopidogrel.

question

Prasugrel is contraindicated in patients with a history of...

answer

prior TIA or stroke.

question

Prasugrel is not recommended for patients...

answer

75 years of age or older due to an increased incidence of fatal and intracranial bleeding, except in higher risk situations such as diabetes mellitus or history of previous MI.

question

Ticagrelor is the first of a new chemical class of antiplatelet agents, the cyclopentyltriazolopyrimidines. Similar to the thienopyridines, ticagrelor is an oral...

answer

P2Y12 receptor antagonist that exerts antiplatelet effects by blocking ADP.

question

In contrast to the other antiplatelet drugs, ticagrelor has a binding site different from ADP, making it an...

answer

allosteric antagonist, and the block is reversible.

question

Unlike the thienopyridines, ticagrelor is not a...

answer

prodrug and therefore does not require metabolic activation in order to inhibit platelets. These properties give ticagrelor several theoretical advantages over clopidogrel.

question

Since ticagrelor does not require metabolic activation, it avoids the variability seen with the...

answer

CYP system and therefore produces a more consistent antiplatelet effect.

question

Ticagrelor is metabolized to adenosine and administration is associated with related effects. Particular patients receiving ticagrelor had significantly more episodes of...

answer

dyspnea (10%-20%) and ventricular pauses lasting more than 3 seconds (6%).

question

Ticagrelor inhibits P-glycoprotein, leading to increased plasma levels of...

answer

digoxin, cyclosporin, and other substrates.

question

Consistent with its reversible mode of action, ticagrelor acts more quickly and is effective for a shorter time than...

answer

clopidogrel. This means it has to be taken twice instead of once a day, which is a disadvantage with respect to compliance, but its effects are more quickly reversible, which can be useful before surgery or if side effects occur.

question

GpIIb/IIIa is a member of a family of adhesive receptors (integrins) composed of α and β transmembrane proteins. GpIIb/IIIa itself is composed...

answer

of αIIb and β3 units and is specific for platelets.

question

Two types of GpIIb/IIIa receptor antagonists are available:

answer

*Noncompetitive (monoclonal antibodies) *Competitive (a peptide and a peptidomimetic)

question

Abciximab is taken up by the reticular endothelial system where it is...

answer

degraded by proteolysis.

question

Following bolus administration of abciximab, free plasma concentrations decrease very rapidly, with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to platelet GpIIb/ IIIa receptors and...

answer

uptake by the reticuloendothelial system. High receptor affinity results in a long biologic half-life of 12 to 24 hours. Platelet function generally recovers over the course of 48 hours, although abciximab remains in the circulation for 15 days or more in a platelet-bound state.

question

Abciximab can redistribute from the originally bound platelet to...

answer

newly produced platelets, thus prolonging the antiplatelet effect.

question

The most commonly used method for assessing the pharmacodynamic effects of the various GpIIb/IIIa antagonists is...

answer

platelet aggregometry. Administration of these agents alone does not prolong PT or aPTT.

question

The benefit of GpIIb/IIIa inhibitors is mainly limited to high-risk patients with...

answer

unstable angina or NSTEMI. The most notable conditions where benefit is shown are in troponin-positive patients, whether or not they undergo revascularization and those with diabetes mellitus.

question

For diabetic patients, abciximab is the only GpIIb/IIIa inhibitor observed to provide a significant survival advantage in patients undergoing...

answer

PCI with angioplasty or stent placement and thus is singled out as the agent of choice for use in diabetic patients undergoing stent implantation.

question

Abciximab also has the greatest weight of data supporting safety of use in patients with severe...

answer

renal insufficiency, likely due to its non-renal mode of metabolism and elimination.

question

Current ACC/ AHA guidelines recommend a platelet GpIIb/IIIa antagonist in patients with moderate- to high-risk ACS in whom...

answer

catheterization and PCI are planned (class I, level A).

question

Eptifibatide or tirofiban should be administered in patients with high-risk ACS in whom...

answer

an invasive management strategy is not planned (class IIa, level A).

question

All patients receiving parenteral GpIIb/IIIa antagonists should be monitored within 24 hours of initiation of therapy for development of...

answer

thrombocytopenia and the drug discontinued if this occurs.

question

Treatment with GpIIb/IIIa receptor antagonists is contraindicated in patients with:

answer

*Severe hypertension (systolic blood pressure >200mmHg or diastolic blood pressure >110mmHg) not adequately controlled on antihypertensive therapy *Major surgery or history of major trauma within the preceding 4 to 6 weeks *History of stroke within 30 days or any history of hemorrhagic stroke (for tirofiban and eptifibatide), increased to 2 years before the use of abciximab *History of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, or aneurysm.

question

For abciximab, additional contraindications are:

answer

*Oral anticoagulants within 7 days unless PT is less than or equal to 1.2 times control *Use of intravenous dextran before percutaneous coronary intervention, or intent to use it during intervention *Presumed or documented history of vasculitis

question

Tirofiban is also contraindicated with a history, symptoms, or findings suggestive of:

answer

*Aortic dissection or pericarditis.

question

As both tirofiban and eptifibatide are principally cleared by the kidney, both should have the dose of the maintenance infusion reduced to half with an estimated creatinine clearance less than:

answer

*50 mL/min *Both are also contraindicated in patients receiving long-term renal dialysis, as is abciximab, but in this case because of a lack of safety data in this population.

question

Administration of abciximab can result in the formation of human antichimeric antibodies (HACA) that could potentially cause...

answer

allergic or hypersensitivity reactions (including anaphylaxis), thrombocytopenia, or diminished benefit upon readministration. *Readministration might be associated with an increased incidence and severity of thrombocytopenia.

question

Extensive research involving garlic shows the herbal may...

answer

reduce blood pressure and thrombus formation, thereby modifying risk of atherosclerosis. Also, garlic may lower serum lipid and cholesterol levels.

question

Garlic seems to irreversibly inhibit...

answer

platelet aggregation in dose-dependant fashion and may potentiate the effect of other platelet inhibitors, such as prostacyclin, indomethacin, and dipyridamole.

question

It has been suggested that given the potential for irreversible inhibition of platelet function, cessation of garlic use...

answer

7 days before surgery is warranted.

question

Ginkgo may inhibit...

answer

platelet-activating factor and alter platelet function. Study of pharmacokinetic data and bleeding risk suggests that patients should stop taking ginkgo at least 36 hours before surgery

question

Ginsenosides inhibit platelet aggregation in vitro and prolong coagulation time of thrombin and activated partial thromboplastin. Because platelet inhibition seems irreversible, it is suggested that...

answer

patients discontinue use of ginseng at least 7 days before surgery.

question

ASRA guidelines state that there does not seem to be a clinically significant increase in surgical bleeding or spinal hematoma overall in patients taking...

answer

herbal medications. Because the use of herbal medications alone does not create a level of risk that interferes with neuraxial blockade, ASRA recommends against mandatory discontinuation of herbal medications or avoidance of regional anesthetic techniques in these patients.

question

Concurrent use of medications, such as oral anticoagulants or heparin, may increase the risk of bleeding in patients taking...

answer

herbal medications.

question

Other herbal medications may increase bleeding, especially in patients already taking drugs and/or other herbs or supplements that affect normal clotting function. These include...

answer

feverfew, ginger, kava kava, clove, and white willow bark. The ASA suggests that patients should be encouraged to discontinue these products 2 weeks before surgery, which is the estimated time for the compounds to be fully metabolized

question

Vitamins E and A have been implicated in increasing risk of bleeding in combination with...

answer

prescribed anticoagulants.

question

Vitamin E supplementation may increase the effects of...

answer

anticoagulants and antiplatelet drugs, thereby increasing the risk of bleeding perioperatively.

question

Vitamin A is found in two major forms of foods, including retinol and carotenes. Of concern is the risk of increased bleeding in patients taking vitamin A and...

answer

warfarin. Vitamin A may increase the anticoagulant effects of warfarin.

question

The lysine analogs (TXA and EACA) prevent excessive plasmin formation by occupying plasminogen's...

answer

lysine-binding site (LBS) for fibrin, thereby precluding plasminogen localization to fibrin for activation by PA. Lysine analogs also bind to tissue plasminogen activator (tPA) kringles, interfering with plasminogen activation.

question

The major action of the lysine analogs (TXA and EACA) in vivo is antifibrinolytic, primarily by blocking the association of...

answer

plasminogen and tPA on the fibrin surface. Although plasmin may still be generated, fibrinolysis is prevented.

question

EACA and TXA are structurally similar to lysine and inhibit the interaction between...

answer

fibrinogen lysine residues and plasminogen LBSs, especially those located on kringle 1.

question

TXA and EACA are rapidly absorbed from the gastrointestinal (GI) tract, allowing oral or intravenous administration, with peak plasma levels at 1 to 2 hours after oral dosing. Elimination is primarily via...

answer

renal excretion and metabolism, approximately 65% excreted in the urine unchanged and 10% as an inactive metabolite, adipic acid. Approximately 85% of an intravenous dose is cleared within 3 hours, but because EACA penetrates the entire extravascular space, urinary excretion may be detected for 12 to 36 hours.

question

EACA and TXA cross the...

answer

blood- brain barrier, enter joint fluid and synovial membranes, are excreted at low levels into breast milk, and pass through the placenta.

question

Compared with EACA, TXA is much more...

answer

potent, inhibiting fibrinolysis at much lower plasma concentrations, with inhibitory effect lasting for 7 to 8 hours.

question

EACA and TXA are associated with...

answer

nasal stuffiness, conjunctival injection, skin rash, and dose-related GI discomfort, including nausea, vomiting, and diarrhea.

question

Lysine analogs have been used successfully to treat...

answer

postpartum hemorrhage and hemorrhage associated with abruptio placentae.

question

Antifibrinolytic therapy has been used in hemophilia:

answer

*As prophylaxis to prevent hemarthrosis *For treatment of hematuria *For treatment of gum bleeding and epistaxis *As adjunctive, prohemostatic treatment during and following surgery *In patients with factor VIII inhibitors

question

Data seems to indicate that on balance, antifibrinolytic therapy is a reasonable approach in preventing rebleeding following traumatic...

answer

hyphema, at least in those who do have added risk factors for hemorrhage.

question

Meta-analysis of trials of prophylactic TXA in orthopedic surgery evaluated 12 trials and concluded that treatment with TXA significantly reduces...

answer

total perioperative blood loss and the proportion of patients requiring transfusion

question

The most important anticoagulant activities of Heparin are the inhibition of...

answer

the coagulation factors thrombin (factor IIa) and factor Xa by heparin bound to AT.

question

Heparin has a polycomponent anticoagulant mechanism inhibiting numerous...

answer

coagulation factors, inhibiting platelet function, and enhancing the antithrombotic functions of vascular endothelium as well as fibrinolysis.

question

In addition, by inhibiting thrombin, heparin affects thrombin-mediated coagulation mechanisms involving...

answer

*Factor V *Factor VIII *Protein C *Thrombin Activatable Fibrinolytic Inhibitor (TAFI) **It also releases: -tissue factor pathway inhibitor (TFPI) -inhibits the release of P-selectin -impairs vascular barrier properties -attenuates nitric oxide-mediated vasodilatation during dynamic changes in blood flow.

question

The primary mechanism of heparin is through association with AT. Heparin binding produces an allosteric modification of...

answer

AT, which promotes stable complexes, exposing the arginine-385 residue of AT, allowing for interaction with the serine-active site of coagulation enzymes.

question

TFPI (tissue factor pathway inhibitor) is a coagulation protease inhibitor synthesized in the...

answer

vascular endothelium, the largest pool of which is bound to the endothelial cell surface. Also found in plasma and platelets, TFPI has three Kunitz domains linked in tandem between a negatively charged amino terminus and a positively charged carboxy terminus. TFPI simultaneously binds to and inhibits the factor VIIa- tissue factor complex and FXa via two of its Kunitz domains.

question

TFPI simultaneously binds to and inhibits the...

answer

factor VIIa- tissue factor complex and FXa via two of its Kunitz domains.

question

Neutralization of heparin by protamine sulfate results in a dramatic decrease in the plasma...

answer

TFPI (tissue factor pathway inhibitor) level.

question

The anticoagulant activity of TFPI can be detected by...

answer

the prothrombin time (PT), the activated partial thromboplastin time (aPTT), and clot-based anti-FXa assays.

question

Heparin is a weak platelet agonist, but is also a potent inhibitor of...

answer

platelet activation induced by thrombin, the LMWHs less so.

question

Heparin also binds to and inhibits von Willebrand factor (vWF), the clinical implication being...

answer

a reduction of thrombotic risk in general and control of platelet- endothelium interactions in specific.

question

Heparin bound to PF4 produces an immunogenic response that can lead to...

answer

the potential life-threatening disorder of heparin-induced thrombocytopenia (HIT).

question

Heparin-binding proteins can be divided into:

answer

1)Proteins that enhance the anticoagulant activity such as AT and HCII found in blood and released by heparin such as TFPI and lipase 2)Proteins that inhibit the anticoagulant activity of heparin such as PF4, histidine-rich glycoprotein (HRG), protamine, and vitronectin.

question

Upon entering the blood stream, heparin binds to a variety of plasma proteins, thereby lowering its...

answer

bioavailability and producing a variable anticoagulant response. Major binding proteins include HRG, PF4, fibronectin, vitronectin, and vWF.

question

Heparin is cleared by two mechanisms. The rapid, saturable phase of elimination is due to receptor-mediated internalization of heparin by...

answer

endothelial cells and macrophages, while a slower, nonsaturable renal mechanism is also operative.

question

The ratio of anti-FXa activity to anti-FIIa activity for UFH is 1, whereas the ratio for the originally developed LMWHs ranges from...

answer

2-4. Newer LMWHs have ratios up to 7.

question

Only heparin molecules that contain at least 18 saccharides (corresponding to a MW of ~5,400 Da) simultaneously bind to...

answer

AT and thrombin, which is required for the inactivation of thrombin by the heparin- AT complex. Smaller heparin molecules are only able to bind to AT and catalyze the inactivation of FXa.

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Fondaparinux (MW 1,727 Da) was the first of a new class of antithrombotic agents distinct from LMWHs and UFH. It is a chemically synthetic pentasaccharide mimicking the active site of heparin that binds to AT, exhibiting only...

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factor Xa inhibitory activity leading to an inhibition of thrombin generation. There is nearly complete bioavailability by the SC route, rapid onset of action, a prolonged half-life in both IV and SC dosing regimens, and it is renally excreted.

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While protamine effectively neutralizes heparin, it has limited value in the neutralization of...

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LMWHs, only partially reversing the anti-FXa activity. Protamine does not reverse the anticoagulant effect of fondaparinux.

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The anticoagulant effect of VKA is due to interference of the cyclic conversion of vitamin K and its 2,3-epoxide, which blocks...

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the regeneration of the reduced form of vitamin K.

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The VKAs interfere by inhibiting the enzyme ...

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vitamin K epoxide reductase, subunit 1 (VKORC1). The reduced form of vitamin K (KH2) is responsible for the carboxylation of glutamic residues on the procoagulant forms of factors II, VII, IX, and X.

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By inhibiting vitamin K conversion, coumarins cause hepatic production of...

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partially carboxylated and decarboxylated proteins with reduced procoagulant activity, resulting in their observed anticoagulant effect.

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It should be noted that VKAs also inhibit carboxylation of the regulatory anticoagulant proteins C, S, and Z, which can lead to...

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an increased procoagulant risk in certain clinical settings.

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The effect of VKAs can be counteracted by..

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vitamin K1 administered therapeutically or from ingestion in food. The counteraction is effectively due to the second reductase step, which is relatively insensitive to VKAs.

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The use of large doses of vitamin K1 will lead to warfarin resistance for up to...

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a week or longer, due to its accumulation in the liver.

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Warfarin is currently the most common form in clinical use. It has a high bioavailability due to its water solubility and is rapidly absorbed from...

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the stomach and duodenum. In addition, it has maximal blood concentrations in healthy volunteers within 90 minutes of oral administration.

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Warfarin will circulate in plasma bound to 98% to 99% to proteins, primarily to albumin, and accordingly only a minor fraction of the drug is...

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biologically active. The drug will then accumulate in the liver, specifically in the microsomes.

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Warfarin is a racemic mixture of S and R enantiomers, which are present in almost equal proportions. Warfarin has a half-life of 36 to 42 hours, which is the result of different metabolism rates of the two enantiomers:

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*The R enantiomer is less potent, is metabolized primarily by two microsomal cytochrome enzymes (CYP1A2 and CYP3A4) to 6- and 8-hydroxywarfarin, and has a half-life of 45 hours. *The S enantiomer is 2.7 to 3.8 times more potent than the R enantiomer, is metabolized primarily by the CYP2C9 enzyme of the P450 system to 7-hydroxywarfarin, and has a half-life of 29 hours. *The inactive hydroxywarfarins are excreted renally.

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Hepatic dysfunction impairs synthesis of vitamin K- dependent factors and potentiates the response to...

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warfarin. Fever or hyperthyroidism may also increase warfarin response by inducing a hypermetabolic state and increasing catabolism of vitamin K- dependent coagulation factors.

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The use of VKAs may uncommonly cause nonhemorrhagic complications such as...

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skin necrosis or limb gangrene. Although not well understood, reports of potential mechanisms include thrombosis, hypersensitivity, hemorrhage, factor VII deficiency, protein C and S deficiency, and direct toxic effects of warfarin.

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Another rare complication of VKAs is "purple toe syndrome" and may develop ...

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several weeks after initiation. Initial reports described patients with bilateral purple discoloration of the feet on the plantar surface and postulated to be due to the direct toxic effect of warfarin on capillaries and venules.

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VKAs readily cross the placenta and produce...

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characteristic embryopathy, central nervous system abnormalities, and fetal bleeding.

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Protamine partially reverses the effect of LMWHs— it reverses all of their anti-IIa effect and a variable proportion of their...

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anti-Xa effect. The degree of reversal appears to correlate in vivo with the average chain length and charge of the LMWH with products such as tinzaparin being more reversible than enoxaparin.

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Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction caused by...

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heparin-dependent, platelet-activating immunoglobulin (Ig) G antibodies that recognize complexes of platelet factor 4 (PF4) bound to heparin. HIT represents a strong, independent risk factor for venous and arterial thrombosis.

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HIT can be defined as any clinical event best explained by...

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platelet-activating anti-PF4/ heparin antibodies (" HIT antibodies") in a patient who is receiving, or who has recently received, heparin (or another polyanion implicated in this syndrome).

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Both platelet activation and PF4-dependent antigen assays are useful to support the diagnosis of....

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heparin induced thrombocytopenia

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When HIT is strongly suspected or confirmed, heparin should be substituted by a rapidly acting, alternative anticoagulant, such as a...

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direct thrombin inhibitor (DTI) or factor Xa inhibitor, generally in therapeutic doses, until the platelet count has recovered. In addition, to rule out DVT, duplex ultrasound examination of the lower limbs should be performed prior to discharge in patients strongly suspected or confirmed as having HIT.

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Two DTIs, lepirudin and argatroban, are approved for management of...

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HIT in the United States.

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The new oral anticoagulants, dabigatran (thrombin inhibitor) and rivaroxaban and apixaban (FXa inhibitors), cannot induce...

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HIT, as they have a different molecular structure than heparin. Although no experience with these agents in acute HIT exists, they are an option for patients with a history of HIT who require anticoagulation.

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An orally active agent belonging to the cyclopentyl-triazolopyrimidine class, ticagrelor acts as a direct inhibitor of...

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P2Y12. Ticagrelor binds to the receptor at a location distinct from the ADP-binding site and blocks ADP-mediated receptor activation in a noncompetitive fashion, likely through an allosteric mechanism.

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Ticagrelor binds to the receptor at a location distinct from the ADP-binding site and blocks ADP-mediated receptor activation in a...

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noncompetitive fashion, likely through an allosteric mechanism.

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Because it does not require metabolic activation, ticagrelor has a...

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rapid onset of action and achieves a level of inhibition of ADP-induced platelet aggregation within 30 minutes that exceeds that obtained with a 300 or 600-mg loading dose of clopidogrel.

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Side effects of ticagrelor include dyspnea, which is usually mild and dose related, asymptomatic bradycardia with ventricular pauses, and a modest increase in the levels of uric acid. This may relate to the capacity of ticagrelor to inhibit...

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adenosine reuptake by erythrocytes, thereby increasing circulating levels of adenosine. In addition to explaining the dyspnea and the bradycardia, the resultant adenosine-induced vasodilatation and increased myocardial perfusion could also endow ticagrelor with beneficial effects that are independent of P2Y12 blockade.

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Thienopyridines inhibit ADP-dependent platelet function by...

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irreversible modification of platelet P2Y1244 through short-lived active metabolites (AMs) generated by liver cytochrome P450 (CYP) isozymes.

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ADP is the natural agonist of the...

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P2Y12 receptor. It is heavily expressed in platelets where it is the molecular target of the active metabolite of the antiplatelet drug clopidogrel.

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Elective surgery with high risk of perioperative bleeding should be postponed until the appropriate course of thienopyridine therapy has been completed:

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*Bare-metal stent: 4-6 weeks *Drug-eluting stent: 12 months

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Elective noncardiac surgery is not recommended after stent placement when thienopyridine therapy or aspirin and thienopyridine therapy needs to be discontinued perioperatively. The prescribed period of therapy is:

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*Bare-metal stent: 4-6 weeks *Drug-eluting stent: 12 months

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When surgery cannot be postponed and thienopyridine therapy must be interrupted, it is recommended that...

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aspirin therapy be continued throughout the perioperative period and that thienopyridine therapy should be restarted as soon as possible after the procedure.

Chapter 15: Anticoagulants – Flashcards

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