LEARNING OBJECTIVES:1.Understand the coagulation mechanism2.Define the terms antithrombotics and thrombolytics3.Classify the drugs used in coagulation disorder4.Describe the mechanism of action of each drug5.Give the clinical significance of each agent6.Discuss the adverse effects of each class or drug

Chapter 34

Drugs Used in Disorders of Coagulation

EVENTS IN HEMOSTASISPLATELET MIGRATION AND AGGREGATION

Product: PLATELET PLUG (white thrombus/primary hemostasis)ACTIVATION OF COAGULATION CASCADE

Product: PERMANENT CLOT (red thrombus/secondary hemostasis)

PLATELET MIGRATION AND ACTIVATION

PLATELET ADHESIONPlatelet membrane

receptors include;The glycoprotein (GP) Ia

receptor binding to collagen (C); GP Ib receptor binding von

Willebrand factor (vWF)

PLATELET ACTIVATIONPlatelet membrane receptors include;

GP IIb/IIIa, which binds fibrinogen and other macromolecules

Aggregating Substances:Adenosine Diphosphate (ADP)Thromboxane A2 (TXA2)Serotonin (5-HT)

Aggregating SubstancesThromboxane A2 (TXA2) is synthesized

from arachidonic acid within platelets and is a platelet activator and potent vasoconstrictor.

Products secreted from platelet granules;Adenosine Diphosphate (ADP), a powerful

inducer of platelet aggregation, and Serotonin (5-HT), which stimulates

aggregation and vasoconstriction.

PLATELET AGGREGRATION

ACTIVATION OF BLOOD COAGULATION CASCADEOccurs within 6-12 hours from time of injuryGOAL: To activate thrombin (Clotting Factor

IIa), which is required in converting fibrinogen (Clotting Factor I) to its activated form (Fibrin)Fibrin – polymerized form of fibrinogen that

stabilizes the platelet plugDeposit onto platelet plug and glues platelets togetherAttracts other cells esp. RBC to deposit onto the platelet

plug (red thrombus)2 Pathways:

Extrinsic - dominantIntrinsic

Blood Coagulation Cascade (Extrinsic Pathway)

Initiation of clotting

soluble insoluble

REGULATION OF THROMBOSISPlasminAntithrombin IIIProtein C and Protein S

PLASMINA protease; responsible for facilitating

FIBRINOLYSISFIBRINOLYSIS – process of fibrin digestion

t-PA

ANTITHROMBIN III; PROTEIN C and SAntithrombin III (ATIII)

ROLE: Directly inactivates activated clotting factors (IIa, IXa, Xa, XIa, XIIa, XIIIa)

Protein C and SAttenuate the blood clotting cascade by

proteolysis of two co-factors Va and VIIIa.

ANTITHROMBOTICSa. Anticoagulants

- slow down clotting/prevent formation of clottingb. Antiplatelets

- prevent platelet aggregationTHROMBOLYTICS

- degrade clots that have already formed

ANTITHROMBOTICS and THROMBOLYTICS

Drugs Used in Coagulation Disorders

ANTICOAGULANTS (ANTITHROMBOTICS)Endogenous anticoagulant – Protein C Mucopolysaccharide Antithrombin III – Heparin

Vitamin K analogue – WarfarinDirect thrombin inhibitors

Hirudin (leech protein) LepirudinBivalirudin ArgatrobanDabigatran

Drugs Used in Coagulation Disorders

ANTIPLATELETS (ANTITHROMBOTICS)GP IIb/IIIa receptor antagonist

Abciximab (monoclonal antibody)EptifibatideTirofiban

ADP receptor antagonistTiclopidineClopidogrel

TXA2 (COX) inhibitorAspirin

PDE/adenosine uptake inhibitorDipyridamoleCilostazol

Drugs Used in Coagulation Disorders

THROMBOLYTICS (FIBRINOLYTICS)StreptokinaseAnistreplaseUrokinaseAlteplaseReteplase

HEPARIN• A heterogeneous mixture of sulfated mucopolysaccharides• An indirect thrombin inhibitor (parenteral)

HEPARINFORMS:

Regular Heparin/ HMW Heparin/ Unfractionated Heparin

LMW HeparinsEnoxaparinDalteparinFondaparinuxFraxiparinDanaproid

MECHANISM OF ACTIONREGULAR HEPARIN:

Binds and forms an active complex to antithrombin III (inhibits clotting factors IIa, IXa, Xa, XIa, XIIa, XIIIa) The binding accelerates ATIII’s action by 1000-fold

LMWHs:More selective binding at Xa.

CLINICAL USESGiven when initiating anti-coagulation

therapyMx of acute coronary syndromeTx (IV) and prevention (IV or SQ) of

pulmonary embolismMx of Deep Vein Thrombosis (DVT)When anticoagulation is necessary

during pregnancy

Toxicity and Miscellaneous effects of Heparin

BLEEDING Close monitoring is recommended

Should be used with caution in hypersensitive patients

Increased hairloss and reversible alopeciaOsteoporosis - long-term therapyHeparin accelerates the clearing of postprandial

lipemia by causing the release of lipoprotein lipase from tissues

Heparin-induced thrombocytopenia (HIT)Long-term use is associated with

mineralocorticoid deficiency

CONTRAINDICATIONSHITHypersensitivity to the

drugActive bleedingHemophiliaSignificant

thrombocytopeniaPurpuraSevere hypertensionIntracranial hemorrhageInfective endocarditis

Active tuberculosisUlcerative lesions of

the gastrointestinal tract

Threatened abortionVisceral carcinomaAdvanced hepatic or

renal disease

CONTRAINDICATIONSShould be avoided

in patients who have recently had surgery of the brain, spinal cord, or eye, and in patients who are undergoing lumbar puncture or regional anesthetic block

Should be used in pregnant women only when clearly indicated

REVERSAL OF EFFECTS OF HEPARINPROTAMINE SULFATE

Highly basic100 units of Heparin = 1 mg Protamine

Sulfate (IV)

WARFARIN & THE COUMARIN

ANTICOAGULANTS

Historical Drugs:Dicumarol: Now used as rodenticide

SE: inc. risk of GI bleeding, ulceration,

Indanediones: Phenindione SE: thrombocytopenia, fatal hypersensitivity rxn

WARFARINThe only oral anticoagulant used in clinicsS-isomer is the active isomerMechanism of Action:

Inhibits hepatic synthesis of Vitamin K-dependent clotting factors

Blockade of gamma-carboxylation of several glutamate residues in clotting factors X, IX, VII, II

8- to 12-hour delay in the action

Mechanism of ActionProtein carboxylation reaction is coupled to the oxidation of Vit.K

Vitamin K epoxide (inactive)

Hydroquinone form (active)

INDICATIONSDeep venous thrombosisIsch.heart diseaseRHDPulmonary Embolism

WARFARINThe therapeutic range for oral

anticoagulant therapy is defined in terms of an Prothrombin Time-International Normalized Ratio (PT-INR) Category PT-INRMost Patients 2-3

Px has prosthetic heart valves

2.5-3.5

DRUG INTERACTIONSINCREASED PT-INR: INCREASED RISK OF

HEMORRHAGE/BLEEDINGPharmacokinetic:

Reduced plasma protein binding: Pyrazolone derivatives

Enzyme Inhibitors: Amiodarone, Cotrimoxazole, Cimetidine, Azole Antifungals, Macrolides, Metronidazole

Pharmacodynamic: ASA (high doses), 3rd Generation Cephalosporins,

Heparin, Chronic liver disease, Hyperthyroidism

DRUG INTERACTIONSDECREASED PT-INR: INCREASED RISK OF

THROMBOSISPharmacokinetic:

Enzyme Inducers: Barbiturates, RifampinSome drugs that prevent absorption

Pharmacodynamic: Vitamin K, Diuretics, Hypothyroidism

UNDERSIRABLE EFFECTSCutaneous necrosis within the 1st week of

treatment“Purple Toe" syndrome - seen after at least 3 weeks

of warfarin use due to cholesterol embolizationBleeding / hemorrhageGI upsetComplications in pregnancy (CI):

Within 1st trimester - abnormal bone development - teratogenic effect

Within 3rd trimester - hemorrhagic disorder in the newborn - present with necrotizing enterocolitis (fatal in newborn)

DIRECT THROMBIN INHIBITORS

PARENTERAL• Hirudin – from leech saliva• Lepirudin - recombinant form of Hirudin• Bivalirudin• Argatroban ORAL• Ximelagatran – withdrawn from the market• Dabigatran

DIRECT THROMBIN INHIBITORS

Exert their anticoagulant effects by directly binding to the active site of thrombin

Intrinsic

Prothrombin

Fibrin

Xa

Extrinsic

Thrombin

Fibrinogen

Therapeutic usesLepirudin - use in patients with thrombosis

related to heparin-induced thrombocytopeniaBivalirudin - FDA-approved for use in

percutaneous coronary angioplastyArgatroban - FDA-approved for use in

patients with HIT with or without thrombosis and coronary angioplasty in patients with HIT

Dabigatran - approved for use in Europe for prevention of venous thromboembolism in patients who have undergone hip or knee replacement surgery

Summary of anticoagulants

ANTITHROMBOTICS (ANTIPLATELET DRUGS)

MECHANISM OF ACTION OF ANTITHROMBOTIC AGENTS

DRUG MECHANISM OF ACTIONASPIRIN Inhibits COX, thus prevents TXA2 and

PGsCLOPIDOGREL & TICLOPIDINE

Inhibit ADP pathway of platelet formation

DIPYRIDAMOLE PDE inhibitor, thus increasing cAMP levels to potentiate PGI2 (platelet aggregation inhibitor)

ABCIXIMAB, EPTIFIBATIDE, TIROFIBAN

Inhibit glycoprotein IIb/IIIa, necessary molecule for platelet aggregation

ASPIRIN

ASPIRINFor primary prophylaxis of myocardial

infarction 325 mg/day

For secondary prevention of vascular events among patients with a history of vascular disease

CLOPIDOGREL AND

TICLOPIDINE

General MOA of Antithrombotic Drugs

USES AND UNDESIRABLE EFFECTS OF ANTITHROMBOTIC AGENTS

DRUG INDICATION UNDESIRABLE EFFECTSASPIRIN Reduces the risk of MI in

patients with unstable angina

GI ulcer, bleeding, hemorrhage

CLOPIDOGREL & TICLOPIDINE

Reduction of atherosclerotic events, prevent thrombosis

Ticlopidine: Nausea, dyspepsia, hemorrhage, leukopenia

Clopidogrel: fewer adverse effects than ticlopidine

DIPYRIDAMOLE Prevents emboli May worsen angina, dizziness, headache, syncope, GI disturbances, rash

ABCIXIMAB, EPTIFIBATIDE, TIROFIBAN

Acute coronary syndrome

Bleeding

THROMBOLYTIC AGENTSStreptokinaseUrokinaseAnistreplaseTissue Plasminogen Activator (TPA)AlteplaseReteplase

USES OF FIBRINOLYTICSIn the management of acute myocardial

infarction Indicated in cases of ;

pulmonary embolism with hemodynamic instability,

severe deep venous thrombosis such as the superior vena caval syndrome, and

ascending thrombophlebitis of the iliofemoral vein with severe lower extremity edema

Recombinant t-PA has also been approved for use in acute ischemic stroke within 3 hours of symptom onset

Drugs Used in Bleeding Disorders

• VITAMIN K• PLASMA FRACTIONS• DESMOPRESSIN ACETATE • FIBRINOLYTIC INHIBITORS: AMINOCAPROIC ACID• SERINE PROTEASE INHIBITORS: APROTININ (removed from the market)

VITAMIN KTwo natural forms exist:

Vitamin K1 (phytonadione) is found in food Vitamin K2 (menaquinone) is found in human

tissues and is synthesized by intestinal bacteriaUsed in treating Warfarin overdosage

Vit.K3 (menadione) – water soluble; ineffective in warfarin overdosage

Vitamin K1 is currently administered to all newborns to prevent the hemorrhagic disease of vitamin K deficiency

PLASMA FRACTIONSUsed for the treatment of blood clotting

factors deficiencies such as;Factor VIII deficiency (classic hemophilia,

or hemophilia A) Factor IX deficiency (Christmas disease, or

hemophilia B) Humate-P

is a factor VIII concentrate approved by the FDA for the treatment of bleeding associated with von Willebrand disease

DESMOPRESSIN ACETATE Increases the factor VIII activity of patients

with mild hemophilia A or von Willebrand disease

Can be used in preparation for minor surgery such as tooth extraction

Available in high-dose intranasal desmopressin

CRYOPRECIPITATEPlasma protein fraction obtainable from

whole bloodContains 300 mg of fibrinogenUsed to treat deficiencies or qualitative

abnormalities of fibrinogenMay also be used for patients with factor

VIII deficiency and von Willebrand disease if desmopressin is not indicated and a pathogen-inactivated, recombinant, or plasma-derived product is not available

AMINOCAPROIC ACIDA synthetic inhibitor of fibrinolysisAn adjunctive therapy in hemophiliaAs therapy for bleeding from fibrinolytic

therapy,Prophylaxis for rebleeding from intracranial

aneurysmsHas been used in patients with postsurgical

gastrointestinal bleeding and postprostatectomy bleeding and bladder hemorrhage secondary to radiation- and drug-induced cystitis

AMINOCAPROIC ACIDAdverse effects of the drug include;

Intravascular thrombosis from inhibition of plasminogen activator

HypotensionMyopathyabdominal discomfortdiarrhea, andnasal stuffiness

Should not be used in patients with disseminated intravascular coagulation or genitourinary bleeding of the upper tract because of the potential for excessive clotting

TRANEXAMIC ACID Is an analog of aminocaproic acidSame properties as Aminocaproic acid