BLOOD FORMING AGENTSBLOOD FORMING AGENTS

Clinical ThrombosisClinical Thrombosis

• > 2.5 million cases of deep venous 2.5 million cases of deep venous thrombosis (DVT) annually thrombosis (DVT) annually

• > 600.000 cases of pulmonary > 600.000 cases of pulmonary embolism (PE) per yearembolism (PE) per year

• > 50.000 deaths per year from PE> 50.000 deaths per year from PE

• > 11.000 post surgical PE deaths per > 11.000 post surgical PE deaths per yearyear

Anti Platelet DrugsAnti Platelet DrugsDrugDrug MechanismMechanism UsesUses

AspirinAspirin Permanently inhibits Permanently inhibits

COX-1COX-1 and COX-2 and COX-2

CAD (CAD (coronary artery coronary artery disease)disease)

Stroke-TIAs (Stroke-TIAs (transient transient ischemic attack)ischemic attack)

NSAIDsNSAIDs Reversibly inhibits Reversibly inhibits

COX-1COX-1

LimitedLimited

DipyridamoleDipyridamole Inhibits PDE; increases cAMPInhibits PDE; increases cAMP TIAsTIAs

TiclopidineTiclopidine

ClopidogrelClopidogrel

Inhibits ADP; Inhibits ADP;

active metaboliteactive metabolite

TIAs; StrokeTIAs; Stroke

CAD; PVD (CAD; PVD (peripheral peripheral vascular disease)vascular disease)

INHIBITORS OF PLATELET AGGREGATIONINHIBITORS OF PLATELET AGGREGATION

Platelets inhibitors - ASAPlatelets inhibitors - ASA

Daily dose -Daily dose - 80- 80-1100 00 mgmg

KardiomagnilKardiomagnil

ANTIPLATELET THERAPYANTIPLATELET THERAPY

Aspirin IndicationsAspirin Indications

1)1) Stroke, TIA (transient ischemic Stroke, TIA (transient ischemic attacks)attacks)

2)2) MI, recurrent MIMI, recurrent MI3)3) Unstable anginaUnstable angina

4)4) CABG potency (CABG potency (coronary coronary artery bypass graftartery bypass graft ))

TICLOPIDINETICLOPIDINE

1)1) Interferes with platelet-fibrinogen binding Interferes with platelet-fibrinogen binding 2)2) Exerts its action for the life of the plateletExerts its action for the life of the platelet3)3) May prolong bleeding timeMay prolong bleeding time4)4) Useful for coronary artery stents and CVA Useful for coronary artery stents and CVA

((cerebrovascular accidentcerebrovascular accident ))5)5) Methylprednisolone may reverse its effectMethylprednisolone may reverse its effect6)6) Associated with TTP (Associated with TTP (thrombocytopenic thrombocytopenic

purpurapurpura), neutropenia, and diarrhea ), neutropenia, and diarrhea

CLOPIDOGRELCLOPIDOGREL

1)1) Interferes with GP IIb/IIIa Interferes with GP IIb/IIIa

((Glycoprotein IIbGlycoprotein IIb// IIIa IIIa ) binding site ) binding site

2)2) Exerts its action for the life of the plateletExerts its action for the life of the platelet

3)3) May prolong bleeding timeMay prolong bleeding time

4)4) Indicated for prevention of MI, CVA Indicated for prevention of MI, CVA ((cerebrovascular accidentcerebrovascular accident)), and vascular death, and vascular death

5)5) Fewer side effects than ticlopidineFewer side effects than ticlopidine

6)6) Dose: 75 mg daily Dose: 75 mg daily

Abciximab (ReoPro)Abciximab (ReoPro)

1)1) Human-mouse monoclonal Human-mouse monoclonal antibodiesantibodies

2)2) Binds to GP (glycoprotein) IIb/IIIa Binds to GP (glycoprotein) IIb/IIIa receptor on plateletsreceptor on platelets

3)3) Half-life 10 min.Half-life 10 min.

4)4) May block receptor for 10 daysMay block receptor for 10 days

5)5) Indicated for prevention of closure of Indicated for prevention of closure of coronary vessels after angioplastycoronary vessels after angioplasty

6)6) May cause thrombocytopeniaMay cause thrombocytopenia

7)7) Used with heparin and ASAUsed with heparin and ASA

Antiplatelet therapyAntiplatelet therapy

Mechanism of heparin actionMechanism of heparin action

АТ ІІІ ІІ а АТ ІІІ Х аХ а55

13

АТ ІІІ – ant thrombin ІІІІІ а – thrombin

Х а – prothrombinase (Stuart-Prover factor)

10

IV or SC administration onlyIV or SC administration only

HEPARINHEPARIN

HEPARIN (Indications)HEPARIN (Indications)

Full Dose:Full Dose: 5000 U or 80 U/kg 5000 U or 80 U/kg IVIV bolus, followed by 1200-1600 bolus, followed by 1200-1600 U/hr adjusted to therapeutic range U/hr adjusted to therapeutic range 1)1) Acute deep venous thrombosisAcute deep venous thrombosis 2)2) Pulmonary emboliPulmonary emboli 3)3) Unstable angina and myocardial infarctionUnstable angina and myocardial infarctionLow Dose:Low Dose: 5000 U 5000 U sqsq q12 h q12 h 1)1) Postoperative prophylaxis of any major abdominal, Postoperative prophylaxis of any major abdominal, thoracic, gynecologic, or orthopedic procedurethoracic, gynecologic, or orthopedic procedure 2)2) Immobilized medical patients >40 yrs. with CHF, CVA, Immobilized medical patients >40 yrs. with CHF, CVA,

malignant diseasemalignant disease 3)3) Prophylaxis for underlying hypercoagulable stateProphylaxis for underlying hypercoagulable stateOther Dose:Other Dose: 1)1) Extracorporeal bypassExtracorporeal bypass 2)2) HemodialysisHemodialysis 3)3) AfterAfter thrombolytic therapy thrombolytic therapy

HEPARIN (Contraindications)HEPARIN (Contraindications)

11)) ThrombocytopeniaThrombocytopenia2)2) Aspirin or alcohol useAspirin or alcohol use3)3) Hepatic or renal diseaseHepatic or renal disease4)4) Other platelet dysfunctionOther platelet dysfunction5)5) GI bleedingGI bleeding6)6) TumorsTumors

HEPARIN (Side Effects)HEPARIN (Side Effects)

1)1) Major side effect is bleedingMajor side effect is bleeding

2)2) Osteoporosis with prolonged Osteoporosis with prolonged useuse

3)3) ThrombocytopeniaThrombocytopenia

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HEPARIN-INDUCED THROMBOCYTOPENIAHEPARIN-INDUCED THROMBOCYTOPENIA 1)1) Occurs in 2-5% of patients receiving standard Occurs in 2-5% of patients receiving standard

heparin by heparin by immune mechanismimmune mechanism

2)2) May occur with minute doses, including heparin May occur with minute doses, including heparin flushesflushes

3)3) More common with bovine than porcine heparinMore common with bovine than porcine heparin

4)4) Asymptomatic thrombocytopenia can occur in 30-Asymptomatic thrombocytopenia can occur in 30-50% of pts who develop HIT antibodies 50% of pts who develop HIT antibodies

5)5) ~~20-50% of thrombocytopenic patients develop 20-50% of thrombocytopenic patients develop arterial or venous thrombosis that may be life arterial or venous thrombosis that may be life threatening threatening

1)1) LepirudinLepirudin

2)2) Argatroban Argatroban

HEPARIN-INDUCED HEPARIN-INDUCED THROMBOCYTOPENIA THROMBOCYTOPENIA

Alternative Anticoagulants- Alternative Anticoagulants- direct direct thrombin inhibitorsthrombin inhibitors

LOW MOLECULAR WEIGHT LOW MOLECULAR WEIGHT HEPARINHEPARIN

1) 1) Molecular weight 3,000- 7,000 DMolecular weight 3,000- 7,000 D

2)2) Inhibits factor Xa rather than thrombinInhibits factor Xa rather than thrombin

3)3) Factor Xa assay used for monitoringFactor Xa assay used for monitoring

4)4) Administered Administered subcutaneously 2 times/dsubcutaneously 2 times/d

5)5) Probably less antigenic than standard Probably less antigenic than standard heparinheparin

6)6) Recommended for prophylaxis and Recommended for prophylaxis and treatmenttreatment

LOW MOLECULAR WEIGHT LOW MOLECULAR WEIGHT HEPARINHEPARIN

1) 1) PT, APTT not usually prolongedPT, APTT not usually prolonged

2) 2) May be May be monitored with anti-factor Xa monitored with anti-factor Xa assayassay

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LOW MOLECULAR WEIGHT HEPARINSLOW MOLECULAR WEIGHT HEPARINS

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Indications for and Contraindications to Parenteral Anticoagulant Agents

Anticoagulant Agent Class Approved & Appropriate Indications

Contraindication

Unfractionated heparin

Enoxaparin(Lovenox)

Dalteparin(Fragmin)

Tinzaparin(Innohep)

Antithrombin III inhibitor

Low-molecular-weight heparin

Low-molecular-weight heparin

Low-molecular-weight heparin

Treatment of venous thromboembolism or unstable angina; used when rapid reversal is important

Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism or unstable angina

Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism or unstable angina

Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism

?Prophylactic treatment

Regional anesthesia

Pregnancy

Prosthetic Heart Valves

Regional anesthesia

Regional anesthesia

Heparin-Antibiotic InteractionsHeparin-Antibiotic Interactions

• The cephalosporins- The cephalosporins- cefamandole, cefotetan, cefamandole, cefotetan, and cefoperazoneand cefoperazone, contain an N-, contain an N-methylthiotetrazole (NMTT) side chain. This methylthiotetrazole (NMTT) side chain. This NMTT group can:NMTT group can:

• - Dissociate from the parent antibiotic in solution - Dissociate from the parent antibiotic in solution or in vivo and or in vivo and competitively inhibit vitamin K competitively inhibit vitamin K action, leading to prolongation of the action, leading to prolongation of the prothrombin time and bleeding. prothrombin time and bleeding.

• - This side chain is also associated with a - This side chain is also associated with a disulfiram-like reaction to alcoholdisulfiram-like reaction to alcohol..

ANTICOAGULANTS ANTICOAGULANTS OF INDIRECT ACTIONOF INDIRECT ACTION

COUMARIN (Description)COUMARIN (Description) 1)1) Isolated by Link in 1939 after previous Isolated by Link in 1939 after previous

observation that cattle developed observation that cattle developed bleeding bleeding disorder after ingestion of spoiled disorder after ingestion of spoiled cloverclover2)2) Is 4-hydroxycoumarin compound, similar Is 4-hydroxycoumarin compound, similar in structure to vitamin Kin structure to vitamin K3)3) Administered p.o., rapid GI absorptionAdministered p.o., rapid GI absorption4)4) Crosses placenta easily (complications!)Crosses placenta easily (complications!)5)5) Interacts with a variety of drugsInteracts with a variety of drugs

LIVERLIVER

COUMARINCOUMARIN (Actions) (Actions)

1)1) Blocks the carboxylation of the Blocks the carboxylation of the vitamin K dependent clotting vitamin K dependent clotting proteins, factors II, VII, IX, and X, proteins, factors II, VII, IX, and X, maintaining them in their maintaining them in their inactive formsinactive forms

2) Blocks the anticoagulant proteins 2) Blocks the anticoagulant proteins C and S C and S

3) 3) Onset – 18-48 hoursOnset – 18-48 hours

COUMARIN COUMARIN LaboratoryLaboratory

1)1) Prolongs the PT and APTTProlongs the PT and APTT

2)2) PT and Prothrombin index -used PT and Prothrombin index -used for monitoring for monitoring

Prothrombin indexProthrombin index INTERNATIONAL NORMALIZED RATIO INTERNATIONAL NORMALIZED RATIO

(INR)(INR)

INR = INR = PATIENT PTPATIENT PT

CONTROL PTCONTROL PT

Decrease no less than 50 %Decrease no less than 50 %

COUMARIN COUMARIN Side EffectsSide Effects

1)1) HemorrhageHemorrhage

2) Fetal abnormalities2) Fetal abnormalities

3)3) Skin necrosis with deficiencies of Skin necrosis with deficiencies of proteins proteins C or S usually on 3rd to 8th C or S usually on 3rd to 8th day of therapyday of therapy

COUMARINCOUMARIN InteractionsInteractionsPOTENTIATORS :POTENTIATORS :

PhenylbutazonePhenylbutazoneCimetidineCimetidineOmeprazoleOmeprazoleAmiodaroneAmiodaroneAnabolic steroidsAnabolic steroids

ANTAGONISTS :ANTAGONISTS :BarbituratesBarbituratesRifampinRifampinPenicillinsPenicillinsAntacidsAntacids

Pharmacodynamics of fibrinolytic drugsPharmacodynamics of fibrinolytic drugs

• After introduction into organism they After introduction into organism they cause lyses of cause lyses of freshfresh (24-72 (24-72 hourshours) ) thrombi in arteries, veins, cavitiesthrombi in arteries, veins, cavities

• The most effective during the first 2-3 The most effective during the first 2-3 hours after initiation of thrombosishours after initiation of thrombosis

Thrombin – only topical !!!Thrombin – only topical !!!

HAEMOSTATICS HAEMOSTATICS with systemic actionwith systemic action

FibrinogenFibrinogen, , Calcium chlorideCalcium chloride, , vitamin vitamin К, К, VikasolumVikasolum

INHIBITORS OF FIBRINOLYSISINHIBITORS OF FIBRINOLYSISof direct action (Contrikal, Trasilol, Gordox)of direct action (Contrikal, Trasilol, Gordox)

of indirect action of indirect action ((Ac aminocapronicum, Ac. tranexamicumAc aminocapronicum, Ac. tranexamicum, , AmbenAmben))

EthamsilateEthamsilate

Stabilizes the walls of vesselsStabilizes the walls of vessels

Urtica (Nettle)Urtica (Nettle)

Viburnum (Snow ball, Viburnum (Snow ball, Water elder)Water elder)

Arnica (arnica)Arnica (arnica)

Polygonum hydropiperPolygonum hydropiper (Water pepper)(Water pepper)

Hippocastanum (Aescusan)Hippocastanum (Aescusan)(Horse chestnut)(Horse chestnut)

Ginkgo bilobaGinkgo biloba(Maidenhair-tree)(Maidenhair-tree)

TanakanTanakan

DRUGS EFFECTING DRUGS EFFECTING HAEMOPOESISHAEMOPOESIS

Food products with ironFood products with iron

MeatMeatSoybeansSoybeans

Dry smoked plumsDry smoked plumsSpinachSpinach

Dry apricotsDry apricotsBuckwheatBuckwheat

RiceRiceBreadBread

Fruits of Fruits of pomegranate pomegranate

Iron from animal products absorbs much Iron from animal products absorbs much more better than from plants (more better than from plants (22 %22 % and 1 % and 1 %))