BLOOD COAGULATION,BLOOD COAGULATION,ANTICOAGULANT, ANTICOAGULANT,

THROMBOLYTICS & THROMBOLYTICS & ANTIPLATELET DRUGSANTIPLATELET DRUGS..

WHAT IS COAGULATION?Coagulation is a complex process by which blood forms clots.

Blood must be remain fluid with in the vasculature and yet clot quickly when expose to non endothelial surface at a site of vascular injury.

It is an important part of haemostasis (the cessation of blood loss from a damaged vessel), where in a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel.

Disorders of coagulation can lead to an increased risk of bleeding (hemorrhage) or clotting (thrombosis).

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Factor Common NameI FibrinogenII ProthrombinIII Tissue Factor(Thromboplastin)IV Ca2+V ProaccelerinVII ProconvertinVIII Antihemophilic GlobulinIX Plasma thromboplastin componentX Stuart FactorXI Plasma thromboplastin

antecedentXII Hageman factorXIII Fibrin Stabilizing Factor

THE COAGULATION CASCADE

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COAGULANTSThese are substances which promote coagulation, and

are indicated in haemorrhagic states.

Fresh whole blood or plasma provide all the factors needed for coagulation and are best therapy for deficiency of any clotting factor.

They also act immediately.

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VITAMIN KIt is a fat soluble dietary principle required for the

synthesis of clotting factors.Dietary sources are-green leafy vegetables, such as

cabbage, spinach and liver, cheese, etc.Vit K acts as a cofactor in the synthesis of coagulation

proteins-prothrombin, factors VII, IX and X.The vit K dependent change confers on them the capacity

to bind Calcium and to get bound to phospholipid surfaces.

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DEFICIENCYDeficiency of vit K occurs due to :-Liver diseaseObstructive jaundiceMalabsorptionLong-term antimicrobial therapyDeficient diet

Dose: Phytonadione 10mg/ml i.m. inj.

Menadione sod.bisulfite: 20 mg.

Toxicity: Flushing Breathlessness Fall in B.P.

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ANTICOAGULANTSAn anticoagulant is a drug that helps prevent

the clotting (coagulation) of blood. These drugs tend to prevent new clots from

forming or an existing clot from enlarging. They don't dissolve a blood clot. Anticoagulants are also given to certain

people at risk for forming blood clots,

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CLASSIFICATION1. Used in vivo:-

A. Parenteral anticoagulants:

Heparin,

Heparinoids-Heparan sulfate,

Danaparoid,Lepirudin,Ancrod.

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B. Oral Anticoagulants:i. Coumarin derivatives:- *Bishydroxycoumarin(dicumarol), *Warfarin sodiumii. Indandione derivatives:- *Phenindione

2. Used in vitro:- A. Heparin(150 U to prevent clotting of 100 ml blood.)

B. Calcium complexing agents:- *Sodium citrate(1.65 g for 350 ml of blood) *Sodium oxalate(10 mg for 1 ml blood)

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HEPARIN

Heparin is a non-uniform mixture of straight chain mucopolysaccharides with MW 10,000 to 20,000.

It contains polymers of two sulfated disaccharide units:

D-glucosamine-L-iduronic acid D-glucosamine-D-glucuronic acidIt carries strong electronegative charges and is

the strongest organic acid present in the body. 12

OCCURRENCE OF HEPARINHeparin is found in the secretory granules of

mast cells.Thus ,heparin is present in all tissues containing mast cells;richest sources are lung, liver and intestinal mucosa.

Commercially it is produced from ox lung and pig intestinal mucosa.

PHARMACOLOGICAL ACTIONS• Heparin is a powerful and instantaneously acting

anticoagulant, effective both in vivo and in vitro.• Heparin produces its anticoagulant effect by

activating plasma antithrombin iii(AT III a serine proteinase inhibitor) and may be other similar cofactors. 13

Heparin

Antithrombin IIIThrombin

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ACTIONS2. ANTIPLATELET:- Heparin in higher doses inhibits platelet

aggregation and prolongs bleeding time.3. LIPAEMIA CLEARING:-Injection of heparin clears turbid post-

prandial lipaemic by releasing a lipoprotein lipase from the vessel wall and tissues, which hydrolyses triglycerides of chylomicrones and VLDL to free fatty acids; these then pass into tissues and the plasma looks clear.

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PHARMACOKINETICSHeparin is a large, highly ionized molecule;

therefore not absorbed orally.Injected i.v. it acts instantaneously,but after

s.c. injection anticoagulant effect develops after 60 min.

Heparin does not cross blood-brain barrier or placenta.

It is metabolized in liver by heparinase and fragments are excreted in urine.Heparin released from mast cells is degraded by tissue macrophages.

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ADVERSE EFFECTS1. Bleeding due to overdose is the most serious

complication of heparin therapy.Haematuria is generally the first sign.

2. Thrombocytopenia is another common problem.

3. Reversible alopecia is infrequent.4. Osteoporosis may develop on long-term use

of relatively high doses.5. Hypersensitivity reactions are rare.

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CONTRAINDICATIONS1. Bleeding disorders,heparin induced

thrombocytopenia.2. Severe hypertension,threatened abortion,

piles,g.i.ulcers.3. Subacute bacterial endocarditis,

large ,tuberculosis.4. Chronic alcoholics, renal failure.5. Aspirin and other antiplatelet drugs should

be used very cautiously during heparin therapy.

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HEPARIN ANTAGONISTProtamine sulfate:- It is a strongly basic, low molecular weight

protein obtained from the sperm of certain fish.

Given i.v. it neutralises heparin weight for weight,i.e. 1 mg is needed for every 100 U of heparin.

In the absence of heparin, protamine itself acts as a weak anticoagulant by interacting with platelets and fibrinogen.

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ORAL ANTICOAGULANTSOral anticoagulants are medicines used for

people who are at risk of developing abnormal blood clotting.

The oral anticoagulants are a class of pharmaceuticals that act by antagonizing the effects of vitamin K.

Clotting in the limb vessels can cause gangrene.

Clots can dislodge and go to the lungs, known as pulmonary embolism.

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EXAMPLES OF ORAL ANTICOAGULANTSRecemic Warfarin sodiumBishydroxycoumarin(Dicumarol)Acenocoumarol(Nicomalone)EthylbiscoumacetatePhenindione

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WARFARINWarfarin is a synthetic derivative of coumarin, a

chemical found naturally in many plants, like, woodruff (Galium odoratum, Rubiaceae), and at lower levels in licorice, lavender, species.

Warfarin is prescribed to people with an increased tendency for thrombosis or in those individuals that have already formed a blood clot (thrombus).

Warfarin is contraindicated in pregnancy, as it passes through the placental barrier and may cause bleeding in the fetus.

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MECHANISM OF ACTION

Warfarin is an analogue of Vitamin K. Warfarin inhibits the vitamin K-dependent synthesis of biologically active forms of the calcium-dependent clotting factors II, VII, IX and X, as well as the regulatory factors protein C.

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MECHANISM OF ACTION

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ADVERSE EFFECTSBleedingAlopeciaDermatitisUrticariaHematuria

TREATMENT: give fresh blood transfusion, supplies clotting factors & replenishes lost blood.

Give vit K-specific antidote but it takes 6-24 hours for clotting factors to be resynthesised & released in blood after vit K administration.

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USES OF ANTICOAGULANTS

The aim of using anticoagulants is to prevent thrombus extension and embolic complications by reducing the rate of fibrin formation.

USES:- 1.Deep vein thrombosis and pulmonary embolism.2.Myocardial infarction3.Unstable angina4.Rheumatic heart disease;Atrial fibrillation 5.Cerebrovascular disease 6.Vascular surgery, prostatic heart valves, retinal vessel thrombosis 7. haemodialysis.

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THROMBOLYTICS(Fibtinolytics)

StreptokinaseUrokinaseAnistreplasetissue Plasminogen Activators (t-PA)

AlteplaseReteplaseTenecteplase

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These drug use to lyse thrombi(clot)

FIBRINOLYSIS

Endothelial cells secrete tissue plasminogen activator (t-PA) at sites of injury.

t-PA binds to fibrin and cleaves plasminogen to plasmin, resulting in fibrin digestion. Plasminogen activator inhibitors-1 and -2 (PAI-1, PAI-2) inactivate t-PA; a2-antiplasmin (a2-AP) inactivates plasmin.

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Plasmin is an endogenous fibrinolytic enzyme that degrades clots by splitting fibrin into fragments.

Plasmin itself can not be used because naturally occurring inhibitors in plasma prevent its effects.

Fibrinolytic drugs catalyze the conversion of precursor plasminogen into active plasmin.

Rapidly lyse or break down thrombi.

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StreptokinaseSource: It is a protein produced by beta-hemolytic

streptococci. It has no intrinsic enzymatic activity.

MOA: It combines with proactivator plasminogen to

form a complex. This complex catalyzes the conversion of

plasminogen to active plasmin. So rapid lysis of the clot by plasmin.This complex also catalyzes the clotting

factor V and VII.34

Plasma half life: (t ½) 40-80 minutesThe streptokinase-plasminogen complex is not

inhibited by natural alpha 2-antiplasmin

Adverse effects: Not clot specific.So can create a generalized lytic state when administered I/V.Thus, both protective haemostatic thrombi and target

thromboemboli are broken down. Hemorrhage --- most serious cerebral hemorrhage Allergic reactions, rarely anaphylaxis and fever.

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A two chain serine protease containing 411 amino acid residues isolated from cultured human kidney cells.

MOA: It converts plasminogen to active plasmin.It is not clot specific:

So can create a generalized lytic state when administered I/V.

Thus, both protective haemostatic thrombi and target thromboemboli are broken down.

Ph. K Given I/V. t ½ : 15-20 minutes Metabolized by liver.

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A complex of purified human plasminogen & bacterial streptokinase that has been acylated to protect the enzymes active site.

On I/V administration, the acyl group spontaneously hydrolyzes.Free activated streptokinase - proactivator complex produces lysis of

clots also degrades fibrinogen.

Advantages: Rapid I/V injection may be given.Greater clot selectivity .More thrombolytic activity.

Dose: A single I/V injection of 30 units over 3-5 minutes

Anistreplase

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t-PA is a natural serine protease.It preferentially activates fibrin bound

plasminogen.Human t-PA has been manufactured by

recombinant DNA technology for therapeutic use.

Alteplase: Recombinant form of t-PA.

USES OF THROMBOLYTICS

1. Acute myocardial infarction: due to coronary artery thrombosis. Best given within 6 hrs.

2. Pulmonary embolism: with hemodynamic instability.

3. Severe deep vein thrombosis: 4. Acute ischemic stroke: (only t-PA)Antifibrinolytics: used for treatment of fibrinolytic toxicy.

eg: Epsilon Amino Caproic Acid (EACA)

Tranexamic acid

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PLATELET ADHESION AND AGGREGATION

GPIa/IIa and GPIb are platelet membrane proteins that bind to collagen.

Von Willebrand factor (vWF), it causing platelets to adhere to the subendothelium of a damaged blood vessel.

PAR1 and PAR4 are protease-activated receptors that respond to thrombin (IIa); P2Y1 and P2Y12 are receptors for ADP when stimulated by agonists, these receptors activate the fibrinogen-binding protein GPIIb/IIIa.

COX-1 to promote platelet aggregation and secretion. Thromboxane A2 (TxA2) is the major product of COX-1 involved in platelet activation. Prostacyclin (PGI2) synthesized by endothelial cells inhibits platelet activation.

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Aspirin:Aspirin irreversibly inhibit COX (up to the

life-time of the platelets 8-10 days). Both PGI2 and TXA2 synthesis are inhibited.To separate this action aspirin in small dose

75-100 mg/day inhibits TXA2 synthesis without significant effect on the endothelial PGI2.

This low dose of aspirin may also causes peptic ulcer bleeding in patients > 60 years.

Antiplatelet Drugs

Ticlopidine:Ticlopidine inhibits ADP- dependent platelet

aggregation.It is more effective than aspirin, but aspirin is

safer and less expensive.It is used to prevent stroke in patient who are

intolerant to aspirin.A/E: neutropenia (do WBC count / 2 weeks), GIT

upset especially diarrhea.

Clopidogrel:It acts like ticlopidine, but not associated with

neutropenia.It is more effective and more expensive than

aspirin, but safer than ticlopidine.

Dipyridamole:It inhibits phosphodiesterase enzyme, so

increasing intraplatelet cAMP.It may also increase PGI2 in vascular

endothelium.It has coronary VD activity.

Epoprostenol:It is a prostacyclin.Used during renal dialysis to prevent platelet

loss. It is used with or without heparin.It is a potent VD.

Other Antiplatelet drugs

Dazoxiben: It inhibits TXA2, but not PGI2. it is being evaluated in cardiac diseases.

Sulphinpyrazone: It is a uricosuric agent and has an antiplatelet effect. It inhibits prostaglandin synthetase.

Fish oil: (omega 3-marine triglyceride): It

may form abnormal thromboxane.

Drug Class Prototype Action Effect

AnticoagulantParenteral

Heparin Inactivation of clottingFactors

Prevent venousThrombosis

AnticoagulantOral

Warfarin Decrease synthesis ofClotting factors

Prevent venousThrombosis

Antiplateletdrugs

Aspirin Decrease plateletaggregation

Prevent arterialThrombosis

Thrombolytic Drugs

Streptokinase Fibinolysis Breakdown ofthrombi

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