Anticoagulants

Dr Rahul KunkulolDepartment of Pharmacology,

RMC,LONI

ANTIPLATELETS

Dr Rahul KunkulolDepartment of Pharmacology,

RMC,LONI

HAEMOSTASIS- Cessation of blood loss from damaged blood

Vascular Phase

Platelet Phase

Coagulation Phase

Fibrinolytic Phase

Vascular Phase

Vasoconstriction

Exposure to tissues activate Tissue

factor and initiate

coagulation

Tissue Factor

Platelet Phase

Platelet adhesion

Platelet plug

Platelet aggregation

WHAT ARE PLATELETS ?

White, discoid

Smallest element of flowing blood • 1 - 2 microns diameter

Lipid bilayer membrane

Normal range 150000 – 450000 microlitre blood

Formed from cytoplasm of megakaryocytes

No nucleus

Normal Function of Platelets

Haemostasis

Preventing

bleeding from wounds

Integrity and repair of the vessel wall

Platelet AggregationFibrinogen binding to Glycoprotein IIb-IIIa on

activated platelets

Collagen VWF

INJURY

Platelet Adhesion& Secretion

Platelet aggregation

Tissue Factor

Coagulation Cascade

Thrombin

Fibrin

Haemostatic plug

Vaso-constriction

Blood VesselEndothelium

Subendothelium

Thrombogenesis

Arterial thrombi Platelet

aggregates bound together by fibrin strands (white clots)

Venous thrombi Consist mainly of

fibrin and RBCs (red clots)

Arterial thrombus

Platelets and ThromboemolismArterial thrombus

(white) Occludes

artery / disintegrates into emboli occluding distal vessels resulting in ischemic necrosis of tissue supplied by the artery.(AMI)

Venous thrombus (red) Veins low pressure

: Reduced blood flow (stasis)

Especially in valve pockets

Causes tissue drained by the vein to be edematous and inflamed (DVT)

Vascular Injury

Trauma Surgical

manipulation Prior thrombosis Atherosclerosis

VascularInjury

PLATELET AGGREGATORS

Collagen

Von willebrand factor

ADP

Thromboxane A2

Stress

Thrombin

Damaged blood vessel

Release of collagen Activation of platelets

Arachidonic acid Release of thrombinRelease of ADP

Cyclic endperoxidase

COX

Release of TXA2

Activation of glycoprotein IIB/IIIA receptors

Fibrinogen fibrin

Activates P2Y1 Gq Gi

Changes in platelet shape

Increases phospoinositol

inhibits adenylcyclase,

decrease CAMP ?

Targets for anti-platelet therapy

Aspirin

NSAIDs

ADP

receptor

COX-1

TXA2

GPIIb - IIIa

Signalling

pathways

ADP receptor antagonistsClopidogrel THROMBIN

receptor

Thrombin inhibitors

II

Fibrinogen

Phosphodiesterase inhibitors

dipyridamole

Fibrinogen Receptor Antagonists

AA

PGI 2- (Prostacyclins)Naturally occurring potent vasodilator and inhibitor of platelet aggregation.

Produced by vessel walls, also present in brain ,gut and kidney.

Formed from PG endperoxidase by the action of COX

Inhibit platelet aggregation by stimulating adenylcyclase increasing cyclic AMP levels in platelets.

Prostacyclins causes hypotension , tachycardia ,headache. intense facial flushing

Very unstable ,1/2 life of 3 mins.

Prostacyclins (Epoprostananol)-used during haemodialysis.

CLASSIFICATION OF ANTIPLATELET AGENT-

1. PGI 2

• Aspirin

2. TXA2 inhibitors-

• Ticlopidine, Clopidogrel

3. ADP antagonists-

• Dipyridamole, Pentoxifylline

4. Phospodiesterase inhibitor-

5. Glycoprotein IIB/IIIA receptors antagonists-

Abciximab, Eptifibatide, Tirofiban

Damaged blood vessel

Release of collagen Activation of platelets

Arachidonic acid Release of thrombinRelease of ADP

Cyclic endperoxidase

COX

Release of TXA2

Activation of glycoprotein IIB/IIIA receptors

Fibrinogen fibrin

Activates P2Y1 Gq Gi

Changes in platelet shape

Increases phospoinositol

inhibits adenylcyclase,

decrease CAMP ?

• MOA-ASPIRIN-

In platelets major COX product is TXA2 , a labile inducer of platelet aggregation and potent vasoconstrictor.Aspirin blocks production of TXA2 by covalently acetylating serine residue near the active site of COX, this enzyme produces cyclic endperoxidase precursor of TXA2.Since platelets do not synthesize new proteins hence the action of aspirin on platelets is permanent (7-10 days).

For complete inactivation of platelet COX dose of aspirin

req. is 160 mg daily.

Reason—Higher doses decrease efficacy of aspirin as they

inhibit production of prostacyclins which is spared

at low doses. (75-150mg) Higher doses also increase toxicity esp.. Bleeding.

USES OF ASPIRIN

Prevention of AMI in pts. Of unstable angina

Prevention of reinfarction in pts. Of AMI and IHD

Prevention of stroke in pts. Of cerbrovascular accidents and h/o TIA

For improving prognosis in patients with atherosclerotic peripheral vascular diseases

Percutaneous angioplasty for coronary thrombosis ,

Primary prophylaxis of thromboembolism in pts with prosthetic heart valves

ADP antagonists- Ticlopidine

Ticlopidine blocks Gi coupled ADP receptors

It is a prodrug requires conversion to active form by Cyp450.

Rapid absorp. ,high bioavailability

Maximal inhibition of platelet inhibition it takes 8-11 days after starting therapy.Dose-loading 500mg for rapid onset of action. Usual dose 250mgBDAE- Nausea ,Vomiting, Diarrhea, Neutropenia, Thrombotic ThrombocytopeniaUses- Prevention cerebrovascular events, in 2ndary prevention of stroke

Unstable angina

Combination –Aspirin + ticlopidine---angioplasty, coronary artery stenting

Clopidogrel

Less toxic then ticlo. less incidence of leucopenia, thrombocytopenia.

Less used than Ticlopidine

MOA, PK profile same as Ticlopidine

Dose 75mg/day

Rest same as Ticlopidine.

Dipyridmole-

• MOAInhibition of PDE (phospodiesterase enzyme) and/ or by blockade of adenosine which act at A2 receptor to stimulate adenylcyclase thus increase CAMP causing platelet inhibition.

Current recommended use- Along with Warffarin in primary prophylaxis of thromboemboli in pts with prosthetic heart valves

Xanthine analogue

Increases deformability of RBCs thus increases microcirculation, reduce fibrinogen levels, inhibit pl. aggregation.

Uses- CVAs esp.TIA(transient ischemic attacks) ,

Ischemic ulcers of legs

Dose 400mg tds

Pentoxifyllines

Glycoprotein IIB/IIIA receptors antagonists

Platelet surface receptor, receptor for fibrinogen and von willebrand factor,which anchors platelets to foreign surface and each other thereby mediating aggregation.Receptor is activated by TXA2, Collagen, and thrombin to developbinding sites for its ligands.

Inhibition of binding to this receptor blocks platelet aggregation induced by the agonist.

Abciximab

Monoclonal antibody cause platelet receptor blockade.

Given IV max. effect seen with in 2hrs, DOA 10-12 hrs.

Use- percutaneous angioplasty for coronary thrombosis

Prevents restenosis, recurrent and death when used in conjugation with aspirin and heparin.

Dose-0.25mg bolus---0.125microgm/kg/min for 12hrs IV

AE-bleeding

Contraindication same as fibrinolytics

Questions

Discuss in detail antiplatelet drugs. Add note on use of low dose Aspirin as an antiplatelet agent.

Short note: Low dose Aspirin Ticlopidine Glycoprotein IIb/IIIa antagonists

Anticoagulants

Dr Rahul KunkulolDepartment of Pharmacology,

RMC,LONI

Coagulation Phase

Two major pathways

• Intrinsic pathway• Extrinsic pathway

13 soluble factors are involved in clotting

Biosynthesis of these factors are dependent on Vitamin K1 and K2

Most of these factors are proteases

Normally inactive and sequentially activated

Hereditary lack of clotting factors lead to hemophilia -A

35

Clotting factors

Intrinsic Pathway All clotting factors

are within the blood vessels

Clotting slower

Activated partial thromboplastin test (aPTT)

Blood sample + calcium Mix with negatively charged

phospholipid Kaoline (aluminum silicate) Determine clotting time

Generally clotting occurs in 26 to 33 seconds

Used to detect defects in the intrinsic pathway

Extrinsic Pathway Initiating factor

outside the blood vessels - tissue factor

Clotting - faster - in Seconds

Prothrombin test (PT) Tissue Thromboplastin factor III Mix with phospholipid extract Add calcium and blood sample Determine clotting time

Generally 12 - 14 seconds

Used to detect defects in extrinsic pathway

Diagnosis of coagulation defects

•Defective Intrinsic Pathway

Prolonged APTTNo change in PT

•Defective Extrinsic Pathway

No change in APTT Prolonged PT

•Defective in Common pathway

Prolonged APTT Prolonged PT

Blood Vessel Injury

IX IXa

XI XIa

X Xa

XII XIIa

Tissue Injury

Tissue Factor

Thromboplastin

VIIa VII

X

Prothrombin II Thrombin IIa

Fibrinogen Fribrin monomer

Fibrin polymerXIII

Intrinsic Pathway Extrinsic Pathway

Factors affected

By Heparin

Vit. K dependent FactorsAffected by Oral Anticoagulants

Activation

Inactive XI Active XIa

XIIa

+

ANTICOAGULANTS These are the drugs used to reduce

coagulability of blood. ClassificationIn vitro anticoagulants In vivo

anticoagulantsHeparin A) -HeparinSodium citrate -Low molecular weight

HeparinSodium oxalate -DanaparoidSodium edetate -Lepirudin

-Heparan sulfate B) Oral anticoagulants

B) Oral anticoagulants Warfarin sodium Bishydroxycoumarin (dicumarol) Acenocoumarol Phenindione

HeparinChemistry & OccurenceStraight chain mucopolysaccharide, glycosaminoglycansMW 10000-20000. Average=15,000 d

(~45monosaccharide chains) Strongest organic acid in the body.Heparin is present in all tissues containing mast cells, richest source are liver, lung (bovine) and intestinal mucosa (porcine)LMWH isolated from standard heparin by gel filtration chromatography or partial depolymerization. (1000-10000 daltons).

MOA Heparin binds to antithrombin III -----

complex Increases thrombin –AT reaction

1000folds. Heparin induces conformational change

in ATIII to expose its interactive sites. Long heparin molecule provides

scaffolding for clotting factors ( Xa & IIa) aswellas ATIII.

At low conc. interferes with intrinsic pathway while at high common pathway.

ATIII inhibits activated clotting factors of intrinsic and common pathway including thrombin, Xa, IXa and thus acts as Succide substrate

ATIII-SUCCIDE SUBSTRATE

Thrombin inhibition catalysed by heparin

AT

R

H

AT H

IIa

AT H

IIa

IIa

AT H

IIa

RP

P

PP

R

R

FXa inhibition catalysed by heparin

AT

R

H

AT H

Xa

AT H

Xa

Xa

AT H

Xa

RP

P

PP

R

R

Anticoagulant Properties of Heparin

1. Inhibits the thrombin-mediated conversion of fibrinogen to fibrin

2. Inhibits the aggregation of platelets by thrombin

3. Inhibits activation of fibrin stabilizing enzyme

4. Inhibits activated factors XII, XI, IX, X and II

Pharmacokinetics

Not effective orally Sc/ iv administration Onset immediate, peak in 5-10mins Metabolized in liver Excretion through kidney.

Unfractionated Heparin

High Dose Treatment of venous/arterial thrombi Requires monitoring IV- 5,000 Units bolus, then 30,000-

35,000 units/24 hrs 80 Units/kg bolus, then 18 Units/kg/hr

to maintain aPTT in therapeutic range therapeutic goal – 2-2.5 times normal

control value (-30 sec)

Low Dose Unfractionated Heparin

Surgical Prophylaxis 5,000 Units SC 2 hr preop 5,000 Units SC every 12 hours

Medical Prophylaxis 5,000 Units SC every 12 hours

No monitoring required

ADVANTAGES OF LMWH

1. Less anti IIa

activity than anti

Xa activity

2. Good pk profile

3. More predictable

dose response

4. Can be given by

subcutaneous

route

5. No monitoring

required, can be

given OPD basis

6. Less anti-platelet

effects

7. Longer t1/2’s

8. Decreased

hospital stay

9. More favorable

benefit –risk ratio

LMWH ENOXAPARIN

1mg/ kg S.C BD for DVT

30mg/ Kg S.C. for DVT prophylaxis of Knee and hip surgery

DALTEPARIN 1mg/ kg S.C BD for

DVT 30mg/ Kg S.C. for

DVT prophylaxis of Knee and hip surgery

Newer

ARDEPARIN

NADROPARI

N

TINZAPRIN

REVIPARIN

Adverse effects

Allergic and anaphylactic manifestations

Bleeding (1-33%)-antidote- Protamine sulphate

Heparin induced thromocytopenia. (more than 25%)

Alopecia Osteoporosis Hyperkalemia

Mechanisms of HIT Type 1 (Non immune):

Fall in platelet count occurs within the first two days after heparin initiation, and returns to normal with continued heparin administration, and is of no clinical consequence.

Direct effect of heparin on platelet activation.

   Type 2 (Immune): Approx 0.3 to 3 percent of patients receiving heparin Mediated by antibodies to a heparin-platelet factor 4

complex. Seen with unfractionated heparin but in not with LMWH

Anticoagulants II

Dr Rahul KunkulolDepartment of Pharmacology,

RMC,LONI

WarfarinWarfarin, a coumarin derivative, is the most commonly used oral anticoagulant (OAC) .

Warfarin is a vitamin K antagonist - Impairs the generation of active vitamin K, decreasing the amounts of vitamin K dependent coagulation factors • (FII, FVII, FIX, FX)Depending on factors such as age, risk factors, recurrence, etc., warfarin may be continued for anywhere from 1 month to lifelong

Oral anticoagulants : warfarin, dicumarol

Coumarins - warfarin, dicumarol Isolated from clover leaves Structurally related to vitamin K Inhibits production of active clotting

factors Absorption rapid –high plasma protein

binding binds to albumin Clearance is slow - 36 hrs Delayed onset 8 - 12 hrs Overdose - reversed by vitamin K infusion Can cross placenta - do not use during

late pregnancies

Mechanism of action

Descarboxy Prothrombin Prothrombin

Reduced Vitamin K Oxidized Vitamin K

NADHNAD

Warfarin

Warfarin Monitoring

• Why monitor? Need to balance proper anticoagulation without bleeding risk.• Monitored with PT, expressed as

INR:

Warfarin Monitori

ng• Where ISI = International

Sensitivity Index, assigned by each thromboplastin manufacturer

• Warfarin is given orally and titrated to achieve an INR of typically 2.0 – 3.0

INR =

[Patient PT / Mean Normal

PT]ISI

INR : International Normalized Ratio.

Different thromboplastins vary in sensitivity

To give PT values a consistent basis of comparison from lab to lab, WHO instituted the INR: A uniform value in which the PT is

expressed as a ratio. Many manufacturers aim for an ISI of

1.0. INR is affected by diet (because of the

vitamin K dependent mechanism of action), other medications,

Monitored routinely, every 2 to 4 weeks

Drug interaction- Prototype Warfarin

Category Mechanisms Examples of drugs

Drugs that Increase Warfarin Activity

Decrease binding to Albumin Aspirin, Sulfonamides

Inhibit Degradation Cimetidine,

Decrease synthesis of Clotting Factors

Antibiotics (oral)

Drugs that promotebleeding

Inhibition of platelets Aspirin

Inhibition of clotting Factors HeparinAntimetabolites

Drugs decreaseWarfarin activity

Induction of metabolizing Enzymes

Barbiturates

Increases synthesis of Clotting Factors

Vitamin K

New Anticoagulants

Limitations of traditional

anticoagulants, both with Heparin and Warfarin, have

prompted the development of

new agents

New Anticoagulants

• Fondaparinux• Danaparoid

Parenteral FXa

Inhibitors

• Hirudin • Argatroban• Bivalirudin• Ximelagatran

Direct Thrombin Inhibitors (DTIs)

FXa InhibitorsParenteral synthetic

pentasaccharide analogs• Synthetic and highly

selective inhibitor of FXa

• Acts as cofactor to AT• Administered by

subcutaneous injection ONCE A DAY

• Absolute bioavailability of 100%

Fondaparinux

(Arixtra®)

FXa InhibitorsParenteral synthetic

pentasaccharide analogs

• LMW mixture of heparinoids (glycosaminoglycans, GAGs); acts as cofactor to AT

• Anticoagulation effect is predominantly mediated by inhibition of FXa

• Also has some anti-IIa effects• Fast acting, generally

predictable dose response

Danaparoid

Direct Thrombin Inhibitors

•Recombinant hirudin, a derivative of the saliva of the medicinal leech Hirudo medicinalis •First direct thrombin inhibitor (DTI) to be approved by the FDA for anticoagulation in patients with (HIT)•Can be monitored with APTT, TT, chromogenic anti-IIa.

Lepirudin

(Recombinant hirudin

)

Direct Thrombin Inhibitors

• A synthetic anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT)

• Active against both free and clot-bound thrombin

• Argatroban is typically monitored by APTT, but other methods like the chromogenic anti-IIa assay may be more accurate.

Argatroban

Direct Thrombin Inhibitors

•Synthetic polypeptide hirudin analog that interacts with the thrombin active site to reversibly inhibit thrombin•Alternative to heparin •Administered parenterally•Short half life•Monitored by Activated Clotting Time (ACT)

Bivalirudin

Direct Thrombin Inhibitors

•Studies have shown similar efficacy and bleeding risk to warfarin•Does not need monitoring•Was not FDA approved: more studies needed to assess liver failure risk

Ximelagatran oral

anticoagulant

• Venous thrombosis, DVT.

• Pulmonary embolism• Chronic atrial

fibrillation.• Recurrent

thromboembolism.• Unstable angina,

acute myocardial infarction.

• Rheumatic heart disease.

USESOF

ANTICOAGULANTS

• Coronary angioplasty, stent placement, cardiopulmonary bypass surgery.

• DIC• Pheripheral arterial

embolism.• CVA-little value.• Vascular surgery,

prosthetic heart valves, retinal vessel thrombosis, haemodialysis.

USESOF

ANTICOAGULANTS

The Extent of Thrombotic Disease Annually in the U.S.

1.5 million MIs-Mortality of 30% (450,000) 500,000 CVAs -Mortality of 30% (150,000) 2 million DVTs 200,000 deaths from PE

Venous Thromboembolism

Third most common cardiovascular diseaseSignificant morbidity and mortalityVTE includes:• Deep Venous Thrombosis

(DVT)• Pulmonary Embolism (PE)

Economy Class Syndrome

Medical condition called Venous ThromboembolismFibrin thrombi.3months anticoagulants theraphy is required in DVT and PEFor prophylaxis of pts.undergoing surgery---LMWH—Decreases risk of leg vein thrombosis & PE.Anticoagulants are indicated for prophylaxis in bedridden, old, postoperative, post stroke, postpartum, leg fracture patients

Deep Vein Thrombosis

Blood clot of lower leg or thigh

Approximately 1 per 1,000 people affected by DVT

Hospitalization for 5 to 7 days

50% of patients with DVT are asymptomatic

Pulmonary EmbolismDislodged blood clot

entering the pulmonary circulation

Accounts for 5-10% of all hospital

deaths

80% of patients die within the

first 2 hours CT Scan of Pulmonary Embolism

Deep Vein ThrombosisEmbolusPulmonary Embolism

AMI AND UNSTABLE ANGINA

Arterial thrombi-platelet thrombi

Use of anticoagulants???Beneficial in preventing mural thrombi at infarction site and venous thrombi in leg veins.Can be given for short periods till the Pt. is ambulatory.Heparin iv for 2-8 days followed by oral anticoagulant for 3 months.

Short term use in unstable angina.

RHD, AF

Warfarin / low dose aspirin / LMWH are effective in preventing stroke due to embolism from fibrillating atria.

Warfarin the most effective.(3-4week theraphy)

Blood Hypercoagulability

Increased procoagulants

Decrease in inhibitors

Impaired fibrinolysis

Occurs in obstretic conditions, mallignancies, infections.

FIBRINOLYTICS

Dr Rahul KunkulolDepartment of Pharmacology,

RMC,LONI

• Enhance degradation of clots

• Activation of endogenous protease• Plasminogen (inactive form)

is converted to Plasmin (active form)

• Plasmin breaks down fibrin clots

Fibrinolysis

FIBRINOLYTICS

• Streptokinase • Urokinase

CONVENTIONAL

NONSELECTIVE

AGENTS

• Recombinant Tissue plasminogen activator (tPA)• Alteplase• Reteplase• Tenectaplase

Fibrin selective agents

Fibrinolysis• Streptokinase - bacterial product

- continuous use - immune reaction • Urokinase - human tissue derived -

no immune response• Tissue plasminogen

activator (tPA) - genetically cloned - no immune reaction - EXPENSIVE

FIBRINOLYT

ICS

• Epsilon Aminocaproic acid

• Tranexamic acid

Inhibitors of

fibrinolysis

Streptokinase

Streptokinase is a protein (but not an enzyme in itself) synthesized by streptococci that combines with the pro-activator plasminogen.

This enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin

Urokinase

Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to active plasmin.

Plasmin formed inside a thrombus by these activators is protected from plasma antiplasmins, which allows it to lyse the thrombus from within

Tissue plasminogen activators (t-PAs).

Plasminogen can also be activated endogenously by tissue plasminogen activators (t-PAs).

Activate plasminogen that is bound to fibrin, which (in theory) confines fibrinolysis to the formed thrombus and avoids systemic activation.

Human t-PA is manufactured as ALTEPLASE by means of recombinant DNA technology.

Tissue plasminogen activators (t-PAs).

RETEPLASE is less expensive than Alteplase. It lacks the major fibrin-binding domain thus is less fibrin-specific than Alteplase

TENECTEPLASE is a mutant form of t-PA that has a longer half-life, and it can be given as an intravenous bolus. Tenecteplase is slightly more fibrin-specific than Alteplase

DOSES

•Dose:250000 U loading dose followed by 100000 U every hr for 24 -72 hrs

Streptokinase

•Loading dose of 300000 U followed by 300000 U/hr for 12 hrs

Urokinase

•60mg iv over 1 hr followed by 40mg iv at a rate of 20mg/ hr

Alteplase (t-PA)

Contraindications to Antithrombotic Therapy

• Pre-existing coagulation or platelet defect, thrombocytopenia, or other bleeding abnormality

• Inaccessible ulcerative lesion(e.g., gastrointestinal tract lesion)

• Central nervous system lesion (e.g., caused by stroke, surgery, trauma)

• Malignant hypertension• Advanced retinopathy• Old age (relative)• Aspirin or other antiplatelet

drugs• Neoplastic disease

General risk factor

s

Contraindications to Antithrombotic Therapy

•Recent thoracic, abdominal, or central nervous system surgery•Recent cerebrovascular accident, trauma, or neoplasm•Bleeding ulcer•Anticipated invasive procedures (arterial punctures, biopsies, central lines)•Concurrent hemostatic dysfunction

Specific to

thrombolytic agents

•AMI•Multiple pulmonary emboli.•Pulmonary embolism with hemodynamic instability•Central DVT•Pheripheral vascular disease

Indications

Drug preparations : to stop bleeding

•Aminocaproic acid•Tranexamic acid•Vitamin K

Systemic use

•Gelatin sponge (Gelfoam)•Gelatin film•Oxidized cellulose ( Oxycel)•Microfibrillar collagen (Avitene)•Thrombin

Local absorbable drugs

(STYPTICS)

Fibrinolytic Inhibitors: Aminocaproic Acid

Similar to the amino acid lysine, is a synthetic inhibitor of fibrinolysis

Competitively inhibits plasminogen activation

Oral dosage of EACA is 6 g four times a day

Tranexamic acid is an analog of aminocaproic acid and has the same properties. It is administered orally with a 15 mg/kg loading dose followed by 30 mg/kg every 6 hours

USES Adjunctive therapy in hemophilia Bleeding from fibrinolytic therapy Prophylaxis for re-bleeding from

intracranial aneurysms. Postsurgical gastrointestinal

bleeding ,post prostatectomy bleeding ,bladder hemorrhage secondary to radiation and drug-induced cystitis.

Adverse effects Intravascular thrombosis from

inhibition of plasminogen activator Hypotension, myopathy, abdominal

discomfort, diarrhea, and nasal stuffiness

Drug preparations: clotting deficiencies

Vitamin K

• Oral : 5 mg tablets

Plasma fractions - for hemophilia

• Antihemophilic factor ( VIII, AHF)• Parenteral

Factor IX complex

• Parenteral : in vials