Blood coagulation and fibrinolysis March 2006



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Blood coagulation and fibrinolysis

  • March 2006




Haemostasis

  • adhesion

  • shape change

  • activation and secretion

  • aggregation

  • interaction with coagulation factors



Drug classes

    • 1. Anticoagulants
    • 2. Antiplatelet drugs
    • 3. Thrombolytic Agents


Anticoagulants



Heparin

  • Glycosaminoglycan containing a mixture of sulfated mucopolysaccharides of various sizes

  • - Unfractionated (5000-30000 Da)

  • - Low molecular weight (LMWH) (1000-10000 Da)



Mechanism of Action

  • Heparin :

  • - enhances the action of Antithrombin III (AT-III) (plasma

  • protease inhibitor) 1000 fold ↑ activity

  • - antithrombin III inhibits clotting factor proteases,

  • Thrombin (IIa), IXa, Xa, XIa and XIIa, by forming stable complexes

  • - heparin binds to AT-III and causes a conformational change

  • thereby activating AT-III

  • LMWH:

  • - predominantly inhibit factor Xa

  • Heparins do not affect thrombin bound to fibrin or Xa bound to platelets





Monitoring Therapy

  • APTT (APTTR)

  • (Activated Partial Thromboplastin Time)

  • Intrinsic pathway (heparin)

  • PT (INR)

  • (Prothrombin Time)

  • Extrinsic pathway (warfarin)



Heparin - indications

  • Rapid onset of action & short half life

  • When immediate anticoagulation required

  • When quick reversal may be required

  • Prevention and treatment of venous thrombosis

  • Pulmonary embolism

  • Acute Coronary syndromes

  • Given intravenously or subcutaneously

  • Can be used in pregnant women



Adverse effects

  • Increased bleeding 3%

  • - antidote (protamine sulfate)

  • Heparin induced thrombocytopaenia

  • - HITs 1% up to 3 days 5% >5 days

  • - Can precipitate thrombosis

  • Osteoporosis with long term high-dose administration 3-6mths

  • Inhibit aldosterone synthesis – rarely causes ↑K+



Unfractionated heparin

  • Unpredictable pharmacokinetics

  • Requires regular monitoring

  • Infusion

  • Higher incidence of HITs

  • Rebound ischaemia



Low Mol Weight Heparins

  • Eg Enoxaparin; Tinzaparin

  • More predictable pharmacokinetics

  • Lower incidence of heparin-associated thrombocytopenia

  • Ease of administration s/c injection

  • No need for monitoring

  • Possible improvement in outcomes of acute coronary syndromes

  • (Such a benefit was suggested with enoxaparin in TIMI 11B, ESSENCE, and EVET)



Oral Anticoagulants



Coumarins

  • Warfarin, Dicumarol

  • Mechanism of action:

  • Block the Vitamin K-dependent glutamate carboxylation of precursor clotting

  • factors II, VII, IX and X

  • Also inhibits Proteins C & S

  • 8-12 hour delay in action because of T1/2 of clotting factors in plasma

  • recovery needs synthesis of new clotting factors

  • action is reversed with vitamin K





Monitoring Therapy

  • PT (INR)

  • (Prothrombin Time)

  • Extrinsic pathway (warfarin)

  • APTT (APTTR)

  • (Activated Partial Thromboplastin Time)

  • Intrinsic pathway (heparin)



Warfarin

  • Highly plasma protein bound

  • Metabolised by liver

  • Substrate of CYP450 enzymes

  • CYP1A2 (minor), 2C8/9 (major), 2C19 (minor), 3A4 (minor); Inhibits CYP2C8/9 (moderate), 2C19 (weak)

  • Excreted in urine and stool



Indications

  • Prophylaxis and treatment of

  • venous thrombosis

  • pulmonary embolism

  • thromboembolic disorders

  • atrial fibrillation with risk of embolism

  • prophylaxis of systemic embolism post MI (LV thrombus)



Adverse effects

  • Bleeding

  • (risk depends on both the INR and patient factors)

  • Contraindicated in pregnancy

  • - teratogenic effects, crosses placenta risk foetal haemorrhage

  • Warfarin induced skin necrosis

  • - paradoxical local thrombosis

  • - increased in patients with protein C or S deficiency

  • "Purple toes syndrome," cholesterol microembolization

  • Hepatic dysfunction



Precautions

  • Patient compliance

  • - eg dementia

  • Patient’s bleeding risk

  • - eg falls, chronic liver disease, alcoholism, past history

  • Dietary factors

  • - eg malnutrition

  • Drug interactions



Interactions

  • Pharmacokinetic

  • - changes in the absorption, protein binding, and/or metabolism

  • - metabolism/elimination via cytochrome P450 system (common)

  • - displacement of warfarin from plasma protein-binding sites eg NSAIDs (less important)

  • Pharmacodynamic

  • - alter the risk of bleeding or clotting by either effect on platelet aggregation or vitamin K catabolism



CYP450 and Warfarin

  • CYP2C8/9 inducers ↓ warfarin effect

  • eg Carbamazepine, phenobarbital, phenytoin, rifampin

  • CYP2C8/9 inhibitors ↑ warfarin effect

  • eg fluconazole, gemfibrozil, ibuprofen, ketoconazole, mefenamic acid, miconazole, nicardipine, pioglitazone, amiodarone, isoniazid, losartan, omeprazole, pantoprazole

  • CYP2C8/9 gene polymorphism



Alcohol and Warfarin

  • Acute ethanol ingestion (binge drinking) decreases the metabolism of warfarin and increases PT/INR

  • Chronic daily ethanol use increases the metabolism of warfarin and decreases PT/INR



Food and Warfarin

  • The anticoagulant effects of warfarin may be decreased if taken with foods rich in vitamin K eg liver, green tea and leafy green vegetables

  • Vitamin E may increase warfarin effect

  • Cranberry juice may increase warfarin effect



Herbal/Nutraceuticals

  • Cranberry, fenugreek, ginkgo biloba, glucosamine, may enhance bleeding or increase warfarin's effect

  • Ginseng (American), coenzyme Q10, and St John's wort may decrease warfarin levels and effects



Antibiotics and Warfarin

  • Cytochrome P450 High risk >75%

  • - eg Erythromycin, Clarithromycin, Ciprofloxacin, Co-trimoxazole, Metronidazole, Ketoconazole, Fluconazole

  • Any broad-spectrum antibiotics can suppress production of vitamin K by the gut flora



Management of elevated INR

  • INR <6 No significant bleeding

  • - Reduce dose or hold the next dose until INR <5

  • INR >6 and <8 No significant bleeding

  • - Hold the next 1or 2 doses until INR <5 then resume lower dose

  • INR >8: No significant bleeding

  • - Hold warfarin until INR <5

  • - Vitamin K orally 5-10 mg or 0.5mg iv if high risk for bleeding

  • Any INR elevation + Serious bleeding

  • - Hold warfarin, give vitamin K (10 mg by slow I.V. infusion), and supplement with fresh plasma transfusion or prothrombin complex concentrate (factor X complex)



Vitamin K and Warfarin

  • Note: Use of high doses of vitamin K (10-15mg) may cause resistance to warfarin for more than a week

  • Heparin or low molecular weight heparin can be given until the patient becomes responsive to warfarin



Newer Anticoagulants



Direct Thrombin Inhibitors

  • Eg Hirudin, a naturally occurring anticoagulant

  • Bind directly to thrombin's catalytic site rather than to antithrombin III

  • Inhibit clot-bound thrombin

  • Increased risk of major hemorrhage with hirudin

  • Possible role in HITs



Ximelegatran

  • Oral direct thrombin inhibitor

  • Concerns re: hepatotoxicity

  • No antidote



Antiplatelet agents



Antiplatelet agents

  • Predominantly prevent arterial thrombosis

  • In acute setting of MI & ischaemic stroke

  • Secondary prevention of vascular events

  • Primary prevention when 10 yr risk >15% and BP controlled



Antiplatelet drug targets

  • Prostaglandin synthesis

  • ADP binding

  • GPIIb/IIIa receptor

  • Cyclic AMP



Antiplatelet agents





COX-1 vs COX-2 inhibitors





Aspirin

  • Pros -

  • Inexpensive

  • Proven efficacy

  • Cons –

  • Intolerance

  • Limited potency



Adverse effects

  • GI ulceration 6-31%

  • Haemorrhage

  • Bronchospasm

  • Interstitial nephritis, papillary necrosis, proteinuria, renal failure

  • Reye’s syndrome in children CI <16yrs

  • Dangerous in overdose



Antiplatelet agents



Clopidogrel

  • Alternative to aspirin

  • First choice for aspirin intolerance

  • In addition to aspirin in context of

  • Primary PCI

  • Acute coronary syndromes

  • Secondary prevention of MI but NOT stroke



Adverse effects

  • GI upset

  • Bleeding

  • Blood dyscrasias



Aspirin + Clopidogrel

  • significant increase in major (3.7 versus 2.7 percent for aspirin alone) and minor bleeding (5.1 versus 2.4 percent)

  •  bleeding risk with clopidogrel plus aspirin in patients who require coronary artery bypass graft surgery (CABG)





GP IIb/IIIa inhibitors for ACS

  • Among patients undergoing PCI with stenting

  • Periprocedural administration of GP IIb/IIIa inhibitors improves outcomes in patients with a non-ST elevation ACS

  • No evidence for benefit in context of thrombolysis



Glycoprotein IIb/IIIa inhibitors

  • Adverse effects

  • Drug-induced thrombocytopaenia

  • Bleeding

  • Emergency CABG (abciximab-treated patients were more likely to require surgical reexploration for bleeding (12 versus 3 percent))



Antiplatelet agents



Dipyridamole

  • pyrimido-pyrimidine derivative

  • vasodilatory effects on coronary resistance vessels

  • increases intracellular platelet cAMP activating the enzyme adenylate cyclase, and inhibiting uptake of adenosine from vascular endothelium and erythrocytes

  • *even the usual oral doses of dipyridamole may enhance exercise-induced myocardial ischemia in patients with stable angina





Summary

  • Aspirin + Clopidogrel proven in

  • - acute MI

  • - ACS

  • - prior to PCA + stenting

  • - but not indicated in stroke prevention



Summary

  • GP IIb/IIIa inhibitors proven benefit

  • - prior to PCI

  • - provided CABG not required

  • Dipyridamole possible role in stroke

  • UFH/LMWH proven benefit in

  • - acute coronary syndromes

  • - short term therapy only



Fibrinolytics



Fibrinolytics

  • Streptokinase, Urokinase, Alteplase (rt-PA), Reteplase, Tenecteplase

  • MOA: Plasminogen activators

  • Plasmin degrades fibrin and breaks up thrombi



Streptokinase

  • Derived from bacterial protein

  • Antigenic (abys after 4 days)

  • Cleaves Plasminogen

  • Low fibrin specificity

  • Cheap



Urokinase

  • Intrinsic compound

  • Isolated from urine or renal cell cultures

  • Non-antigenic

  • Cleaves plasminogen

  • Not licensed for MI



Tissue plasminogen activator

  • Intrinsic compound

  • Recombinant DNA manufacture

  • Non-antigenic

  • Short half-life – give heparin afterwards

  • Higher fibrin specificity

  • Expensive

  • ? More effective



Reteplase/Tenecteplase

  • Variants of TPA

  • Longer half-life

  • Easy to use

  • More fibrin specific



Indications

  • Acute trans-mural MI within 12 hrs

  • Ischaemic stroke within 3 hrs

  • Massive PE

  • Peripheral arterial thrombus

  • Blocked lines

  • Massive DVT

  • Thrombosed prosthetic valves



Indications in MI

  • Clinical history of MI and either ST elevation or new LBBB

  • True posterior MI

  • As early as possible

  • Little benefit after 12 hrs and no benefit after 24



Contra-indications

  • Aortic dissection

  • Recent or active bleeding

  • Recent major surgery

  • Bleeding diathesis or coagulation disorder

  • Pregnancy

  • Previous intracranial bleed

  • Recent embolic CVA



Complications

  • Bleeding

  • Allergic reactions

  • Hypotension

  • Arrhythmias

  • Re-perfusion injury




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