2. • Whenever a blood vessel is severed or ruptured, hemostasis is achieved by
• Vascular spasm
• Platelet plug formation
• Formation of blood clot
• Growth of fibrous tissue into the blood clot.
• Coagulation is a complex process by which blood forms clots.
• Disorders of coagulation can lead to an increased risk of bleeding
(hemorrhage) or clotting (thrombosis)
Introduction
3. Platelet activation and thrombosis.
• Platelets circulate in an inactive form in
the vasculature.
• Damage to the endothelium and/or
external stimuli activates platelets
that adhere to the exposed
subendothelial von Willebrand factor
and collagen.
• Adhesion leads to activation of the
platelet, shape change, and the
synthesis and release of thromboxane
(TxA2), serotonin (5-HT), and
adenosine diphosphate (ADP).
• Platelet stimuli cause conformational
change in the platelet integrin
glycoprotein (GP) IIb/IIIa receptor,
leading to the high-affinity binding of
fibrinogen and the formation of a
stable platelet thrombus.
8. ANTICOAGULANTS
• An anticoagulant is a substance that prevents coagulation; that is, it stops
blood from clotting.
• The parenteral anticoagulants include
• heparin, low-molecular-weight heparin (LMWH), fondaparinux (a synthetic
pentasaccharide), lepirudin, desirudin, bivalirudin, and argatroban.
• Currently available oral anticoagulants include
• warfarin;
• dabigatran etexilate - an oral thrombin inhibitor; and
• rivaroxaban, apixaban, and edoxaban - oral factor Xa inhibitors.
9. Heparins-
• A sulfated polysaccharide isolated from mammalian tissues rich in mast cells.
• Acts by activating antithrombin and accelerating the rate at which
antithrombin inhibits clotting enzymes, particularly thrombin and factor Xa.
• Only pentasaccharide-containing heparin chains composed of at least 18
saccharide units (~molecular weight 5400) are of sufficient length to bridge
thrombin and antithrombin together.
10. Unfractionated Heparin LMWH Fondaparinux
Activates antithrombin and acclerates the rate at which
antithrombin inhibit factor Xa and thrombin
Antithrombin, the obligatory plasma cofactor for heparin
To activate antithrombin, heparin binds to the serpin via a
unique pentasaccharide sequence
mean molecular weight of 15,000, and a range of 5000–
30,000
Consisting of smaller fragments of heparin
prepared from unfractionated heparin by
controlled enzymatic or chemical
depolymerization.
Mean molecular weight ~ 5000, one-third
the mean molecular weight of
unfractionated heparin.
synthetic analogue of the antithrombin-binding
pentasaccharide sequence
as effective as heparin or LMWH - DVT or PE
Prophylaxis: 5000 units S/C bd – tds
Therapeutic
• MI: IV bolus 5000 u or 70 u/kg f/b infusion @ 12–15 u/kg/
hr
• DVT: IV bolus of 80 u/kg f/b infusion @ 18 u/kg/ hr
Monitoring-
APTT-Therapeutic range:2-3 times of control value
Anti factor Xa level :0.3-0.7 units/ml
S/E- Bleeding, HIT,Osteoporosis
Elevated Transaminases
Antidote-Protamine
Dosing-
therapeutic dose-1mg/kg SC BD
Prophylaxis-40mg SC OD
Monitoring
Usually not done
• Anti factor Xa levels:0.2-0.5prophylaxis
• 0.5 – 1.2 units/ml therapeutic
• S/E-occurs rarely
Antidote-Protamine only partially reverse
• Complete bioavailability after SC
(as no binding with endothelium or plasma protein)
• Half life is longer than LMWH (OD dose)
• Clearance – Renal (<30 GFR C/I)
2.5mg sc od - prophylaxis
5mg sc od - if less than 50 kg
10 mg sc if > 100kg
Monitoring not needed
major bleeding 50% lower enoxaparin; NO HIT
No antidote
11. Parenteral Direct Thrombin Inhibitors
• Directly to thrombin and block its interaction with its substrates.
• Approved parenteral direct thrombin inhibitors include recombinant
hirudins (lepirudin and desirudin), argatroban, and bivalirudin .
• Lepirudin and Argatroban -HIT,
• Desirudin - Thromboprophylaxis after elective hip arthroplasty, and
• Bivalirudin - an alternative to heparin undergoing PCI, including those with
HIT.
12. Indications of Anticoagulant Therapy
• Prevention and Treatment of Deep Venous Thrombosis
• Treatment of Pulmonary Emboli
• Prevention of stroke in patients with atrial fibrillation, artificial heart
valves, established thrombosis (DVT, Cardiac)
• Ischaemic heart disease
• During procedures such as cardiac catheterisation
14. ORAL ANTICOAGULANTS
• For many years, vitamin K antagonists such as warfarin were the only
available oral anticoagulants.
• This situation changed with the introduction of the direct oral
anticoagulants (DOAC), which include
• dabigatran, rivaroxaban, apixaban, and edoxaban.
15. Warfarin
• Warfarin inhibits vitamin k epoxide reductase
• Warfarin accumulates in the liver where the two isomers are metabolized via
distinct pathways.
• CYP2C9 mediates oxidative metabolism of the more active S isomer.
• Polymorphisms in VKORC1 also can influence the anticoagulant response to
warfarin.
• VKORC1 variants are more prevalent than variants of CYP2C9.
• Asians more common
16. MECHANISM OF ACTION
• A racemic mixture of S- and R-enantiomers, S-warfarin is most active.
• By blocking vitamin K epoxide reductase inhibits the conversion of
oxidized vitamin K.
• It inhibits vitamin K–dependent γ-carboxylation of factors II, VII, IX, and X
• As reduced vitamin K serves as a cofactor for γ-glutamyl carboxylase,
• catalyzes the γ-carboxylation process, thereby converting prozymogens to
zymogens capable of binding calcium and interacting with anionic phospholipid
surfaces.
17.
18.
19. • Because of its delayed onset of action, patients with established OR high
risk of thrombosis are given concomitant initial treatment with a rapidly
acting parenteral anticoagulant, such as heparin, LMWH, or fondaparinux.
• concomitant treatment should be continued until the INR has been therapeutic for
at least 2 consecutive days.
• A minimum 5-day course of parenteral anticoagulation is recommended
• to ensure that the levels of factor Xa and prothrombin have been reduced into the
therapeutic range with warfarin.
• More frequent monitoring is necessary
• when new medications are introduced as many drugs enhance or reduce the
anticoagulant effects of warfarin.
25. Warfarin instead of the NOAC agents:
• Patients already on warfarin who are comfortable with periodic INR
measurement and whose INR has been well controlled with an annual time in
the therapeutic range of greater than 65 percent.
• Patients with mechanical heart valves of any type or those with severe mitral
stenosis of any cause.
• Patients who are not likely to comply with the twice daily dosing
dabigatran or apixaban and who are unable to take once-a-
day rivaroxaban or edoxaban.
26. • Patients for whom the NOAC agents will lead to an unacceptable
increase in cost.
• Patients with chronic severe kidney disease whose estimated glomerular
filtration rate is less than 30 mL/min.(apixaban approved United States ).
• Patients for whom the NOAC agents are contraindicated, including those
on enzyme-inducing antiepileptic drugs (eg, phenytoin) and patients
with human immunodeficiency virus infection (HIV) on protease
inhibitor-based antiretroviral therapy.
27.
28. Features of an ideal anticoagulant
• High efficacy to safety index
• Predictable dose response
• Administration by parenteral and oral routes
• Rapid onset of action
• Availability of a safe antidote
• Freedom from side effects
• Minimal interactions
29. Direct Oral Anticoagulants
• An alternatives to warfarin.
• These agents include
• Dabigatran - inhibits thrombin, and
• rivaroxaban, apixaban, and edoxaban - inhibit factor Xa.
• All of these drugs have
• a rapid onset and offset of action and
• half-lives that permit once- or twice-daily administration.
• produce a predictable level of anticoagulation,
30. MECHANISMS OF ACTION
Sites of action —
The direct thrombin inhibitors and direct factor Xa inhibitors block major
procoagulant activities involved in the generation of a fibrin clot .
• Thrombin –
• Thrombin (factor IIa) is the final enzyme of the clotting cascade that produces fibrin;
• formed by the proteolytic cleavage of prothrombin by factor Xa.
• Thrombin has a central role in coagulation:
• it cleaves fibrinogen to fibrin;
• activates other procoagulant factors including factors V, VIII, XI, and XIII; and activates platelets .
• enhance the specificity of the enzyme .
• active in both circulating and clot-bound forms
31. • Factor Xa –
• acts at the convergence point of the intrinsic and extrinsic coagulation pathways;
• formed by the proteolytic cleavage of factor X .
• active in circulating and clot-bound forms.
• Inhibition can prevent amplified thrombin generation
• as one molecule of factor Xa can cleave over 1000 molecules of prothrombin to thrombin .
• Direct factor Xa inhibitors are able to block the action of both forms of factor
Xa,
• whereas indirect factor Xa inhibitors such as heparin and fondaparinux (the
antithrombin-binding pentasaccharide) are only able to inactivate factor Xa in the fluid
phase, via antithrombin
32. INDICATIONS
• Venous thromboembolism (VTE) prophylaxis & TREATMENT
• Atrial fibrillation (AF)
• Acute coronary syndromes (ACS)
• Heparin-induced thrombocytopenia (HIT)
• These agents are not used in individuals with prosthetic heart valves, severe
renal insufficiency, pregnancy, or antiphospholipid syndrome (APS)
33.
34. • Rivaroxaban and apixaban simplify treatment and facilitate out-of-hospital
management of most patients with DVT and many with PE
• With these advantages, clinical guidelines now endorse the direct oral
anticoagulants
• first-line treatment of venous thromboembolism in patients without active cancer.
• For those with active cancer - LMWH remains the preferred therapy.
35. MONITORING
• Designed to be administered without routine monitoring,
• Situations where determination of the anticoagulant activity of the new
oral anticoagulants can be helpful.
• assessment of adherence, detection of accumulation or overdose, identification of
bleeding mechanisms, and determination of activity prior to surgery or intervention.
• Qualitative assessment of anticoagulant activity,
• Prothrombin time - factor Xa inhibitors and
• aPTT - dabigatran.
36. SIDE EFFECTS
• Bleeding is the most common side effect.
• The new oral anticoagulants has increased risk of gastrointestinal bleeding.
• likely occurs because unabsorbed active drug in the gut exacerbates bleeding from lesions.
• Less intracranial bleeding than warfarin.
• The direct oral anticoagulants target downstream coagulation enzymes,
• produce less impairment of hemostatic plug formation at sites of vascular injury
37. • Dabigatran etexilate
• a prodrug, only 7% is absorbed and the remainder passes through the gut
• where at least two-thirds is metabolically activated to dabigatran by gut esterases.
• Dyspepsia occurs in up to 10% of patients treated with dabigatran - improves with
time and can be minimized by administering the drug with food.
• Dyspepsia is rare
• rivaroxaban, apixaban, and edoxaban.
38. PERIPROCEDURAL MANAGEMENT
• Like warfarin, the new oral anticoagulants must be stopped before
procedures associated with a moderate or high risk of bleeding.
• held for 1–2 days, or longer - renal function is impaired.
• Assessment of residual anticoagulant activity before procedures
associated with a high bleeding risk is prudent.
39.
40.
41. • P-gp inhibitors :Concomitant administration of strong P-gp inhibitors
(such as amiodarone, verapamil, quinidine, ketoconazole and
clarithromycin) is expected to result in increased dabigatran plasma
concentrations.
• P-gp inducers : Concomitant administration of a P-gp inducer (such
as rifampicin, St. John´s wort (Hypericum
perforatum),carbamazepine, or phenytoin) is expected to result in
decreased dabigatran concentrations and should be Avoided.
Interaction- Dabigatran
42. • CYP3A4 and P-GP inhibitors
• May ↑ the serum concentration of rivaroxaban
• CYP3A4 and P-GP inducers
• May ↓ the serum concentration of rivaroxaban
• Anticoagulants
• ↑ risk of bleeding
• NSAIDs and platelet aggregation inhibitors
• ↑ risk of bleeding
Drug Interactions- Rivaroxaban
44. MANAGEMENT OF BLEEDING
• With minor bleeding,
• holding one or two doses of drug is usually sufficient.
• Serious bleeding
• similar to that with warfarin except that vitamin K administration is of no benefit.
• The anticoagulant and antiplatelet drugs should be held,
• Resuscitation with fluids and blood products as necessary, and,
• if possible, the bleeding site should be identified and managed.
45. • Timing of the last dose of anticoagulant is important;
• Administration of oral activated charcoal
• may help to prevent absorption of drug administered in the past 2–4 h.
• Anticoagulant reversal should be considered
• life-threatening bleeding, such as intracranial bleeding,
• bleeding continues despite supportive measures or
• urgent surgery.
46.
47.
48.
49. PREGNANCY
• As small molecules, the direct oral anticoagulants can all pass through the
placenta.
• Contraindicated in pregnancy
• Women of childbearing potential - appropriate contraception is
important.
• The direct oral anticoagulants should be avoided in nursing mothers
• Their safety in children has yet to be established.
50. Specific considerations: when to use each drug
• Chronic Kidney Disease:
• CrCl < 25 to 30ml/min:
• recommend warfarin therapy
• CrCl 30-49 ml/min:
• Consider Rivaroxaban 15mg daily or
• Apixaban 5mg twice daily
• use the 2.5mg lower dose if two of the following are present:
• age >80 years,
• body weight < 60kg,
• creatinine > 1.5mg/dl
• CrCl > 50ml/min:
• All choices are appropriate
51. • Patients with recurrent gastrointestinal (GI) bleed:
• Dabigatran and rivaroxaban had higher rates of GI bleeding when compared to
warfarin.
• For apixaban, there was no difference in GI bleeding compared to Warfarin.
• In patients who have difficulty with recurrent GI bleeding,
• reasonable to consider apixaban until more data are available with the other agents.
