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Coagulant and anticoagulants

This document discusses coagulants and anticoagulants. It describes how coagulants promote coagulation and control bleeding, including systemic coagulants like vitamin K, tranexamic acid, and fibrinogen. Local coagulants called styptics are also discussed. Anticoagulants prevent coagulation and control conditions involving excessive clotting. Common anticoagulants described are heparin, low molecular weight heparin, warfarin and newer oral anticoagulants. Warfarin is a vitamin K antagonist that inhibits vitamin K-dependent clotting factors. Its mechanism of action and factors affecting dosing are summarized.

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Coagulants and anti-coagulants Dr. Rupendra K. Bharti MBBS MD
Coagulants • Coagulation: The process of changing of blood from a fluid state to a solid state is known as coagulation. Normally, this is a natural process in the body to prevent blood loss by plugging the injured site. • The vascular system must maintain an intricate balance between the tendency to clot or form a solid state, and the need to “unclot,” or reverse coagulation, to keep the vessels open and the blood flowing.
After an injury to the body tissues, there is a natural mechanism, which helps to stop the blood loss by involvement of a complex haemostatic mechanism. This mechanism is as follows:
BLOOD CLOTTING FACTORS Component or Factor Common Synonym I Fibrinogen II Prothrombin III Tissue thromboplastin IV Calcium V Proaccelerin VI Accerin, supposed to be active form of factor V VII Proconvertin VIII Antihemophilic factor (AHF) IX Christmas factor, plasma thromboplastin component (PTC) X Stuart-Prower factor XI Plasma thromboplastin antecedent (PTA) XII Hageman factor XIII Fibrin-stabilizing factor XIV Prekallekrein XV kallekrein XVI Platelet factor
COAGULANTS Coagulants are the drugs that promote coagulation and control bleeding. • They are also called hemostatic agents. • These drugs are of two types – Systemic coagulants. – Local coagulants (styptics).
COAGULANTS Systemic coagulants Local coagulants (styptics) 1. Vitamin-K 2. Ethamsylate 3. Desmopressin 4. Fibrinogen 5. Anti-hemophillic factor 6. Tranexamic acid 7. Epsilon aminocaproic acid 1. Adrenaline 2. Fibrin glue 3. Gelatin 4. Thrombin 5. Oxidizes cellulose 6. Hemocoagulase 7. Tranexamic acid
Systemic coagulants Vitamin-K • Vitamin K (Coagulation vitamin) is essential for the coagulation process. • It is not directly involved in the clotting process but required for the synthesis of four clotting factors in the liver: Factor II,VII,IX and X.
• It occurs naturally in two forms: – Phylloquinone (K1) from plant source and – Menaquinone (K2) which is synthesized by colonic bacteria (E.coli) in the colon. • K3 is the synthetic form and is available as – Fat-soluble forms (Menadione, Acetomenaphthone) and – water-soluble forms (Menadione sod. Bisulfate and Menadione sod. Diphosphate).
• Dietary sources: – Green leafy vegetables such as cabbage, spinach and liver, cheese, cereals, nuts, and egg yolk etc. – Wheat germ oil is the richest source. • Physiological functions: – Vit-K is essential for formation of clotting factor-II, VII, IX, X, protein-C & S.
Deficiency Symptoms • Vit-K is only temporarily concentrated in liver and this store can be exhausted within one week. • The deficiency of vit-K occurs due to liver disease, obstructive jaundice, malabsorption, long-term antimicrobial therapy, which alters intestinal flora. • The most important manifestation is bleeding tendency due to lowering of the levels of prothrombin and other clotting factors in blood.
• Haematuria is usually first to occur; other common sites of bleeding are gastrointestinal tract, nose and under the skin where it presents in the form of haemorrhagic spots. • Recommended dietary allowance (RDA) – Normal adult requirement is 50–100 μg/day. – As it can be synthesized in the colon, even 3–10 μg/day may be sufficient.
Vit-K use: • For prevention of haemorrhagic disease of the newborn: All newborns especially premature infants have low levels of prothrombin and other clotting factors. – Vit- K: 1 mg IM soon after birth has been recommended routinely. – Alternatively, 5–10 mg IM to the mother 4–12 hours before delivery can be given.
• Patients on prolonged antimicrobial therapy. • As an antidote in overdose of oral anticoagulants. • In patients suffering from liver disease (cirrhosis, viral hepatitis).
• Patients with obstructive jaundice or malabsorption syndromes (sprue, regional ileitis, steatorrhoea, etc). – The therapy given is Vit-K 10 mg IM/day, or orally along with bile salts for better absorption. • Menadione (K3) should not be used in patients with G-6-PD deficiency. • In the newborn menadione or its salts can precipitate kernicterus.
Ethamsylate • It increases capillary wall stability by antihyaluronidase action. • It decreases PGI2 synthesis, and corrects abnormalities of platelet adhesion and promotes platelet aggregation. • It is used in the prevention and treatment of capillary bleeding.
• Common indications – menorrhagia, PPH, after abortion, epistaxis, after tooth extraction and hematuria. • Side effects – nausea, rash, headache, and acute hypotension if given by fast IV injection. • It is given in a dose of 250–500 mg TDS orally or IV.
Desmopressin • It is an analogue to vasopressin & increases the plasma concentration of factor-VIII, von Willebrand factor and directly activates platelets. • It is a selective V2 agonist, 12 times more potent than AVP. • Desmopressin is useful for the treatment of hemophilia-A and von-willebrand disease.
Fibrinogen • It is obtained from human plasma and is a promising haemostatic agent. • It is used to control bleeding in – Haemophilia – Hypofibrinogenemia – Antihaemophilic globulin deficiency. • It is available as IV infusion 0.5 per bottle.
Anti-hemophillic factor • It contains coagulation factor VIII and is concentrated human (Antihaemophilic globulin) AHG obtained from pooled human plasma. • It is also synthesized by recombinant DNA technology. • It is therapeutically used in haemophilia and AHG deficiency. • It is given in a dose of 10–20 IU/kg by IV infusion, repeated 6–12 hourly.
Tranexamic acid & Epsilon aminocaproic acid • They are antifibronolytic agent. • They inhibit the activation of plasminogen and dissolution of clot. • They are available as oral and IV form. • Tranexamic acid is given in a dose of 500-1000mg TDS, orally & IV. • Side effects – nausea, vomiting, thromboembolic states, allergic reactions, disturbed colour vision, etc.
• They are indicated in: – To counteract the effect of fibrinolytic drugs. – For controlling the bleeding in • tonsillectomy, • prostatic surgery, • tooth extraction in haemophiliacs. – Menorrhagia, menometrorrhagia & DUB. – Recurrent epistaxis.
LOCAL COAGULANTS (STYPTICS) • Local coagulants are also known as styptics or haemostatics (haemo-blood and statics- to stop). • These substances are used locally to stop the bleeding from the oozing surfaces such as abrasions, bleeding tooth socket after tooth extraction etc.
• Normal haemostasis involves three steps: – Vasoconstriction or contraction of injured vessel wall for a few minutes. – Adhesion and aggregation of platelets to form a plug. – Formation of a blood clot.
• This is followed by dissolution of the clot by the process of fibrinolysis and maintenance of normal circulation. • The most preferred and effective method of stopping the external bleeding is manual pressure, cotton-gauze pressure pack or by suturing.
Role of adrenaline • Control of bleeding may be aided by applying adrenaline locally as it causes local vasoconstriction. • A cotton pad soaked with 0.1% adrenaline is used to control capillary bleeding such as epistaxis and after tooth extraction etc. • Adrenaline is available in combination with lignocaine to provide better surgical field, but should be avoided in patients suffering from hypertension or cardiovascular disease.
Thrombin • Obtained from bovine plasma is used topically to control capillary bleeding. • It may cause hypersensitivity reactions also.
Gelatin foam, oxidized cellulose • Theses are absorbable materials, available as film or sponge and are used in surgical procedures to control the bleeding of capillaries or arterioles. • After applied dry, they swell up and form meshwork, which helps in the clotting mechanism and stops bleeding. • These materials are absorbed within 4 weeks. • The main adverse effects seen with these are tissue necrosis, vascular stenosis & nerve damage.
Astringents • Such as tannic acid or metallic salts (alum) are occasionally applied for bleeding gums, cuts during shaving, bleeding piles, etc.
ANTI-COAGULANTS
Blood Vessel Injury IX IXa XI XIa X Xa XII XIIa Tissue Injury Tissue Factor Thromboplastin VIIa VII X Prothrombin Thrombin Fibrinogen Fribrin monomer Fibrin polymer XIII Intrinsic Pathway Extrinsic Pathway Factors affected By Heparin Vit. K dependent Factors Affected by Oral Anticoagulants Recall !
Why anticoagulants ?  To reduce the coagulability of blood  Blood clots – Thrombus  Arterial Thrombosis:  Adherence of platelets to arterial walls – “White” in color - Often associated with MI, stroke and ischemia  Venous Thrombosis:  Develops in areas of stagnated blood flow (deep vein thrombosis), “Red” in color- Associated with Congestive Heart Failure, Cancer, Surgery  Thrombus dislodge from arteries and veins and become an embolus  Venous emboli can block arterioles in the lung and pulmonary circulation  Thromboembolism
Figure. Classification of established anticoagulants and new anticoagulants that were recently licensed for use or are in advanced stages of clinical development. fIXa indicates factor IXa. *Indirectly inhibit coagulation by interacting with antithrombin. †AVE5026 is an ultralow-molecular-weight heparin that primarily inhibits fXa and has minimal activity against thrombin.
Anticoagulant drugs to treat thromboembolism Drug Class Prototype Action Effect Anticoagulant Parenteral Heparin Inactivation of clotting Factors Prevent venous Thrombosis Anticoagulant Oral Warfarin Decrease synthesis of Clotting factors Prevent venous Thrombosis Antiplatelet drugs Aspirin Decrease platelet aggregation Prevent arterial Thrombosis Thrombolytic Drugs Streptokinase Fibinolysis Breakdown of thrombi
Available Anticoagulants Parenteral anticoagulants: – Indirect thrombin inhibitors: – Heparin, – Low molecular weight heparin, – Fondaparinux, – Danaparoid – Direct thrombin inhibitors: – Lepirudin, – Bivalirudin
CLASSIFICATION OF ORAL ANTICOAGULANTS  Coumarin Derivatives  Warfarin, Acenocoumarol (Acitrom)  Indandione Derivatives  Phenindione, Anisindione  Newer anticoagulants • Direct thrombin inhibitor – Dabigatran etexilate (Pradaxa) • Direct factor Xa inhibitors – Rivaroxaban (Xarelto) – Apixaban – Edoxaban (DU-176b) – Betrixaban
WARFARIN • 1948: synthesis of warfarin by student Harold Campbell. • Most widely used anticoagulant in the world • Coumarin derivative, water soluble vit K antagonist. • Low cost and highly effective, if given in right way. The name warfarin is derived from WARF (Wisconsin Alumni Research Foundation) and –arin from coumarin.
Vitamin K-dependent clotting factors (FII, FVII, FIX, FX, Protein C/S/Z) Epoxide Reductase  -Carboxylase (GGCX) MECHANISM OF ACTION: Warfarin inhibits the vitamin K cycle Warfarin Inactivation CYP2C9 Pharmacokinetic Post translational modification
PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT PROTEINS Peak anticoagulant effect may be delayed by 72 to 96 hours COAGULATION FACTORS HALF-LIFE (h) II 60 VII 4-6 IX 24 X 48-72 Protein –C 8 Protein- S 30
VKORC1: New Target Protein for Warfarin Epoxide Reductase  -Carboxylase (GGCX) Clotting Factors (FII, FVII, FIX, FX, Protein C/S/Z) Rost et al. & Li, et al., Nature (2004) (VKORC1)
Effect of VKORC1 Genotype on Anticoagulation • Three polymorphic variants of VKORC1 • Non-A, Non-A : wild type – Requiring more warfarin dose • Non-A/A : Heterozygous – Requiring 25% dose reduction • A/A : Homozygous - Requiring 50% dose reduction • Means wild type having more resistance to warfarin while homozygous is more sensitive. • Asians have the highest prevalence of VKORC1 variants, followed by whites and blacks • Polymorphisms in VKORC1 likely explain 30% of the variability in warfarin dose requirements. • VKORC1 variants are more prevalent than variants of CYP2C9 Genotype Freq in Asians (%) Dose reduction Non-A,Non-A : wild type 7 -- Non-A/A : Heterozygous 30 26 A/A : Homozygous 63 50
DOSING • Usual dose is 5 mg/day (1-20 mg) • Lower doses require in • Elderly • Pt on increased risk of bleeding eg. Pt on aspirin • Heart failure • Liver disease • Renal impairment • Malnutrition • Thyrotoxicosis • Asian patients: Explained by genetic variation in hepatic enzymes (CYP3C9 & VKORC1 Polymorphism) • High intake dietary Vit-K (green vegetables e.g. broccoli) reduces the efficacy of Warfarin. • Practically best time to give warfarin is ~ 6 PM.
Why to add concomitant parenteral anticoagulation ? • Because of delayed onset of action, concomitant parenteral anticoagulant should be given in pts with established thrombosis or high risk for thrombosis until INR has been in therapeutic range for at least 2 days. • Warfarin monotherapy decreases the levels of two endogenous anticoagulants, proteins C and S, thus increasing thrombogenic potential. Overlapping warfarin for at least 5 days with an immediately effective parenteral anticoagulant counteracts the procoagulant effect of unopposed warfarin. • Usually a minimum 5 days of concomitant parenteral anticoagulation is recommended.
Commencement of oral anticoagulant therapy • If the baseline INR≤1.3 the patient will receive 5mg of warfarin once daily on days 1 and 2. • The INR is checked on day 3 and 4 and the warfarin dose is adjusted according to the schedule.
Monitoring • B/z of narrow therapeutic window of warfarin • Standard procedure is to check the PT-INR as follows: INR daily until it is in therapeutic range 3 times weekly for 2 weeks Once stable & warfarin dose is known INR every 3-4 weeks or more frequently if introduction of any new medications
What is PT-INR • Warfarin therapy is most often monitored using the prothrombin time, a test sensitive to reductions in the levels of prothrombin, factor VII, and factor X. • This test involved addition of thromboplastin (a reagent containing TF, phospholipid & Ca++) to citrated plasma and determining the time to clot formation. • Thromboplastins vary in their sensitivity to reductions in the levels of the vitamin K–dependent clotting factors • INR represent the PT according to international reference thromboplastin, as approved by WHO.
INTERNATIONAL NORMALISED RATIO (INR) INR = [PTpt] ISI [PTRef] PTpt – prothrombin time of patient PTRef – prothrombin time of normal pooled sample ISI – International Sensitivity Index  Highly sensitive thromboplastins have an ISI of 1.0  Most current thromboplastins have ISI values that range from 1.0 to 1.4
Common drugs influencing INR values : INR  / PT decreases INR  /PT increases amoxicillin Quinolones cephalosporin's macrolid antibiotics paracetamol salicylate amiodaron allopurinol omeprazole heparin NSAID & COX2 inh. tricyclic antidepressants Rifampicin Antihistamines barbiturates carbamazepine digoxin Diuretics Caffeine's pentoxiphyllin Vitamin K
Indications • Atrial fibrillation • Prosthetic heart valve • Venous thromboembolism • Primary pulmonary hypertension • Rarely after Acute MI (If associated with high risk of thromboembolism e.g. AF, mobile or pedunculated mural thrombus or prior venous thromboembolism)
Side effects of Warfarin  Bleeding  Skin necrosis  Purple toe syndrome  Teratogenicity  Osteoporosis  Others: Agranulocytosis, leukopenia, diarrhoea, nausea, anorexia.
Bleeding • Most common complication • In form of • Mild: epistaxis, hematuria • Severe: Retroperotoneal or gastrointestinal bleeding • Life-threatening : Intracranial bleed • Rate of major bleeding (defined as any visit to hospital for hemorrhage) is 1- 3% per person-year • Half of the complications occurs because INR exceeds therapeutic range • Can be minimized by keeping INR in therapeutic range
Interventions according to INR/symptoms Asymptomatic pts with raised INR INR INTERVENTION 3.5 - 4.5 Withhold warfarin until in therapeutic range Decrease the dose of warfarin > 4.5 Low dose sublingual/oral Vit K (not routinely) 4.5 – 9.0 Vit k 1 mg > 9.0 Vit k 2-3 mg Higher doses of vitamin K (up to 10 mg) can be administered if more rapid reversal of the INR is required Although vitamin K administration results in a more rapid reduction in the INR, there is no evidence that it reduces the risk of hemorrhage
Symptomatic pts with raised INR SYMPTOMS INTERVENTION Mild bleeding Withhold warfarin Severe bleeding Vit K 10 mg slow i/v infusion ± FFP (15 ml/kg) Life threatening bleeding or pt can’t tolerate volume overload Prothrombin complex concentrate (II,IX & X) Prosthetic valves pts Vit K should be strictly avoided, unless there is life threatening intracranial bleed (Valve thrombosis) Subcutaneous Vit K gives variable results and should be avoided
SKIN NECROSIS • Rare but very serious complication of warfarin (prevalence of 0.01-0.1 %) • Occurs 2 to 5 days after initiation of warfarin • Usually occurs after high dose of warfarin • Typical presentation is : – Well-demarcated erythematous lesions form on the thighs, buttocks, breasts, or toes. – Typically, the center of the lesion becomes progressively necrotic. – Examination of skin biopsies taken from the borders of these lesions reveals thrombi in the microvasculature
Warfarin (Coumadin)–induced skin necrosis on the lower abdomen & breast
• Mechanism : Not well understood but a precipitous fall in plasma protein C or S levels (natural anticoagulants) before warfarin exert anticoagulant effect, results in procoagulant state triggering thrombosis of adipose tissue microvasculatures. • Treatment : – Discontinuation of warfarin and reversal with vitamin K, if needed – An alternative anticoagulant, such as heparin or LMWH, should be given to patients with thrombosis – Protein C concentrates or recombinant activated protein C may accelerate healing of the skin lesions in protein C deficient patients – Frozen plasma may be useful for those with protein S deficiency – Occasionally, skin grafting is necessary when there is extensive skin loss. • Prevention : – Start with low dose warfarin in pts with known Protein C or S deficiency – Overlapping with a parenteral anticoagulant when initiating warfarin therapy
Purple toes syndrome • Extremely uncommon cutaneous complication • Characterized by the sudden appearance of bilateral, painful, purple nonhemorrhagic lesions on the toes and sides of the feet that blanch with pressure • Usually develops 3-8 weeks after the start of warfarin therapy • Mechanism: release of atheromatous plaque emboli • Discontinue COUMADIN therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary. Pharmacotherapy. 2003 May;23(5):674-7
Teratogenicity • Occurs in 3.5 – 6 % • Depends on time of gestation and dose of warfarin given • Usually in first trimester of pregnancy • It causes characteristic embryopathy consist of : • Nasal hypoplasia and • Chondrodysplasia punctata (epiphyseal and vertebral bone stippling) • Cleft lip and (or) palate • Choanal stenosis/atresia • Central nervous system abnormalities • Coarctation of aorta (Rare malformations described following first trimester exposure to warfarin) • Occurs especially if warfarin dose is > 5 mg/day
Lateral view X-ray showing calcifications and irregular ossification of lumbar and sacral vertebrae, consistent with warfarin embryopathy
OSTEOPOROSIS • Long- term use of warfarin (> 1 yr) • More common in males • 60% increased risk of osteoporosis-related fracture in men • Mechanism: combination of reduced intake of vitamin K, which is necessary for bone health, and inhibition by warfarin of vitamin K-mediated carboxylation of certain bone proteins, rendering them nonfunctional • Beta-adrenergic antagonists may protect against osteoporotic fractures
Warfarin in special conditions…
Pregnancy • It causes… • Fetal abnormalities (Teratogenic)- in first trimister • Chances of intracranial bleeding in baby while passage through birth canal – in third trimister • Because of this, warfarin is contraindicated in 1st (first 12 weeks) & 3rd trimsters (last 2 weeks) • Warfarin does not passes in breast milk & is safe for nursing mothers.
ACENOCOUMAROL (acitrom) • Same as warfarin with following differences: – Shorter half life 10-16 hrs – More rapid onset of action – Shorter duration of action (2 days) – Causes GI disturbances, oral ulcerations and dermatitis • 4 mg on day one, 4-8 mg on the day 2nd then maintenance dose 1-8 mg according to response by PT test
THE OVERALL ANTICOAGULATION QUALITY IS SIGNIFICANTLY BETTER WITH WARFARIN AS COMPARED TO ACENOCOUMAROL 72% 67% 64% 66% 68% 70% 72% %Responders Warfarin Acenocoumarol Thrombosis And Haemostasis 1994; 71(2): 188-191
Newer Oral Anticoagulants
What’s wrong with warfarin? 1. Narrow therapeutic range 2. Slow onset of action 3. Slow offset of action (long duration of action, long elimination half life) 4. Multiple drug and dietary interactions 5. Monitoring required to maintain in therapeutic range 6. Difficult to manage for invasive procedures 7. Under-use of therapy due to fear of adverse events and complexity of management
Newer oral anticoagulants
Classification • Direct thrombin (IIa) inhibitor • Dabigatran (Pradaxa) • Factor Xa inhibitors • Rivaroxaban (Xarelto) • Apixaban • Edoxaban
Dabigatran etexilate (Pradaxa) • Oral Direct thrombin (factor IIa) inhibitor • It is a prodrug & does not exhibit any pharmacological activity • Initially recommended by FDA on October 19, 2010 for Non-valvular AF
Mechanism of Action • Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. • Both free and clot-bound thrombin, and thrombin- induced platelet aggregation are inhibited by the active moieties.
Pharmacokinetics • Dabigatran etexilate mesylate is absorbed as the dabigatran etexilate ester. • The ester is then hydrolyzed, forming dabigatran, the active moiety. • The t1/2 is 15 to 17 hrs. • 90% is excreted unchanged in urine. • The absolute bioavailability of dabigatran following oral administration is approximately 3 to 7% .
• Dabigatran is also a substrate for P- glycoprotein ( a trans-membrane pump expelling drugs out of cell). • So P- glycoprotein inhibitors (e.g. amiodarone, verapamil & clarithromycin) can increase whereas inducers (e.g. rifampicin, st. john’s wart) may reduce dabigatran level in plasma.
INDICATIONS AND USAGE  Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation  Treatment of Deep Venous Thrombosis and Pulmonary Embolism  Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism
Recommended dose
SOME SPECIAL POINTS TO MENTION….
• If a dose of dabigatran is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; • the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. • The dose of dabigatran should not be doubled to make up for a missed dose.
Converting pts from or to Warfarin • From warfarin to dabigatran – Stop warfarin & start dabigatran once INR fall below 2 • From dabigatran to warfarin – Adjust the starting time of warfarin based on creatinine clearance CrCL (ml/min) Days before stopping dabigatran > 50 3 days 50 - 30 2 days 30 - 15 1 day < 15 or dialysis not recommended
Converting pts from or to parenteral anticoagulants From parenteral anticoagulants to dabigatran – Intermittent parenteral anticoagulant – Start dabigatran 0-2 hrs before next dose – Continuous parenteral anticoagulant (e.g. UFH) – Start dabigatran at the time of stopping parenteral anticoagulant • From dabigatran to parenteral anticoagulants • Wait for 12 hrs (CrCl> 30 ml/min) or 24 hrs (CrCl< 30 ml/min) after last dose of dabigatran before starting parenteral anticoagulant
Dabigatran in pts planned for elective surgery • If possible, stop dabigatran 1-2 days before (CrCl> 50 ml/min) or 3-5 days before (CrCl< 50 ml/min) invasive or surgical procedures. • Longer periods may be considered if pt undergoing 1. Major surgery 2. Spinal puncture 3. Placement of spinal or epidural catheter or port
BLEEDING ON DABIGATRAN TREATMENT Pcc: prothrombin complex concn.
Monitoring anticoagulant effect of dabigatran • Need not to assess regularly (ex. In the setting of emergency surgery) • In emergency most accessible tests are 1. TCT 2. aPTT • If the TCT is normal, it is safe to assume that the level of dabigatran is very low and that the patient’s risk of bleeding development is similar to that of other patients undergoing the procedure
Antidote • Specific agent not available • Though limited data, following agents may be used – Activated prothrombin complex concentrate – Recombinant factor VIIa – Concentrate of coagulant factors II, IX and X – Hemodialysis (because only 35% of dabigatran is bound to plasma proteins) Protamine sulfate and Vit-K are not helpful
Adverse effects • Bleeding – increases with age • GI events – Dyspepsia (12%) – Abdominal pain – Gastritis including GERD, esophagitis, erosive gastritis, gastric hemorrhage and GI ulcers • Hypersensitivity reaction (<0.1%) • An unexplained increase in acute myocardial infarction in the dabigatran group versus warfarin (~0.2% increased risk for a AMI re-ly trial)
Factor Xa inhibitors »Rivaroxaban »Apixaban
Rivaroxaban (Xarelto)
Rivaroxaban (Xarelto) • Direct factor Xa inhibitor • Half life: 7 - 9 hours • Peak plasma concentration 0.5 – 3 hours after administration • Have excellent bio-availability of 80-100% • 2/3rd of rivaroxaban is metabolized by CYP3A4 system in liver • 1/3rd of rivaroxaban excreted unchanged in urine while ½ of the metabolized excreted renally while other half via fecal route.
• To reduce the risk of DVTs and PEs in patients undergoing knee or hip replacement surgery (Jul 1, 2011) • For prevention of thromboembolism and stroke in patients with nonvalvular atrial fibrillation (Nov 4, 2011 ) • Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as to reduce the risk of recurrent DVT and PE (Nov 2, 2012) Rivaroxaban: FDA Approval (First approved in July 1st, 2011)
Doses of rivaroxaban – Therapeutic dose : 20 mg once daily – Prophylactic dose : 10 mg once daily • No specific dose adjustment advised in moderate renal function impairment but it should be used with caution • Contraindicated in severe renal impairment • No dose adjustment required for body weight
Apixaban (Eliquis)
Apixaban (Eliquis) • Direct factor Xa inhibitor • Half life – 8 to 11 hours • Peak plasma concentration 1 – 3 hours after administration • Have excellent bio-availability of 66% • Metabolized in liver • 25 % of apixaban is renally excreted, so no dose adjustment are required in renal failure pts • 75% excreted by fecal route
• Apixaban only partially metabolized by CYP3A4 system, so strong CYP3A4 inhibitor/ inducer may affect its plasma level but this appears to be minimal as per its anticoagulants effect are concerned • Apixaban is minimally interact with P glycoprotein hence its effects are not affected significantly. Hence no clinically significant drug interactions
• To reduce the risk of stroke and dangerous blood clots (systemic embolism) in patients with atrial fibrillation that is not caused by a heart valve problem (Dec 28, 2012 ) FDA recommendation (FDA first approved on Dec. 28, 2012)
Recommended Dose Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation – The recommended dose of apixaban for most patients is 5 mg taken orally twice daily. – The recommended dose is 2.5 mg twice daily in patients with any 2 of the following characteristics: • age ≥80 years • body weight ≤60 kg • serum creatinine ≥1.5 mg/dL
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery The recommended dose is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery. • In patients undergoing hip replacement surgery, the recommended duration of treatment is 35 days. • In patients undergoing knee replacement surgery, the recommended duration of treatment is 12 days.
Treatment of DVT and PE The recommended dose of apixaban is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily. Reduction in the Risk of Recurrence of DVT and PE The recommended dose of apixaban is 2.5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE.