ANTICOAGULATION & ANAESTHESIA

COAGULATION PATHWAY

COAGULATION TESTS

PROTHROMBIN TIMEMeasures of the extrinsic pathway of coagulation. This test is also called "ProTime INR" and "PT/INR". They are used to determine the clotting tendency of blood, in the measure ofwarfarin dosage, liver damage, and vitamin K status. PT measures factors I (fibrinogen), II (thrombin), V, VII, and X. That is classic extrinsic pathway. It is used in conjunction with the activated partial thromboplastin time (aPTT) which measures the intrinsic pathway.

The reference range for prothrombin time is usually around 12-16 seconds, and the INR in absence of anticoagulation therapy is 0.8-1.2. The target range for INR in anticoagulant use (e.g. warfarin) is 2 to 3. The INR is the ratio of a patient's prothrombin time to a normal (control) sample, raised to the power of the ISI value for the analytical system used. INR= (PT test/PT control)^ISI
The ISI value indicates how a particular batch of tissue factor compares to an international reference tissue factor. The ISI is usually between 1.0 and 2.0.

PARTIAL THROMBOPLASTIN TIME

performance indicator measuring the efficacy of both the "intrinsic" (now referred to as the contact activation pathway) and the common coagulation pathways. detecting abnormalities in blood clotting monitor the treatment effects with heparin, a major anticoagulant The test is termed "partial" due to the absence of tissue factor from the reaction mixture. The typical reference range is between 30 seconds and 50 s (depending on laboratory).

. Normal PTT times require the presence of the

following coagulation factors: I, II, V, VIII, IX, X, XI, & XII. Notably, deficiencies in factors VII or XIII will not be detected with the PTT test. Prolonged APTT may indicate: use of heparin (or contamination of the sample) antiphospholipid antibody (especially lupus anticoagulant, which paradoxically increases propensity to thrombosis) coagulation factor deficiency (e.g. hemophilia) Sepsis - coagulation factor consumption Presence of antibodies against coagulation factors (Factor inhibitors)

BLEEDING TIME

Bleeding time is a medical test done on someone to assess their platelet function Ivy method Normal values fall between 3 10 minutes depending on the method used. Duke Method The usual time is about 25 minutes. Bleeding time is affected by platelet function, certain vascular disorders and von Willebrand Diseasethrombocytopenia, disseminated intravascular coagulation (DIC), Bernard-Soulier disease, and Glanzmann's thrombasthenia. Aspirin and other cyclooxygenase inhibitors can prolong bleeding time significantly. It is also prolonged in hypofibrinogenemia

CLOTTING TIME
Clotting time is the time required for a sample of blood to coagulate in vitro under standard conditions. There are various methods for determining the clotting time, the most common being the capillary tube method. It is affected by calcium ion levels and many diseases. Normal value of clotting time is 5 to 8 minutes.

ACTIVATED CLOTTING TIME

Activated clotting time (ACT), also known as activated coagulation time is a test of coagulation.[1] The ACT test is used to monitor the effect of highdose heparin before, during, and shortly after surgeries that require intense anticoagulant administration, such as cardiac bypass surgery, cardiac angioplasty, and dialysis.[1] It is ordered in situations where the partial thromboplastin time (PTT) test is not clinically useful or takes too long

D-DIMER ASSAY
D-dimer is a fibrin degradation product (or FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. D-dimer concentration may be determined by a blood test to help diagnose thrombosis D-dimer testing is of clinical use when there is a suspicion of deep venous thrombosis (DVT), pulmonary embolism (PE) or disseminated intravascular coagulation (DIC) It is under investigation in the diagnosis of aortic dissection.[3][4]

ANTICOAGULANTS

ANTI PLATELET DRUGS Irreversible cyclooxygenase inhibitors

Aspirin Clopidogrel (Plavix) Prasugrel (Effient) Ticagrelor (Brilinta) Ticlopidine (Ticlid) Cilostazol (Pletal) Abciximab (ReoPro) Eptifibatide (Integrilin) Tirofiban (Aggrastat) Dipyridamole (Persantine) Thromboxane synthase inhibitors Thromboxane receptor antagonists

Adenosine diphosphate (ADP) receptor inhibitors

Phosphodiesterase inhibitors

Glycoprotein IIB/IIIA inhibitors (intravenous use only)

Adenosine reuptake inhibitors

Thromboxane inhibitors

Terutroban

HEPARIN & LMWH WARFARIN THROMBIN INHIBITORS

ASPIRIN

IT ACETYLATES AND INHIBITS THE ENZYME COX1 & TX-SYNTHASE- INACTIVATING THEM IRREVERSIBLY. Prolongation of bleeding time by 5-7 days. Aspirin reduces the risk of heart attacks and strokes by preventing blood clots from forming on the surface of ruptured atherosclerotic plaques. For long-term prevention of cardiovascular disease, the recommended dose of aspirin is 75 to 325 mg once daily.

ASPIRIN OF PROVEN BENEFIT

ASPIRIN OF UNCERTAIN BENEFIT

ANGINA STROKE POST CABG CORONARY ARTERY STENTS PREVENTION OF CLOTS FOR HIP SURGERY

PERIPHERAL VASCULAR DISEASE DIABETES ( NO ANGINA ,PREVIOUS ATTACK OR STROKE) PRIMARY PREVENTION ( NO H/O ANGINA) PREVENTION OF RECURRENT DVT IN PATIENTS WHO HAVE COMPLETED TRT WITH WARFARIN.

CLOPIDOGREL

oral, thienopyridine class antiplatelet agent . irreversibly inhibiting a receptor calledP2Y12, an adenosine diphosphate (ADP) chemoreceptor on platelet cell membranes. Adverse effects include hemorrhage, severe neutropenia, and thrombotic thrombocytopenic purpura (TTP). Platelet inhibition can be demonstrated two hours after a single dose of oral clopidogrel, but the onset of action is slow, so that a loadingdose of 300 mg is usually administered.

TICLOPIDINE
antiplatelet drug in the thienopyridine family adenosine diphosphate (ADP) receptor inhibitor The usual dose is 250 mg twice daily by the oral route.

WARFARIN
Interferes with synthesis of vit-K dependent clotting factors in liver. Interfere with regeneration of active hydroquinone form of vit-K which carries out the final step of carboxylating glutamate residues of prothrombin,factor vii,ix & x. Synthesis of clotting factors diminish within 2-4 hours & anticoagulant effect develops over next 36-72 hrs.

Patients are regularly monitored by PT & INR. INR of 2-3 is ideal for long term therapeutically active thromboprophylaxis. Warfarin is initiated with parenteral anticoagulant. Dose-5 mg followed by 2.5 mg daily. 5 days required to achieve a steady state reduction in activity of vit-K dependent clotting factors.

UNFRACTIONATED HEPARIN
Acts indirectly by inhibiting plasma antithrombin iii. The heparin AT III complex then binds clotting factors of intrinsic & common pathway and inactivates them. At low concentration factor xa mediated conversion of protrombin to thrombin is selectively affected. The anticoagulant action is mediated by inhibition of factor Xa & IIa mediated conversion of fibrinogen to fibrin.

Dose- 5000 u SC every 8-12 hrs Children- 50-100 u/kg Dose monitored by ACT & APTT Danger of haematoma formation ,should never be administered intramuscularly. Effect of UFH reversed by protamine sulfate. 1 mg for 100 u of UFH.

Heparin is given IV in bolus form of 80 U/KG followed by continous infusion of 18 u/kg/hr . Adverse effects Bleeding Thrombocytopenia Transient & reversible alopecia Osteoporosis

LMWH
Selectively inhibit factor Xa with little effect IIa Smaller effect on aPTT & whole blood clotting time . Lesser antiplatelet action. Lower haemorrhagic complications. Better sc bioavailability. Longer half-life Since aPTT / CT are not prolonged lab monitoring not necessary.

INDICATIONS
Prophylaxis of DVT & pulmonary embolism in high risk cases undergoing surgery;stroke & immobilised pt. Treatment of established DVT. Unstable angina Maintain patency of cannula in dialysis patients & in extracorporeal circulation.

WEIGHT ENOXAPARIN DALTEPARIN TINZAPARIN <50 20 mg 2500 units daily 3500 units daily 50-90 91-130 131-170 >170 40 mg 60 mg* 80 mg* 5000 units daily 7500 units daily* 10 000 units daily* 4500 units daily 7000 units daily* 9000 units daily* 75 units/kg/day*

0.6 mg/kg/day 75 units/kg/day*

Treatment 1 mg/kg 12 hourly 100 u/kg 12 hourly or 1.5 mg/kg/day or 200u/kg/day 175 u/kg daily

ANAESTHETIC CONSIDERATIONS

Management of pt on anticoagulant for surgery is very crucial. It is involving the decision to continue/discontinue of the anticoagulant h/ever this decision must weigh the effect of stopping the medication Risk of thromboembolism vs bleeding intraop Major bleeding event can be fatal but pt who bleeds can be resuscitated.Recurrent thromboembolism is fatal,if not causes permanent disability.

Two principal issues should be addressed: .

Is interruption of antithrombotic therapy needed perioperatively?? If antithrombotic therapy is interrupted,is bridging anticoagulant needed?? (bridging anticoagulation: administration of a short acting anticoagulant,eg:LMWH/UFH during interuption of anticoagulant therapy)

Important factor to consider are: Anticoagulation: indication for anticoagulant therapy, nature of anticoagulant drug , degree of anticoagulant required Surgery risk factor: urgency, nature and site of surgery Patient risk factor

CHADS SCORE
C H A D S

PRESENCE OF CHF HYPERTENSION AGE 75 YR AND OLDER DIABETES MELLITUS STROKE OR TIA ,HISTORY

Discontinuing anticoagulant is usually necessay for major surgery but increase risk of thrombotic events. Bridgetherapy,the temporary periop substitution of LMWH/UFH in place of warfarin is an effective means of reducing risk of thromboembolism but may increase risk of bleeding

the timing of warfarin withdrawal and starting bridge therapy are critical to balance these risk
General management of patient on anticoagulantWarfarin-LMWH/UFH-Antiplatelet

GENERALANAESTHESIA:IS NOT A CONTRAINDICATION FOR PT ON ANTICOAGULANT

Precaution should be considered: Avoid IM/Subcutaneous drug administration Premed should be oral or IV If IM administration is necessary ,the arm should be used(since local haemorrhage is easier to detect & treat) All venopuncture/arterial puncture should be carried out meticulously

CVL by subclavian/int jugular route is contraindicated If CVL is necessary ,use antecubitalfossa External jugular can be used as haematoma formation can be treat with external pressure Atraumatic laryngoscopy and tracheal intubation Avoid nasal intubation/NG tube No precaution are necessary for pt receiving prophylactic low dose heparin

STOPPING WARFARIN BEFORE OPERATION

CheckINR INR 2-3:discont warfarin 5 days beforeop INR 3-4.5:discont 6 days before op Target preop INR <1.2 Elderly assoiated with lower rate of decrease in INR If INR >1.5 (1-2 days before surg), togive1-2mg oral vitaminK

WARFARIN NEED NOT BE STOPPED FOR ALL PROCEDURES

Procedure that can be performed without discontinuing warfarin Opthalmicsurg: Cataractsurg Trabeculectomy Dentalsurg: Extraction Endodontic Prosthetics Dentalhygiene Dermatologic Simpleexcision GIT: Colonoscopy without biopsy ERCP Biliary stent without sphincterotomy

STARTING HEPARIN BEFORE THE OPERATION

Assessment of the pt which require bridging therapy based on individual risk factors recommendation for periop bridge therapy: High risk gr: bridging anticoagulant with therapeutic dose of s/c LMWH/iv UFH Moderate risk gr : therapeutic dose of LMWH/UFH or low dose s/c LMWH Low risk: low dose s/c LMWH or no bridging

Therapeutic dose of UFH Commonly used prevly but declined in recent years Its a dose adjusted IV infusion administered to achieve a target APTT of 1.5-2 times the control Infusion stopped 4hrs before surgery Resume back during initial 24hrs after surgery Alternative to IV UFH is S/C UFH (no need APTT monitoring)

Therapeutic dose LMWH Preferable recently No need laboratory monitoring Start LMWH (enoxaparin 1mg/kg or deltaparin 100IU/kg subcutaneously every 12hrs) 36hrs after last dose of warfarin Give last dose of LMWH 12 hrs prior to surgery (preferable 24hrs)

LOW DOSE LMWH

Eg: s/c heparin 5000 IU bd / enoxaparin 30mg bd Typically used for DVT prevention Used in lower risk pt for thromboembolism

AFTER SURGERY.

Minor surgery (high risk group) : Reinitiate LMWH at full dose 24hrs after surg Major surgery/ high risk of bleeding: Use prophylactic dose on the first 2 post op day then full dose of LMWH or Delay the initiation of therapeutic dose for 4872hrs postop Discuss with surgeon regarding reinitiation of anticoagulant

RESTARTING WARFARIN AFTER THE OPERATION

Restart warfarin as prev dose 1 day postop (12-24hrspostop) when haemostasis are adequate Daily PT/INR till discharge and periodically after discharge till INR reach therapeutic range Discontinue LMWH when INR is between 2-3 for 2 consecutive day

Pt on antiplatelet.. Pt on aspirin or clopidogrel need to discont tx for 710 days prior to op Resuming back antiplatelet after 24hrs If pt are at high risk for cardiac event -Cont the aspirin upto and beyond the surgery -If pt on clopidogrel ,stopped atleast 5 days prior to surgery (preferably 10 days)

REGIONALANAESTHESIA
The choice of regional anesthesia may offer considerable advantages over general anesthesia for various surgical procedures or for certain patients. however the benefit of of RA outweigh the risk of altered haemostasis. Such as in patients with compromised cardiorespiratory function

spinal hematoma is the most significant hemorrhagic complication of regional anesthesia due to the catastrophic nature of bleeding into a fixed and noncompressible space

Guidelines for Regional Anesthesia while on Anticoagulation SubcutaneousHeparin IntravenousHeparin LowMolecularWeightHeparin warfarin AntiplateletMedications

SC HEPARIN

Prophylactic (lowdose) sc heparin (5000u/24h): not a contraindication for regional anesthesia considering: - The coagulation tests are within normal limits (check for Heparin Induced Thrombocytopenia if pt on SC heparin for more than 4 days), - The patient is not receiving other coagulationaltering drugs (e.g.NSAIDs), - Puncture or removal of the catheter 2-4h after the last heparin dose and aPTTnormal

INTRAVENOUSHEPARIN

Should be avoided in patients with concomitant coagulopathies Heparin administration should be delayed for 1hour after needle placement Indwelling neuraxial catheters should be removed 24hours after the last heparin dose and reevaluation of the patient's coagulation status has occurred. Re-heparinization should occur one hour after catheter removal. For postoperative analgesia use the lowest effective local anesthetic concentration (probably with opioids ),to facilitate neurological monitoring.
.

Therapeutic anticoagulation with heparin is a contraindication to regional block except: --intravenous heparin infusion should be discontinued for 4hours --the activated partial thromboplastin Time (APTT) should be normal before attempting a block or removing a catheter

Patients receiving LMWH. LMWH have longer half-lives than unfractionated heparin, which allows once daily administration They have fibrinolytic properties as well as anti-Xa activity There is no LMWH monitoring test for routine Traumatic needle or catheter placement may signify an increased risk of spinal hematoma and initiation of LMWH therapy in this setting should be delayed for 24 hours

Preoperative administration of LMWH: Neuraxial blockade should be performedafter 12h of administration of thromboprophylaxis doses Do not puncture after 2-4h of LMWH administration ,as during this time the anticoagulant effect is at its maximum. If high-dose LMWH is used for therapeutic anticoagulation it takes about 24 hours for coagulation to return to normal. Therefore,an interval of 24 hours should elapse before attempting central neuraxial block or peripheral nerve block.

POSTOPERATIVE ADMINISTRATION OF LMWH

Once-daily dose LMWH:-The first dose is administered 6-8h postoperatively ,and the second dose 24h after the first. -Catheter removal 10-12h after LMWH administration -atleast 2hrs before next LMWH administration.

TWICE DAILY DOSE LMWH

-The first dose is administered 24h postoperatively.

-Indwelling catheters should be removed prior to initiation of LMWH.

-If a continuous technique is selected,the epidural catheter may be left indwelling overnight and removed the following day, with initiation of LMWH occurring atleast two hours after catheter removal

FONDAPARINUX

this new thromboprophylactic drug is a synthetic pentasaccharide,which has potent anti-Xa activity. It has a longer elimination half-life than LMWH of 17 hours in young patients and 21 hours in healthy elderly patients. It is administered 6 hours after surgery, which makes decisions regarding regional anaesthesia easier. However, its long half-life means that it should be used with caution in patients with neuraxial or peripheral nerve catheters insitu. An interval of atleast 24hours should elapse before removal of neuraxial or peripheral nerve catheters

Postthrombolitic: Absolute contraindication for regional anaesthesia

WARFARIN

For Thromboembolic prophylaxis in many cardiovascular conditions. Many older patients presenting for surgery are taking long-term warfarin therapy. For all but the most minor surgical procedures, warfarin should be stopped INR should be <1.4, with no other coagulation defects. This normally takes about 4days and substitute with LMWH(either prophylaxis or therapeutic dose,depending on thrombosis risk stratification,)

Vitamin K and FFP may prove helpful in more urgent cases. If the patient has received only one dose of warfarin preoperatively (to continue with warfarin postoperatively) ,check INR before puncture and before catheter removal. During continuous epidural analgesia, if the patient receives low doses of warfarin:INR should be kept<1.5. Catheter removal when INR<1.5, Neurological monitoring for more than 24h if INR>1.5 during catheter removal.Definitely postponed if INR>3

Aspirin and non-steroidalanti-inflammatory drugs(NSAIDs) impair platelet function by irreversibly inhibiting platelet cyclooxygenase(COX). Aspirin inhibits COX irreversibly while NSAIDs do so reversibly. Therefore the antiplatelet effect of aspirin persists until a new platelet population is manufactured (atleast7days), where as platelet function returns to normal within 3 days after stopping NSAIDs. Despite their widespread use for many years, there have been only five case reports of vertebral canal haematoma in patients receiving aspirin or NSAIDs alone.It is safe to proceed with central neuraxial block in patients taking these drugs,(a view endorsed by the American Society of Regional Anaesthesia. 2

Clopidogrel or ticlodipine(ADP receptor antagonists). a thienopyridine derivative and is a potent antiplatelet agent. It inhibits ADP-induced platelet aggregation and binding between platelets and fibrinogen. These effects are irreversible and platelet function does not return to normal until atleast 7days after stopping the drug. Neuraxial blockade is contraindicated before7 days from the discontinuation of clopidogrel and 14 days for ticlodipine

Platelet glycoproteinIIb/IIIaantagonists Eg:abciximab,eptifibatide andtirofiban A new class of antiplatelet agents for use in patients with acute coronary syndromes. The drugs target the platelet IIb/IIIa receptor complex. TheIIb/IIIa complex functions as a receptor for mainly fibrinogen and Vitronectin,but also fibronectin and von Willebrands factor. They have been recommended to prevent coronary ischaemic events in high-riskpatients Central neuraxial block should be avoided until platelet aggregation has returned to normal; a minimum of 8 hours after tirofiban and eptifibatide and 24 48hours after abciximab

Perioperative Management of Antithrombotic Therapy Patients Who Require Urgent Surgical or Other Invasive Procedures Pt on warfarin: In the non bleeding patient who requires rapid(within12h) reversal of the anticoagulant effect because of an urgent surgical or other invasive procedure,treatment options with fresh-frozen plasma/prothrombin concentrates/recombinant factorVIIa If surgery is urgent but can be delayed for 18 to 24h,the anticoagulant effect of VKAs is likely to be neutralized by IV vitaminK ,at a dose of 2.5 to 5.0mg without the need for bloodproduct

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