TRAUMA DUE TO TRAUMA DUE TO TREATMENTTREATMENT

Prof.S.Ramaswamy’s unit,M1Prof.S.Ramaswamy’s unit,M1Dr.Sangeetha.C.JosephDr.Sangeetha.C.Joseph

Case Case

Najumuneesha , 50 years , FNajumuneesha , 50 years , F Presenting complaints:Presenting complaints:

– Headache- 3 daysHeadache- 3 days– Vomiting- 3 daysVomiting- 3 days– Breathlessness- exacerbated since 3 days Breathlessness- exacerbated since 3 days – Decreased urine output- exacerbated since 3 Decreased urine output- exacerbated since 3

daysdays

History of presenting complaintsHistory of presenting complaints

– Known case of RHD for past 4 years on Known case of RHD for past 4 years on treatmenttreatment

– Complaints of headache – Complaints of headache – severe, occipital headache, continuously present severe, occipital headache, continuously present Not relieved with any medicationNot relieved with any medication No history trauma/ seizures . No history trauma/ seizures . History of altered sensorium – on & offHistory of altered sensorium – on & off

– Vomiting-Vomiting- Nausea, non projectile,non bilious.Nausea, non projectile,non bilious.

History of presenting complaints History of presenting complaints (contd.)(contd.)

It was associated with exacerbation of It was associated with exacerbation of breathlessness breathlessness – History of orthopnea and PND present.History of orthopnea and PND present.

History of decreased urine output and facial History of decreased urine output and facial puffiness was presentpuffiness was present

Past history: Past history: – Known case of RHD for 4 years on treatment . No Known case of RHD for 4 years on treatment . No

history of Hypertension, Diabetes mellitus, history of Hypertension, Diabetes mellitus, Tuberculosis, Asthma. No history of trauma in the Tuberculosis, Asthma. No history of trauma in the past. No surgery in past. Not willing for valve surgery.past. No surgery in past. Not willing for valve surgery.

Family history-Family history-– Nil relevantNil relevant

Treatment history-Treatment history-– T. Digoxin,Penicillin, Lasix, Slactone, Warfarin-3mg T. Digoxin,Penicillin, Lasix, Slactone, Warfarin-3mg

ODOD Personal History-Personal History-

– Decreased urine outputDecreased urine output Menstrual history-Menstrual history-

– Has attained menopauseHas attained menopause

On ExaminationOn Examination

Patient conscious, obeying few commandsPatient conscious, obeying few commands GCS- 11/15GCS- 11/15 Afebrile, facial puffinessAfebrile, facial puffiness Pallor+, bilateral pedal oedemaPallor+, bilateral pedal oedema No icterus/ cyanosis/ clubbingNo icterus/ cyanosis/ clubbing Vital signs- Vital signs- PR- 92/ min, irregularly PR- 92/ min, irregularly

irregular, BP- 130/90, RR- 20/ min, Temp- irregular, BP- 130/90, RR- 20/ min, Temp- 99.4˚F ,JVP elevated 99.4˚F ,JVP elevated

CVS:CVS:– apex in 5th left intercostal space in 1 cm lateral to apex in 5th left intercostal space in 1 cm lateral to

mid clavicular linemid clavicular line– P2 palpableP2 palpable– S1 variable intensity, P2 LoudS1 variable intensity, P2 Loud– MDM +, OS +MDM +, OS +

CHEST CHEST – NVBS heard, B/L basal crepts+NVBS heard, B/L basal crepts+

PER ABDOMENPER ABDOMEN– Soft, No HSMSoft, No HSM

CNSCNS

GCS- 11/15GCS- 11/15 PUPILS- B/L equally reacting to lightPUPILS- B/L equally reacting to light Tone normal in all 4 limbsTone normal in all 4 limbs Deep tendon reflexes B/L normal and B/L Deep tendon reflexes B/L normal and B/L

plantar flexor.plantar flexor. No s/o meningeal irritation No s/o meningeal irritation Fundus normalFundus normal

INVESTIGATIONSINVESTIGATIONS

Hb-9gm/dlHb-9gm/dl TC-7400TC-7400 DC-P54 L44DC-P54 L44 PCV-25%PCV-25% ESR-6/14ESR-6/14 PLC-1.8PLC-1.8 RBS-112RBS-112 BLOOD UREA-18BLOOD UREA-18 S.CRATININE-0.9S.CRATININE-0.9 RUE-WNLRUE-WNL

INVINV DAY 1DAY 1 DAY 3DAY 3 DAY 6DAY 6 DAY 8DAY 8

PTPT

Control-Control-1111

40.740.7 38.438.4 18.218.2 12.112.1

aPTTaPTT

Control-Control-2121

21.321.3 22.422.4 21.221.2 2121

INRINR 4.654.65 3.643.64 2.12.1 1.71.7

ECG—Atrial fibrillation/RVRECG—Atrial fibrillation/RVR

ECHO-MS severe,PHT severeECHO-MS severe,PHT severe LA dilated,no LA clotLA dilated,no LA clot advised to stop warfarinadvised to stop warfarin

All cardiac drugs continued except WarfarinAll cardiac drugs continued except Warfarin Vit K givenVit K given By day 6 pt became fully conscious and was By day 6 pt became fully conscious and was

relieved of headache and vomitingrelieved of headache and vomiting Repeat CT brain –resolved SDHRepeat CT brain –resolved SDH

FINAL DIAGNOSISFINAL DIAGNOSIS

RHD/MS SEVERE/PHT/CCF/ATRIAL RHD/MS SEVERE/PHT/CCF/ATRIAL FIBRILLATION/WARFARIN INDUCED FIBRILLATION/WARFARIN INDUCED ACUTE SDHACUTE SDH

WARFARINWARFARIN

HEMOSTASISHEMOSTASIS

VASCULAR SPASMVASCULAR SPASM

PLATELET PLUGPLATELET PLUG

BLOOD COAGULATIONBLOOD COAGULATION

GROWTH OF FIBROUS TISSUE IN CLOTGROWTH OF FIBROUS TISSUE IN CLOT

WHEN DOES BLOOD COAGULATE?WHEN DOES BLOOD COAGULATE?

Procoagulants > AnticoagulantsProcoagulants > Anticoagulants Injury to blood vesselInjury to blood vessel Blood stasisBlood stasis

INITIATION OF BLOOD COAGULATIONINITIATION OF BLOOD COAGULATION

Extrinsic PathwayExtrinsic Pathway

Tissue traumaTissue trauma

Leakage of Tissue FactorLeakage of Tissue Factor

XX XaXa

Prothrombin activatorProthrombin activator

CaCa+2+2,, factor VII factor VII

CaCa+2+2

Prothrombin Prothrombin ThrombinThrombin(factor II)(factor II)

CaCa+2+2

Intrinsic PathwayIntrinsic Pathway

Blood trauma/ contact with collagenBlood trauma/ contact with collagen

Activation of factor Activation of factor XII, IX, VIIIXII, IX, VIII

XX XaXa

CaCa+2+2

ProthrombinProthrombin activatoractivator

Prothrombin Prothrombin Thrombin Thrombin(factor II)(factor II)

Activation of certain factors (VII, II, X and protein C and S) is essential for coagulation. This activation requires vit K (reduced form)

Vitamin KVitamin K

Synthesis of Synthesis of Functional Functional

Coagulation Coagulation FactorsFactors

VIIVII

IXIX

XX

IIII

Vitamin K-Dependent Clotting Vitamin K-Dependent Clotting FactorsFactors

WarfarinWarfarin

Synthesis of Synthesis of Non Non

Functional Functional Coagulation Coagulation

FactorsFactors

Antagonismof

Vitamin K

Warfarin Mechanism of ActionWarfarin Mechanism of Action

Vitamin KVitamin K

VIIVII

IXIX

XX

IIII

WARFARIN: MECHANISM OF ACTIONWARFARIN: MECHANISM OF ACTION

Inactive factors II, VII, IX, and X

Proteins S and C

Proteins S and CActive factors II, VII, IX, and X

Vitamin K epoxide

Vitamin K reduced

WA

RF

AR

IN

Prevents the reduction of vitamin K, which is essential for Prevents the reduction of vitamin K, which is essential for activation of certain factorsactivation of certain factors

Has no effect on previously formed thrombusHas no effect on previously formed thrombus

PLASMA HALF-LIVES OF VITAMIN K-PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT PROTEINSDEPENDENT PROTEINS

Factor IIFactor II 72h72h

Factor VIIFactor VII 6h6h

Factor IXFactor IX 24h24h

Factor XFactor X 36h36h

Peak anticoagulant effect may be delayed by 72 to 96 hoursPeak anticoagulant effect may be delayed by 72 to 96 hours

Warfarin - PathophysiologyWarfarin - Pathophysiology

Anticoagulant effect mediated by inhibition Anticoagulant effect mediated by inhibition of vitamin K dependent of vitamin K dependent -carboxylation of -carboxylation of factors II, VII, IX, Xfactors II, VII, IX, X– Proteins become biologically inactiveProteins become biologically inactive

Effect of warfarin delayed until clotting Effect of warfarin delayed until clotting factors are cleared from the circulation factors are cleared from the circulation ~ 36-~ 36-72hrs72hrs

Equilibrium reached in about 1 weekEquilibrium reached in about 1 week

INDICATIONSINDICATIONS

Prophylaxis and treatment of venous Prophylaxis and treatment of venous thromboembolism thromboembolism (deep vein thrombosis and (deep vein thrombosis and pulmonary embolism)pulmonary embolism)

Prophylaxis and treatment of Atrial fibrillationProphylaxis and treatment of Atrial fibrillation Valvular stenosisValvular stenosis Heart valve replacementHeart valve replacement Myocardial infarction Myocardial infarction

WHY TO MONITOR WARFARIN THERAPY?WHY TO MONITOR WARFARIN THERAPY?

Narrow therapeutic rangeNarrow therapeutic range Can increase risk of bleedingCan increase risk of bleeding

MONITORING OF WARFARIN THERAPYMONITORING OF WARFARIN THERAPY

Prothrombin timeProthrombin time PT ratioPT ratio INR (International Normalized Ratio)INR (International Normalized Ratio)

PROTHROMBIN TIME (PT)PROTHROMBIN TIME (PT)

Time required for blood to coagulate is called Time required for blood to coagulate is called PTPT

Performed by adding a mixture of calcium Performed by adding a mixture of calcium and thromboplastin to citrated plasmaand thromboplastin to citrated plasma

As a control, a normal blood sample is tested As a control, a normal blood sample is tested continuouslycontinuously

PT ratio (PTR) = PT ratio (PTR) = Patient’s PTPatient’s PT

Control PTControl PT

PROBLEMS WITH PT/PTRPROBLEMS WITH PT/PTR

Thromboplastins are extracts from brain, Thromboplastins are extracts from brain, lung or placenta of animalslung or placenta of animals

Thromboplastins from various Thromboplastins from various manufacturers differ in their sensitivity to manufacturers differ in their sensitivity to prolong PTprolong PT

May result in erratic control of anticoagulant May result in erratic control of anticoagulant therapytherapy

INTERNATIONAL NORMALISED RATIO (INR)INTERNATIONAL NORMALISED RATIO (INR)

INR = [PTINR = [PTptpt] ] ISIISI

[PT[PTRefRef]]

PTPTpt pt – prothrombin time of patient– prothrombin time of patient

PTPTRef Ref – prothrombin time of normal pooled sample– prothrombin time of normal pooled sample

ISI – International Sensitivity IndexISI – International Sensitivity Index

OPTIMIZING WARFARIN THERAPYOPTIMIZING WARFARIN THERAPY

Dosage to be individualized according to Dosage to be individualized according to patient’s INR response. patient’s INR response. Use of large loading dose may lead to Use of large loading dose may lead to hemorrhage and other complications.hemorrhage and other complications.

Initial dose: 2-5 mg once dailyInitial dose: 2-5 mg once daily Maintenance dose: 2-10 mg once dailyMaintenance dose: 2-10 mg once daily Immediate anticoagulation required:Immediate anticoagulation required: Start Start

heparin along with loading dose of warfarin 10 heparin along with loading dose of warfarin 10 mg. Heparin is usually discontinued after 4-5 mg. Heparin is usually discontinued after 4-5 days. days. Before discontinuing, ensure INR is in Before discontinuing, ensure INR is in therapeutic range for 2 consecutive daystherapeutic range for 2 consecutive days

How frequently we should monitor?How frequently we should monitor?

Monitor daily until INR is in therapeutic Monitor daily until INR is in therapeutic rangerange

then 3 times weekly for 1-2 weeks,then 3 times weekly for 1-2 weeks, then less often (every 4 to 6 weeks) then less often (every 4 to 6 weeks)

Commencement & discontinuation of Commencement & discontinuation of AC AC guidelines british committee for hematologyguidelines british committee for hematology

RecommendationRecommendation For outpatients who do not require rapid For outpatients who do not require rapid

anticoagulation a slow loading regimen is safe and anticoagulation a slow loading regimen is safe and achieves therapeutic anticoagulation in the majority of achieves therapeutic anticoagulation in the majority of patients within3 to 4 weeks. This appears to avoid patients within3 to 4 weeks. This appears to avoid overanticoagulation andbleeding associated with rapid overanticoagulation andbleeding associated with rapid loading.loading.

For patients requiring rapid initiation of oral For patients requiring rapid initiation of oral anticoagulation, regimens that start with 5mg doses or anticoagulation, regimens that start with 5mg doses or a single 10mg dose followed by 5mg doses may be a single 10mg dose followed by 5mg doses may be preferable to regimens that start with repeated 10mg preferable to regimens that start with repeated 10mg doses in certain patientgroups, e.g. the elderly (>60 doses in certain patientgroups, e.g. the elderly (>60 years old), those with liver disease or cardiac years old), those with liver disease or cardiac failureand those at high risk of bleeding.failureand those at high risk of bleeding.

Guide lines for dosingGuide lines for dosingRECOMMENDATIONSRECOMMENDATIONSamerican college of cardiologyamerican college of cardiology

LEVEL 1LEVEL 1– W dose adjusted based on target INRW dose adjusted based on target INR– Better to avoid a loading dose of 10 mgBetter to avoid a loading dose of 10 mg

LEVEL 2LEVEL 2– All should have baseline INR valueAll should have baseline INR value– Daily PT / INR chart till INR value becomes stableDaily PT / INR chart till INR value becomes stable

LEVEL 3LEVEL 3– Patients with significant drug interactions / risk factors Patients with significant drug interactions / risk factors

start on low dose warfarin start on low dose warfarin – If significant drug interaction daily PT / INR until INR If significant drug interaction daily PT / INR until INR

stable stable

Current Daily Dose (mg)Current Daily Dose (mg)

2.0 2.0 5.05.0 7.57.5 10.010.0 12.512.5WarfarinWarfarin

INRINR Dose Adjustment*Dose Adjustment* Adjusted Daily Dose (mg)Adjusted Daily Dose (mg)1.01.0--2.02.0 Increase x 2 daysIncrease x 2 days 5.05.0 7.57.5 10.010.0 12.512.5 15.015.02.02.0--3.03.0 No changeNo change —— —— —— —— ——3.03.0--6.06.0 Decrease x 2 daysDecrease x 2 days 1.251.25 2.52.5 5.05.0 7.57.5 10.010.0

6.06.0--10.010.0†† Decrease x 2 daysDecrease x 2 days 00 1.251.25 2.52.5 5.05.0 7.57.510.010.0--18.018.0§§ Decrease x 2 daysDecrease x 2 days 00 00 00 00 2.52.5

>18.0>18.0§§ Discontinue warfarinDiscontinue warfarin and consider hospitalization/reversaland consider hospitalization/reversalof anticoagulationof anticoagulation

†† Consider oral vitamin K, 2.5Consider oral vitamin K, 2.5––5 mg5 mg§§ Oral vitamin K, 2.5Oral vitamin K, 2.5––5 mg5 mg* Allow 2 days after dosage change for clotting factor equilibra* Allow 2 days after dosage change for clotting factor equilibration. Repeat tion. Repeat prothrombinprothrombin time 2 days after increasing or time 2 days after increasing or decreasing decreasing warfarinwarfarin dosage and use new guide to management (INR = International Nordosage and use new guide to management (INR = International Normalized Ratio). After increase or malized Ratio). After increase or decrease of dose for two days, go to new higher (or lower) dosagdecrease of dose for two days, go to new higher (or lower) dosage level (e.g., if 5.0 qd, alternate 5.0/7.5; if alternate 2.5/5.e level (e.g., if 5.0 qd, alternate 5.0/7.5; if alternate 2.5/5.0, 0, increase to 5.0 qd).increase to 5.0 qd).

Dosage Adjustment AlgorithmDosage Adjustment Algorithm

OPTIMAL THERAPEUTIC RANGEOPTIMAL THERAPEUTIC RANGE

IndicationIndication INRINR

Prophylaxis of venous Prophylaxis of venous thromboembolismthromboembolism

2.0-3.02.0-3.0

Treatment of venous Treatment of venous thromboembolismthromboembolism

2.0-3.02.0-3.0

Atrial fibrillationAtrial fibrillation 2.0-3.02.0-3.0

Mitral valve stenosisMitral valve stenosis 2.0-3.02.0-3.0

Heart valve replacementHeart valve replacement

Bioprosthetic valveBioprosthetic valve

Mechanical valveMechanical valve

2.0-3.02.0-3.0

2.5-3.52.5-3.5

Myocardial Myocardial infarction,recurrent DVT and infarction,recurrent DVT and PTEPTE

2.0-3.02.0-3.0

2.5-3.5 2.5-3.5 (high risk patients)(high risk patients)

Warfarin Indications – SystemicWarfarin Indications – Systemic

Indications

Atrial Fibrillation

Valvular

Nonvalvular

Cardioversion

Mural Thrombus

Cardiomyopathy

Mechanical Prosthetic Valve Mitral

Mechanical Prosthetic Valve Aortic

Bioprosthetic Valve

2.5

2.5

2.5

2.5 / 3.0

2.5

2.5

3.0 – 3.5

2.5 – 3.0

2.5

Target INR .

Oral Anticoagulants inAtrial Oral Anticoagulants inAtrial FibrillationFibrillation

Usually indefinite Oral Anticoagulation for prevention of Thromboembolism

Valvular

Rheumatic Heart Disease (MS)

Prosthetic Heart Valve Prior Thromboembolism

Persistent Atrial Thrombus on TEE

INR – 2 to 3

INR – 2.5 to 3.5

Nonvalvular

Age ≥ 60 years with DM or CAD (INR – 2-3)(Aspirin is added) Age ≥ 75 years (INR – 2)

Heart Failure

LVEF < 30%

Thyrotoxicosis

Hypertension

FACTORS INFLUENCING DOSE RESPONSEFACTORS INFLUENCING DOSE RESPONSE

Inaccurate lab testingInaccurate lab testing Poor patient compliancePoor patient compliance Concomitant medicationsConcomitant medications Levels of dietary vitamin KLevels of dietary vitamin K Alcohol Alcohol Hepatic dysfunctionHepatic dysfunction FeverFever

CONTARINDICATIONS AND CONTARINDICATIONS AND PRECAUTIONSPRECAUTIONS

Hypersensitivity to warfarinHypersensitivity to warfarin Condition with risk of hemorrhageCondition with risk of hemorrhage Hemorrhagic tendencyHemorrhagic tendency Inadequate laboratory techniquesInadequate laboratory techniques Protein C & S deficiencyProtein C & S deficiency Vitamin K deficiencyVitamin K deficiency Intramuscular injectionsIntramuscular injections

SIDE EFFECTSSIDE EFFECTS

Hemorrhage Hemorrhage Skin necrosisSkin necrosis Purple toe syndromePurple toe syndrome Microembolization Microembolization TeratogenecityTeratogenecity

Agranulocytosis, leukopenia, diarrhoea,Agranulocytosis, leukopenia, diarrhoea,

nausea, anorexia.nausea, anorexia.

Major A/E is bleedingMajor A/E is bleeding Risk of bleeding depends onRisk of bleeding depends on 1.intensity of anticoagulation1.intensity of anticoagulation 2.concomitant clinical disorders2.concomitant clinical disorders 3.use of other medications3.use of other medications 4.management quality4.management quality

Bleeding risk high in elderly d/tBleeding risk high in elderly d/t

Increased age and sensitivity at usual dosesIncreased age and sensitivity at usual doses Co-morbid conditionsCo-morbid conditions Increased drug interactionsIncreased drug interactions

Etiology in elderlyEtiology in elderly

Older adults-increased risk for SDH d/t Older adults-increased risk for SDH d/t fragility of bridging cerebral veins----as fragility of bridging cerebral veins----as cerebral atrophy develops----brain shrinks cerebral atrophy develops----brain shrinks away from dura and bridging veins----away from dura and bridging veins----predisposed to tearing due to increased predisposed to tearing due to increased stress.stress.

Males increased risk for SDH-etiology not Males increased risk for SDH-etiology not clearclear

Conversion from Heparin to WarfarinConversion from Heparin to Warfarin

May begin concomitantly with Heparin Therapy

Heparin should be continued for a minimum of four days

Time to peak antithrombotic effect of Warfarin therapy is delayed 96 hours (despite INR)

When INR reaches desired therapeutic range, discontinue heparin (after a minimum of four days)

SWITCHOVER FROM ONE BRAND OF SWITCHOVER FROM ONE BRAND OF WARFARIN TO ANOTHER/ ACENOCOUMAROLWARFARIN TO ANOTHER/ ACENOCOUMAROL

Check patient’s INRCheck patient’s INR Start with dose of 2 mg; increase dose Start with dose of 2 mg; increase dose

slowly as requiredslowly as required

Signs of Warfarin OverdosageSigns of Warfarin Overdosage

Any unusual bleeding:Any unusual bleeding:– Blood in stools or urineBlood in stools or urine– Excessive menstrual bleedingExcessive menstrual bleeding– BruisingBruising– Excessive nose bleeds/bleeding gumsExcessive nose bleeds/bleeding gums– Persistent oozing from superficial injuriesPersistent oozing from superficial injuries– Bleeding from tumor, ulcer, or other lesionBleeding from tumor, ulcer, or other lesion

Causes of excessive anticoagulationCauses of excessive anticoagulation

High dose warfarinHigh dose warfarin Drug interactionsDrug interactions Genetic polymorphisms- variations in pts’ Genetic polymorphisms- variations in pts’

response to warfarinresponse to warfarin Superimposed diseases (liver, malabsorption Superimposed diseases (liver, malabsorption

syndromes)syndromes) Vitamin K deficiencyVitamin K deficiency

– Poor dietary intakePoor dietary intake– TPNTPN– Prolonged course of ABXProlonged course of ABX

THE OVERALL ANTICOAGULATION QUALITY THE OVERALL ANTICOAGULATION QUALITY IS SIGNIFICANTLY BETTER WITH WARFARIN IS SIGNIFICANTLY BETTER WITH WARFARIN AS COMPARED TO ACENOCOUMAROLAS COMPARED TO ACENOCOUMAROL

72%

67%

64%

66%

68%

70%

72%

% R

espo

nder

s

Warfarin Acenocoumarol

Thrombosis And Haemostasis 1994; 71(2): 188-191

New Anticoagulation DrugsNew Anticoagulation Drugs

Direct Thrombin InhibitorsDirect Thrombin Inhibitors– Ximelagatran, Ximelagatran, hirudin, bivalirudin, and hirudin, bivalirudin, and

argatrobanargatroban

Synthetic pentasaccharideSynthetic pentasaccharide Acivated Protein CAcivated Protein C Tissue Factor Pathway Inhibitor (TFPI)Tissue Factor Pathway Inhibitor (TFPI)

Why do we need new Why do we need new anticoagulation drugs?anticoagulation drugs?

Heparin-induced thrombocytopeniaHeparin-induced thrombocytopenia Heparin prophylaxis is imperfectHeparin prophylaxis is imperfect Heparin-associated osteoporosisHeparin-associated osteoporosis Warfarin takes several days for its effectWarfarin takes several days for its effect Warfarin is not as effective in some situations e.g Warfarin is not as effective in some situations e.g

antiphospholipid syndromeantiphospholipid syndrome Warfarin interacts with many other drugsWarfarin interacts with many other drugs Warfarin is dangerous if not monitoredWarfarin is dangerous if not monitored

Synthetic PentasaccharideSynthetic Pentasaccharide

E.g FondaparinuxE.g Fondaparinux Synthetic, single molecular entitySynthetic, single molecular entity Targets Factor XaTargets Factor Xa Does not cause thrombocytopeniaDoes not cause thrombocytopenia Shown promise in DVT prevention during Shown promise in DVT prevention during

orthopedic procedures.orthopedic procedures. Also being examined in ischaemic heart Also being examined in ischaemic heart

diseasedisease

XimelagatranXimelagatran

Promising oral direct thrombin inhibitorPromising oral direct thrombin inhibitor Converted to the active form melagatran in Converted to the active form melagatran in

vivovivo No dosing problemsNo dosing problems No monitoring needed.No monitoring needed. Recent atrial fibrillation study showed it to Recent atrial fibrillation study showed it to

possibly be superior to warfarin.possibly be superior to warfarin.

Dilemma for the physician in SDHDilemma for the physician in SDH

Continuing anticoagulants-may increase Continuing anticoagulants-may increase volume of haemorrhagevolume of haemorrhage

Early reinstitution of drug-may cause Early reinstitution of drug-may cause recurrence of bleedrecurrence of bleed

Reversal of drug-pt at risk for systemic Reversal of drug-pt at risk for systemic embolizationembolization

Neurological complications of acNeurological complications of ac

Cause bleeding in -----brainCause bleeding in -----brain ------spinal cord------spinal cord ------peripheral nerve------peripheral nerve BRAIN---SDH,ICH etcBRAIN---SDH,ICH etc SPINAL CORD-subdural hematomaSPINAL CORD-subdural hematoma PERIPHERAL NERVE-most frequent is PERIPHERAL NERVE-most frequent is

femoral nerve compression d/t bleeding into femoral nerve compression d/t bleeding into iliacus muscleiliacus muscle

How safely and for how long can W be How safely and for how long can W be withheld in pts when admitted with major withheld in pts when admitted with major

bleedsbleeds??

Depends on relative risk and benefit of Depends on relative risk and benefit of treatmenttreatment

Studies have shown that the risk of TE is Studies have shown that the risk of TE is low in prosthetic valve pts when W is low in prosthetic valve pts when W is withheld following a major bleedwithheld following a major bleed

No definite recommendations are thereNo definite recommendations are there Around 2 wks can be taken roughly for Around 2 wks can be taken roughly for

safetysafety

No study has evaluated the optimal time for No study has evaluated the optimal time for restarting in pts with SDHrestarting in pts with SDH

If no evacuation done—rpt CT in 1-2 wks—If no evacuation done—rpt CT in 1-2 wks—serial CT in 4-6 wks---resolved----restart ACserial CT in 4-6 wks---resolved----restart AC

Risk of ischemic stroke in pts with prosthetic Risk of ischemic stroke in pts with prosthetic heart valves after W discontinuation is 3% in heart valves after W discontinuation is 3% in 30 days30 days

Recurrence of SDH after resuming Recurrence of SDH after resuming treatment is very lesstreatment is very less

Withdrawal of oral anticoagulantWithdrawal of oral anticoagulanttreatmenttreatment

Whether treatment should be withdrawnWhether treatment should be withdrawn abruptly or gradually withdrawn ("tailed off")abruptly or gradually withdrawn ("tailed off") is still debatable.is still debatable. Theoretically, the "Theoretically, the "rebound hypercoagulabilityrebound hypercoagulability""

which results from sudden discontinuation might which results from sudden discontinuation might predispose to rebound thrombosis.predispose to rebound thrombosis.

Some clinicians tail off long term treatment over Some clinicians tail off long term treatment over

several weeks but withdrawl for short term several weeks but withdrawl for short term treatment can be done suddenly.treatment can be done suddenly.

Discontinuation of acDiscontinuation of acbritish committee british committee standards of hematologystandards of hematology

Concern of a ‘Concern of a ‘rebound hypercoagulablerebound hypercoagulable state’ after stopping state’ after stopping oral anticoagulant therapy has resulted in uncertainty as to oral anticoagulant therapy has resulted in uncertainty as to whether treatment should be stopped abruptly or gradually.whether treatment should be stopped abruptly or gradually.

Laboratory markers indicate a hypercoagulable state in some Laboratory markers indicate a hypercoagulable state in some patients following withdrawal of oral anticoagulant therapy, patients following withdrawal of oral anticoagulant therapy, regardless of the speed of withdrawal (Palareti and Coccheri regardless of the speed of withdrawal (Palareti and Coccheri 1996, Palareti1996, Palareti, et al , et al 1994).1994).

In many patients this is probably the result of a In many patients this is probably the result of a pre-existing pre-existing prothrombotic state that may have contributed to the prothrombotic state that may have contributed to the thrombotic event necessitating anticoagulant treatment.thrombotic event necessitating anticoagulant treatment.

RecommendationRecommendation Oral anticoagulant therapy can be discontinued abruptly Oral anticoagulant therapy can be discontinued abruptly

when the duration of therapy is completed.when the duration of therapy is completed.

Reversal OptionsReversal Options

Holding warfarin doseHolding warfarin dose Holding dose + Vit KHolding dose + Vit K

– Vit KVit K Oral Oral SubcutaneousSubcutaneous IntraveneousIntraveneous

FFPFFP FactorVIIa-15-20mcg/kgFactorVIIa-15-20mcg/kg Prothrombin complex concentrateProthrombin complex concentrate

In Asymptomatic pts ;In Asymptomatic pts ; INR-3.5-4.5=stop W till INR returns to INR-3.5-4.5=stop W till INR returns to

normal therapeutic rangenormal therapeutic range INR->4.5=low doses of sublingual vit KINR->4.5=low doses of sublingual vit K INR-4.5-9=vit K 1mg will be enoughINR-4.5-9=vit K 1mg will be enough INR>9=vit K 2-3mg can be usedINR>9=vit K 2-3mg can be used

In pts with serious bleeding,In pts with serious bleeding, Vit K 10mg can be given as slow IV Vit K 10mg can be given as slow IV

infusion,addtl doses if neededinfusion,addtl doses if needed Add FFP to give vit K dependent Add FFP to give vit K dependent

coagulation factorscoagulation factors Life threatening bleeding FVIIa/prothrombin Life threatening bleeding FVIIa/prothrombin

concentratesconcentrates

Recommendations for reversalRecommendations for reversalguide lines on oral ac by british society of hematologyguide lines on oral ac by british society of hematology

A A Life threatening haemorrhageLife threatening haemorrhage Immediately give 5 mg vitamin Immediately give 5 mg vitamin

K, by slow intravenous infusion and a concentrate of factor II, K, by slow intravenous infusion and a concentrate of factor II, IX, X, with factorVIIconcentrate.IX, X, with factorVIIconcentrate.

BB Less severe haemorrhage such as haematuria and epistaxisLess severe haemorrhage such as haematuria and epistaxis Withhold warfarin for one or more days and consider giving Withhold warfarin for one or more days and consider giving

vitaminK, 0. 5-2 mg intravenouslyvitaminK, 0. 5-2 mg intravenously

C C INR of > 4.5 without haemorrhageINR of > 4.5 without haemorrhage Withdraw warfarin for one or two days then reviewWithdraw warfarin for one or two days then review

DD Unexpected bleeding at therapeutic levelsUnexpected bleeding at therapeutic levels Investigate possibility of underlying cause such as Investigate possibility of underlying cause such as

unsuspected renal or alimentary tract diseaseunsuspected renal or alimentary tract disease

MessageMessage …… ……

OAC therapy – associated with inherent risk of bleeding

Proper anticoagulant initiation, dosages according to desired INR alleviates the risk of bleeding

Maintenance dosage and duration of therapy as per the underlying clinical condition and other risk factors

Physician’s role is vital in treatment, education, counseling and communication

THANK YOUTHANK YOU