Bleeding and AnticoagulationBleeding and Anticoagulation

Dr Oliver ChapmanDr Oliver Chapman

20112011

SummarySummary

Objectives:Objectives:– Understand haemostatic mechanismsUnderstand haemostatic mechanisms– Learn about the commoner haemorrhagic Learn about the commoner haemorrhagic

disorders and their treatmentdisorders and their treatment– Understand how to initiate and manage Understand how to initiate and manage

anticoagulation anticoagulation

CasesCases

PlateletsPlatelets

Platelet adhesion / aggregationPlatelet adhesion / aggregation

Case ScenariosCase Scenarios

(1)(1) Abnormal bleedingAbnormal bleeding

(2)(2) ““Peri operative screen” / Abnormal coagulation Peri operative screen” / Abnormal coagulation screenscreen

– Routine coagulation testing to predict postoperative bleeding risk in unselected patients prior to surgery or other invasive procedures is not recommended

– A bleeding history, including family history, evidence of excessive post-traumatic or postsurgical bleeding and use of antithrombotic drugs should be taken in all patients prior to surgery or invasive procedures.

Summary of key recommendations

1 Indiscriminate coagulation screening prior to surgery orother invasive procedures to predict postoperative bleedingin unselected patients is not recommended. (Grade B,Level III).2 A bleeding history including detail of family history,previous excessive post-traumatic or postsurgical bleedingand use of anti-thrombotic drugs should be taken in allpatients preoperatively and prior to invasive procedures.(Grade C, Level IV).3 If the bleeding history is negative, no further coagulationtesting is indicated. (Grade C, Level IV).4 If the bleeding history is positive or there is a clear clinicalindication (e.g. liver disease), a comprehensive assessment,guided by the clinical features is required. (Grade C,Level IV).

Bleeding HistoryBleeding History

IncludeIncludePrevious / current haemostatic challengesPrevious / current haemostatic challenges– Operation eg appendicectomy / T’s & A’sOperation eg appendicectomy / T’s & A’s– Dental extractionsDental extractions– Lacerations / suturesLacerations / sutures– MensesMenses

Drug HistoryDrug History– Including anti platelet Rx / NSAID’sIncluding anti platelet Rx / NSAID’s

Family historyFamily history

Laboratory testsLaboratory tests

Laboratory tests 1Laboratory tests 1– PlateletsPlatelets

FBC – platelet count and filmFBC – platelet count and film

Bleeding time Bleeding time **

Platelet function tests (only at centres) Platelet function tests (only at centres) **

* * = =in liason with haematologyin liason with haematology

Platelets - Blood filmPlatelets - Blood film

Bleeding TimeBleeding Time

Platelet function testsPlatelet function tests

If screening test abnormal and platelet If screening test abnormal and platelet count and VWD screen normal refer for count and VWD screen normal refer for platelet function test:platelet function test:

www.platelet-research.orgwww.platelet-research.org

Platelet disordersPlatelet disorders

QuantitativeQuantitative– Thrombocytopenia.Thrombocytopenia.

QualitativeQualitative– Functional disorders – Congenital vs Functional disorders – Congenital vs

AcquiredAcquired

Congenital platelet function Congenital platelet function disordersdisorders

Bernard SoulierBernard Soulier– Rare. AR inheritance. Platelet GP Ib-IX deficiency – Rare. AR inheritance. Platelet GP Ib-IX deficiency –

adhesion problem.adhesion problem.

Glanzmann’s ThrombastheniaGlanzmann’s Thrombasthenia– Rare. AR inheritance. Platelet GP IIb-IIIa deficiency – Rare. AR inheritance. Platelet GP IIb-IIIa deficiency –

aggregation problem.aggregation problem.

Storage Pool DisordersStorage Pool Disorders– α-SPD (gray platelet syndrome) / Dense granule α-SPD (gray platelet syndrome) / Dense granule

storage pool disorders (δ-SPDs) such as Chediak-storage pool disorders (δ-SPDs) such as Chediak-Higashi, Hermansky-Pudlak syndrome, Higashi, Hermansky-Pudlak syndrome, thrombocytopenia with absent radii (TAR syndrome), thrombocytopenia with absent radii (TAR syndrome), or Wiskott-Aldrich syndrome. or Wiskott-Aldrich syndrome.

Acquired platelet dysfunction Acquired platelet dysfunction disordersdisorders

(1)(1) Drugs eg aspirin, NSAID’s, clopidogrel, Drugs eg aspirin, NSAID’s, clopidogrel, dipyridamoledipyridamole

(2)(2) UraemiaUraemia

(3)(3) Myelodysplastic , Myeloproliferative Myelodysplastic , Myeloproliferative disordersdisorders

Platelet disorders - treatmentPlatelet disorders - treatment

Treatment of aquired platelet disordersTreatment of aquired platelet disorders– Stop offending drugs (aspirin – 7 days, other Stop offending drugs (aspirin – 7 days, other

NSAID’s generally 1-2 days)NSAID’s generally 1-2 days)– ddAVP in uraemiaddAVP in uraemia– Platelet transfusion (if active, significant Platelet transfusion (if active, significant

bleeding aim to maintain platelets >50), bleeding aim to maintain platelets >50), otherwise >10.otherwise >10.

– NB Avoid platelet transfusions in HIT, TTP NB Avoid platelet transfusions in HIT, TTP and PTP (unless life threatening bleeding)and PTP (unless life threatening bleeding)

Laboratory testsLaboratory tests

Laboratory tests 2Laboratory tests 2– CoagulationCoagulation

Prothrombin Time (PT)Prothrombin Time (PT)

Activated Partial Thromboplastin Time (APTT)Activated Partial Thromboplastin Time (APTT)

Fibrinogen Fibrinogen

Measurement of clotting factor levels Measurement of clotting factor levels **

* * = =in liason with haematologyin liason with haematology

Clotting factor disordersClotting factor disorders

Prothrombin TimeProthrombin Time– Normal 10-14sNormal 10-14s– Prolonged in deficiency Factor VII (and early warfarin)Prolonged in deficiency Factor VII (and early warfarin)

APTT ratioAPTT ratio– NormalNormal– Prolonged in deficiency Factors VIII, IX, XI, XIIProlonged in deficiency Factors VIII, IX, XI, XII

Both PT / APTT-R prolongedBoth PT / APTT-R prolonged– Fibrinogen and other common pathway factors (FII, V, X)Fibrinogen and other common pathway factors (FII, V, X)

– NB International Normalised Ratio should only be used in the NB International Normalised Ratio should only be used in the context of patients on warfarincontext of patients on warfarin

Haemorrhagic disorders - Haemorrhagic disorders - coagulationcoagulation

Prolonged coagulation screening testProlonged coagulation screening test

– Inhibitor (antibody - rare) vs Deficiency Inhibitor (antibody - rare) vs Deficiency (common)(common)

– 50:50 mix50:50 mixDeficiency : prolongation correctsDeficiency : prolongation corrects

Inhibitor : no correction of prolongation Inhibitor : no correction of prolongation

Clotting factor deficienciesClotting factor deficiencies

CongenitalCongenital

AcquiredAcquired

Congenital deficienciesCongenital deficiencies

Haemophilia A, BHaemophilia A, B– Joint, muscle bleedsJoint, muscle bleeds– X linkedX linked

– Other factors (very Other factors (very rare)rare)

HaemophiliaHaemophilia

DO NOT DELAY TREATMENTDO NOT DELAY TREATMENT– Delays in administration of clotting factor Delays in administration of clotting factor

therapy / treatment significantly increase therapy / treatment significantly increase morbidity / costs of therapy and long term morbidity / costs of therapy and long term disabilitydisability

– Patients at UHCW when bleeding are ALL Patients at UHCW when bleeding are ALL triaged orange minimum ie assessment in 30 triaged orange minimum ie assessment in 30 minutes (and treatment within 60 minutes)minutes (and treatment within 60 minutes)

Von Willebrands DiseaseVon Willebrands Disease

VWF carrier molecule for F VIIIVWF carrier molecule for F VIII

VWF deficiency leads to VIII deficiencyVWF deficiency leads to VIII deficiency

Characterised by mucocutaneous bleeding Characterised by mucocutaneous bleeding (bruising, epistaxis, GI bleeds, (bruising, epistaxis, GI bleeds, menorrhagia)menorrhagia)

Autosomal inheritanceAutosomal inheritance

Common (up to 1:1000)Common (up to 1:1000)

Acquired haemorrhagic coagulation Acquired haemorrhagic coagulation disorders -disorders -

Acquired factor deficienciesAcquired factor deficiencies– WarfarinWarfarin– Vitamin K deficiency eg sick patients on broad Vitamin K deficiency eg sick patients on broad

spectrum antibioticsspectrum antibiotics– DICDIC– Massive transfusion (whole blood volume Massive transfusion (whole blood volume

replaced)replaced)– Liver diseaseLiver disease

Haemorrhagic disorders - treatmentHaemorrhagic disorders - treatment

Treatment of Treatment of congenitalcongenital factor factor deficienciesdeficiencies– Factor concentrates (except FV deficiency) Factor concentrates (except FV deficiency)

NOTNOT FFP or cryoprecipitate because of risks FFP or cryoprecipitate because of risks of viral transmissionof viral transmission

– Specialist involvementSpecialist involvement

Haemorrhagic disorders - treatmentHaemorrhagic disorders - treatment

Treatment of acquired coagulation Treatment of acquired coagulation disorders if bleedingdisorders if bleeding– PT / APTT prolonged – FFP 10-15mls /kgPT / APTT prolonged – FFP 10-15mls /kg– Fibrinogen low – Cryoprecipitate (2 pools)Fibrinogen low – Cryoprecipitate (2 pools)

Case 1Case 1

4 year old boy fell 4 year old boy fell over and developed over and developed painful swelling of left painful swelling of left elbowelbow– What tests?What tests?

Case 1Case 1

FBC – normalFBC – normal

Coagulation screenCoagulation screen– PT 12s (N)PT 12s (N)– APTR 2.0 (prolonged)APTR 2.0 (prolonged)– Fibrinogen 2.3 (N)Fibrinogen 2.3 (N)

What are the possible diagnoses?What are the possible diagnoses?

What tests? – bonus What tests? – bonus

Case 2Case 2

76 yr old woman admitted with Right sided 76 yr old woman admitted with Right sided pneumonia, temp 39.5 C, bruising over pneumonia, temp 39.5 C, bruising over arms, legs.arms, legs.

FBC – Hb 12.0, WCC 20.0, Platelets 22FBC – Hb 12.0, WCC 20.0, Platelets 22

What test next?What test next?

Case 2Case 2

Coagulation screen Coagulation screen – PT 20sPT 20s– PTT 48sPTT 48s– Fibrinogen 0.7Fibrinogen 0.7

– ? Likely diagnosis? Likely diagnosis– What is the treatment? What is the treatment? – If she were bleeding actively?If she were bleeding actively?

Case 3Case 3

65 year woman with known atrial 65 year woman with known atrial fibrillation admitted with haematemesis.fibrillation admitted with haematemesis.

FBC – Hb 7.0, WCC 8, Platelets 190FBC – Hb 7.0, WCC 8, Platelets 190

PT 40, APTT 34, Fibrinogen 2.0PT 40, APTT 34, Fibrinogen 2.0

What is the likely cause?What is the likely cause?

How would you treat? How would you treat?

WarfarinWarfarin

Warfarin in VTE - durationWarfarin in VTE - duration

Calf vein thrombosisCalf vein thrombosis - 3 months- 3 monthsProvoked proximal DVT eg post-opProvoked proximal DVT eg post-op - 3 months- 3 monthsIdiopathic proximal DVTIdiopathic proximal DVT - 6 months- 6 monthsPulmonary EmbolismPulmonary Embolism - 6 months- 6 monthsRecurrent DVT / PERecurrent DVT / PE - Indefinite- Indefinite

NB If persisting risk factor eg paralysis, immobilised NB If persisting risk factor eg paralysis, immobilised limb / cancer consider extending treatment duration – limb / cancer consider extending treatment duration – INDIVIDUALISED THERAPY (the future?)INDIVIDUALISED THERAPY (the future?)

Warfarin and AFWarfarin and AF

Risk factors for CVA in non-rheumatic AF Risk factors for CVA in non-rheumatic AF include:include:– CCF, previous CVA, age > 75 yrs, hypertension, DMCCF, previous CVA, age > 75 yrs, hypertension, DM– Patients with no risk factors – stroke risk <1%/yr, treat Patients with no risk factors – stroke risk <1%/yr, treat

with aspirin only – low CHADwith aspirin only – low CHAD22 score score

Risk of serious bleeding on warfarin 2%, and of Risk of serious bleeding on warfarin 2%, and of fatal bleeding 0.6%fatal bleeding 0.6%

Therefore consider whether warfarin indicated if Therefore consider whether warfarin indicated if lone warfarin. Also consider bleeding risk – lone warfarin. Also consider bleeding risk – increased if recurrent falls etc.increased if recurrent falls etc.

Starting warfarinStarting warfarin

2 regimes based on degree of urgency for 2 regimes based on degree of urgency for therapeutic anticoagulationtherapeutic anticoagulation– Rapid anticoagulation in patients requiring Rapid anticoagulation in patients requiring

heparin ie post thrombosis etcheparin ie post thrombosis etc– Slow induction of anticoagulation in Slow induction of anticoagulation in

outpatients not requiring heparin ie outpatients not requiring heparin ie prophylaxis eg AFprophylaxis eg AF

Rapid WarfarinisationRapid Warfarinisation

Gedge Nomogram - recommendedGedge Nomogram - recommendedShown to be safer than traditional Fennerty Shown to be safer than traditional Fennerty Nomogram in patients >65 years.Nomogram in patients >65 years.

Similar time to achievement of therapeutic range Similar time to achievement of therapeutic range (<1/7 difference)(<1/7 difference)

Also concerns with Fennerty Nomogram in other Also concerns with Fennerty Nomogram in other patients with Congestive Cardiac Failure, Hepatic patients with Congestive Cardiac Failure, Hepatic Dysfunction, other bleeding risks etcDysfunction, other bleeding risks etc

Day INR Warfarin dose – young / low bleeding risk (mg)1

Warfarin dose – patients >65 years / high bleeding risk (mg) 2

1 <1.4 10 10

2 <1.8 10 5

1.8-2.0 1 1

>2.0 0 0

3 <2.0 10 5

2-2.2 5 4

2.3.2.5 4 4

2.6-2.9 3 3

3.0-3.2 2 2

3.3-3.5 1 1

>3.5 0 0

4 <1.4 9 8

1.4-1.5 8 7 etc…

1 Modified Fennerty Nomogram : Fennerty A et al (1984) Br Med J; 288: 1268-702 Gedge Nomogram : Gedge J et al (2000) Age and Ageing; 29: 31-34

Non Urgent WarfarinisationNon Urgent Warfarinisation

Liaise with anticoagulation teamLiaise with anticoagulation team

Numerous equivalent low dose protocols eg Numerous equivalent low dose protocols eg Jane S et al (2004) Clinical Laboratory Jane S et al (2004) Clinical Laboratory Pathology; 26: 43-47Pathology; 26: 43-47

Still beware patients at risk of Still beware patients at risk of overanticoagulation eg amiodarone and overanticoagulation eg amiodarone and consider reducing dosesconsider reducing doses

Warfarin Maintenance / Dose Warfarin Maintenance / Dose ModificationsModifications

Assuming target INR range 2-3Assuming target INR range 2-3– INR<1.5INR<1.5 Increase by 1mgIncrease by 1mg– INR 1.6-1.8INR 1.6-1.8 Increase by 0.5mgIncrease by 0.5mg– INR 1.9-3.1INR 1.9-3.1 No changeNo change– INR 3.2-3.5INR 3.2-3.5 Reduce by 0.5 mgReduce by 0.5 mg– INR 3.6-4.5INR 3.6-4.5 Omit dose, reduce by 0.5mgOmit dose, reduce by 0.5mg– INR 4.6-5.0INR 4.6-5.0 Omit dose, reduce by 1mgOmit dose, reduce by 1mg– INR 5.1-6.0INR 5.1-6.0 Omit 2 doses, reduce by 1mgOmit 2 doses, reduce by 1mg– INR 6.1-8.0INR 6.1-8.0 Omit 3 doses and repeatOmit 3 doses and repeat

– NB If interacting medication prescribed more frequent NB If interacting medication prescribed more frequent monitoring will be requiredmonitoring will be required

Warfarin and SurgeryWarfarin and Surgery

Individualized depending on risk of thrombosis (lone AF Individualized depending on risk of thrombosis (lone AF low risk vs. mechanical mitral valve high risk) vs. risk of low risk vs. mechanical mitral valve high risk) vs. risk of bleeding.bleeding.In elective surgery In elective surgery – If low risk of thrombosis may be adequate to simply stop warfarin If low risk of thrombosis may be adequate to simply stop warfarin

4 days pre op and restart post op. Most operations can proceed 4 days pre op and restart post op. Most operations can proceed safely with INR <1.5 (NB not neurosurgery)safely with INR <1.5 (NB not neurosurgery)

– If high risk may require bridging therapy with heparin when INR If high risk may require bridging therapy with heparin when INR becomes sub therapeutic – discuss with senior colleaguebecomes sub therapeutic – discuss with senior colleague

Emergency surgery is likely to require reversal as per Emergency surgery is likely to require reversal as per bleeding patients in all but minor proceduresbleeding patients in all but minor procedures

Warfarin overdose / bleedingWarfarin overdose / bleeding

OverdoseOverdose– INR >8.0 and no bleeding give oral Vitamin K (5mg) and inform INR >8.0 and no bleeding give oral Vitamin K (5mg) and inform

anticoagulation teamanticoagulation team

Reversal agents / bleedingReversal agents / bleeding– Vitamin KVitamin K

Oral – takes 24 hours to reduce INR – little useOral – takes 24 hours to reduce INR – little useIV – takes 6 hours to reduce INRIV – takes 6 hours to reduce INR

– Fresh frozen plasmaFresh frozen plasma10-15 mls/kg ie large volume, usually takes 1-2 hours to administer10-15 mls/kg ie large volume, usually takes 1-2 hours to administer

– Prothrombin complex concentrate eg octaplexProthrombin complex concentrate eg octaplexAdminister over 5-10 minutes slow IV push. Instantaneous reversal Administer over 5-10 minutes slow IV push. Instantaneous reversal but risk of DIC / MI etcbut risk of DIC / MI etc

Heparin - usesHeparin - uses

Prophylaxis vs. TherapeuticProphylaxis vs. Therapeutic

ProphylaxisProphylaxis– No monitoring required (UFH or LMWH)No monitoring required (UFH or LMWH)– Generally give clexane 40 mg in most situationsGenerally give clexane 40 mg in most situations

TherapeuticTherapeutic– Monitoring mandatory daily + regular FBC with Monitoring mandatory daily + regular FBC with

UFH/ intravenous heparinUFH/ intravenous heparin– Monitoring of LMWH generally not requiredMonitoring of LMWH generally not required

IV Heparin Infusion ProtocolIV Heparin Infusion Protocol

(1) Loading bolus dose 80 u/ kg by slow IV injection over 5 minutes(1) Loading bolus dose 80 u/ kg by slow IV injection over 5 minutes

(2) Preparation of infusion(2) Preparation of infusion

20,000 units heparin made up to 50 mls with 0.9% saline (final concentration 400 20,000 units heparin made up to 50 mls with 0.9% saline (final concentration 400 units/ml)units/ml)

(3) Initial infusion rate 0.045 ml / kg / hr (3) Initial infusion rate 0.045 ml / kg / hr

(Round to nearest 0.1 ml/hr )(Round to nearest 0.1 ml/hr )

Eg - patient 70 kg – infusion rate 70 x 0.045=3.2 ml/hrEg - patient 70 kg – infusion rate 70 x 0.045=3.2 ml/hr

(4) Check APTR after 6 hours of infusion and adjust infusion rate as below:(4) Check APTR after 6 hours of infusion and adjust infusion rate as below:

APTR < 1.2 APTR < 1.2 Repeat bolus (80 u/kg) +Increase infusion rate by 0.01 ml/kg/hrRepeat bolus (80 u/kg) +Increase infusion rate by 0.01 ml/kg/hr

APTR 1.2-1.5APTR 1.2-1.5 Repeat bolus (40 u/kg) +Increase infusion rate by 0.005 Repeat bolus (40 u/kg) +Increase infusion rate by 0.005 ml/kg/hrml/kg/hr

APTR 1.51-2.5APTR 1.51-2.5 No changeNo change

APTR 2.51-3.0APTR 2.51-3.0 Decrease infusion rate by 0.005 ml/kg/hrDecrease infusion rate by 0.005 ml/kg/hr

APTR >3APTR >3 Stop infusion for 1 hour +Reduce infusion rate by 0.0075 Stop infusion for 1 hour +Reduce infusion rate by 0.0075 ml/kg/hrml/kg/hr

(5) Check APTR 6 hours after any dosage change and every 24 hours if stable(5) Check APTR 6 hours after any dosage change and every 24 hours if stable

(6) Monitor platelet count every 4 days (risk of Heparin Induced Thrombocytopenia and (6) Monitor platelet count every 4 days (risk of Heparin Induced Thrombocytopenia and Thrombosis Syndrome HITTS)Thrombosis Syndrome HITTS)

Data based on Raschke RA et al. The weight-based heparin dosing nomogram compared with “standard care” Data based on Raschke RA et al. The weight-based heparin dosing nomogram compared with “standard care”

nomogram. Ann Intern Med 1993; 119:874-881nomogram. Ann Intern Med 1993; 119:874-881

LMWH monitoringLMWH monitoring

Generally not required Generally not required unless pregnant, unless pregnant, renal failure or severe obesity renal failure or severe obesity

In specific situations (given above) can In specific situations (given above) can measure anti Xameasure anti Xa– Measure 4 hours post dose, aiming 0.6-1.0 Measure 4 hours post dose, aiming 0.6-1.0

u/mlu/ml

ProphylaxisProphylaxis

– In UK VTE causes 25-32,000 deaths / year In UK VTE causes 25-32,000 deaths / year in hospitalised patients in hospitalised patients (1) (1)

– i.e. exceeds deaths from breast cancer, i.e. exceeds deaths from breast cancer, AIDS and traffic accidents combined.AIDS and traffic accidents combined.

– i.e. >25x greater than the 955 i.e. >25x greater than the 955 (2)(2) annual annual deaths from MRSAdeaths from MRSA

– Immediate cause of death in 5-10% of all Immediate cause of death in 5-10% of all patients who die in hospital patients who die in hospital (3,4)(3,4)

Venous Thrombo-Embolism (VTE) Venous Thrombo-Embolism (VTE) in hospital inpatientsin hospital inpatients

Risk factorsRisk factors– Previous VTEPrevious VTE– Surgery / traumaSurgery / trauma– Increasing age eg >60 yearsIncreasing age eg >60 years– MalignancyMalignancy– Obesity (BMI>30)Obesity (BMI>30)– SepsisSepsis

– ImmobilisationImmobilisation– StrokeStroke– Cardiac failureCardiac failure– Pregnancy, HRT, oral contraceptivesPregnancy, HRT, oral contraceptives– Inflammatory bowel diseaseInflammatory bowel disease– Nephrotic syndromeNephrotic syndrome– Myeloproliferative disorders eg Essential ThrombocythaemiaMyeloproliferative disorders eg Essential Thrombocythaemia– Congenital thrombophiliasCongenital thrombophilias