Evaluation of the bleeding patient V. Kinsella M.D. January,27 2006

Evaluation of the Evaluation of the bleeding patientbleeding patient

V. Kinsella M.D.V. Kinsella M.D.

January,27 2006January,27 2006

MILD bleedingMILD bleeding

1.1. Platelets secretion disordersPlatelets secretion disorders

2.2. vW deficiencyvW deficiency

3.3. Platelets dense granules Platelets dense granules deficiencydeficiency

4.4. Unknown Unknown

Hemostasis and thrombosisHemostasis and thrombosis Dependent on 3 Dependent on 3

factors:factors:

1.1. Vascular Vascular endotheliumendothelium

2.2. PlateletsPlatelets

3.3. Coagulation Coagulation systemsystem

1.Clinical aspects of 1.Clinical aspects of bleedingbleeding

1.Clinical aspects of 1.Clinical aspects of bleedingbleeding

Evaluation of patients with bleeding is Evaluation of patients with bleeding is a multi-step process:a multi-step process:

Complete historyComplete history

Detailed physical examDetailed physical exam

Laboratory evaluationLaboratory evaluation

history

1.1. Is there a Is there a personal or family historypersonal or family history of bleeding after surgical procedures, of bleeding after surgical procedures, dental procedures, childbirth, or dental procedures, childbirth, or trauma?trauma?

2.2. WhenWhen the bleeding episode started? the bleeding episode started?

3.3. Has the patient received Has the patient received medications medications that can cause or make worse a that can cause or make worse a bleeding problem? bleeding problem?

history

Many drugs can contribute to bleeding;Many drugs can contribute to bleeding; semisynthetic penicillinssemisynthetic penicillins

cephalosporinscephalosporinscalcium channel blockercalcium channel blocker dipyridamoledipyridamolethiazides thiazides alcoholalcohol

quinine, quinidinequinine, quinidine chlorpromazine, sulfonamides chlorpromazine, sulfonamides INH, rifampin INH, rifampin methyldopa methyldopa phenytoin, barbiturates, phenytoin, barbiturates, warfarin, heparin, thrombolytic agents warfarin, heparin, thrombolytic agents NSAIDs, ASA NSAIDs, ASA allopurinol allopurinol

TMP/SMX TMP/SMX

physical exam

1. Assess volume status (correct shock if 1. Assess volume status (correct shock if present) present)

2. Look for hepatosplenomegaly2. Look for hepatosplenomegaly

3. Do a rectal exam for evidence of GI 3. Do a rectal exam for evidence of GI bleeding bleeding

4. Examine oropharynx for evidence of 4. Examine oropharynx for evidence of petechiaepetechiae

Clinical aspects of bleedingClinical aspects of bleeding

physical exam5.5. Look for physical signs and symptoms of Look for physical signs and symptoms of

diseases related to diseases related to capillary fragility:capillary fragility: Cushing’s syndrome, Marfan syndrome or Cushing’s syndrome, Marfan syndrome or

exogenous steroidsexogenous steroids "senile purpura”"senile purpura”

Petechiae secondary to coughing, sneezing, Petechiae secondary to coughing, sneezing,

Valsalva maneuver, blood pressure Valsalva maneuver, blood pressure measurementmeasurement

vasculitis ("palpable purpura")vasculitis ("palpable purpura")

Telangiectasias (Osler-Weber-Rendu Telangiectasias (Osler-Weber-Rendu syndrome) (HHT)syndrome) (HHT)

petechiaepetechiae

Do not blanch with Do not blanch with pressurepressure

(angiomas) (angiomas)Not palpableNot palpable

(vasculitis) (vasculitis)

(typical of platelet disorders)

vasculitis (palpable rash)vasculitis (palpable rash)

2. Hematologic disorders 2. Hematologic disorders causing bleedingcausing bleeding

– Platelet disordersPlatelet disorders

– Coagulation factor disordersCoagulation factor disorders

Clinical Clinical differentiation differentiation

Platelets x Platelets x

Coagulation DefectsCoagulation Defects

Platelets DefectsPlatelets Defects• Generally have immediate onset of Generally have immediate onset of

bleeding after traumableeding after trauma

• Bleeding is predominantly in skin, Bleeding is predominantly in skin, mucous membranes, nose, GI tract, mucous membranes, nose, GI tract, and urinary tractand urinary tract

• Bleeding may be observed as Bleeding may be observed as petechiae (<3 mm) or ecchymoses petechiae (<3 mm) or ecchymoses (>3 mm(>3 mm

Clinical aspects of bleedingClinical aspects of bleeding

Coagulation DefectsCoagulation Defects

"Deep" bleeding (in the joint spaces, "Deep" bleeding (in the joint spaces, muscles, and retroperitoneal spaces) muscles, and retroperitoneal spaces) is common. Observed on exam as is common. Observed on exam as hematomas and hemarthroses. hematomas and hemarthroses.

HematomaHematoma

(typical of coagulation factor

disorders)

Hemarthrosis (acute)Hemarthrosis (acute)

Laboratory Evaluation of BleedingLaboratory Evaluation of Bleeding

CBC and smearCBC and smear Platelet countPlatelet count ThrombocytopeniaThrombocytopeniaRBC and platelet morphologyRBC and platelet morphology TTP, DIC, etc.TTP, DIC, etc.

CoagulationCoagulation PT extrinsic/common pathwaysPT extrinsic/common pathways

PTT Intrinsic/common pathwaysPTT Intrinsic/common pathways

Coag. factor assays Specific factor Coag. factor assays Specific factor deficienciesdeficiencies

50:50 mix Inhibitors (e.g., antibodies)50:50 mix Inhibitors (e.g., antibodies)

Fibrinogen assay Decreased fibrinogenFibrinogen assay Decreased fibrinogen

Thrombin time Qualitative/quantitative fibrinogen Thrombin time Qualitative/quantitative fibrinogen defects defects

D-dimer Fibrinolysis (DIC)D-dimer Fibrinolysis (DIC)

Laboratory Evaluation of BleedingLaboratory Evaluation of Bleeding

Platelet functionPlatelet function von Willebrand factorvon Willebrand factor vWDvWDBleeding timeBleeding time In vivoIn vivo test test (non-specific)(non-specific)

Platelet function analyzer (PFA)Platelet function analyzer (PFA) Qualitative platelet Qualitative platelet disorders disorders

Laboratory Evaluation of the Laboratory Evaluation of the Coagulation PathwaysCoagulation Pathways

Partial thromboplastin time(PTT)

Prothrombin time(PT)

Intrinsic pathway Extrinsic pathway

Common pathwayThrombin timeThrombin

Surface activating agent (Ellagic acid, kaolin) Phospholipid Calcium

ThromboplastinTissue factorPhospholipidCalcium

Fibrin clot

XIIaXIIa

Coagulation cascadeCoagulation cascade

IIa

Intrinsic system Intrinsic system (surface contact)(surface contact)

XIIXII

XIXI XIa

Tissue factorTissue factor

IXIX IXa VIIa VIIVII

VIIIVIII VIIIaVIIIa

Extrinsic system Extrinsic system (tissue damage)(tissue damage)

XX

VV VaVa

IIII

FibrinogenFibrinogen FibrinFibrin

(Thrombin)(Thrombin)IIa

Vitamin K dependant factorsVitamin K dependant factors

Xa

Initial Evaluation of a Bleeding Patient Initial Evaluation of a Bleeding Patient

Normal PT Normal PTT

Consider evaluating for:Platelet disorder Mild factor deficiencyFactor XIIIMonoclonal gammopathyAbnormal fibrinolysis2 anti-plasmin deficiencyVascular disordersDysfibrinogenemia

Initial Evaluation of a Bleeding Patient Initial Evaluation of a Bleeding Patient

Elevated PT Normal PTT

Test for factor deficiency: 1.Multiple factor deficiencies (common)(Liver disease, vitamin K deficiency, warfarin, DIC) 2. Deficiency of factor VII (rare)

Repeatwith

50:50mix

50:50 mix is normal

50:50 mix is abnormal

Test for inhibitor activity: 1.Specific: Factor VII (rare) 2.Non-specific: Anti-phospholipid

Initial Evaluation of a Bleeding PatientInitial Evaluation of a Bleeding Patient

Normal PTAbnormal PTT

Test for factor deficiency:Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Multiple factor deficiencies (rare)

Repeatwith

50:50mix

50:50 mix is normal

50:50 mix is abnormal

Test for inhibitor activity: Specific factors: VIII, IX, XI Non-specific (anti-phospholipid)

Initial Evaluation of a Bleeding Patient Initial Evaluation of a Bleeding Patient

Abnormal PTAbnormal PTT

Test for factor deficiency:Isolated deficiency in common pathway: Factors V, X, Prothrombin, FibrinogenMultiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC)

Repeatwith

50:50mix

50:50 mix is normal

50:50 mix is abnormal

Test for inhibitor activity: Specific : Factors V, X, prothrombin, fibrinogen (rare) Non-specific: anti-phospholipid (common)

Bleeding timeBleeding time

5-10% of patients hospitalized patients have 5-10% of patients hospitalized patients have a prolonged bleeding a prolonged bleeding timetime

Most of the prolonged bleeding times are due to Most of the prolonged bleeding times are due to aspirin or drug ingestionaspirin or drug ingestion

Prolonged bleeding time does not predict excess Prolonged bleeding time does not predict excess surgical blood losssurgical blood loss

Not recommended for routine testing in Not recommended for routine testing in preoperative patientspreoperative patients

Thrombin TimeThrombin Time Measures rate of fibrinogen conversion to Measures rate of fibrinogen conversion to

fibrinfibrin

Procedure:Procedure:– Add thrombin with patient plasmaAdd thrombin with patient plasma– Measure time to clotMeasure time to clot

Variables:Variables:– Source and quantity of thrombinSource and quantity of thrombin

Causes of prolonged Thrombin TimeCauses of prolonged Thrombin Time

HeparinHeparin HypofibrinogenemiaHypofibrinogenemia DysfibrinogenemiaDysfibrinogenemia ParaproteinParaprotein Thrombin inhibitors (Hirudin)Thrombin inhibitors (Hirudin) Thrombin antibodiesThrombin antibodies

PLATELETSPLATELETS

Approach to the thrombocytopenic Approach to the thrombocytopenic patientpatient

HistoryHistory

1.1. Is the patient bleeding?Is the patient bleeding?

2. Are there symptoms of a secondary 2. Are there symptoms of a secondary illness? (neoplasm, infection, illness? (neoplasm, infection, autoimmune disease)autoimmune disease)

3. Is there a history of medications, 3. Is there a history of medications, alcohol use, or recent transfusion?alcohol use, or recent transfusion?

Approach to the thrombocytopenic Approach to the thrombocytopenic patientpatient

HistoryHistory4. Are there risk factors for viral infection?4. Are there risk factors for viral infection?

5.Is there a family history of thrombocytopenia?5.Is there a family history of thrombocytopenia?

6. Do the sites of bleeding suggest a platelet 6. Do the sites of bleeding suggest a platelet defect?defect?

Approach to the thrombocytopenic Approach to the thrombocytopenic patientpatient

Assess the number and function of plateletsAssess the number and function of platelets

– CBC with peripheral smearCBC with peripheral smear– Bleeding time Bleeding time – Platelet aggregation studyPlatelet aggregation study– PFAPFA

Classification of platelet Classification of platelet disordersdisorders

Quantitative disordersQuantitative disorders

– Abnormal distributionAbnormal distribution

– Dilution effectDilution effect

– Decreased productionDecreased production

– Increased destructionIncreased destruction

Classification of platelet Classification of platelet disordersdisorders

Qualitative disordersQualitative disorders

– Inherited disorders (rare)Inherited disorders (rare)

– Acquired disordersAcquired disorders ImmuneImmune MedicationsMedications Chronic renal failureChronic renal failure Cardiopulmonary bypassCardiopulmonary bypass Liver diseaseLiver disease

Inherited platelet disordersInherited platelet disorders

Rare congenital abnormalities on synthesis Rare congenital abnormalities on synthesis or release of secretory granulesor release of secretory granules

Inherited platelet disordersInherited platelet disorders

Gray platelets syndrome: Gray platelets syndrome: No alpha granulesNo alpha granules

Inherited platelet disordersInherited platelet disorders May-Hegglin: May-Hegglin: ThrombocytopeniaThrombocytopenia

Large plateletsLarge platelets

Neutrophils – Dohle bodiesNeutrophils – Dohle bodies

Inherited platelet disordersInherited platelet disorders

Glazmann’s thrombasthenia: Glazmann’s thrombasthenia: Congenital deficiency or abnormality of GP Congenital deficiency or abnormality of GP

IIb-IIIaIIb-IIIa

Bernard-Solier syndrome:Bernard-Solier syndrome:Congenital deficiency or abnormality of GP Congenital deficiency or abnormality of GP

IbIb

Acquired platelet disordersAcquired platelet disorders

Decreased production:Decreased production: Ineffective thrombopoiesis - MDS Ineffective thrombopoiesis - MDS

Increased destruction:Increased destruction:ImmuneImmuneNon-immuneNon-immune

Poor aggregationPoor aggregation

Increased platelets destructionIncreased platelets destruction

1. Immune-mediatedIdiopathic - ITPDrug-inducedCollagen vascular diseaseLymphoproliferative diseaseSarcoidosis

2.Non-immune mediatedDICMicroangiopathic hemolytic anemia

ITP is a diagnosis of ITP is a diagnosis of exclusion ! exclusion !

Initial Treatment of ITPInitial Treatment of ITPPlatelet count Symptoms Treatment >50,000 None

20-50,000 Not bleeding None

Bleeding GlucocorticoidsIVIG

<20,000 Not bleeding Glucocorticoids

BleedingGlucocorticoids

IVIGHospitalizationRituximab

COAGULATION COAGULATION FACTOR DEFECTS FACTOR DEFECTS

Inherited Coagulation factor Inherited Coagulation factor bleeding disordersbleeding disorders

– vonWillebrand’s diseasevonWillebrand’s disease

– Hemophilia (A and B)Hemophilia (A and B)

vonWillebrand diseasevonWillebrand disease– Most common hereditaryMost common hereditary coagulation disorder coagulation disorder

– Autossomal dominantAutossomal dominant

– Incidence 1:1000Incidence 1:1000

Erik A. vonWillenbrand M.D.

(1870-1949)

vonWillebrand factorvonWillebrand factor

– Synthesis in endothelium and Synthesis in endothelium and megakaryocytesmegakaryocytes

– Forms large multimers Forms large multimers – Carrier of factor VIIICarrier of factor VIII

– Anchors platelets to subendotheliumAnchors platelets to subendothelium

– Bridge between plateletsBridge between platelets

vonWillebrand diseasevonWillebrand disease

Abnormal synthesis of von Willebrand Abnormal synthesis of von Willebrand factor (vWF) causes decreased factor (vWF) causes decreased platelet adhesion and decreased platelet adhesion and decreased serum levels of factor VIIIserum levels of factor VIII

vonWillebrand diseasevonWillebrand disease

ClassificationClassification

– Type 1 Type 1 Partial quantitative deficiency Partial quantitative deficiency (“decreased”)(“decreased”)

– Type 2 Type 2 Qualitative deficiencyQualitative deficiency (“abnormal”)(“abnormal”)

– Type 3Type 3 Total quantitative deficiencyTotal quantitative deficiency (“absent”) (“absent”)

vonWillebrand diseasevonWillebrand disease

vonWillebrand type

Assay 1 2 3

vWF antigen Normal

vWF activity

Multimer analysis Normal Normal Absent

Laboratory evaluation:Laboratory evaluation:

Treatment of von Willebrand Treatment of von Willebrand DiseaseDisease

DDAVP (deamino-8-arginine vasopressin)DDAVP (deamino-8-arginine vasopressin) plasma VWF levels by stimulating secretion plasma VWF levels by stimulating secretion

from endotheliumfrom endothelium– Duration of response is variableDuration of response is variable– Not generally used in type 2 diseaseNot generally used in type 2 disease– Dosage 0.3 µg/kg q 12 hr IVDosage 0.3 µg/kg q 12 hr IV

Treatment of von Willebrand Treatment of von Willebrand DiseaseDisease

CryoprecipitateCryoprecipitate– Source of fibrinogen, factor VIII and VWFSource of fibrinogen, factor VIII and VWF– Only plasma fraction that consistently contains Only plasma fraction that consistently contains

VWF multimersVWF multimers

Factor VIII concentrate (Intermediate purity)Factor VIII concentrate (Intermediate purity)– Virally inactivated product Virally inactivated product – Humate-P or Koate-HS Humate-P or Koate-HS

HemophiliaHemophilia

Clinical manifestations (hemophilia A & Clinical manifestations (hemophilia A & B are indistinguishable)B are indistinguishable)

1.1. Prolonged bleeding after surgery or Prolonged bleeding after surgery or dental extractionsdental extractions

2.2. Hemarthrosis (most common)Hemarthrosis (most common)

3.3. Soft tissue hematomasSoft tissue hematomas

4.4. Other sites of bleedingOther sites of bleedingUrinary tractUrinary tractCNS, neck (may be life-threatening)CNS, neck (may be life-threatening)

Dosing guidelines for hemophilia ADosing guidelines for hemophilia A Mild bleeding:Mild bleeding: Hemarthrosis, oropharyngeal or dental, epistaxis, hematuriaHemarthrosis, oropharyngeal or dental, epistaxis, hematuria

Target: 30% dosing q8-12h; 1-2 days (15U/kg)Target: 30% dosing q8-12h; 1-2 days (15U/kg)

Major bleedingMajor bleeding– CNS trauma, hemorrhage, lumbar punctureCNS trauma, hemorrhage, lumbar puncture– SurgerySurgery– Retroperitoneal hemorrhageRetroperitoneal hemorrhage– GI bleedingGI bleeding

Target: 80-100% q8-12h; 7-14 days (50U/kg)Target: 80-100% q8-12h; 7-14 days (50U/kg)

Adjunctive therapyAdjunctive therapy– -aminocaproic acid (Amicar) or DDAVP (for mild disease only)-aminocaproic acid (Amicar) or DDAVP (for mild disease only)

Treatment of hemophilia BTreatment of hemophilia B

Agent Agent – High purity factor IXHigh purity factor IX– Recombinant human factor IXRecombinant human factor IX

DoseDose– Initial dose: 100U/kgInitial dose: 100U/kg– Subsequent: 50U/kg every 24 hoursSubsequent: 50U/kg every 24 hours

Acquired bleeding disorders:Acquired bleeding disorders:

1.1. Vitamin K deficiencyVitamin K deficiency

2.2. Liver disease Liver disease

3.3. Warfarin overdoseWarfarin overdose

4.4. DICDIC

5.5. Inhibitors to CFInhibitors to CF

Vitamin K deficiencyVitamin K deficiency

Vitamin K deficiencyVitamin K deficiency Source of vitamin K :Source of vitamin K :

Green vegetables Green vegetables Synthesized by intestinal floraSynthesized by intestinal flora

Required for synthesisRequired for synthesisFactors II, VII, IX ,XFactors II, VII, IX ,XProtein C and SProtein C and S

Causes of deficiencyCauses of deficiency ::MalnutritionMalnutritionBilliary obstructionBilliary obstructionMalabsorptionMalabsorptionAntibiotic therapyAntibiotic therapy

Vitamin K deficiencyVitamin K deficiency

Treatment:Treatment:

Vitamin KVitamin K replacement replacement

Fresh frozen plasmaFresh frozen plasma

DICDIC

Disseminated Intravascular CoagulationDisseminated Intravascular Coagulation

SepsisSepsis

TraumaTrauma– Head injuryHead injury– Fat embolismFat embolism

MalignancyMalignancy

Obstetrical Obstetrical complicationscomplications– Amniotic fluid embolismAmniotic fluid embolism– Abruptio placentaeAbruptio placentae

Vascular disordersVascular disorders

Reaction to toxin (e.g. Reaction to toxin (e.g. snake venom, drugs)snake venom, drugs)

Immunologic disordersImmunologic disorders– Severe allergic reactionSevere allergic reaction– Transplant rejectionTransplant rejection

Activation of both coagulation and fibrinolysisTriggered by

Disseminated Intravascular Coagulation Disseminated Intravascular Coagulation (DIC)(DIC)

MechanismMechanismSystemic activation

of coagulation

Intravasculardeposition of fibrin

Activation of fibrinolysis

Depletion of plateletsand coagulation factors

BleedingThrombosis of smalland midsize vessels

tissue hypoxia and organ failure

Pathogenesis of DICPathogenesis of DIC

Coagulation Fibrinolysis

Fibrinogen

FibrinMonomers

FibrinClot

(intravascular)

Fibrin(ogen)Degradation

Products

Plasmin

Thrombin Plasmin

Release of thromboplastic

material intocirculation

Consumption ofcoagulation factors;

presence of FDPs aPTT PT TT

Fibrinogen

Presence of plasmin D-dimer

Intravascular clot Platelets

Schistocytes

Disseminated Intravascular Disseminated Intravascular CoagulationCoagulation

Treatment approachesTreatment approaches

Treatment of underlying disorderTreatment of underlying disorder

Anticoagulation with heparinAnticoagulation with heparin

Platelet transfusionPlatelet transfusion

Fresh frozen plasmaFresh frozen plasma

Coagulation inhibitor concentrate (ATIII)Coagulation inhibitor concentrate (ATIII)

Hemostasis in liver diseaseHemostasis in liver disease

Liver Disease and HemostasisLiver Disease and Hemostasis

1.1. Decreased synthesis of Decreased synthesis of II, VII, IX, X, XI, and fibrinogenII, VII, IX, X, XI, and fibrinogen

2.2. Dietary Vitamin K deficiency (Inadequate intake or Dietary Vitamin K deficiency (Inadequate intake or malabsortion)malabsortion)

3.3. DysfibrinogenemiaDysfibrinogenemia

4.4. Enhanced fibrinolysis (Decreased alpha-2-antiplasmin)Enhanced fibrinolysis (Decreased alpha-2-antiplasmin)

5.5. DICDIC

6.6. Thrombocytopenia due to hypersplenismThrombocytopenia due to hypersplenism

Management of Hemostatic Defects in Management of Hemostatic Defects in Liver DiseaseLiver Disease

Treatment for prolonged PT/PTTTreatment for prolonged PT/PTT Vitamin K 10 mg SQ x 3 days - usually Vitamin K 10 mg SQ x 3 days - usually

ineffectiveineffective

Fresh-frozen plasma infusion:Fresh-frozen plasma infusion: 25-30% of plasma volume (1200-1500 ml) 25-30% of plasma volume (1200-1500 ml) (immediate but temporary effect)(immediate but temporary effect)

Treatment for low fibrinogenTreatment for low fibrinogen Cryoprecipitate (1 unit/10kg bodyCryoprecipitate (1 unit/10kg body

Warfarin ToxicityWarfarin Toxicity

Warfarin overdoseWarfarin overdoseManaging high INR valuesManaging high INR values

Clinical situation Guidelines

INR therapeutic-5 Lower or omit next dose;Resume therapy when INR is therapeutic

INR 5-9; no bleeding Lower or omit next one or two dose;Resume therapy when INR is therapeutic

Omit dose and give vitamin K ( 1-2 mg po)

Rapid reversal: vitamin K 2-4 mg po (repeat)

INR >9; no bleeding Omit dose; vitamin K 10 mg po; repeat as necessaryResume therapy at lower dose when INR therapeutic

Chest 2004:126; 213 S (supplement)

Warfarin overdoseWarfarin overdoseManaging high INR values in bleeding patientsManaging high INR values in bleeding patients

Clinical situation Guidelines

Serious bleeding at Any elevation INR Omit warfarin

Vitamin K 10 mg slow IV infusion

Omit warfarinRepeat vitamin K injections every 12 hrs FFP, PCC or Factor VIIa (depending on urgency)

Any life-threatening Vitamin K 10 mg slow IV infusionPCC ( or recombinant human factor VIIa)Repeat vitamin K injections every 12 hrs

Chest 2004:126; 213 S (supplement)

Approach to Post-operative Approach to Post-operative bleedingbleeding

1.1. Is the bleeding local or due to a hemostatic failure?Is the bleeding local or due to a hemostatic failure?

Local: Single site of bleeding usually rapid with Local: Single site of bleeding usually rapid with minimal coagulation test abnormalitiesminimal coagulation test abnormalities

Hemostatic failure: Multiple site or unusual pattern Hemostatic failure: Multiple site or unusual pattern with abnormal coagulation testswith abnormal coagulation tests

Approach to Post-operative Approach to Post-operative bleedingbleeding

2.2. Evaluate for causes of peri-operative Evaluate for causes of peri-operative hemostatic failurehemostatic failure

Preexisting abnormalityPreexisting abnormality

Special cases (e.g. Cardiopulmonmary bypass)Special cases (e.g. Cardiopulmonmary bypass)

3.3. Diagnosis of hemostatic failureDiagnosis of hemostatic failure Review pre-operative testingReview pre-operative testing

Obtain updated testingObtain updated testing

Approach to bleeding disordersApproach to bleeding disordersSummarySummary

Identify and correct any specific defect of Identify and correct any specific defect of hemostasishemostasis– Laboratory testing is always needed to establish the cause of Laboratory testing is always needed to establish the cause of

bleedingbleeding

– Screening tests (PT,PTT, platelet count) will often allow placement Screening tests (PT,PTT, platelet count) will often allow placement into one of the broad categoriesinto one of the broad categories

– Specialized testing is usually necessary to establish a specific Specialized testing is usually necessary to establish a specific diagnosisdiagnosis

Use non-transfusional drugs whenever possibleUse non-transfusional drugs whenever possible

RBC transfusions for surgical procedures or large RBC transfusions for surgical procedures or large blood lossblood loss

THANK YOU!THANK YOU!

Recombinant human factor VIIa Recombinant human factor VIIa (rhVIIa; (rhVIIa; NovosevenNovoseven))

MechanismMechanism– Direct activation of common pathwayDirect activation of common pathway

UseUse– Factor VIII inhibitorsFactor VIII inhibitors– Bleeding with other clotting disordersBleeding with other clotting disorders– Warfarin overdose with bleeding Warfarin overdose with bleeding

– CNS bleeding with or without warfarinCNS bleeding with or without warfarin

– DoseDose– 90 µg/kg IV q 2 hr 90 µg/kg IV q 2 hr – ““Adjust as clinically indicated”Adjust as clinically indicated”

Cost (70 kg person) - $1 per µgCost (70 kg person) - $1 per µg– ~$5,000/dose or $60,000/day~$5,000/dose or $60,000/day

Drugs and blood products Drugs and blood products used for bleedingused for bleeding

Treatment Approaches toTreatment Approaches tothe Bleeding Patientthe Bleeding Patient

Red blood cellsRed blood cells Platelet transfusionsPlatelet transfusions Fresh frozen plasmaFresh frozen plasma CryoprecipitateCryoprecipitate AmicarAmicar DDAVPDDAVP Recombinant Human factor VIIaRecombinant Human factor VIIa

RBC transfusion therapyRBC transfusion therapyIndicationsIndications

Improve oxygen carrying capacity of bloodImprove oxygen carrying capacity of blood

– BleedingBleeding

– Chronic anemia that is symptomaticChronic anemia that is symptomatic

– Peri-operative managementPeri-operative management

Red blood cell transfusionsRed blood cell transfusionsSpecial preparationSpecial preparation

CMV-negative CMV-negative patients Prevent CMV transmission

Irradiated RBCs Immune deficient recipient Prevent GVHD

or direct donor

Leukopoor Previous non-hemolytic Prevents reaction transfusion reactionCMV negative patients Prevents transmission

Washed RBC PNH patients Prevents hemolysisIgA deficient recipient Prevents anaphylaxis

Transfusion-transmitted diseaseTransfusion-transmitted disease

Infectious agent Risk

HIV 1/500,000Hepatitis C 1/600,000Hepatitis B 1/500,000Hepatitis A <1/1,000,000HTLV I/II 1/640,000CMV 50% donors are sero-positiveBacteria 1/250 in platelet transfusionsCreutzfeld-Jakob disease UnknownOthers Unknown

Platelet transfusionsPlatelet transfusions

SourceSource– Platelet concentrate (Random donor)Platelet concentrate (Random donor)– Pheresis platelets (Single donor)Pheresis platelets (Single donor)

Target levelTarget level– Bone marrow suppressed patient (>10-20,000/µl)Bone marrow suppressed patient (>10-20,000/µl)– Bleeding/surgical patient (>50,000/µl)Bleeding/surgical patient (>50,000/µl)

Fresh frozen plasmaFresh frozen plasma Content - plasma (decreased factor V and VIII)Content - plasma (decreased factor V and VIII) IndicationsIndications

– Multiple coagulation deficiencies (liver disease, trauma)Multiple coagulation deficiencies (liver disease, trauma)– DICDIC– Warfarin reversalWarfarin reversal– Coagulation deficiency (factor XI or VII)Coagulation deficiency (factor XI or VII)

Dose (225 ml/unit)Dose (225 ml/unit)– 10-15 ml/kg10-15 ml/kg

NoteNote– Viral screened productViral screened product– ABO compatibleABO compatible

CryoprecipitateCryoprecipitate

Prepared from FFPPrepared from FFP ContentContent

– Factor VIII, von Willebrand factor, fibrinogenFactor VIII, von Willebrand factor, fibrinogen

IndicationsIndications– Fibrinogen deficiencyFibrinogen deficiency– UremiaUremia– von Willebrand diseasevon Willebrand disease

Dose (1 unit = 1 bag)Dose (1 unit = 1 bag)– 1-2 units/10 kg body weight1-2 units/10 kg body weight

Hemostatic drugsHemostatic drugsAminocaproic acid (Amicar)Aminocaproic acid (Amicar)

MechanismMechanism– Prevent activation plaminogen -> plasminPrevent activation plaminogen -> plasmin

DoseDose– 50mg/kg po or IV q 4 hr50mg/kg po or IV q 4 hr

UsesUses– Primary menorrhagiaPrimary menorrhagia– Oral bleedingOral bleeding– Bleeding in patients with thrombocytopeniaBleeding in patients with thrombocytopenia– Blood loss during cardiac surgeryBlood loss during cardiac surgery

Side effectsSide effects– GI toxicityGI toxicity– Thrombi formationThrombi formation

Hemostatic drugsHemostatic drugsAminocaproic acid (Amicar)Aminocaproic acid (Amicar)

MechanismMechanism– Prevent activation plaminogen -> plasminPrevent activation plaminogen -> plasmin

DoseDose– 50mg/kg po or IV q 4 hr50mg/kg po or IV q 4 hr

UsesUses– Primary menorrhagiaPrimary menorrhagia– Oral bleedingOral bleeding– Bleeding in patients with thrombocytopeniaBleeding in patients with thrombocytopenia– Blood loss during cardiac surgeryBlood loss during cardiac surgery

Side effectsSide effects– GI toxicityGI toxicity– Thrombi formationThrombi formation

Hemostatic drugsHemostatic drugsDesmopressin (DDAVP)Desmopressin (DDAVP)

MechanismMechanism– Increased release of VWF from endotheliumIncreased release of VWF from endothelium

DoseDose– 0.3µg/kg IV q12 hrs0.3µg/kg IV q12 hrs– 150mg intranasal q12hrs150mg intranasal q12hrs

UsesUses– Most patients with von Willebrand diseaseMost patients with von Willebrand disease– Mild hemophilia AMild hemophilia A

Side effectsSide effects– Facial flushing and headacheFacial flushing and headache– Water retention and hyponatremiaWater retention and hyponatremia

OverviewOverview1.1. Clinical aspects of bleedingClinical aspects of bleeding

1.1. Hematologic disorders causing bleedingHematologic disorders causing bleedingCoagulation factor disordersCoagulation factor disordersPlatelet disordersPlatelet disorders

2.2. Approach to laboratory abnormalitiesApproach to laboratory abnormalities Diagnosis and management of Diagnosis and management of

thrombocytopeniathrombocytopenia

3.3. Approach to acquired bleeding disordersApproach to acquired bleeding disordersHemostasis in liver diseaseHemostasis in liver diseaseSurgical patientsSurgical patientsWarfarin toxicityWarfarin toxicity

4.4. Drugs and blood products used for bleedingDrugs and blood products used for bleeding

Clinical Features of Bleeding DisordersClinical Features of Bleeding Disorders

Platelet Coagulation disorders factor disorders

Site of bleeding Skin Deep in soft tissues Mucous membranes (joints, muscles) (epistaxis, gum, vaginal, GI tract)

Petechiae Yes No

Ecchymoses (“bruises”) Small, superficial Large, deep

Hemarthrosis / muscle bleeding Extremely rare Common

Bleeding after cuts & scratches Yes No

Bleeding after surgery or trauma Immediate, Delayed (1-2 days), usually mild often severe

Pre-analytic errorsPre-analytic errors

Problems with blue-top tubeProblems with blue-top tube– Partial fill tubesPartial fill tubes– Vacuum leak and citrate Vacuum leak and citrate

evaporationevaporation

Problems with phlebotomyProblems with phlebotomy– Heparin contaminationHeparin contamination– Wrong labelWrong label– Slow fillSlow fill– UnderfillUnderfill– Vigorous shakingVigorous shaking

Biological effectsBiological effects– Hct ≥55 or ≤15Hct ≥55 or ≤15– Lipemia, Lipemia,

hyperbilirubinemia, hyperbilirubinemia, hemolysishemolysis

Laboratory errorsLaboratory errors– Delay in testingDelay in testing– Prolonged incubation at Prolonged incubation at

37°C37°C– Freeze/thaw deteriorationFreeze/thaw deterioration

Coagulation factor deficienciesCoagulation factor deficiencies

Sex-linked recessiveSex-linked recessive Factors VIII and IX deficiencies cause bleedingFactors VIII and IX deficiencies cause bleeding

Prolonged Prolonged PTT; PTT; PT normalPT normal

Autosomal recessive Autosomal recessive (rare)(rare)Factors II, V, VII, X, XIFactors II, V, VII, X, XIFibrinogen deficiencies cause bleedingFibrinogen deficiencies cause bleeding

Prolonged Prolonged PTPT and/or and/or PTTPTT

Factor XIII deficiency is associated with bleeding andFactor XIII deficiency is associated with bleeding andimpaired wound healingimpaired wound healing

PT/ PTT normal; PT/ PTT normal; clot solubilityclot solubility abnormal abnormal

Factor XII, prekallikrein, HMWK deficiencies Factor XII, prekallikrein, HMWK deficiencies do not cause bleedingdo not cause bleeding

Classification of platelet Classification of platelet disordersdisorders

Associated with bleedingAssociated with bleeding

– Immune-mediated (Idiopathic) Immune-mediated (Idiopathic) thrombocytopenic purpurathrombocytopenic purpura

– Most othersMost others

Classification of platelet Classification of platelet disordersdisorders

Associated with thrombosisAssociated with thrombosis

– Thrombotic thrombocytopenic purpuraThrombotic thrombocytopenic purpura

– Heparin-induced thrombocytopeniaHeparin-induced thrombocytopenia

– Trousseau’s syndromeTrousseau’s syndrome

– DICDIC

Hemophilia A and BHemophilia A and BHemophilia A Hemophilia B

Coagulation factor deficiency Factor VIII Factor IX

Inheritance X-linked X-linkedrecessive recessive

Incidence 1/10,000 males 1/60,000 males

Severity Related to factor level<1% - Severe - spontaneous bleeding1-5% - Moderate - bleeding with mild injury5-25% - Mild - bleeding with surgery or trauma

Complications Soft tissue bleeding

Treatment of hemophilia ATreatment of hemophilia A

Intermediate purity plasma productsIntermediate purity plasma products– Virucidally treatedVirucidally treated– May contain von Willebrand factorMay contain von Willebrand factor

High purity (monoclonal) plasma productsHigh purity (monoclonal) plasma products– Virucidally treatedVirucidally treated– No functional von Willebrand factorNo functional von Willebrand factor

Recombinant factor VIIIRecombinant factor VIII– Virus free/No apparent riskVirus free/No apparent risk– No functional von Willebrand factorNo functional von Willebrand factor

Complications of therapyComplications of therapy

Formation of inhibitors (antibodies)Formation of inhibitors (antibodies)– 10-15% of severe hemophilia A patients10-15% of severe hemophilia A patients– 1-2% of severe hemophilia B patients1-2% of severe hemophilia B patients

Viral infectionsViral infections– Hepatitis BHepatitis B Human parvovirusHuman parvovirus– Hepatitis CHepatitis C Hepatitis AHepatitis A– HIVHIV OtherOther

Features of Acute and Chronic ITPFeatures of Acute and Chronic ITP

Features Acute Chronic

Peak age Children (2-6 yrs) Adults (20-40 yrs)

Female:male 1:1 3:1

Antecedent infection Common Rare

Onset of symptoms Abrupt indolent

Platelet count at presentation <20,000 <50,000

Duration 2-6 weeks Long-term

Spontaneous remission Common Uncommon