Faculty Disclosure -...

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Faculty DisclosureRONALD A SACHER, MD,FRCPC FCAP

On the speakers bureau of BAYER BIOLOGICALS(also a consultant);GLAXO SMITH KLINE AND ORTHO BIOTECH.

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Faculty DisclosureRonald A.Sacher, MD, FRCPC, FCAP

Dr. Sacher has no financial interests/relationships with Novo-Nordisk but will mention non –FDA approved (off-label) uses of Novo-seven.

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Agenda

12:00-1:30Holiday Break (Lunch)

11:30-12:00Beyond Accreditation: Knowing-and Telling- that you’re doing a good job

8:30-9:00How much RhIg is enough?

10:30-11:00Transfusion committee revitalization: making audits work

10:00-10:30Thanksgiving Break

9:30-10:00rVIIa: Univer$al hemo$ta$i$?9:00-9:30Plasma: Liquid Gold or Fool’s Gold?

TimeTopic: CP104 Transfusion Medicine College

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Agenda

Commencement

4:30-5:00JUST DO IT!: Diagnosis and management of acute transfusion reactions

4:00-4:30T&S and the Three Day Rule-Does it make sense in today’s market?

1:30-2:00Making a living in Transfusion Medicine in a community hospital

3:30-4:00So now you tell me! Managing recalls and Market withdrawals

3:00-3:30Spring Break2:30-3:00My patient refuses blood!2:00-2:30When blood is not available!

TimeTopic: CP104 Transfusion Medicine College

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UHC: rVII APLICATIONSRONALD A.SACHER MD

PROFESSOR OF INTERNAL MEDICINE AND PATHOLOGYDIRECTOR OF HOXWORTH BLOOD CENTER

UNIVERSITY OF CINCINNATI MEDICAL CENTER

NORMAL HEMOSTASISABNORMAL HEMOSTASISINDICATIONS FOR r VII THERAPYOFF- LABEL

© College of American Pathologists 2004. Materials are used with the permission of Ronald A. Sacher, MD, FCAP.

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NovosevenUNIVERSAL HEMOSTATIC/WONDER DRUG ???

WALL STREET JOURNAL March 17,2004Sales have increased 10 fold since 1997Mostly for off-label use

To staunch severe bleeding from car accidents, gunshot wounds and post-operative hemorrhageCost of one dose….$5,000.00Usual dose is 90 u/kg q 2 hourly (if bleeding continues and if there was a response after first dose)

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NORMAL HEMOSTASIS

HEMOSTASIS IS THE GOAL OF A DELICATELY BALANCED BIOCHEMICAL SYSTEMIMBALANCE CAN LEAD TO HEMORRHAGIC OR THROMBOTIC PHENOMENAAPPRECIATION OF THE COAGULATION PATHWAY IS NECESSARY IN THE INVESTIGATION AND MANGEMENT OF HEMORRHAGIC PROBLEMS

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HemostasisSubendothelialSubendothelial matrixmatrix

PlateletsPlateletsHemostaticHemostatic plugplug

FibrinFibrinEndothelial cellEndothelial cell

RBCRBCWBCWBC

WBCWBC

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NORMAL HEMOSTASIS

• First step in hemostasis is formation of a platelet aggregate

• At the molecular level interaction of coagulation factors takes place on the surface of activated platelets

• The Tissue Factor–FVIIa complex is the physiological activator of normal hemostasis

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Resting platelet

GP IIb/IIIareceptors in unreceptive

state

Inhibition of platelet aggregation

GP IIb/IIIa receptors occupied by antagonists

Agonist

ADP, thrombin, collagen

GP IIb/IIIa antagonist

Fibrinogen

Aggregating platelets

1111

Contact Tissue Factor + VIITissue Factor + VII

XIIIXIIIaa

XIIIXIII

ThrombinThrombin

FibrinFibrin(strong)(strong)

FibrinogenFibrinogen FibrinFibrin(weak)(weak)

IXIXXIXI

XIXIaaIXIXaa

XXaaVVaa

XIIXIIaaProthrombinProthrombin

TFTF--VIIVIIaa

((ProthrombinaseProthrombinase))

PLPL

PLPL((TenaseTenase

))VIIIVIIIaaPLPL

XX

Intrinsic Pathway

HKHKaa

Extrinsic Pathway

Common Pathway

TF Pathway

Coagulation Pathways

Protein C, Protein S, Antithrombin III

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rVIIa: mechanism of action

Fibrinogen Fibrin

Clot

F:XIIIa

Prothrombin (II) Thrombin (IIa)

Factor X Factor Xa

TissueFactor rFVIIa

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Platelets

rFactorVIIarFactorVIIa

Recombinant Factor VIIa (rFVIIa) in high concentration binds to platelets; this complex catalysis further coagulation. The local coagulation activation is greatly enhanced

TissueFactorTissueFactor-- Factor Factor VIIa VIIa

ComplexComplex

Recombinant Factor VIIa Platelet Recombinant Factor VIIa Platelet BindingBinding

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Initiation of coagulation

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[[FVIIaFVIIa] (] (nMnM))

Relative Relative FluorescenceFluorescence

Monroe et al. Monroe et al. BrBr J J HaematolHaematol 1997;99:542.1997;99:542.

2.02.0

1.51.5

1.01.0

0.00.0

0.50.5

00 150150 300300 450450 600600

ActivatedUnactivatedActivated,without Ca+2

FVIIa Binding to Platelets

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HEMORRHAGIC DISORDERSPATHOGENESIS

FAILURE OF PRIMARY HEMOSTASIS

PLATELET/VESSEL WALL INTERACTIONFAILURE OF SECONDARY HEMOSTASIS

FORMATION OF STABLE FIBRIN

UNIMPEDED ACTION OF FIBRINOLTYIC PATHWAY

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HEMORRHAGIC DISORDERSPLATELET BLEEDING DISORDERS

QUANTITATIVE/THROMBOCYTOPENIACAUSES OF THROMBOCYTOPENIA

IMPAIRED PRODUCTIONDISORDERED DISTRIBUTIONDILUTIONDESTRUCTION

IMMUNENON-IMMUNE

DIC,MICRO-ANGIOPATHIC HEMOLYTIC ANEMIATHROMBOTIC THROMBOCYTOPENIC PURPURA

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HEMORRHAGIC DISORDERSPLATELET BLEEDING DISORDERS

QUALITATIVE/THROMBOPATHIAINHERITED

eg.VON WILLEBRAND DISEASEACQUIRED

eg UREMIADRUGSDYSPROTEINEMIASDICMYELOPROLIFERATIVE DISORDERS

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PLATELET INHIBITORS

ASAClopidogrel (Plavix), TiclidAggrastat (tirofiban) ReoPro (abciximab) Integrilin (eptifibatide)

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HEMORRHAGIC DISORDERSCOAGULOPATHIES

INHERITEDHEMOPHILIASVON WILLEBRAND’S DISEASE

ACQUIREDDISSEMINATED INTRAVASCULAR COAGULATIONLIVER DISEASEDEFICIENCY OF VITAMIN K DEPENDANT FACTORSWARFARIN OVERDOSEINHIBITORS OF COAGULATION

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HEMORRHAGIC DISORDERSPATHOGENESIS

PATIENTS WITH COAGULATION INHIBITORSANTIBODIES TO COAGULATION PROTEINS

SPECIFICANTI FACTOR VIII /IX /OTHERS

ALLO-ANTIBODIESHEMOPHILIA(15%)

AUTO-ANTIBODIESSPONTANEOUS(POST-PARTUM/ELDERLY/SLE/CLL)

NON-SPECIFICPARAPROTEINEMIASDYSPROTEINEMIAS

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HEMORRHAGIC DISORDERSUREMIA

PATHOGENESISPLATELET DYSFUNCTION

CALCIUM/PROSTAGLANDIN/ADHESION DEFECTSANEMIA MAY DECREASE MARGINATION

MANAGEMENTDEFECT MAY BE CORRECTED BY DIALYSISCORRECTION OF ANEMIA(EPO OR ACUTELY BY TX-IDEALLY TO AN HEMATOCRIT OF > 30%PLATELET TX GENERALLY INEFFECTIVECRYOPRECIPITATE INFUSION (EFFECT LASTS 24 HRS)DESMOPRESSIN(DDAVP)

MAXIMUM EFFECT WITHIN 4 HRSEFFECT DIMINISHES WITH REPEATED INFUSIONS

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HEMORRHAGIC DISORDERSHEPATIC FAILURE

PATHOGENESISDECREASED SYNTHESIS OF COAGULATION FACTORSDYSFUNCTIONAL FIBRINOGEN SYNTHESISDISSEMINATED INTRAVASCULAR COAGULATION

REDUCED CLEARANCE OF ACTIVATED COAGULATION FACTORSDEFICIENCY OF ANTITHROMBINTHROMBOCYTOPENIASPECIFIC COMPLICATIONS IN PORTAL HYPERTENSION

IMPAIRED PRIMARY HEMOSTASIS/VASCULAR FRAGILITYCOMPLICATIONS OF MASSIVE TRANSFUSIONSFIBRINOLYSIS

DECREASED CLEARANCE OF ACTIVATED PROTEOLYTIC ENZYMES(eg tPA)

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HEMORRHAGIC DISORDERSDRUG INDUCED COAGULOPATHY

WARFARINImmediate reversal in hemorrhagic crises

FRESH FROZEN PLASMA15 ML/Kg OR 4-5 UNITS PER ADULT

VITAMIN K ADMINISTRATION10 MG IVI/SQ OTHERWISE 2-10 mgORAL VIT K (1 mg) LOWERS THE INR MORE RAPIDLY THAN SUB Q IN ASYMPTOMATIC PATIENTS(INR 4.5-10)

ANN INTERN MED 2002 137:251-254

HEPARIN25-50 mg PROTAMINE AS GUIDED BY THE ACT OR PTT

DIRECT THROMBIN INHIBITORSR-HIRUDIN ,ARGATROBAN,BIVALIRUDINNO ANTIDOTE/ RENAL FILTRATION OR HEPATIC CLEARANCE

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HEMORRHAGIC DISORDERSDISSEMINATED INTRAVASCULAR

COAGULOPATHYPATHOGENESIS

END POINT OF MANY DIFFERENT STIMULIINTRAVASCULAR THROMBIN GENERATION

MANAGEMENTTREATMENT OF THE CAUSEREPLACEMENT OF BLOOD COMPONENTS

PLATELETS >50,000(SURGICAL SETTING)FIBRINOGEN >100 mg/dL(10-15 u of cryoprecipitate

USE OF INHIBITORSACTIVATED PROTEIN C(APC)ANTITHROMBIN

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HEMORRHAGIC DISORDERSMANAGEMENT IN TRAUMA

SPECIFIC ISSUES:MASSIVE BLEEDINGCOMPLEX/ MULTIFACTORIALCOMPLICATING FACTORS

HYPOTHERMIADILUTIONAL COAGULOPATHY/THROMBOCYTOPENIAFUNCTIONAL COAGULOPATHIES

HEPATIC DYSFUNCTION / SHOCKED LIVERDISSEMINATED INTRAVASCULAR COAGULOPATHY

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HEMORRHAGIC DISORDERSRECOMBINANT FACTOR VIIa

SUCCESS USING PLASMA DERIVED FACTOR VIIa PROMPTED DEVELOPMENT OF THE RECOMBINANT PRODUCTDATA SUGGEST THAT rVIIa ACTS PREFERENTIALLY AT THE SITE OF INJURY THUS THROMBOEMBOLIC RISK LOWMAY BE USEFUL IN HEMORRHAGIC LIVER DISEASE

SUCCESSFULLY USED IN LIVER TRANSPLANTATION

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LABELLED INDICATION:TREATMENT OF BLEEDING IN PATIENTS WITH HEMOPHILIA A or B WITH INHIBITORSMARKETING APPROVAL OBTAINED FROM FDA IN 1999

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ADVANTAGES OF r VIIaNOT ENZYMATICALLY ACTIVE THUS DOES NOT ACTIVATE COAGULATION SYTEMICALLYACTIVITY IS NOT AFFECTED BY NATURAL ANTI-COAGULANTS/INHIBITORSSAFETY ADVANTAGE OVER PLASMA DERIVED FACTOR CONCENTRATES

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OFF-LABEL USAGE:NEONATAL COAGULOPATHIESSEVERE HEPATIC DISEASE/ LIVER TRANSPLANTATIONHIGH RISK SURGICAL PROCEDURESTRAUMATIC BLOOD LOSSBONE MARROW TRANSPLANTATIONTHROMBOCYTOPENIC BLEEDINGPLATELET FUNCTION DISORDERSURGENT REVERSAL OF ANTICOAGULANTSCONGENITAL DEFICIENCIES OF V,VII,X,XIVon WILLEBRAND DISEASE W/INHIBITORS

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NEONATAL /PEDIATRIC COAGULOPATHYLIFE THREATENING HEMORRHAGE IN PRE-TERMS

SEVERAL CASE REPORTS / VARYING DOSES BOLUS AND/OR REPETITIVE DOSES5-200 ug/Kg…..CESSATION OF BLEEDING,IMPROVED PTWITHIN 10 MINS…..SUSTAINED TO 6 HRS

RETROSPECTIVE SERIES IN PEDIATRICS3 MONTHS -19 YEARSVARIABLE COAGULOPATHIES50-100 ug/KgCORRECTION OF LABORATORY PARAMETERS

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HEPATIC DYSFUNCTIONLAPAROSCOPIC LIVER BX-66 PATIENTS (MULTICENTER RCCT )

EFFICACY OF 4 DOSES (5,20,80,120 ug/Kg ON CLINICAL AND LABORATORY PARAMETERSPT CORRECTED TO NORMAL IN MAJ. OF PTSHEMOSTASIS ACHIEVED IN 48/65(74%) IN 10 MINS AND MAINTAINED FOR 1`8 HRSNO PTS NEEDE OPERATIVE INTERVENTION OR TRANSFUSIONS

COAGULOPATHY OF FULMINANT HEPATIC FAILURE PRIOR TO LIVER T/PLANT(CASE CONTROLLED-HISTORICAL CONT)

15 PTS (8 PLASMA,7 PLASMA + rVIIaALL PTS NORMALIZED THEIR PT IN THE rVIIa GROUP VS 0

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HEPATIC DYSFUNCTIONNON-BLEEDING VOLUNTEERS W/CIRRHOSIS

DOSE ESCALATION STUDY/SINGLE CENTER10 PATIENTS W/ ELEVATED PT-3 SUCCESSIVE DOSES OF 5,20,80 ug/Kg-OVER 3 WEEKSTRANSIENT NORMALIZATION OF PT IN ALL GROUPS…DOSE DEPENDENT DURATION

BLEEDING ESOPHAGEAL VARICESOPEN LABEL TRIAL(10 PTS -80 ug/Kg)EFFECT ON PTIMMEDIATE NORMALIZATION OF PT WITHIN 30 MINS IN ALL PATIENTS

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ORTHOTOPIC LIVER TRANSPLANTATIONCOMPLICATED BY COAGULOPATHY OF LIVER FAILURE + SURGERYSINGLE CENTER OPEN LABEL STUDY

6 PATIENTS X 80 ug/Kg IMMED.PRE-OPREDUCED BLOOD COMPONENT USE VS HISTORIC CLWELL TOLERATED

CASE REPORT OF SUCCESS IN WILSON’S DISEASE (2 PTS-50-6- ug/Kg IMMED PRE-OP)

LIVER FAILURE + DICCASE REPORTS

CONCOMITANT BLEEDING ATTENUATED IN 2 CASE REPORTS ASSOCIATED WITH DIC

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REVERSAL OF ANTICOAGULANT THERAPYWARFARIN REVERSAL

2 REPORTS (1 CASE REPORTS 1 AND SERIES OF 13 PTS)

IMMEDIATE REVERSAL OF INR IN 5 PTSNO GREATER PERI-OPERATIVE BLEEDING- 5 PTS )IMPROVEMENT IN HEMORRHAGIC MANIFESTATIONS

FONDAPARINUXONE PCRT IN HEALTHY SUBJECTS( 16 subjects)

90 ug/Kg r VIIa (8)vs F+Placebo(4) vs rVIIa + Placebo(4)NORMALIZATION OF PTT IN ALL rVVIa SUBJECTSNORMALIZATION OF THROMBIN GENERATION

DIRECT ANTI-THROMBIN INHIBITORS

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PERI-OPERATIVE /TRAUMATIC BLOOD LOSS(PROCEDURE ASSOCIATED OR COAGULOPATHIC)

USUALLY TRIED WHEN TRADITIONAL THERAPY FAILSRETROPUBIC PROSTATECTOMY(DB-PCRCT)

REDUCTION IN PERIOPERATIVE BLOOD LOSS AND TXDOSE DEPENDENT C/W PLACEBO (20 ug/Kg : 40 uG/Kg )40 ug/Kg NO TX VS 58% PLACEBO

CARDIAC VALVE SURGERY30 ug/Kg OPEN LABEL Q 3 hrs…..4 DOSES

REDUCED PT BY > 12 SECSREDUCTIONS IN BLOOD LOSS AFETR SINGLE DOSE IN ALL

MISCELLANEOUS CASE REPORTS IN TRAUMAMILITARY AND COMPLEX SURGERY

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PLATELET DISORDERSTHROMBOCYTOPENIA

74 PTS /PHASE I/II STUDY(IV BOLUS 50-100ug/Kg)IMPROVEMENT IN BLEEDING TIMES IN PTS WITH PLATELET COUNTS < 20,000CORRECTION OF BLEEDING EVENTS IN 6 PTS

2 PTS W/SEVERE LIFE THREATENING HEMORRHAGE AND ITP

THROMBOCYTOPATHIA2 CASE REPORTS IN GLANZMANN’S THROMBASTHENIA

W/PROCEDURES incl SURGERY

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OTHER COAGULOPATHIESVON WILLEBRAND DISEASE

CONGENITALCASE REPORT WITH RECURRENT BLEEDING

ACQUIREDINHIBITOR ASOCIATED W/MGUS

HERMANSKY PUDLAK SYNDROMEFACTOR VII DEFICIENCYFACTOR X DEFICIENCY W/AMYLOID

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BONE MARROW TRANSPLANTATION2 REPORTS( BOLUS + INFUSIONAL)

PULMONARY HEMORRHAGE(1)HEMORRHAGIC CYSTITIS(3)GI BLEEDING(2)DIFFUSE ALVEOLAR HEMORRHAGE(1)

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RECOMBINANT F VII aSUMMARY OF APPLICATIONS

ACTIVATED FVII/TF INTEGRAL IN NORMAL HEMOSTASISAMPLIFIES BOTH PRIMARY AND SECONDARY COMPONENTSrVIIa REPLACEMENT THERAPY HAS SEVERAL BROAD POTENTIAL APPLICATIONS AND APPEARS TO BE SUCCESSFUL EVIDENCE OF EFFICACY OFF-LABEL IS MOSTLY ANECDOTALSEVERAL TRIALS ARE UNDERWAY TO VALIDATE THE PERCEIVED THERAPEUTIC APLLICATIONS

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NovoSeven :USAGESINCE 1997 SALES HAVE INCREASED TENFOLD

WALL STREET JOURNAL 3/17/04APPLICATIONS

SEVERE BLEEDING FROM CAR ACCIDENTSGUNSHOT WOUNDSPOST-SURGERY HEMORRHAGE

IS IT THE NEW WONDER DRUG FOR HEMOSTASIS?ANECDOTALNOVO NORDISK HAS PROVIDED LITTLE EVIDENCE ABOUT THE DRUGS SAFETY AND EFFICACY IN THESE UNAPPROVED USES

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