The Most Commonly Administered

Hemostatic Agent in the U.S.

Research Support/P.I. None

Employee Saint Louis University/SSM Cardinal Glennon

Consultant Nothing to Disclose

Major Stockholder Nothing to Disclose

Speakers Bureau Nothing to Disclose

Honoraria Nothing to Disclose

Advisory Board Nothing to Disclose

Program Information Source Personnel Review of Literature

Program Funding Source No funding received

What is the most commonly administered Hemostatic agent in the U.S. ?

A. AdvateB. KogenateC. XynthaD. Other

How many people in the U.S. have Hemophilia ?A. 20,000B. 200,000C. 2,000,000

Are the indications for rFVIII known ?Has rFVIII been shown to be effective for these indications ?Has the dose of rFVIII been determined for its indications?Have the toxicities of rFVIII been studied/known ?

Plasma

Transfused:Fresh Frozen

FP24SD FFP

Cryopoor PlasmaFresh

Source:Plasmapheresis

Recovered – Whole Blood or FFP

Plasma: Liquid Component of Blood.What’s Left After Cellular Elements Removed

1. 1818 First described Human to Human Blood Transfusion (Blundell)

Fresh Frozen PlasmaA History Lesson

Plasma Transfusion History

1. Blood Substitutes: Salt Solutions/Ringers 18592. 1870s Bowditch and Luciani infused Sheep Serum into Frog Heart3. By 1884 Pre-Clinical Studies established the presence of vaso-active substances released by blood clotting4. 1917-19 Replace 96% of dog blood with horse plasma5. WWI Advantage of citrated plasma over whole blood recognized6. 1918 First use of human plasma (fresh) transfusion – Influenza Antitoxin7. 1930’s citrated plasma (fresh) routinely used for transfusion8. 1935 plasma used as a hemostatic agent for the first time9. WWII Frozen and Dried Plasma developed10.1932-41 Cryoprecipitate/Labile Factors Present in Plasma

Fresh Frozen PlasmaA History Lesson

FFP Use in Children

1. 1934 First Description FFP use in Child (sepsis)2. 1936-1963 Case Reports and Small Series3. 1964 First Randomized Controlled Trial

SepsisNutritional Protein Deficiencies

BurnsNephrotic Syndrome

HemophiliaSickle Cell Anemia

Acute Lymphoblastic LeukemiaImmune Thrombocytopenia Purpura

FFP Use in Children

1. 1934 First Description FFP use in Child (sepsis)2. 1936-1963 Case Reports and Small Series3. 1964 First Randomized Controlled Trial4. 1968 First Large Neonatal Series

• 53 Subjects (13/40)with Heart Disease• Surgery with Extracorporeal Circulation• Randomized FFP or Standard Care• 250/500 mls FFP• No reduction in bleeding

• 286 Consecutive Low Birth Weight Neonates• Coagulation Status Assessed By The Thrombotest• 59 Died; 21 Had ICH• Thrombotest < 10% increased risk for Death/ICH• Plasma 10 ml/kg lower risk of death p=0.07• 10 ml/kg plasma “usually raises the thrombotestlevel to about 30%.”

Thrombotest: Designed to Monitor CoumadinDeveloped in late 1950s by OwrenBovine Plasma Deficient to II,VII,IX and XCan Use Capillary Specimen

Proposed Indications For FFPClinical Indication Number of

Controlled StudiesRandomization Number of

patientsStudy Outcome

Volume Expansion 3 FFP(10 mls/kg) v. SupportFFP(15 mls/kg) v. AlbuminFFP (10 mls/kg) v. Support

603835

No BenefitNo BenefitNo Benefit

Prevent ICH in Neonates 4 Fresh Plasma 3 ml/kg v. SupportFFP (10 mls/kg)v. SupportFFP (10 mls/kg)v. SupportFFP(30mls/kg)v. gelatin v. glucose

806673776

No BenefitNo BenefitEffectiveNo Benefit

Neonatal RDS 1 FFP (15mls/kg) v. Exch. v. Support 101 No BenefitNeonatal Sepsis 1 FFP (15 mls/kg) v. IVIg 67 No BenefitCorrection of Clotting Tests 0

Treatment of Bleeding or Peri-procedural prophylaxis

2 FFP (250 mls) v. SupportFFP (10 mls/kg) v. HES

1342

No BenefitNo Benefit

TTP 0Single Clotting Factor Deficiency 0

Warfarin Toxicity 0Massive Hemorrhage 0DIC 1 FFP(15 mls/kg) v. Exch. v. Support 33 No BenefitBurns 1 High volume v. Low volume FFP 385 MixedHUS 2 FFP (10 mls/kg) v. Support

FFP (10 mls/kg) v. Support7932

No BenefitNo Benefit

Liver Disease 0Blood Reconstitution:

Hyperbilirubinemia 0Polycythemia 5 Part. Exch. with FFP v. Support

Part. Exch. with FFP v. SupportPart. Exch. with FFP v. SalinePart. Exch. with FFP v. SalinePart. Exch. with FFP v. Haemaccel v. Saline

4993304764

No BenefitMixedNo BenefitNo BenefitNo Benefit

Cardiopulmonary bypass 2 Whole blood v. FFP ReconstitutionFFP v. Albumin Reconstitution

20056

EffectiveMixed

Coagulation Factors

Normal Range 50-150 % or 50-150 u/dl (units per deciliter)

What is a unit ?

The amount of coagulation factor activity present in 1 ml of normal plasma

Normal factor IX activity = 1 u/ml X 100 ml/dl = 100 u/dl = 100%

Target factor activity for bleeding hemophilia patient is 40-50%

10 ml/kg FFP increase factor IX level by 10% - inadequate for hemostasis(need 40 ml/kg)

Proposed Indications For FFPClinical Indication Number of

Controlled StudiesRandomization Number of

patientsStudy Outcome

Volume Expansion 3 FFP(10 mls/kg) v. SupportFFP(15 mls/kg) v. AlbuminFFP (10 mls/kg) v. Support

603835

No BenefitNo BenefitNo Benefit

Prevent ICH in Neonates 4 Fresh Plasma 3 ml/kg v. SupportFFP (10 mls/kg)v. SupportFFP (10 mls/kg)v. SupportFFP(30mls/kg)v. gelatin v. glucose

806673776

No BenefitNo BenefitEffectiveNo Benefit

Neonatal RDS 1 FFP (15mls/kg) v. Exch. v. Support 101 No BenefitNeonatal Sepsis 1 FFP (15 mls/kg) v. IVIg 67 No BenefitCorrection of Clotting Tests 0

Treatment of Bleeding or Peri-procedural prophylaxis

2 FFP (250 mls) v. SupportFFP (10 mls/kg) v. HES

1342

No BenefitNo Benefit

TTP 0Single Clotting Factor Deficiency 0

Warfarin Toxicity 0Massive Hemorrhage 0DIC 1 FFP(15 mls/kg) v. Exch. v. Support 33 No BenefitBurns 1 High volume v. Low volume FFP 385 MixedHUS 2 FFP (10 mls/kg) v. Support

FFP (10 mls/kg) v. Support7932

No BenefitNo Benefit

Liver Disease 0Blood Reconstitution:

Hyperbilirubinemia 0Polycythemia 5 Part. Exch. with FFP v. Support

Part. Exch. with FFP v. SupportPart. Exch. with FFP v. SalinePart. Exch. with FFP v. SalinePart. Exch. with FFP v. Haemaccel v. Saline

4993304764

No BenefitMixedNo BenefitNo BenefitNo Benefit

Cardiopulmonary bypass 2 Whole blood v. FFP ReconstitutionFFP v. Albumin Reconstitution

20056

EffectiveMixed

FFP used to Correct Abnormal Clotting Tests

PT/aPTT

Johnson et al Arch Dis Child 1982; 57: 950-52Puetz et al J Pediatr Hematol Oncol 2009; 31: 901-906.Holland et al Am J Clin Pathol 2006; 126: 133-139

Proposed Indications for FFP

Number of Pediatric Randomized Trials: 22

Number of Adult Randomized Trials: 43

Number of Adult Randomized Trials Showing Benefit: 3

Stanworth et al British Journal of Haematol 2004; 126: 139-152Yang L. Transfusion 2012 epub Jan 18

FFP Use in Children

Describe FFP Use in Children in the U.S.

Who, What, Where, When, Why

Retrospective, Cohort Study Preexisting De-Identified Data

Pediatric Health Information System (PHIS) Administrative Database

43 Tertiary Pediatric U.S. Children’s HospitalsAffiliated with Child Health Corporation of America (CHCA)

Puetz et al. J Pediatrics 2012 Feb;160(2):210-215

CHCA Participating Children’s Hospitals

PHIS FFP Admissions

2002-2009

3,252,149 Admissions Overall

92,731 FFP Admissions

The Percent of FFP Admissions (2.85)Did Not Change Between 2002-2009 (p = 0.10)

54% Infants

34% CPB Code

Complications

Association not Causation

PHIS FFP Admissions

Overall: Venous Thrombosis 10% Arterial Thrombosis 5%

Rate of Venous Thrombosis With FFP Admissions Increased Tenfold

PHIS FFP AdmissionsComplications

• 12 y.o. male with O.M.• Developed Mastoiditis and Septicemia• Treated with Antimicrobials and Surgery• Supported with FFP• Developed Venous Sinus Thrombosis• Completely Recovered

First English Language Case Report - 1934Hemolytic StreptococciAntimicrobial – IM Injections of Autogenous Lysate (bacteriophage)FFP Neutralized the “toxin of the disease”Did FFP contribute to the sinus thrombosis?

Are the indications for known ?

Has been shown to be effective for these indications ?

Has the dose of been determined for its indications?

Have the toxicities of been studied/known ?

The Most Commonly AdministeredHemostatic Agent in the U.S.

rFVIII

rFVIII

rFVIII

rFVIII

FFP

FFP

FFP

FFP

2,000,000 vs 20,000