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