The Composition and Use The Composition and Use of Plasma Componentsof Plasma Components

Ira A. Shulman, MDIra A. Shulman, MDUniversity of Southern CaliforniaUniversity of Southern California

James P. AuBuchon, MDJames P. AuBuchon, MDDartmouthDartmouth--Hitchcock Medical CenterHitchcock Medical Center

Terry Gernsheimer, MDTerry Gernsheimer, MDUniversity of WashingtonUniversity of Washington

for thefor the

Clinical Transfusion Medicine CommitteeClinical Transfusion Medicine CommitteeAABBAABB

May 15, 2006May 15, 2006

WHOLEBLOOD

1UnitRBC

Platelet-Rich Plasma(PRP)

1 UnitPlasma

1 Unit (~250 mL)Fresh Frozen Plasma

1 Unit cryoprecipitate+ 1 Unit plasma(Cryoprecipitate-Reduced)

Centrifuge

Centrifuge

Freeze, Thaw,CentrifugeFreeze within 8 hr*

1 Unit Platelets

What is What is ““FFPFFP””??

Plasma can also be frozen after 8h but before 24hPlasma can also be frozen after 8h but before 24h

What About FFP Made from What About FFP Made from Apheresis Collections?Apheresis Collections?

Volume:Volume: 200 200 –– 600 mL600 mL

Content:Content: PlasmaPlasmaAnticoagulantAnticoagulant

PLASMA250 mL

200 mL200 mL

300 mL300 mL500 mL500 mL

600 mL600 mL

==

Stored frozen Stored frozen coldercolder

than than --1818°°CC

FFPThawed at

30-37ºC

FFP,Thawed

4ºC>24 h

ThawedPlasma

(to 5 d after thawing)(to 5 d after thawing)

Handling Options for FFPHandling Options for FFP

Coagulation Factor Activity ofCoagulation Factor Activity ofThawed PlasmaThawed Plasma

NSNS6680808282848484848585XX

<.05<.0541416565656566667676107107VIIIVIII

NSNS202072727272767681819090VIIVII

NSNS161666666868717175757979VV

NSNS1180808080818181818181IIII

NSNS00225225224224224224224224225225FibrFibr

pp% change% changeDay 1 to 5Day 1 to 5Day 5Day 5Day 4Day 4Day 3Day 3Day 2Day 2Day 1Day 1

Downes K Downes K et al. Transfusionet al. Transfusion 2001;41:570.2001;41:570.(Tabular entries as % activity.)(Tabular entries as % activity.)

The Challenge of Frozen Plasma UsageThe Challenge of Frozen Plasma Usage

A readily available source of procoagulants A readily available source of procoagulants that can be life saving for patients in need that can be life saving for patients in need of hemostatic assistance of hemostatic assistance --

-- But there is lack of consensus around But there is lack of consensus around definition of the circumstances when this definition of the circumstances when this component will truly benefit a patient.component will truly benefit a patient.

Abnormalities in Coagulation Testing Abnormalities in Coagulation Testing do do notnot necessarily indicate a necessarily indicate a

Clinical CoagulopathyClinical Coagulopathy

ProcoagulantProcoagulant Consumed inConsumed in ConcentrationConcentrationCoagulation?Coagulation? NormalNormal HemostaticHemostatic

FibrinogenFibrinogen YesYes 200200--400 mg/dL 50400 mg/dL 50--100 mg/dL100 mg/dLFactor VFactor V YesYes 1 U/mL1 U/mL 55--25%25%

Factor VIIFactor VII NoNo 1 U/mL1 U/mL 55--25%25%Factor VIIIFactor VIII YesYes 1 U/mL 151 U/mL 15--25%25%

Normal concentration: 1 U/mL = 100% activityNormal concentration: 1 U/mL = 100% activity

••BleedingBleeding with deficiency of multiple coagulation factorswith deficiency of multiple coagulation factors••BleedingBleeding with specific factor deficiency, no concentrate availablewith specific factor deficiency, no concentrate available••PrePre--op setting with deficiency of multiple coagulation factorsop setting with deficiency of multiple coagulation factors••PrePre--op setting with specific factor deficiency, no concentrate availop setting with specific factor deficiency, no concentrate availableable••Massive transfusion with coagulation abnormalitiesMassive transfusion with coagulation abnormalities••Bleeding or urgent invasive procedureBleeding or urgent invasive procedure while on warfarin therapywhile on warfarin therapy••Thrombotic thrombocytopenic purpura (TTP)Thrombotic thrombocytopenic purpura (TTP)••Rare specific plasma protein deficiencies, e.g., C1Rare specific plasma protein deficiencies, e.g., C1--esterase inhibitoresterase inhibitor

REFERENCE: http://www.fda.gov/cber/gdlns/circbld.pdfREFERENCE: http://www.fda.gov/cber/gdlns/circbld.pdf

Clinical Indications for PlasmaClinical Indications for Plasma

Mild elevations of PT or aPTT overestimate clinical benefit Mild elevations of PT or aPTT overestimate clinical benefit of transfusing FFP for patients in of transfusing FFP for patients in mostmost clinical situations.clinical situations.

1.3 x upper limit of reference range (in seconds)1.3 x upper limit of reference range (in seconds)-- or or ––

1.5 x midpoint of reference range (in seconds)1.5 x midpoint of reference range (in seconds)

McVay PA McVay PA et al. AJCPet al. AJCP 1990;94:7371990;94:737--53.53.McVay PA McVay PA et al. Transfusionet al. Transfusion 1991;31:1641991;31:164--71.71.Counts RB Counts RB et al. Ann Surget al. Ann Surg 1979; 190:911979; 190:91--9.9.Ciavarella D Ciavarella D et al. Br J Haematolet al. Br J Haematol 1987;67:3651987;67:365--8.8.Auble T Auble T et al.et al. Acad Emerg MedAcad Emerg Med 2002;5672002;567--574574

Recommended transfusion trigger points Recommended transfusion trigger points in appropriate situations:in appropriate situations:

NOTINR=1.5

Using Screening Tests to Predict Plasma NeedUsing Screening Tests to Predict Plasma Need

<1.3<1.3 >1.3>1.3 >1.5>1.5x upper limit ofreference rangex upper limit ofreference range

PTPT PTTPTT

100%100%

75%75%

50%50%

25%25%

Patients withPatients withGeneralized Generalized BleedingBleeding

Counts RB Counts RB et al. Ann Surget al. Ann Surg 1979;190:911979;190:91--9.9.

<1.3<1.3 >1.3>1.3 >1.5>1.5x upper limit ofreference rangex upper limit ofreference range

Using Screening Tests to Predict Plasma NeedUsing Screening Tests to Predict Plasma NeedPatients experiencing massive transfusion after traumaPatients experiencing massive transfusion after trauma

Orlin Orlin et al. Bloodet al. Blood. 1980;56:1055. 1980;56:1055--9. 9.

10010080806060

4040

2020

1010

% R

EMA

ININ

G (l

og s

cale

)%

REM

AIN

ING

(log

sca

le) PT or PTT (ratio to control)

PT or PTT (ratio to control)

3.23.2

2.82.8

2.42.4

2.02.0

1.61.6

1.21.2

PTPT

350350 10501050 17501750 24502450 31503150 38503850 45504550PLASMA REMOVED (mL)PLASMA REMOVED (mL)

FIBRINOGENFIBRINOGEN

PTTPTT

FACTOR XFACTOR X

FACTOR VIIIFACTOR VIII

Using Screening Tests to Predict Plasma NeedUsing Screening Tests to Predict Plasma NeedEffect of plasma dilution on Effect of plasma dilution on procoagulantsprocoagulants

TestTest GroupGroup nn BleedingBleeding HbHb ChangeChangeComplicationsComplications ((mg/mg/dLdL))

PT PT NormalNormal 100100 4%4% -- 0.30.3±±0.90.91.3 x ULN 43 6%1.3 x ULN 43 6% -- 0.20.2±±0.80.8

PTT PTT Normal 103 5% Normal 103 5% -- 0.30.3±±0.90.91.3 x ULN 34 3%1.3 x ULN 34 3% -- 0.10.1±±0.60.6

McVayMcVay PA PA et al. AJCPet al. AJCP 1990;94:7371990;94:737--53.53.

Best predictor of bleeding was a finding of malignancy in the biBest predictor of bleeding was a finding of malignancy in the biopsy.opsy.

Using Screening Tests to Predict Plasma NeedUsing Screening Tests to Predict Plasma NeedPatients undergoing Patients undergoing percutaneouspercutaneous liver needle biopsyliver needle biopsy

ULN = Upper limit of normalULN = Upper limit of normal (No pre(No pre--biopsy FFP prophylaxis given.)biopsy FFP prophylaxis given.)

88

1212

44

1616

1010 2020 3030 4040 5050 6060 7070 8080 9090 100100

MeanMean

Using Screening Tests to Predict Plasma NeedUsing Screening Tests to Predict Plasma NeedPatients undergoing laparoscopic liver needle biopsyPatients undergoing laparoscopic liver needle biopsy

Ewe K. Ewe K. Dig Dig DisDis SciSci 1981;26:3881981;26:388--93.93.Note: 10% change in activity = approximately 1 secNote: 10% change in activity = approximately 1 sec

LiverLiverBleedingBleedingTime (min)Time (min)

PT (% normal activity)PT (% normal activity)

RBC Loss(mL)

RBC Loss(mL)

10001000

800800

600600

400400

200200

OperativeOperative 24 hTotal24 hTotal

72 hTotal72 hTotal

Coumadin (therapeutic; n=20)Coumadin (therapeutic; n=20)

Controls (n=20)Controls (n=20)

Gastrectomy Patient GroupGastrectomy Patient Group

RANGERANGE

Predicting Plasma NeedPredicting Plasma NeedEffect of Effect of coumadincoumadin therapy on therapy on perioperativeperioperative blood lossblood loss

RustadRustad H H et al. et al. ActaActa Med ScandMed Scand 1963;173:1151963;173:115--9.9.

Predicting Plasma NeedPredicting Plasma NeedEffect of Effect of coumadincoumadin therapy on posttherapy on post--operative blood lossoperative blood loss

GroupGroup nn PostPost--Op Blood Loss (Op Blood Loss (mLmL))

ControlsControls 2626 813 (125813 (125--2125)2125)Therapeutic Therapeutic coumadinizationcoumadinization 2626 624 (210624 (210--1650)1650)

Procedure: Procedure: MitralMitral commissurotomycommissurotomy

Storm O Storm O et al. Circet al. Circ 1955;12:9811955;12:981--5.5.

Predictive ValuePredictive ValueSensitivitySensitivity SpecificitySpecificity PositivePositive NegativeNegative

PT ratioPT ratio1.3 1.3 89% 89% 50% 50% 33% 33% 94%94%1.8 1.8 44% 96% 80%44% 96% 80% 84%84%

PTT ratio PTT ratio 1.3 1.3 56%56% 56% 26% 82%56% 26% 82%1.8 56%1.8 56% 96% 83% 96% 83% 87%87%

Platelet countPlatelet count< 50,000/mL < 50,000/mL

oror 89%89% 93% 73% 93% 73% 96%96%FibrinogenFibrinogen

< 50 mg/dL< 50 mg/dL

Ciavarella D Ciavarella D et al. Br J Haematolet al. Br J Haematol 1987;67:3651987;67:365--8.8.

Indices Predictive of Indices Predictive of MicrovascularMicrovascular BleedingBleeding

PT ratio = PatientPT ratio = Patient’’s PT (sec) / midpoint (sec) of PT reference ranges PT (sec) / midpoint (sec) of PT reference rangePTT ratio = PatientPTT ratio = Patient’’s PTT (sec) / midpoint (sec) of PTT reference ranges PTT (sec) / midpoint (sec) of PTT reference range

An Analysis of the LiteratureAn Analysis of the Literature

AngiographyAngiographyAngiographyAngiographyBronchoscopyBronchoscopyLiver biopsyLiver biopsyLiver biopsyLiver biopsyLiver laparoscopyLiver laparoscopyLiver laparoscopyLiver laparoscopyTransjugularTransjugular liver biopsy liver biopsy TransjugularTransjugular liver biopsy liver biopsy TransjugularTransjugular liver biopsy liver biopsy Para/Para/thoracentesisthoracentesisTransjugularTransjugular kidney biopsy kidney biopsy Kidney biopsyKidney biopsy

RISK DIFFERENCERISK DIFFERENCE

FAVORS TRANSFUSIONFAVORS TRANSFUSION FAVORS NO TRANSFUSIONFAVORS NO TRANSFUSION00 0.250.25--0.250.25

Segal and Segal and DzikDzik. . TransfusionTransfusion 2005;45:14132005;45:1413--25.25.

Normal vs. Abnormal Coagulation TestsNormal vs. Abnormal Coagulation Tests

ScoreScore MedicalMedical SurgicalSurgical TraumaTrauma TotalTotal

0 0/37 1/320 (0.3%) 0 0/37 1/320 (0.3%) 0/42 1/299 (<1%)0/42 1/299 (<1%)

33--7 7/77 (9%) 2/194 (1%) 7 7/77 (9%) 2/194 (1%) 1/84 (1%) 10/355 (<3%)1/84 (1%) 10/355 (<3%)

>>8 4/8 (50%) 0/4 8 4/8 (50%) 0/4 1/11 (9%) 5/23 (22%)1/11 (9%) 5/23 (22%)

Total 11/122 (9%) 3/518 (0.6%) Total 11/122 (9%) 3/518 (0.6%) 2/137 (1.4%) 16/777 (2%)2/137 (1.4%) 16/777 (2%)

Score calculationScore calculation

3 points for each of the following: 3 points for each of the following: PT 18PT 18--24 seconds, PTT 4824 seconds, PTT 48--64 seconds, Platelet Count 2064 seconds, Platelet Count 20--49,000/microL, serum 49,000/microL, serum creatininecreatinine > 1.4> 1.4

4 points for each of the following:4 points for each of the following:PT >24 seconds, PTT >64 seconds, Platelet Count <20,000/microLPT >24 seconds, PTT >64 seconds, Platelet Count <20,000/microL

Bleeding Prediction Score = sum of pointsBleeding Prediction Score = sum of points

DeLougheryDeLoughery TG TG et al. Transfusionet al. Transfusion 1996;36:8271996;36:827--3131

Predicting BleedingPredicting BleedingBy bleeding score and serviceBy bleeding score and service

IntraIntra--Op Assessment: The ThromboelastogramOp Assessment: The Thromboelastogram

Normal

Normal

Coagulopathy

Coagulopathy

Low platelets

Low platelets

Fibrinolysis

Fibrinolysis

Hypercoagulable

Hypercoagulable

Thromboelastography ProfilesThromboelastography Profiles

Murphy PT Murphy PT et al. Clin Lab et al. Clin Lab HaematolHaematol 1998;20:2531998;20:253--7 7 MakrisMakris M M et al.et al. ThrombThromb HaemostHaemost 1997;77:4771997;77:477--80.80.Br J Br J HaematolHaematol 2001;114:2712001;114:271--80. 80.

Correcting OverCorrecting Over--CoumadinizationCoumadinization

Clinical SignificanceClinical SignificanceINR >8 due to INR >8 due to coumadincoumadin Major bleeding in 12/77 (13%)Major bleeding in 12/77 (13%)Two fatalities (3%) without FFP or vitamin K treatmentTwo fatalities (3%) without FFP or vitamin K treatment

Correction with FFP Correction with FFP REVERSAL ALMOST REVERSAL ALMOST IMMEDIATEIMMEDIATE BUT NOT NECESSARILY LASTINGBUT NOT NECESSARILY LASTINGFFP transfusion FFP transfusion INR = 2.3 (1.6INR = 2.3 (1.6--3.8)3.8)

Correction with Vitamin KCorrection with Vitamin KREVERSAL IN REVERSAL IN 66--12h12hAdministration: oral, subcutaneous or IV (more rapid action)Administration: oral, subcutaneous or IV (more rapid action)Dose may be repeated, as necessary.Dose may be repeated, as necessary.

Ansell J. Chest.2001;119:22S-38S.

GUIDELINESCLINICAL

SITUATION GUIDELINESCLINICAL

SITUATION

Correcting OverCorrecting Over--CoumadinizationCoumadinization

Ansell J et al. Chest 2004;126(3Suppl):204S-233S.

Recommendations of American College of Chest PhysiciansRecommendations of American College of Chest Physicians

PLASMAPLASMA

USUAL DOSE FOR CONTROL OF BLEEDING: 10USUAL DOSE FOR CONTROL OF BLEEDING: 10--20 mL/kg20 mL/kg

Plasma DosagePlasma Dosage

DeterminantsDeterminantsPatient sizePatient sizeBleeding siteBleeding siteFactor activity: Initial, targetFactor activity: Initial, targetFactor concentration in plasma and recoveryFactor concentration in plasma and recoveryFactor halfFactor half--life in vivolife in vivoUnit volumeUnit volumeRRxx: 2 units??: 2 units??

ProcoagulantProcoagulant Recovery and SurvivalRecovery and Survival

PREPRETRANSFUSIONTRANSFUSION

0%0%

10%10%

20%20%

30%30%

40%40%

50%50%

HOURS POST TRANSFUSIONHOURS POST TRANSFUSION00 11 22 33 44 55 66 77 88 99 1010

70 kg patient with 3000 70 kg patient with 3000 mLmL plasma volume receiving FFP (20 plasma volume receiving FFP (20 mLmL/kg) /kg)

Factor VII (tFactor VII (t1/21/2=5h)=5h)

Fibrinogen (tFibrinogen (t1/21/2=3=3++d)d)

Factor X (tFactor X (t1/21/2=20h)=20h)Factor VIII (tFactor VIII (t1/21/2=12h)=12h)

ASSUMPTIONS:ASSUMPTIONS:Stable plasma volume after expansionStable plasma volume after expansion Synthetic capacity to maintain preSynthetic capacity to maintain pre--transfusion transfusion 85% 85% procoagulantprocoagulant activity in plasmaactivity in plasma procoagulantprocoagulant activityactivity100% recovery100% recovery

PLASMA VOLUME =PLASMA VOLUME =3000 3000 mLmL

PLASMA VOLUME =PLASMA VOLUME =4400 4400 mLmL

PRO

CO

AG

ULA

NT

AC

TIVI

TYPR

OC

OA

GU

LAN

T A

CTI

VITY

Considerations in Massive HemorrhageConsiderations in Massive Hemorrhage

Surgical bleeding vs. Surgical bleeding vs. coagulopathiccoagulopathic bleeding?bleeding?

Adequacy of resuscitation?Adequacy of resuscitation?

Extent of hypothermia and acidosis?Extent of hypothermia and acidosis?

Hardy JF et al. Hardy JF et al. VoxVox Sang 2005;89:123Sang 2005;89:123--7.7.

Body Temperature (Body Temperature (ºº C)C)

Effect of Body Temperature on CoagulationEffect of Body Temperature on Coagulation

Rohrer MJ, Rohrer MJ, NataleNatale AM. AM. CritCrit Care MedCare Med 1992;20:14021992;20:1402--5.5.

0

10

20

30

40

50

60

28 31 34 37 39 41

PTT

(sec

onds

)

Effect of Acid/Base Balance on Coagulant ActivityEffect of Acid/Base Balance on Coagulant Activity

MengMeng ZH ZH et al. J Traumaet al. J Trauma 2003;55:8862003;55:886--91.91.

00

0.50.5

11

1.51.5

22

2.52.5

33

6.26.2 6.66.6 77 7.47.4 7.87.8 8.28.2 8.68.6 99

pHpH

Rel

ativ

e R

ate

of II

a G

ener

atio

nR

elat

ive

Rat

e of

IIa

Gen

erat

ion

Clinical StatusClinical Status Conditional Probability of Conditional Probability of DDeveloping eveloping CoagulopathyCoagulopathy

No risk Factor No risk Factor 1% 1%

Severe trauma*Severe trauma* 10%10%+Systolic BP < 70mm Hg+Systolic BP < 70mm Hg 39%39%

+pH < 7.1+pH < 7.1 49%49%

Severe trauma + Temp < 34Severe trauma + Temp < 34ººCC 49%49%+Systolic BP < 70mm Hg+Systolic BP < 70mm Hg 85%85%

+pH < 7.1+pH < 7.1 98%98%

Cosgriff Cosgriff et al. J Traumaet al. J Trauma 1997;42:8571997;42:857--61.61.*Injury severity score of >25.*Injury severity score of >25.

Cumulative Effects of Hypotension and HypothermiaCumulative Effects of Hypotension and Hypothermia

Stored frozen Stored frozen coldercolder

than than --18C18C

FFPThawed at4ºC, then

centrifuged

Cryo

Handling of Plasma CryoprecipitateHandling of Plasma Cryoprecipitate

Cryo-reducedPlasma

-- DerivativesDerivatives-- TTP exchangeTTP exchange

CryoprecipitateCryoprecipitate

Factor VIII (> 80 U)Factor VIII (> 80 U)vWFvWF

Fibrinogen (~200 mg)Fibrinogen (~200 mg)

Indications for CryoprecipitateIndications for Cryoprecipitate

Clinically significant deficiency ofClinically significant deficiency of

FibrinogenFibrinogenFactor VIII*Factor VIII*von Willebrand Factor*von Willebrand Factor*

*Use of a commercial, viral inactivated clotting factor concentr*Use of a commercial, viral inactivated clotting factor concentrate ate may be preferablemay be preferable

Adverse Effects of Plasma TransfusionAdverse Effects of Plasma Transfusion

Allergic reactionAllergic reactionAnaphylaxisAnaphylaxisVolume overloadVolume overloadTransfusionTransfusion--related acute lung injury (TRALI)related acute lung injury (TRALI)Viral infections (HIV, HBV, HCV)Viral infections (HIV, HBV, HCV)OthersOthers