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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