The Composition and Use of
Plasma Components
Ira A. Shulman, MD
University of Southern California
James P. AuBuchon, MD
Puget Sound Blood Center
Terry Gernsheimer, MD
University of Washington
for the
Clinical Transfusion Medicine Committee
AABB
Last Updated January 2010
Please note that this slide set includes
additional information in the “notes”
section for each slide.
Revised/updated January 2010 by
Nicole L. Draper, M.D.
Mary Berg, M.D.
University of Colorado
What is “FFP”?
WHOLE
BLOOD
Centrifuge
Platelet-Rich Plasma
(PRP)
1Unit
RBC
Centrifuge
1 Unit Platelets
Freeze
1 Unit (~250 mL)
Frozen Plasma
1 Unit
Plasma
Freeze, Thaw,
Centrifuge
1 Unit cryoprecipitate
+ 1 Unit plasma
(Cryoprecipitate-Reduced)
What About FFP Made from
Apheresis Collections?
Volume:
200 – 600 mL
Content:
Plasma
Anticoagulant
200 mL
250 mL
300 mL
500 mL
600 mL
PLASMA
=
Plasma Types
• Fresh Frozen Plasma (FFP): frozen within
8 hours of collection
• Plasma Frozen within 24 Hours (FP24):
frozen within 24 hours of collection
• Thawed Plasma (TP): derived from FFP or
FP24 and maintained for a maximum of 5
days after the day of thaw.
Handling Options for FFP
FFP
Stored frozen
colder
than -18°C
FFP,
Thawed
Thawed at
30-37ºC
Store at
1-6ºC
>24 h
Thawed
Plasma
(up to 5 d after thawing)
Coagulation Factor Activity of
Thawed Plasma
Day 1 Day 2 Day 3 Day 4 Day 5
% change
Day 1 to 5
p
Fibr
225
224
224
224
225
0
NS
II
81
81
81
80
80
1
NS
V
79
75
71
68
66
16
NS
VII
90
81
76
72
72
20
NS
VIII
107
76
66
65
65
41
<.02
X
85
84
84
82
80
6
NS
Tabular entries as % activity
NS = not statistically significant
Downes K et al. Transfusion 2001;41:570.
FFP vs FP24
Coagulation factor activity in FFP and FP24 at the time of thaw
and after 120 hours of 1 to 6°C storage
Analyte
Minimum activity
for hemostasis
FFP at 120hr
(mean ± 2SD)
FFP at 120hr
(mean ± 2SD)
FV
25%
67 ± 19
59 ± 22
FVIII
30%
43 ± 10
48 ± 12
PC
NE
107 ± 19
89 ± 17
NE = not established
PC = Protein C
Only results from group O products were used for statistical comparisons of factor VIII
Scott E, et al. Transfusion 2008;49:1584-91
The Challenge of Frozen Plasma Usage
A readily available source of
procoagulants
that can be life saving for patients
in need
of hemostatic assistance - But there is lack of consensus
around definition of the circumstances
when this component will truly benefit
a patient.
Clinical Indications for Plasma
• Bleeding or preoperative patients with deficiency of multiple
coagulation factors
• Massive transfusion with clinically significant coagulation
deficiencies
• Bleeding or urgent invasive procedure while on warfarin
therapy
• Bleeding or preoperative patients with specific factor
deficiency, no concentrate available
• Thrombotic thrombocytopenic purpura (TTP)
• Rare specific plasma protein deficiencies, e.g., C1-esterase
inhibitor, no recombinant product available
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM1
87348.pdf
Abnormalities in Coagulation Testing
do not necessarily indicate a
Clinical Coagulopathy
Procoagulant
Fibrinogen
Factor V
Factor VII
Factor VIII
Consumed in
Coagulation?
Yes
Yes
No
Yes
Concentration
Normal
Hemostatic
200-400 mg/dL 50-100 mg/dL
1 U/mL
5-25%
1 U/mL
5-25%
1 U/mL
15-25%
Normal concentration: 1 U/mL = 100% activity
Edmunds LH. Hemostasis and thrombosis: basic principles and clinical practice. 4th ed. 2001 p1031-43
Using Screening Tests to Predict Plasma Need
Mild elevations of PT or aPTT overestimate clinical benefit of
transfusing FFP for patients in most clinical situations.
Recommended transfusion trigger points
in appropriate situations:
1.3 x upper limit of reference range (in seconds)
- or –
1.5 x midpoint of reference range (in seconds)
NOT
INR=1.5
-McVay PA et al. AJCP 1990;94:737-53.
-McVay PA et al. Transfusion 1991;31:164-71.
-Counts RB et al. Ann Surg 1979; 190:91-9.
-Ciavarella D et al. Br J Haematol 1987;67:365-8.
-Auble T et al. Acad Emerg Med 2002;567-574
-Stanworth SJ, Hematology Am Soc Hematol Educ
Program 2007:179-86
Using Screening Tests to Predict Plasma Need
Patients with Generalized Bleeding
Patients experiencing massive transfusion after trauma
100%
75%
50%
25%
PT
<1.3 >1.3 >1.5
X upper limit of
Reference Range
PTT
<1.3 >1.3 >1.5
X upper limit of
Reference Range
Counts RB et al. Ann Surg 1979;190:91-9.
Using Screening Tests to Predict Plasma Need
Factor VIII
100
80
3.2
Factor X
60
2.8
40
PTT
Fibrinogen
2.4
PT
20
2.0
1.6
10
1.2
350
1050
1750
2450
3150
Plasma Removed (mL)
3850
PT or aPTT (ratio to control)
% Factor Concentration Remaining (log scale)
Effect of plasma dilution on procoagulants
4550
Orlin et al. Blood. 1980;56:1055-9.
Using Screening Tests to Predict Plasma Need
Patients undergoing percutaneous liver needle biopsy
Test
Group
n
Bleeding
Complications
Hb Change
(mg/dL)
PT
Normal
1.3 x ULN
100
43
4%
6%
- 0.3±0.9
- 0.2±0.8
PTT
Normal
1.3 x ULN
103
34
5%
3%
- 0.3±0.9
- 0.1±0.6
ULN = Upper limit of normal
(No pre-biopsy FFP prophylaxis given.)
Best predictor of bleeding was a finding of malignancy in the biopsy.
McVay PA et al. AJCP 1990;94:737-53.
Using Screening Tests to Predict Plasma Need
Liver Bleeding Time (min)
Patients undergoing laparoscopic liver needle biopsy
16
12
8
Mean
4
10
20
30
40
50
60
70
80
90
100
PT (% normal activity)
Note: 10% change in activity = approximately 1 sec
Bleeding >12 minutes: 4.3% PT >13.5 sec, 4.7% normal PT
Ewe K. Dig Dis Sci 1981;26:388-93.
Predicting Plasma Need
Effect of Coumadin therapy on perioperative blood loss
Gastrectomy Patient Group
RBC Loss (mL)
1000
Controls (n=20)
800
Coumadin (therapeutic; n=20)
600
RANGE
400
200
Operative
24 h
total
72 h
total
Rustad H et al. Acta Med Scand 1963;173:115-9.
Predicting Plasma Need
Effect of Coumadin therapy on post-operative blood loss
Group
Controls
Therapeutic coumadinization
n
26
26
Post-Op Blood Loss (mL)
813 (125-2125)
624 (210-1650)
Procedure: Mitral commissurotomy
Storm O et al. Circ 1955;12:981-5.
Indices Predictive of Microvascular Bleeding
Sensitivity
PT ratio
1.3
1.8
PTT ratio
1.3
1.8
Platelet count
< 50,000/mL
or
Fibrinogen
< 50 mg/dL
Specificity
Predictive Value
Positive
Negative
89%
44%
50%
96%
33%
80%
94%
84%
56%
56%
56%
96%
26%
83%
82%
87%
89%
93%
73%
96%
PT ratio = Patient’s PT (sec) / midpoint (sec) of PT reference range
PTT ratio = Patient’s PTT (sec) / midpoint (sec) of PTT reference range
Ciavarella D et al. Br J Haematol 1987;67:365-8.
An Analysis of the Literature
Normal vs. Abnormal Coagulation Tests
Risk Difference
Angiography
Angiography
Bronchoscopy
Liver biopsy
Liver biopsy
Liver laparoscopy
Liver laparoscopy
Transjugular liver biopsy
Transjugular liver biopsy
Transjugular liver biopsy
Para/thoracentesis
Transjugular kidney biopsy
Kidney biopsy
-0.25
Favors Transfusion
0
0.25
Favors NO Transfusion
Segal and Dzik. Transfusion 2005;45:1413-25.
Predicting Bleeding
By bleeding score and service
Score
Medical
Surgical
1/320 (0.3%)
Trauma
0
0/37
3-7
7/77 (9%)
2/194 (1%)
1/84 (1%)
10/355 (<3%)
>8
4/8 (50%)
0/4
1/11 (9%)
5/23 (22%)
Total
11/122 (9%)
2/137 (1.4%)
16/777 (2%)
3/518 (0.6%)
0/42
Total
1/299 (<1%)
• 3 points for each of the following:
PT 18-24 seconds, PTT 48-64 seconds, Platelet Count 20-49,000/microL, serum creatinine
> 1.4
• 4 points for each of the following:
PT >24 seconds, PTT >64 seconds, Platelet Count <20,000/microL
• Bleeding Prediction Score = sum of points
DeLoughery TG et al. Transfusion 1996;36:827-31
Intra-Op Assessment: The Thromboelastogram
Thromboelastography Profiles
Hypercoagulable
Fibrinolysis
Low platelets
Coagulopathy
Normal
Correcting Over-Coumadinization
Clinical Significance
INR >8 due to Coumadin  Major bleeding in 12/77 (13%)
Two fatalities (3%) without FFP or vitamin K treatment
Correction with FFP
REVERSAL ALMOST IMMEDIATE BUT NOT NECESSARILY LASTING
FFP transfusion  INR = 2.3 (1.6-3.8)
Correction with Vitamin K
REVERSAL IN 6-12h
Administration: oral, subcutaneous or IV (more rapid action)
Dose may be repeated, as necessary
Murphy PT et al. Clin Lab Haematol 1998;20:253-7
Makris M et al. Thromb Haemost 1997;77:477-80.
Br J Haematol 2001;114:271-80.
Correcting Over-Coumadinization
Recommendations of American College of Chest Physicians
Clinical
Situation
Guideline
Clinical
Situation
Guideline
Ansell J et al. Chest 2004;126(3Suppl):204S-233S.
Plasma Dosage
PLASMA
PLASMA
Rx: 2 units??
Determinants
• Patient size
•
•
•
•
•
Bleeding site
Factor activity: Initial, target
Factor concentration in plasma & recovery
Factor half-life in vivo
Unit volume
USUAL DOSE FOR CONTROL OF BLEEDING: 10-20 mL/kg
Procoagulant Recovery and Survival
Procoagulant Activity
50%
PLASMA VOLUME =
4400 mL
40%
Fibrinogen (t1/2=3+d)
30%
Factor X (t1/2=20h)
Factor VIII (t1/2=12h)
20%
Factor VII (t1/2=5h)
10%
PLASMA VOLUME =
3000 mL
0%
PRE
TRANSFUSION
0
Hours Post Transfusion
7
1 2 3
4 5 6
8
9
10
70 kg patient with 3000 mL plasma volume receiving FFP (20 mL/kg)
ASSUMPTIONS:
-Stable plasma volume after expansion
-85% procoagulant activity in plasma
-100% recovery
-Synthetic capacity to maintain pre-transfusion
procoagulant activity
Considerations in Massive Hemorrhage
• Surgical bleeding vs. coagulopathic bleeding?
• Adequacy of resuscitation?
• Extent of hypothermia and acidosis?
Hardy JF et al. Vox Sang 2005;89:123-7.
Effect of Body Temperature on Coagulation
60
PTT (seconds)
50
40
30
20
10
0
28
31
34
37
39
41
Body Temperature (º C)
Rohrer MJ, Natale AM. Crit Care Med 1992;20:1402-5.
Relative Rate of IIa Generation
Effect of Acid/Base Balance on Coagulant Activity
3
2.5
2
1.5
1
0.5
0
6.2
6.6
7
7.4
7.8
8.2
8.6
9
pH
Meng ZH et al. J Trauma 2003;55:886-91.
Cumulative Effects of Hypotension and Hypothermia
Clinical Status
Conditional Probability of
Developing Coagulopathy
No risk Factor
1%
Severe trauma*
+Systolic BP < 70mm Hg
+pH < 7.1
10%
39%
49%
Severe trauma* + Temp < 34ºC
+Systolic BP < 70mm Hg
+pH < 7.1
49%
85%
98%
*Injury severity score of >25
Cosgriff et al. J Trauma 1997;42:857-61.
Cryoprecipitated AHF
Handling of Plasma
Cryoprecipitate
Cryo-reduced
Plasma
FFP
Stored frozen
colder
than -18C
Thawed at
4ºC, then
centrifuged
Cryoprecipitate
Factor VIII (> 80 U)
vWF
Fibrinogen (~200 mg)
Cryo
-Derivatives
-TTP exchange
Indications for Cryoprecipitate
Clinically significant deficiency of
Fibrinogen
Factor VIII *
von Willebrand Factor *
Note: cryoprecipitate also contains significant
amounts of Factor XIII and Fibronectin
* Use of a commercial, viral inactivated clotting factor concentrate
may be preferable
Adverse Effects of Plasma Transfusion
• Allergic reaction
• Anaphylaxis
• Volume overload
• Transfusion-related acute lung injury (TRALI)
• Viral infections (HIV, HBV, HCV)
• Others
TRALI
• Leading cause of transfusion related death
reported to the FDA
• For FY2005 – FY2008, the FDA reported 48%
(55/114) of TRALI fatalities were attributed to
plasma transfusions
• American Red Cross 2003-2005
• 63% (24/38) of suspected TRALI fatalities involved
plasma
• 75% (18/24) related to female antibody-pos donors
• Many blood centers now collect mostly or only
plasma from male donors
Eder A, et al. Transfusion 2007;47:599-607
http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/TransfusionDonationFatalities/
ucm118316.htm
TRALI
• Male only plasma donors in UK beginning
Oct 2003
• Plasma accounted for 31/93 TRALI cases
1996-2003
• 36 TRALI cases analyzed in 2003, 23 cases in
each of 2004, 2005 and 10 in 2006
• 8 cases of antibody-proven TRALI attributed to
FFP in 2003, 6 cases in 2004, no cases in 2005
or 2006
Chapman et al. Transfusion. 2009 Mar;49(3):440-452.
TRALI
Outcomes of patients who did and did not receive
FFP
FFP
(n = 44)
Outcome
No FFP
(n = 71)
p value
New bleeding episodes
3 (6.8%)
2 (2.8%)
0.369
New onset acute lung
injury
8 (18.2%)
3 (4.2%)
0.021
Hospital mortality
11 (25.6%)
20 (28.2%)
0.763
Median ICU stay, days*
2.4
2
0.184
* In survivors
Dara, et al. Crit Care Med. 2005 ;33(11):2667-2671
Web Sites for Additional
Resources
• www.fda.gov/BiologicsBloodVaccines/
BloodBloodProducts/default.htm
• www.gpoaccess.gov/cfr/index.html