Current Component Therapy by Diane Eklund, MD

Appropriate Component Therapy
Diane K. Eklund, M.D.
Transfusion Medicine Symposium
August 6, 2016

Disclosures
» I have no financial relationships
related to this presentation.
» I will not be speaking about any
specific commercial product,
device, or medication.
» I will not be speaking of any off
label use of medications or
devices

Goals and Objectives
• Discuss blood management and the associated decrease in
utilization of blood products
• Discuss the impact of new anticoagulant and antiplatelet drugs
on prevention and treatment of bleeding
• Discuss massive transfusion protocols and their impact on
reducing coagulopathic bleeding
Objectives:
• Demonstrate knowledge of appropriate blood component usage
• Identify the blood component for which transfusion does not
need to be ABO compatible
• List 2 transfusion alternatives for reducing the risk of
transfusion-transmitted CMV infection

2005 by TACTICS (Training And Competency for Trent Intra-operative Cell Salvage)
Essential test only
Multiple tests per sample
Nutritional and/or
Medical Support –
correct anemia prior
to surgery
Hemodilution;
Intraoperative
Salvage/Recovery
Improved surgical
devices or techniques
Volume
expanders

• Two early studies in
particular are
frequently quoted:
– TRICC trial
• Hebert, et al, NEJM,
1999
• Concluded that a
restrictive strategy of
red cell transfusion is
at least as effective as
and possibly superior
to a liberal transfusion
strategy in critically ill
patients, with the
possible exception of
patients with acute MI
and unstable angina

– CRIT study
• Corwin, et al,
Critical Care
Medicine, 2004
• Concluded the
increased
number of
transfused RBC
units is an
independent
predictor of
worse clinical
outcome

Conclusions
A liberal transfusion
strategy, as compared with
a restrictive strategy, did not
reduce rates of death or
inability to walk
independently on a 60-day
follow-up or reduce in-
hospital morbidity in elderly
patient at high
cardiovascular risk.

Transfusion Strategies for Acute Upper
Gastrointestinal Bleeding
Càndid Villanueva, M.D., et al.
NEJM, Volume 368(1):11-21
January 3, 2013
A randomized clinical trial shows that among patients with upper GI bleeding,
withholding transfusion until the hemoglobin level falls below 7 g per deciliter results in
better outcomes than using 9 g per deciliter as the trigger for transfusion

Outcomes Using Lower vs Higher Hemoglobin Thresholds for Red Blood Cell Transfusion
JAMA. 2013;309(1):83-84.
30-Day mortality was evaluated in 4975 patients included in 11 of 19 trials. Adapted from Analysis 3.2 in Carson JL, Carless PA,
Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion.
Figure Legend:

1. Bernard et al, JAmCollSurg 2009;208
2. Ferraris et al, Arch Surg. 2012;147(1)
3. Napolitano et al, CritCareMed 20099;37(12)
Why give 2,
when 1 will do?
Complications are dose dependent!

Peri-operative Management
• Optimize hemoglobin levels prior to surgery – anemia clinics
popping up
– Treat anemia with supplements or drugs if available
• Give Iron, folate, B12 as needed
• Use ESAs in treating anemia, where appropriate and
approved
– Limit autologous donations to ideal candidates
• The surgical procedure is known to require transfusions and
the use of autologous will likely prevent the need for
allogeneic blood
• Post-donation hemoglobin level is sufficiently high to prevent
jeopardy during surgery (don’t leave them anemic!)
• There is no medical contraindication to the donation process
or to the quality of blood
– Coordinate pre-op lab draws
• Order essential tests only
• Request multiple tests per sample
• Collect smaller volume samples
– Iatrogenic blood loss can be close to 100 mL a day!
– Maximize coagulation function
• Stop anti-platelet drugs if possible
• Reevaluate coagulation therapies (i.e. coumadin)

Peri-operative Management
Continued…
– Review use of herbal supplements
• Anise and Dong Quai potentiate the
effects of other anticoagulants
• Omega 3 fatty acids, garlic, ginger,
Ginkgo, Ginseng, and vitamin E
have anti-platelet properties
• Ginseng may inhibit the
coagulation cascade
• Fucus has heparin-like activity
• St. John’s Wort interferes with drug
metabolism including Warfarin
– Prescription or Poison? ; Dasgupta,
2010

Red Blood Cells
• The only proven use for RBCs is to improve oxygenation
• The number of units transfused should always be
determined by improvement in the symptoms of the patient
• Transfusion “triggers” are no longer useful in appropriate
RBC transfusion protocols – never transfuse because of a
number, always because of symptom(s) of inadequate
oxygenation or because of evidenced-based literature
– Consider the patient’s:
• Age
• Sex
• Rapidity of onset of anemia
• Physiologic adaptation to anemia
• Status of cardiopulmonary function
• History of ischemic co-morbidities
• Signs and symptoms such as pallor, syncope,
dyspnea, orthostatic hypotension, tachycardia,
tachypnea, angina, TIA or abnormal arterial
oxygenation

Red Blood Cells
• It is best to transfuse type-specific RBCs; however, blood
shortages will occasionally dictate the use of other compatible
RBCs
– Never hesitate to give Rh negative components to Rh
positive patients
– Always use O negative products judiciously
• Change to O positive in emergencies if the patient is
male or a female of non-childbearing age
• Even in young females, switch to O positive in massive
transfusion situations or give type specific
• Crossmatch is required except in an emergency
• “Type and Cross” vs. “Type and Screen”
– Always obtain an antibody screen prior to anticipation of
need for transfusion; this will significantly shorten the
overall time to receiving blood when the need for
crossmatch arises; it will also alert the physician to
potentially complex crossmatch problems and rare
antibodies
– Only crossmatch when there is a reasonable indication that
blood will likely be transfused; never tie-up inventory and
use technology time with an unnecessary type and cross

Red Blood Cells
• RBC antigen exposure, particularly in the frequently
transfused patient, can lead to antibody formation in some
patients, further leading to difficult future crossmatches
• Once a clinically significant antibody is formed, the
corresponding antigen must be avoided in all future RBC
transfusions, even if the strength of the antibody reaches
undetectable levels
• Antigen-matching beyond ABO for each transfusion is not
cost effective; the chronically transfused patient might
benefit from further defining the patient’s extended antigen
profile for crossmatching procedures
– Sickle cell patients should always receive blood negative
for Ee, Cc, and Kell antigens, even if they don’t make the
antibodies)
• Today, many clinicians are considering even more
extended matching
– If someone chronically transfused is known to be an
“antibody maker”, extended antigen matching should
also be considered

Red Blood Cells
• Special RBC products:
– Washed (rarely indicated)
• May be needed in patients with hypersensitivity to plasma
proteins and severe allergic responses to transfusion
• Absolutely required for patients with IgA deficiency and likely
presence of IgA antibodies
• May be needed for neonates, depending on additive solutions or
age of product
– Frozen, deglycerolized
• May be needed for patients with rare atypical antibodies or
hypersensitivity to plasma proteins
– Irradiated
• Required for prevention of transfusion associated Graft vs. Host
Disease in the immunocompromised patient
– CMV-negative products (applies to all blood components)
• Leukoreduction usually considered equivalent, and possibly
even safer than serologic testing for prevent of CMV
transmission
• Studies show that newly infected donors, testing CMV-negative
by serology (window period), are much more infectious to the
recipient than known CMV-positive donors where CMV resides in
the white blood cell and is removed by leukoreduction!
• Statistically, the false negative rate of CMV-negative by
serological methods probably equals the residual risk of
leukoreduction

Storage Effects Consequences
Decreased 2,3-diphosphoglycerate (2,3 DPG) Increased oxygen affinity and decreased oxygen
unloading by hemoglobin
ATP depletion Erythrocyte shape change
Increased osmotic fragility
Decreased deformability
Microvesiculation and loss of lipid membrane Decreased erythrocyte viability
Lipid peroxidation (degradation of lipids) Cellular injury and death
Bioactive substance generation: histamine,
cytokines, lipids
Febrile transfusion reactions
Neutrophil priming/endothelial activation
Cellular injury
TRALI
Multiple organ failure (?)
Immune modulation(?)
S-nitrosohemoglobin deficiency Impaired vasodilatory response to hypoxia
Fresh RBCs for Adults?
The Red Blood Cell “Storage Lesion”

Fresh Red Blood Cells?
• > 25 major studies addressing fresh vs. non-fresh, showing mixed
results
– Primarily observational studies
– Some show favor for fresh RBCs
– Some show no advantage at all
– Papers describe the definition of fresh differently
• Published 2012 [the Age of Red Blood Cells in Premature Infants (ARIPI)
trial], found no difference in outcomes among pediatric patients when
comparing older with fresher blood
• Similar results with the TOTAL trial (ASH, 2015)
• Published 2014 [REDS-III RECESS trial(Recipient Epidemiology and
Donor Evaluation Study)]
– Conclusion: The trial had good compliance with the randomized
storage age assignment with a minimal amount of overlap. RBC
storage duration was not significantly associated with 7-day change
in multiple organ disfunction syndrome (MODS), serious adverse
events, or 28-day mortality
• ABLE (age of blood evaluation) 2015
– Transfusion of fresh red cells, as compared with standard-issue red
cells, did not decrease the 90-day mortality among critically ill adults

Red Blood Cells
• Major indications include:
– Significant acute bleeding with symptoms of
hypovolemia that no longer respond to crystalloid
or colloid infusions
– Symptomatic chronic anemia where other
therapies such as iron, folate, and B12 will unlikely
correct the anemia
– Anemia with a hemoglobin of <7.0 gm/dL and
impending surgery with expected blood loss
– Sickle cell disease patients needing anesthesia, or
exchange transfusion (“trigger” for H/H may apply)
• One unit of RBCs, in the ideal adult patient (70Kg, not
currently bleeding or hemolyzing) will raise the
hemoglobin by 1 gm/dL or hematocrit by 3
percentage points

Components to Stop the Bleeding!

Crystal Therapy
Bloodstone, carnelian, sapphire,
lodestone (magnetite), ruby, red jasper,
or clear quartz may be used to stop
and help prevent bleeding
Tannins have an astringent effect
electro-negatively charged surface
activates clotting process

Historic Introduction of Plasma
• Plasma was the first blood product,
born ~75 years ago
– Produced for WW II
– Dubbed the “Plasma War”
• Should it be a liquid or a dried powder?
– The American National Red Cross
collected more than 13 million units of
blood between 1942 and 1945; more than
12 million were converted into plasma,
with the red blood cells being discarded

Historic Introduction of Plasma
• Liquid vs. Dried Powder
– John Elliott chose liquid and is
famous also for developing the
vacuum bulb-tube which
became the TransfusoVac bottle,
replacing the open beaker and
the milk bottle in transfusion
practice
– Max Strumia chose dried plasma
secondarily to his work using
plasma as an antimicrobial agent
– Dried was appealing for the war
but lost favor with the realization
that hepatitis transmission was
a major problem
• (This would have been a
problem for both liquid and
dried, but at the time was
attributed to dried)

Clinical Indications for Plasma Products?
• U.S. use of plasma is disproportionately
high compared to other countries with
similar levels of health care
– U.S. use of plasma has doubled since 1979
• Few if any quality studies as to the safety
and effectiveness of plasma; little evidence
for prophylactic use of plasma; no
evidence to justify a certain dose
• 1/3 of all requests for plasma made to
correct an elevated INR prior to a
procedure

Transfusion Rates of FFP
Country # FFP units / 1000 population
France (1996) 4.0
Denmark (2001) 5.16
Australia (2001) 5.33
New Zealand (2003) 5.5
UK (2001) 6.5
Finland (2004) 8.6
Norway (2003) 8.7 (7.0)
Canada (2005) 8.9
US (2011) 12.0
• In the U.S., 5,700,000 units of plasma were produced
for transfusion in 2009, a 0.3% increase from 2006
and a 23% increase from 2005 – WHY?
• Use is now decreasing due to blood management
initiatives and evidenced-based studies
• Similarly, usage is going down in other countries
• We still use the most overall!
May 1960
Wallis, Transfusion 2004
Palo, Transfusion 2006
Cobain, Transfusion Medicine 2007
Devine, Transfusion 2007
National Blood Collection and Utilization
Report 2011

Each solid circle
represents a unique
hospital, with the
observed transfusion rate
percentages for that
hospital (red blood cells,
fresh-frozen plasma, and
platelets) plotted against
the hospital's 2008 volume
of isolated primary CABG
operations. The solid line
indicates the overall mean
transfusion rate across all
hospitals. The dashed
lines indicate the upper
and lower 99.9%
prediction limits based on
the binomial distribution.
Bennett-Guerrero, E. et al. 2010;304:1568-1575
Variation in Use of Blood Transfusion in Coronary Artery Bypass Graft Surgery
Figure 1. Observed Variation in Hospital-Specific Transfusion Rates for Primary Isolated CABG Surgery With
Cardiopulmonary Bypass During 2008 (N = 798 Sites)

INR Thresholds for Prophylactic and
Therapeutic Use of FFP
• Transfusion, Nov., 2004, 44(11); 1674-5
– 30% of requests for FFP outside the operating room were for
attempted correction of the INR
• Assumptions (none validated, nor with good clinical
evidence)
– Elevated INR identifies patients at increased risk of bleeding
– Pre-procedure plasma will “correct” the abnormality
– Risk-benefit or cost-benefit ratios of plasma given before the
procedure is higher than if given after the procedure to
individuals who actually bleed
• Several reviews have underscored that the pre-procedure
INR does not predict the risk of bleeding at the time of
invasive bedside procedures and that 1-4 units of plasma
fails to correct mild to moderate prolongation of the INR in
nearly all cases
– American Journal of Clinical Pathology, July 2006: only 50%
of patients with an INR of 1.7 showed a significant change in
INR with plasma transfusion
• Yet, ~30% of plasma transfusions were given to correct INR
of 1.5

The INR
• INR (international normalized ratio) was developed
to standardize the prothrombin time across
laboratories
• INR was developed specifically for patients on
warfarin
• INR is a unitless ratio
• INR value accounts for the PT of the patient, the
lab’s reference range and the sensitivity of the
reagents used
• There is NO literature evidence that the INR predicts
bleeding

The INR
• INR has been the traditional measure of anticoagulation
reversal
• INR has a non-linear relationship to the level of coagulation
factors in the blood
• INR test is widely misinterpreted:
• INR value is “abnormal” even among patients with levels of
clotting factors that are perfectly adequate for hemostasis
• Physicians who claim that a patient has a “coagulopathy”
as evidenced by an INR of 1.6 are misinformed
• Would be similar to claiming that a platelet count of
140,000 represents clinically important
thrombocytopenia
• FFP has little effect on mildly prolonged INR values
• Very large increases in factor levels, requiring large
volumes of FFP are required if one (incorrectly) wishes to
achieve “normal” INR results

Does an elevated INR need to be
corrected prior to surgery?
• The relationship between clotting factors and PT is exponential
• Abnormal test results can occur in people with adequate coag factor concentrations
% Coagulation Factors INR and Coagulation Reserve
100%
50%
30%
PT (sec) 12 13 14 15 16 17 18 19 20 21 22
INR 1.0 1.3 1.7 2.0 2.2 3.0
Zone of Normal Hemostasis
(physiologic reserve)
Zone of
Therapeutic
Anticoagulation
zone of adequate factor levels zone of anticoagulation
1 - 2 FFP
1 - 2 FFP

Diminishing Returns With a Low INR
2 4 6 8 10 12 14
Number of FFP units
Adapted from Holland and Brooks, AJCP 2006
INR
3
2.6
2.4
2.0
1.8
1.6
1.4
1.2
1.0

INR of the Products on the Shelf
(from normal donors)
0.9 1.0 1.1 1.2 1.3
INR
Holland, Transfusion 2005
% of
units
70
60
50
40
30
20
10
0

Paucity of studies to support that abnormal
coagulation test results predict bleeding in the setting
of invasive procedures: an evidence-based review
Segal and Dzik, Transfusion, 9/2005
• Review of 25 studies (with mixed quality of
evidence)
• In summary, a systematic review of the
published literature provides little evidence
that pre-procedure elevation of the INR or PT
predicts an increase in bleeding at the time
of an invasive diagnostic procedure

Paucity of studies to support that abnormal coag test results predict
bleeding in the setting of invasive procedures: evidence-based review
Segal and Dzik, Transfusion, 9/2005
• Review of 25 studies (with mixed quality of evidence)
• In summary, a systematic review of the published literature provides little
evidence that pre-procedure elevation of the INR or PT predicts an increase
in bleeding at the time of an invasive diagnostic procedure
Fig. 1 Mostly negligible risk differences (and 95% CIs) between patients with abnormal and normal coagulation test results

Little evidence that plasma is needed
for any of these common procedures:
• Central venous catheters
• Liver biopsies
• Thoracentesis and paracentesis
• Bronchoscopy and transbronchial biopsy
• Renal biopsy

Evidence against prophylactic use of FFP
• NNNI (Northern Neonatal Nursing Initiative Trial; Tin, et al.,
Lancet, 1996):
– Randomized 776 neonates and compared FP with volume
expanders in the prevention of intraventricular hemorrhage – no
significant difference in outcomes in 2 groups
• Leese, et al., Ann Royal College Surg Engl, 1991):
– 275 patients with acute pancreatitis, randomized to either FP or
colloid solution – no evidence of benefit for plasma
• Peterson, Anesthesiology, 1991:
– Consecutive central lines prior to cardiac surgery with no
increase in hemorrhagic complications in heparin-anticoagulated
patients
• Ewe K, Dig Dis Sci, 1981:
– Bleeding times after laparoscopic liver biopsy showed no
correlation between bleeding time and coagulation variables; even
patients with INR > 3 and platelets <50K did not bleed more than
patients with better test results

“Can We Predict Bleeding?
• Review article, Seminars in Thrombosis
and Hemostasis, Feb 2008, Authors
Watson and Greaves
• A “Structured Bleeding History” is likely
a more powerful tool for prediction of
bleeding than any of the current available
laboratory approaches

Bleeding History
For each of the following findings, add the indicated number of points:
Epistaxis: infrequent, brief, self-limited episodes 1
Easy bruising with trauma 1
Prolonged bleeding after brushing teeth 1
Dental extraction: prolonged bleeding (> 1 hour) 2
Hemoptysis, Hematemesis 2
Melena 2
Ob/Gyn bleeding (menorrhagia, post-partum) 2
Post-operative bleeding (> 1 hour or delayed) 3
Intracranial hemorrhage 3
Umbilical hemorrhage 4
Positive family history 4
Excessive bleeding following injury to mouth or loss of deciduous teeth 5
Prolonged bleeding (> 1 hour) from minor injuries 5
Epistaxis: frequent, prolonged, or requiring treatment 5
Hematuria 5
Hemarthrosis in absence of major trauma 8
Telangiectasia 8
Petechiae 8

Bleeding History
Likelihood for a coagulopathy:
>10 Highly suspicious
5 – 9 Suspicious
< 5 Not suspicious
Each of the above conditions should have no surgical or
anatomic lesion to account for the bleeding

Is fresh-frozen plasma clinically effective?
An update of a systematic review of randomized controlled trials
Lucy Yang, Simon Stanworth, Sally Hopewell, Carolyn Doree and Mike Murphy
Transfusion, 2012

Background
• Use of plasma continues to increase for both
prophylactic and therapeutic settings
• In 2004, a paper of similar title was published in the
British Journal of Haematology (authors Stanworth,
et al.)
– British Committee for Standards in Haematology reviewed
57 trials in the literature
– Found that there was little evidence for the effectiveness
of prophylactic use of FFP
– Most studies were small and did not provide adequate
information on the ability of the trial to detect meaningful
differences in outcomes between 2 patient groups
– No study examined assessed whether or not adverse
effects might negate clinical benefits of treatment with
FFP
• This paper is an update of the paper from 2004 and
includes an examination of all new randomized
controlled trials (RCTs) since the prior publication

Additional Background Information
• Recurring theme for transfusion of plasma is
that there is a variation in practice and
uncertainty around the evidence-based
indications for appropriate use
• In the U.S., 5,700,000 units of plasma were
produced for transfusion in 2009, a 0.3%
increase from 2006 and a 23% increase from
2005
• Two reasons given for transfusion:
– Prevent bleeding
– Stop bleeding

Is fresh frozen plasma clinically effective? An update of a systematic review of
randomized controlled trials
Transfusion, 2012 Lucy Yang, et al.

Results
• 21 additional publications of RCTs were eligible
for inclusion in this updated review
• 8 ongoing trials and 4 recently completed trials
awaiting publication were also eligible for
inclusion
• Many trials suffered from methodological
limitations (didn’t fulfill all criteria of study
quality)

Results
• Liver disease
– When combining the results with the 2004 review, a total of 10 trials
enrolling 381 patients, there were no significant benefits across a range of
clinical indications and outcomes
• Cardiac Surgery
– When combined with the results of the 2004 review, 19 trials
enrolling 948 patients in total showed no consistent clinical benefit
of plasma
• Warfarin reversal
– Results indicated more rapid INR correction with coagulation factor
concentrates (prothrombin complex concentrates or PCCs)
compared to plasma and with plasma compared to vitamin K, but
uncertainty regarding the effects on reducing mortality
– When adding to the results of the 2004 review, a total of 5 trials with
227 study participants showed similar results as above

Discussion
• Using data from both the 2004 and the 2012
publication, 80 RCT studies have been
completed and published in the past 50 years
• Of the new studies, 8 evaluated prophylactic
use and 13 evaluated therapeutic use in
patients with bleeding and active disease
• Overall, there was little evidence of any
consistent benefit from using plasma infusion
in either group

INR Action/Recommendation
Greater than therapeutic,
but < 5 and no significant
bleeding
Lower the warfarin dose, or omit a dose and resume
therapy at a lower dose when INR is therapeutic
5 – 9 with no significant
bleeding
Omit 1 or 2 warfarin doses and resume therapy at a lower
dose when INR is therapeutic or omit a dose and give
vitamin K (1-2.5 mg p.o.) if patient is at risk of bleeding
5 – 9 and rapid reversal
required for surgery
Give vitamin K (≤ 5 mg p.o.) with the expectation that INR
will be reduced in 24 hours
> 9 and no significant
bleeding
Omit warfarin and administer vitamin K (2.5-5 mg p.o.) and
monitor INR more frequently, repeating vitamin K dose if
needed
> 9 and serious bleeding Hold Warfarin. Give Vitamin K (10 mg IV) and plasma
infusion or rVIIa
Life-threatening bleeding Hold Warfarin. rFVIIa or plasma infusion supplemented
with vitamin K (10 mg IV)
Guidelines for Administration of Vitamin K –
American College of Chest Physicians

• Correction of excessive microvascular bleeding with known
coagulopathy or when coagulation test results are delayed
• Multiple coagulation factor deficiencies associated with severe
bleeding and/or DIC
– Plasma is not indicated in DIC with no evidence of bleeding; there
is no evidence that prophylactic replacement regimens prevent DIC
or reduce transfusion requirements
• Urgent reversal of Warfarin
– PCC might be more appropriate
• contains factors II, VII, IX and X, protein C and protein S
• Plasmapheresis for TTP/HUS to replace enzyme
• Single coagulation factor deficiencies for which no virus-safe
fractionated product is available
• Currently applies mainly to factor V and antithrombin
deficiencies
• Massive transfusion
Appropriate Clinical Indications for
Plasma Products

• Do not use for prophylactic treatment of mild elevations of
PT (INR <2.0) or aPTT
• Do not use for non-urgent reversal of warfarin
• Do not use for reversal of heparin effect
• Do not use for hypovolemia or augmentation of albumin
concentration
• Do not use for promotion of wound healing or general
well-being
• Do not use for treatment of immunodeficiency states
• Do not use for therapeutic apheresis (except for TTP/HUS
or long term daily procedures)
• Do not use where specific therapy is available (FVIII,
vitamin K)
Plasma Product Contraindications

What happens when…
• Hemoglobin is 11 g/dL (>12.5 g/dL)
– We don’t transfuse RBCs (risk > benefit)
• Platelet count is 105,000 (>150,000)
– We don’t transfuse platelets (risk > benefit)
• Creatinine is 2.1 mg/dL (<1.2 mg/dL)
– We don’t start dialysis
• Why then transfuse FFP for a PT (INR) that is
mildly elevated????

Plasma Products
• Fresh Frozen Plasma (FFP) – Plasma placed in a <
-18oC freezer within 8 hours; expiration date 1
year; volume 200-250 mL or 400-500 mL (jumbo)
• “normal” levels of coagulation factors
• OK to use for 24 hours after thawing
• Frozen Plasma (FP) –As above, but frozen within
24 hours; contains coagulation factors in
concentrations similar to that of FFP with variably
reduced amounts of Factor VIII and Factor V
• Thawed Plasma – FFP or FP that has been thawed
and stored between 1-6o C; expires 5 days after
start of thaw
• Adequate for virtually all hemostasis, unless used to
replace labile factors (i.e. FVIII); even FVIII is at a
hemostatic level of 30-35% (clotting adequate at 25-30%)
as is FV (clotting adequate at 15-25%)

Plasma Products Continued
• Cryoprecipitate Reduced Plasma - Deficient in Von
Willebrand factor, Factor VIII, Factor XIII, fibrinogen
and fibronectin; thought by some to have value in
treatment of TTP (but now that we know more about
ADAMTS13 deficiency, probably not)
• Liquid Plasma – separated and infused no later than
5 days after the expiration date of whole blood
stored at 1-6o C; source of plasma proteins; variable
coagulation activity; can be used for 26 days

Coagulation factor Day 1 Day 2 Day 3 Day 4 Day 5 Mean Change from
Day 1 to Day 5 (%)
P values
FVIII (%), Blood group A 107
+/- 26
76
+/- 19
66
+/- 18
65
+/- 17
63
+/- 16
41 <0.004*
FVIII (%), Blood group B 103
+/- 44
74
+/- 37
71
+/- 35
67
+/- 36
67
+/- 33
35 <0.02*
FVIII (%), Blood group O 70
+/- 16
51
+/- 10
43
+/- 10
43
+/- 7
41
+/- 8
41 <0.001*
Factor II (%) 81
+/- 9
81
+/- 9
81
+/- 9
80
+/- 10
80
+/- 10
1 NS
Factor V (%) 79
+/- 7
75
+/- 8
71
+/- 9
68
+/- 9
66
+/- 9
16 NS
Factor VII (%) 90
+/- 18
81
+/- 15
76
+/- 15
72
+/- 14
72
+/- 15
20 NS
Factor X (%) 85
+/- 13
84
+/- 13
84
+/- 15
82
+/- 11
80
+/- 11
6 NS
Fibrinogen 225
+/- 12
224
+/- 13
224
+/- 13
224
+/- 17
225
+/- 12
0 NS
*Comparison of FVIII activity at Day 1 and that at Day 3 was statistically significant.
Downes, Katharine A., Wilson, Erica, Yomtovian, Roslyn & Sarode, Ravindra
Serial measurement of clotting factors in thawed plasma stored for 5 days.
Transfusion 41 (4), 570-570, 2001
TABLE 1. Mean coagulation factor levels at 24-hour intervals by blood group

Plasma Products Continued
• Dose to replace factors, 10-20 mL/kg (3-6 units
for an adult)
• Compatibility testing not required, but ABO
compatible plasma must be used

Plasma Dosing
Is there an optimal dose?
• National guidelines generally specify a dose of around
10 to 20 mL/kg
• A study in Transfusion, 2006, Abdel-Wahab, et al.,
prospectively evaluated the effects of FFP on PT/INR
in hospital patients with a pretransfusion PT between
13.1 seconds and 17 seconds (INR equivalent, 1.1-
1.85)
• 324 plasma units evaluated in 121 patients
• <1% of patients had normalization of PT/INR after
transfusion and only 15% demonstrated a correction
of half way to normal

Plasma Dosing
• If, and only if, someone requires plasma transfusions, what
is the correct dose?
• “Efficacy of standard dose and 30 ml/kg fresh frozen plasma
in correcting laboratory parameters of haemostasis in
critically ill patients” British J of Haem, 4/2004
– Group 1 (10 patients) received 12.2 ml/kg and group 2 (12
patients) 33.5 ml/kg FFP
– PT, aPTT and factors I–XII were measured before and
after FFP infusion
– This study assessed the effect of FFP on laboratory
coagulation parameters in patients on the ICU and
compared the effect of different doses of FFP.
• The results suggested that in many patients FFP was
not indicated (based on coagulation factor levels)
• Coagulation screening tests were poor predictors of
significantly low coagulation factor levels
• A standard regimen of 1 L or about 12·5 mL/kg of FFP
lead to relatively small and, in most patients,
inadequate increments in coagulation factor levels
• 30 ml/kg of FFP adequately corrected all individual
coagulation factors

Another Historic Milestone for Plasma
• More than 45 years ago plasma
was frozen immediately after
collection, thawed rapidly and
sent to the bedside with ice
crystals still present, in order to
preserve Factor VIII
• Clinicians would infuse quickly
and any remaining ice crystals
would be discarded with the
“sludge” that formed in the
crystals
• Responding to complaints about
the efficacy of the products,
Judith Pool, an American
scientist, studied the sludge, and
discovered cryoprecipitate
• Today we have a finely tuned
method to collect and freeze this
“sludge”

Cryoprecipitate
• Cryoprecipitate (~15 mL) contains:
– factor VIII (80 to 100 U)
– von Willebrand factor
– fibrinogen [150 to 300 mg (4.4-8.8 µmol/L)]
• FFP has 500mg
– fibronectin (20%-25% total protein)
– factor XIII (40 to 60 U)
– IgG (5%-8% total protein)
– IgM (1%-2% total protein)
– albumin (5%-8% total protein)
– platelet microparticles
• Cryoprecipitate is a poor source of vitamin K-dependent
factors and, therefore, should not be used in this setting
• To infuse: thaw at 30-37C; use single within 6 hours and pooled
within 4 hours
• No crossmatch/compatibility required - any blood group is safe to
use

Cryoprecipitate Dosing
• 1 bag contains ~400 mg fibrinogen
• 4 or 5 bags (1 pool) contains ~2000 mg fibrinogen
• Recovery with transfusion = 75%
• 5 bags (1 pool) cryoprecipitate provides ~1500mg
fibrinogen to the patient
Therefore:
• In a 70 kg patient, with a plasma volume of ~3.5 L, 1
pool will raise fibrinogen by ~40-45 mg/dL
pool will raise fibrinogen by ~30-35 mg/dL
pool will raise fibrinogen by ~60 mg/dL
• Fibrinogen replacement: Effect should be monitored by
fibrinogen level assay and clinical response
Again, keep in mind that 1 unit of plasma has ~500 mg of
fibrinogen

Cryoprecipitate: The Current State of Knowledge
Callum, et al., Transfusion Medicine Reviews 2009
• Review article
– “The role of this complex product in the management
of hemostasis has not been well studied (excluding
patients with factor VIII deficiency)”
– “There are insufficient data to determine the clinical
setting where this product might be clinically
efficacious despite its widespread use in multiple
different clinical scenarios.”
– “There are insufficient data in the literature to
determine the efficacy, safety, and dosage in the
patient population.”
– “Despite 45 years of the use of this product, we still
have a lot to learn regarding the optimal use of
cryoprecipitate.”

Appropriate Use of Cryoprecipitate
• There is evidence that the use of cryoprecipitate is rising in
many countries, although the exact reasons remain unclear
– A specific purified fibrinogen concentrate is available, and it
may represent a safer concentrate for direct fibrinogen
replacement in isolated deficiencies, such as inherited
hypofibrinogenemia (although transfusable fibrinogen
concentrates are not widely available in the U.S.)
• The value of cryoprecipitate to correct surgical bleeding in the
absence of a specific factor VIII, vWF, or fibrinogen deficiency
is unclear
• The American Society of Anesthesiologists task force on blood
component therapy recommends the perioperative
administration of cryoprecipitate in only 3 circumstances:
– prophylaxis in nonbleeding perioperative or peripartum
patients with congenital fibrinogen deficiencies or vWD
unresponsive to DDAVP
– for bleeding patients with vWD
– for the correction of microvascular bleeding in massively
transfused patients (not routine patients) with fibrinogen
concentrations less than 80 to 100 mg/dL (0.80-1.00 g/L) or
when fibrinogen concentrations cannot be measured in a
timely manner

Appropriate Use of Cryoprecipitate (Cryo)
• Frozen plasma will correct low fibrinogen if the volumes for infusion
are tolerable
• Cryo should not be considered for transfusion solely as a more
concentrated form of FP (for example, where there are concerns
about fluid overload), as it only contains significant levels of FVIII,
VWF, fibronectin, FXIII and fibrinogen
– Cryo is not a source of all coagulation factors and therefore is not
appropriate replacement therapy in patients with global
coagulation factor deficiencies, for example, with liver disease
• Cryo use should be reserved for patients with documented isolated
hypofibrinogenemia - few prospective trial data to define the optimal
use of cryo
• Appropriate indications:
– Hypofibrinogenemia, massive transfusion, TPA-associated
bleeding, as a tissue sealant (fibrinogen)
– Uremic bleeding and von Willebrand Disease (factors VIII and
vWF)
• Inappropriate indications:
– Warfarin reversal
– Surgical hemostasis
– Hepatic coagulopathy

Prothrombin Complex Concentrates

What are PCCs?
• Prothrombin complex concentrates (PCCs) are pooled,
virus-inactivated human plasma products that
conveniently and rapidly provide coagulation factors
• The majority of PCCs contain the vitamin K-dependent
coagulation factors (II [prothrombin], VII, IX and X), as
well as therapeutically effective concentrations of
thromboinhibitors (protein C and S).
• PCCs are most commonly indicated and used in vitamin
K antagonist reversal (oral anticoagulant reversal)
• In Europe they are also indicated for treatment and
perioperative prophylaxis of bleeds in acquired
deficiency of the prothrombin complex coagulation
factors (II, VII, IX and X)

• American College of Chest Physicians guidelines suggest
four-factor prothrombin complex concentrates as the first
choice for warfarin reversal in the setting of major bleeding
• Four-factor PCCs contain (relatively new to the U.S.):
• Six vitamin K-dependent factors:
• Factors II, VII, IX, X, proteins C and S
• Three-factor PCCs (available in the U.S.) contain:
• Three therapeutically useful factors:
• Factors II, IX, X
• Given that Factor VII is the most severely depleted in
warfarin-treated patients, these are not effective in
correcting the hemostatic defect!
When clinicians in the U.S. request three-factor PCCs
to correct warfarin effects, educate them as to the
inadequacy of this approach!

Four-factor PCCs
(currently approved in US – KCentra)
FFP
Smaller volume /
Higher concentration of factors
Potential of volume overload
More rapid delivery More time to infuse
May be thrombogenic
Expensive 1/10 the price of PCCs
No strong clinical evidence that PCCs are better than FFP; studies using
corrected INR as an endpoint are misinformed about INR as a surrogate for
clinical effectiveness

Four-factor prothrombin complex concentrate versus
plasma for rapid vitamin K antagonist reversal in patients
needing urgent surgical or invasive interventions: a phase
3b, open-label, non-inferiority, randomised trial
Joshua N Goldstein, DrMD, Majed A Refaai, MD, Truman J Milling, MD, Brandon Lewis, DO, Robert Goldberg-Alberts, MA, Bruce
A Hug, MD, Ravi Sarode, ProfMD
The Lancet
DOI: 10.1016/S0140-6736(14)61685-8
Copyright © 2015 Elsevier Ltd

Figure 1
The Lancet DOI: (10.1016/S0140-6736(14)61685-8)

Figure 2
The Lancet DOI: (10.1016/S0140-6736(14)61685-8)

Interpretation
•For the endpoint of rapid INR reduction, the results
demonstrate that 4F-PCC is non-inferior and superior to
plasma for rapid INR reduction in patients on VKA therapy
•Furthermore, 4F-PCC could be given more rapidly than
plasma
•We noted that 4F-PCC was superior to plasma for
haemostatic efficacy
•We did not detect any between-treatment differences for
the occurrence of thromboembolic events or deaths, a
finding in agreement with the existing scientific literature
•Additionally, although these data guide clinicians on how
best to achieve urgent VKA reversal, the scientific literature
concerning which patients should be urgently reversed
before surgical or invasive interventions continues to
evolve

The ASH Choosing Wisely® campaign: five hematologic
tests and treatments to question
Lisa K Hicks, Harriet Bering, Kenneth R Carson, Judith Kleinerman, Vishal Kukreti, Alice Ma, Brigitta U Mueller, Sarah H O’Brien, Marcelo
Pasquini, Ravindra Sarode,Lawrence Solberg Jr, Adam E Haynes, Mark A Crowther
1. In situations where transfusion of RBCs is necessary, transfuse the
minimum number of units required to relieve symptoms of anemia or to
return the patient to a safe hemoglobin range (7-8 g/dL in stable,
noncardiac in-patients)
2. Do not test for thrombophilia in adult patients with venous
thromboembolism occurring in the setting of major transient risk factors
(surgery, trauma, or prolonged immobility)
3. Do not use inferior vena cava filters routinely in patients with acute
venous thromboembolism
4. Do not administer plasma or prothrombin complex concentrates for
nonemergent reversal of vitamin K antagonists (ie, outside of the setting of
major bleeding, intracranial hemorrhage, or anticipated emergent surgery)
5. Limit surveillance CT scans in asymptomatic patients after curative-intent
treatment for aggressive lymphoma

Platelets
• In the 70 kg adult (not septic, bleeding, etc.), one dose of
platelets should raise the platelet count approximately 30-
40,000/uL
– Rarely happens because the majority of platelet usage is in
patients with complicating factors (counts may rise less than
20,000/uL)
• No crossmatch required; apheresis products are not significantly
RBC-contaminated
– Crossmatch required for RBC antigens if product
contaminated with RBCs
• ABO-matched platelets have a slightly longer in vivo survival rate
– But, supply rarely allows for the ability to match blood types
• A dose is considered to be one apheresis platelet or 4-6 whole
blood-derived (aka random-donor) platelets
• Alloimmunization occurs when a patient makes antibodies to
donor HLA antigens or to donor platelet specific antigens
– Once alloimmunized, platelets lacking the offending antigens
must be used for transfusion. Finding such platelets may be
difficult or impossible and transfusion of “unmatched”
platelets may result in little to no post-transfusion increment
• Platelet crossmatching
• HLA matched products

Dose of Prophylactic Platelet Transfusions and
Prevention of Hemorrhage
Slichter, et al., NEJM 2010
• Randomly assigned hospitalized cancer patients to
a low dose, medium dose or high dose regimen
(1.1x1011, 2.2x1011, or 4.4x1011 platelets per square
meter of body surface area) when morning platelet
counts were 10,000 or lower
• Patients assessed for clinical signs of bleeding
daily
• Concluded that low doses of platelets administered
as a prophylactic transfusion led to a decreased
overall number of platelets transfused per patient
but an increased number of transfusions given
• Dose of platelets had no effect on the incidence of
bleeding

Platelets
• Causes of low post-transfusion platelet counts include:
• Sepsis
• Ongoing oozing
• Disseminated intravascular coagulopathy (DIC)
• Splenomegaly
• Hepatomegaly
• Drugs
• A corrected count increment (CCI) can help to determine if
someone is alloimmunized or truly refractory to platelets:
absolute platelet increment/uL X BSA (m2)
____________________________________________________________________________
number of platelets transfused (1011)

Platelets
• CCI example:
– Starting platelet count is 10,000/uL
– One hour post-transfusion count is 50,000/uL
– Number of platelets in the bag is ~3-4 X 1011
– So…..
(50,000-10,000) X 2
3 (X 1011, not used to calculate)
• CCI > 10,000 indicates no refractoriness
• CCI < 5,000 indicates likely refractoriness

Platelets
•Causes of low post-transfusion platelet
counts include:
•Sepsis
•Ongoing oozing
•Disseminated intravascular coagulopathy (DIC)
•Splenomegaly
•Hepatomegaly
•Drugs

Platelets
•When to transfuse:
–Platelet count less than 5,000 –
10,000/uL
–Platelet count less than 50,000 if major
surgery is anticipated or if life-
threatening bleeding is occurring
–Documented or anticipated platelet
dysfunction, regardless of the platelet
count
–Excessive bleeding regardless of
platelet count
–In patients on cardiopulmonary bypass
or on ECMO

Anticoagulants and Antiplatelet Agents

Clotting factors affected by vitamin K:
II,VII, IX, X, C, S
Warfarin (Coumadin)

Reversing Warfarin
• Vitamin K: effective, inexpensive, misunderstood
• K used for “Koagulation”
• Vitamin K effectively reverses INR when given IV or orally
• Vitamin K anaphylactoid reactions are very rare
• Plasma
• Used for “emergency” reversal of warfarin
• Very loosely defined, usually not an emergency but
rather a physician wishing to perform an invasive
procedure
• Probably justified for intracranial bleeding
• When plasma is used to reverse warfarin for serious
bleeding, vitamin K must also be given
• Factor VII in FFP has a short half-life and Factor IX
has a large volume of distribution
• If vitamin K is not given, FVII and FIX will decline

Recombinant Factor VIIa and PCCs
• rFVIIa not recommended as a solo agent to reverse
warfarin
• One would not expect a single-factor agent to
restore a hemostatic defect resulting from depletion
of four vitamin K dependent procoagulant factors
• FEIBA contains Factors II and IX, and X, non-activated,
and activated Factor VII
• Activated factors can cause unwanted thrombosis
• Contraindicated for all but those hemophiliacs who
make inhibitors to factor replacements
• K-centra contains non-activated II, VII, IX, X, and anti-
thrombotic proteins C and S
• Can also cause unwanted thrombosis

Reversal of drug-induced anticoagulation:
old solutions and new problems
Walter “Sunny” Dzik
Transfusion
May 2012

This Review
• All anticoagulant therapies are
accompanied by bleeding complications
• This review summarizes use of blood
products for urgent reversal of drug-
induced anticoagulation

New Oral Anticoagulants:
Convenient to Use But Not Reversible
• Direct thrombin inhibitors (i.e. Dabigatran) or inhibitors
of Factor Xa (i.e. Rivaroxaban or Apixaban)
• Approved for stroke prevention in A-fib patients
• Widely quoted that these drugs are safer than warfarin
with few bleeding events; however, after being in use for
a while, this is less clearly the case
• No good evidence available on how to successfully
reverse these agents should bleeding occur
• Mixed results using PCCs, rFVIIa, etc
• Dialysis or therapeutic apheresis can be effective
• Local hemostatic agents used as topicals could be
effective
• Conclusion: Be skeptical of upcoming claims
regarding reversal agents

THREE ANTIDOTES
No reversal agent (antidote, neutralizing drug) is presently clinically available if (a) major
bleeding occurs or (b) urgent reversal for emergent surgery is needed in patients on one of
the new oral anticoagulants (apixaban = Eliquis®; dabigatran = Pradaxa®; edoxaban =
Savaysa®; rivaroxaban = Xarelto®).
The following three drugs are in development, but are at least 2 years away from being
clinically available, should they prove to be beneficial:
1. ARIPAZINE (PER977; ciraparantag)
What is it? This is a synthetic small molecule (D-arginine compound) which has broad activity
against various old and new oral anticoagulants
What anticoagulant drugs might it reverse? Apixaban, edoxaban, rivaroxaban, dabigatran,
heparin, LMWH.
Clinical trial status: A human volunteer study of 80 individuals receiving aripazine published this
week in the New England Journal of Medicine [ref 1] shows that clotting assays (whole-blood clotting time)
that were prolonged by edoxaban, decreased after the test persons received aripazine. Another healthy
volunteer study is presently ongoing [NCT02207257].
2. ANDEXANET (PRT064445)
What is it? Recombinant, modified factor Xa molecule that is being developed as a direct reversal
agent for patients receiving a Factor-Xa inhibitor who suffer a major bleeding episode or who require
emergency surgery. It sort-of sops up the anti-Xa anticoagulant, making a patient’s own factor Xa available
again to participate in the coagulation process.
What anticoagulant drugs might it reverse? Apixaban, edoxaban, rivaroxaban.
Clinical trial status: Healthy volunteer studies to (a) evaluate the ability of Andexanet to reverse the
effects of several anticoagulant drugs on laboratory tests and (b) reverse apixaban and rivaroxaban are
presently ongoing.
3. IDARUCIZUMAB (BI 655075)
What is it? It is a humanized antibody fragment directed against dabigatran; generated from mouse
monoclonal antibody against dabigatran; humanized and reduced to a FAb fragment.
What anticoagulant drugs might it reverse? Dabigatran.

Conclusion
The ultimate goal for society is the
development of an oral anticoagulant that can
be taken once a day, that will effectively reduce
the risk of stroke or thrombosis in patients with
a wide range of thrombophilic disorders, that is
inexpensive and non-toxic, and that can be
promptly reversed should bleeding occur
Sort of sounds like warfarin, doesn’t it?

Antiplatelet Agents
• Millions of patients are prescribed antiplatelet agents (APAs)
for a variety of clinical conditions such as coronary artery
syndrome, stroke, transient ischemic attacks and peripheral
arterial disease
• Millions more self-medicate with aspirin or herbs and
supplements known to affect platelet function
• Older APAs have a low bleeding risk profile; newer APAs
have a higher bleeding risk profile
• When patients on APAs present with bleeding or when they
need urgent surgical intervention, treating physicians and
transfusion medicine specialists are challenged with how to
reverse or counteract effects of APAs

APAs classified into 4 groups
• Group 1: COX-1 inhibitors (aspirin and nonsteroidal anti-inflammatory drugs)
• Group 2: ADP receptor (P2Y12) inhibitors [ticlopidine (Ticlid), clopidogrel
(Plavix), prasugrel (Efient)]
• Group 3: GPIIb/IIIa inhibitors (fibrinogen receptor antagonists) including
Abciximab (ReoPro), Eptifibatide (Integrilin), and Tirofiban (Aggrastat)
• Group 4: Miscellaneous
• Dipyridamole (Persantin) and cilostazol (Pletal) inhibit the 2,3 phosphodiesterase
enzyme inhibiting aggregation (weak)
• Aggrenox is a combination of ASA and dipyridamole and is very effective against
platelet function
• Fish oil and many herbs can inhibit platelet function

Summary of APAs
• APAs are used increasingly in our aging patient population
• With more potent APAs there is an increased risk and extent
of bleeding
• Judicious use of specific tests to assess anti-platelet drug
effect and platelet transfusion therapy can assist clinicians
in the management of patients who present with bleeding
complications or trauma or who require urgent surgery
• Prospective clinical trials to optimize the dose and timing of
platelet transfusion with greatly add to our knowledge of the
efficacy of platelet transfusion

Platelet Function Tests
Comparison of platelet function tests in predicting clinical outcome in
patients undergoing coronary stent implantation
Breet, et al., JAMA 2010 Feb 24;303(8):754-62
•None of the tests identified patients at risk for bleeding
•Conclusions
– Of the platelet function tests assessed, light transmittance
aggregometry, Verify Now, Platelet works, and Innovance , the
predictive accuracy was only modest
– None of the tests provided accurate prognostic information to identify
patients at higher risk of bleeding following stent implantation
•Other described limitations:
– Prolonged (dysfunction) for blood group O samples than for other
blood groups
– Prolonged when platelet count or hematocrit is significantly decreased
(PFA-100 closure times are usually prolonged when platelet count is
<50,000/μl or hematocrit is <25%)
– Clinical performance for platelet dysfunction may be influenced by
other pre-analytical variables
• Age?
• Diurnal variations?

Thromboelastography [TEG] and Rotational
Elastometry [ROTEM]
Not just for platelet function, but also to detect low fibrinogen,
presence of heparin, fibrinolysis…

How do I transfuse platelets to reverse
anti-platelet drug effect?
Ravi Sarode
Transfusion
April 2012

Platelet Transfusion for Reversing Drug
Effects
• Patient is on ASA
• Not considered to be a very potent agent in terms
of increased bleeding risk
• If the patient requires surgery (other than
neurosurgery) and is on a standard dose of ASA
(81-325 mg per day) no prophylactic platelets are
recommended
• If the patient requires neurosurgery, give one dose
of platelets within a few hours prior to surgery
• NSAIDS
• Discontinue drug 12 hours before elective surgery
if possible
• Platelets are not required for urgent surgery

Effects
• Patient is on P2Y12 (ADP receptor) inhibitor
• ticlopidine (Ticlid), clopidogrel (Plavix), prasugrel
(Efient)
• Increased bleeding tendency
• Urgent surgery required? Significant bleeding? Give
one dose of platelets
• Neurosurgery or eye surgery? Give two doses of
platelets (100K functional platelets)
• Patient is on both ASA and P2Y12 inhibitor
• Same as above
• Patient is on Aggrenox (ASA and dipyridamole)
• Urgent surgery other than neurosurgery? No platelets
necessary
• Neurosurgery? One dose of platelets

Effects
• Patient is on GPIIb/IIIa inhibitor
• Fibrinogen receptor antagonists including Abciximab
(ReoPro), Eptifibatide (Integrilin), and Tirofiban
(Aggrastat)
• Coronary intervention, and the patient bleeds
excessively after heparin has been reversed with
protamine, give one dose of platelets
• Patient on miscellaneous Anti-platelet agents
• Dipyridamole (Persantin) and cilostazol (Pletal),
Aggrenox, a combination of ASA and dipyridamole,
and fish oil and other herbs that inhibit platelet
function
• Prophylactic platelet transfusions are not indicated

Alternative to Platelet Transfusion
• Desmopressin (DDAVP)
• Stimulates the release of stored VWF from
the endothelium thereby indirectly improving
platelet function
• Recombinant Factor VIIa
• Increases thrombin generation on the
platelet surface thereby reversing the effect
of anti-platelet drugs

Massive Transfusion Protocols
Why might a protocol-driven, ratio-
based, massive transfusion
protocol improve trauma patient
outcomes?

Fig. 1. A diagram showing some of the mechanisms leading to coagulopathy in
the injured. Trauma can lead to hemorrhage which can lead to resuscitation,
which in turn leads to dilution and hypothermia causing coagulopathy and
further hemorrhage. This is classic “dilutional coagulopathy”. Hemorrhage can
also cause shock which causes acidosis and hypothermia that in turn lead to
coagulopathy, the “fatal triad”. Trauma and shock can also cause the Acute
Coagulopathy of Trauma-Shock (ACoTS) associated with factor consumption
and fibrinolysis. Coagulopathy is further associated with trauma-induced
inflammation and modified by genetics, medications, and acquired diseases.
Trauma Hemorrhage
The Coagulopathy of Trauma: A Review of Mechanisms
Hess, et al., J Trauma. 2008;65:748 –754
Resuscitation
Inflammation
Other Diseases
Medications
Genetics
COAGULOPATHY
Dilution
Hypothermia Hypothermia
Acidemia Fibrinolysis
Factor
Consumption
ACoTS
Shock

Risk Factors for Trauma-Induced
Coagulopathy
• Extent of tissue damage
• Shock (3-fold increase)
• Pre-hospital IV fluids > 3000 mL
• Hypothermia (< 35 C)
• Acidosis (3-fold increase)
• Inflammation
• Preexisting coagulopathic comorbidities
– Cirrhosis, hemophilia and other bleeding disorders,
anticoagulant or antiplatelet therapy
Wafaisade, A, et al. Emerg Med J. 2010
Kauvar DS, et al. J Trauma, 2006

Massive Transfusion Protocols for Patients With
Substantial Hemorrhage
Young, et al, Transfusion Medicine Reviews 10/2011
• Reviewed multiple protocols
• Concluded:
– Massive transfusion protocols with higher ratios of
plasma and platelets to red blood cells appear to
be associated with improved survival in patients
with massive hemorrhage
– Further research needed

Table 2. Studies Evaluating the Impact of an MTP on Outcomes in Trauma Patients, Young, et al
Author(s) Design Number of
MT Patients
Ratios used
PRBC/Plasma/PLT
Impact of MTP on Outcomes Limitations and
Comments
Cotton et al
(2008)
Retrospective (before
and after) cohort study,
single civilian center
264 3:2:3 Reduction in 24-hour blood
utilization, 30-day mortality,
multiple-organ failure, and
abdominal compartment
syndrome
Single center,
retrospective, no
standardized activation
criteria
Cotton et al
(2009)
Prospective cohort
study, single civilian
center
125 3:2:3 Poor compliance with MTP
guidelines is associated with worse
outcomes; failure to activate MTP
early and to transfuse predefined
ratios of plasma and PLTs associated
with higher 24-hour and30-day
mortality
Single center, no
criteria. Prospective
examination of protocol
compliance and provider-
related factors and their
impact on patient
outcomes
Dente
et al (2009)
157 1:1:1 Reduction in 24-hour mortality and
reduction in 30-daymortality in blunt
trauma
Single center,
retrospective with
historical controls, high
MTP failure rate
Duchesne et al
(2009)
Retrospective registry
review, single civilian
center
435 1:1:1 Reduction in 24-hour and30-day
mortality
Single center,
retrospective but has
criteria
O' Keeffe et al
(2008)
132 5:2:3 Reduction in blood and blood
component utilization, time to
delivery of initial products, and
hospital charges
Single center,
retrospective, no
criteria; also used
cryoprecipitate and rFVIIa
Riskin et al
(2009)
77 3:2:3 Reduction in time to delivery of initial
products and 30-daymortality
Small study size, single
center, retrospective, no
standard activation
criteria

Management of bleeding and coagulopathy following major
trauma: an updated European guideline
Donat R Spahn, et al.
Current concepts of pathogenesis of coagulopathy following traumatic injury.
Spahn et al. Critical Care 2013 17:R76 doi:10.1186/cc12685

Hematocrit
Recommendation 10
We do not recommend the use of single Hct measurements as an isolated
laboratory marker for bleeding
• A major limit of the Hct's diagnostic value is the confounding influence of resuscitative measures
on the Hct due to administration of intravenous fluids and red cell concentrates
• Initial Hct does not accurately reflect blood loss because patients bleed whole blood and
compensatory mechanisms that move fluids from interstitial space require time and are not
reflected in initial Hct measurements
Antifibrinolytic agents
Recommendation 24
•We recommend that tranexamic (TXA) acid be administered as early as
possible to the trauma patient who is bleeding or at risk of significant
hemorrhage
Plasma
Recommendation 26
•We recommend the initial administration of plasma or fibrinogen in patients
with massive bleeding
•If further plasma is administered, we suggest an optimal plasma:red blood
cell ratio of at least 1:2
•We recommend that plasma transfusion be avoided in patients without
substantial bleeding

Fibrinogen and cryoprecipitate
Recommendation 27
•We recommend treatment with fibrinogen concentrate or cryoprecipitate in
the continuing management of the patient if significant bleeding is
accompanied by signs of a functional fibrinogen deficit or a plasma
fibrinogen level of less than 1.5 to 2.0 g/l
Platelets
Recommendation 28
•We recommend that platelets be administered to maintain a platelet count
above 50 × 109/l
•We suggest maintenance of a platelet count above 100 × 109/l in patients
with ongoing bleeding and/or TBI
Antiplatelet agents
Recommendation 29
•We suggest administration of platelets in patients with substantial bleeding
or intracranial hemorrhage who have been treated with antiplatelet agents
•We suggest the measurement of platelet function in patients treated or
suspected of being treated with antiplatelet agents; if platelet dysfunction is
documented in a patient with continued microvascular bleeding, we
suggest treatment with platelets

Prothrombin complex concentrate
Recommendation 31
•We recommend the early use of prothrombin complex concentrate (PCC)
for the emergency reversal of vitamin K-dependent oral anticoagulants
Recombinant activated coagulation factor VII
Recommendation 33
•We suggest that the use of recombinant activated coagulation factor VII
(rFVIIa) be considered if major bleeding and traumatic coagulopathy
persist despite standard attempts to control bleeding and best-practice
use of conventional haemostatic measures
•We do not suggest the use of rFVIIa in patients with intracerebral
hemorrhage caused by isolated head trauma

Plasma in Massive Transfusions
• A cautionary tale:
– Administration of plasma is associated with
significant increase in overall complications
but without significant differences in mortality
– An increase in lung injury, multiorgan
dysfunction and sepsis seen with increased
plasma transfusions
– Incremental risk of compatible but ABO non-
identical plasma (for patients receiving more
than 5 units of plasma), especially for group O
patients transfused with group AB plasma
• Probably due to antigen complexes formed
from residual antigens remaining in plasma
– Most plasma today from men, except for AB
because of shortages
• Women are associated with the highest risk
of TRALI

Objectives:
• Demonstrate knowledge of appropriate blood component
usage
• Identify the blood component for which transfusion
does not need to be ABO compatible
• Cryoprecipitate
• Platelets
• List 2 transfusion alternatives for reducing the risk of
transfusion-transmitted CMV infection
• Leukoreduction
• Serologic testing - CMV negative results

Current Component Therapy by Diane Eklund, MD

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