s1643 your turn: management of the bleeding patient · coagulation factor xa, inactivated-zhzo 28...
Post on 14-Dec-2018
214 Views
Preview:
TRANSCRIPT
S1643 Your Turn: Management of the
Bleeding Patient
Thomas DeLoughery, MD
Theresa A. Nester, MD, FCAP
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Objectives
2
• Act as a transfusion medicine consultant for an
actively bleeding patient
• Educate pathologists on the reversal of new
anticoagulant agents and recent platelet
transfusion guidelines
• Help develop protocols for patients who are on
warfarin and are experiencing intracranial
hemorrhage
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Case 1
3
A 68 year old woman has sustained a hip fracture after
falling off her horse.
• The patient takes warfarin for atrial fibrillation.
• Current INR is 3.5. Other coagulation tests are
normal. Hemoglobin = 8.5 g/dL.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Vitamin K
• Both oral and IV very effective
− PO "targeted" to liver
− IV faster
• Sub-q and IM not effective in RCT and should not be used!
• Slow infusions of diluted vitamin K has very low incidence
of anaphylaxis – 50ml over 20 minutes
• No "rebound" with reversal
4© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
5.8
2.9
6.2
4.2
5© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Routes of Vitamin K
6
Route Initial INR 24hr INR
LDIV 11.9 3.2
HDIV 13.9 2.8
SC 14.9 4.9
PO 9.4 2.4
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Oral
IV
7© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
FACTOR IN VIVO ½ LIFE % NEEDED FOR
HEMOSTASIS I 3-6 Days 12 - 50 II 2-5 Days 10 - 25 V 5- 36 Hours 10 - 30 VII 2 –5 Hours > 10 VIII 8 – 12 Hours 30 - 40 IX 18 – 24 Hours 15 - 40 X 20 - 42 Hours 10 - 40 XI 40 – 80 Hours 20 - 30
XIII 12 Days < 5
FACTOR HALF LIVES
8© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Plasma for Warfarin Reversal
• FFP contains all plasma coagulation proteins including the
vitamin K dependent ones (2, 7, 9, 10)
− Factor VII with shortest half-life ~ 3-6 hours
• 1 unit FFP raises factors ~ 5%
• Dose is 15 mls of plasma/kg
9© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Case 2
10
A 74 year old man on warfarin following a left lower
leg deep vein thrombosis has tripped off of a curb 20
minutes ago. He now complains of headache. Head
CT shows an acute subdural hematoma.
INR = 3.5
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Kcentra®- a 4 factor prothrombin complex
concentrate (PCC)
11
For patients with a history of warfarin usage presenting with life-threatening bleeding the following is recommended:
1. Give vitamin K 10mg IV over 15-30 minutes
2. If INR is ≥ 1.5 - < 4.0, infuse 25 IU/kg (+/- 10%) Kcentra.
3. If INR is 4.0 - 6.0, infuse 35 IU/kg (+/- 10%) Kcentra.
4. If INR is >6.0, infuse 50 IU/kg (+/- 10%) Kcentra.
NOTE: USE GREAT CAUTION IF PATIENT HAS HAD
THROMBOTIC EVENT IN LAST 3 MONTHS.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
12© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Take Home Point:
When using a 4-factor Prothrombin complex
concentrate to reverse the effect of warfarin,
plasma should not be needed.
But do administer IV
vitamin K!
IV vitamin K will
have effect in 4-6
hours.
13© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
3- factor PCCs are also available
14
Brand names: Bebulin®, Profilnine®
These contain factors II, IX, and X but not much
factor VII.
Therefore, if this concentrate is used off-label,
a small amount of plasma is still needed to
achieve reversal.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Case 3
15
A 65 year old man on Dabigatran due to atrial
fibrillation presents with a perforated gastric
ulcer. Urgent surgery is required.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Direct Oral Anticoagulant (DOAC) Monitoring
• Increasing use of DOAC in population
• Not required for routine use
• Can be use to assess
− Compliance
− Need for reversal
− Presurgerical
• Routine tests variably effected by drugs
16© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Routine Tests
• Dabigatran – PTT
− Thrombin time more sensitive
• Rivaroxaban – INR
− Anti-Xa more sensitive
• Apixaban – Ø
− Anti-Xa more sensitive
• Edoxaban – INR
− Anti-Xa more sensitive
• For life threatening bleeding treat without waiting for levels
17© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
DOAC Reversal
• Specific reversal agent available for
Dabigatran
• Idarucizimab
• Coagulation factor Xa (recombinant),
inactivated-zhzo
18© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Dabigatran Reversal
19© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Idarucizumab
20© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Clinical use of Idarucizumab
• Effective in ~ 98% of patients in reversing
thrombin and Ecarin time
• 98% of patients could undergo emergency
surgery
• ~ 2% of patients required redosing for
bleeding
• 30 day thrombosis seen in ~ 5% patients
21
N Engl J Med 2017
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Conclusion
• Idarucizumab reverses dabigatran
• But need to treat cause of bleeding also
− 2.5 - 11 hours to stop bleeding after antibody
administered
• Allowed emergency surgery
• Should be used for ICH or urgent surgery
22© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Our Protocol
1. Indication: ICH for patient on dabigatran
2. Baseline thrombin time and aPTT
− Not to screen for use but to assess drug use
3. Five grams administered as 2.5 gram bolus one
right after other
4. Consider for emergency surgery if TT/aPTT
elevated
23© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Xa Blockers
• Prothrombin Complex concentrates
– Animal and human studies
• No difference in bleeding outcomes in warfarin vs DOAC
ICH patients
24© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Coagulation factor Xa (recombinant), inactivated-
zhzo
• “Andexxa”
• Recombinant fXa derivative
▪ Catalytically inactive
▪ Lacks the Gla-domain
− Bolus then 2 hour infusion
• Reverses both direct and indirect Xa inhibitors
• Approved May 2018 but available in limited quantities.
25© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
26© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
27© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Coagulation factor Xa, inactivated-zhzo
28
• Will reverse rivaroxaban and apixaban
• Will likely work for other “bans” as well but not FDA
approved
• Should theoretically work to reverse Fondaparinux,
but is no trial data yet.
Package insert contains a black box warning if patient
has had recent thromboembolic events.
Very expensive, use only for life threatening bleeding.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
What if you don’t have the fancy new drugs
• Prothrombin Complex Concentrates
(4 factor)
• Increasing data on effectiveness
• Dose - 50 units/kg
29© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Case 4
30
• A 47 year old man with alcoholic cirrhosis presents
with hematemesis.
• Hgb = 8.0/gldL
• PT/INR = 1.9
• aPTT= 42 seconds
• Platelet count= 50K/µL
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Liver Disease
• Multiple defects in coagulation
❖Decreased synthesis of factors
❖Decreased platelets
❖Decreased platelet function
• But clinical data also shows increase in
thrombosis
❖Risk of thrombosis increased three-fold
31© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Incidence of venous thromboembolism based
on Child-Pugh Stage.
Dabbagh O et al. Chest 2010;137:1145-114932© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Hemostasis in Liver Disease
• Levels of natural anticoagulants and inhibitors of
coagulation also reduced
− Antithrombin
− Protein C
− Protein S
• Coagulation is “rebalanced”
− Thrombin generation is normal
33© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
34
Hepatology 44:440-445, 2006
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Transfusions in Upper GI Bleeding
• Large Spanish study of UGI
• N = 921
− Ulcers 49%
− Varices 21%
• RCT
− Restrictive: Hgb = 7 (7-9)
− Liberal: Hbg = 9 (9-11)
35
NEJM 368:11-21, 2013
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Results
36
Result Restrictive Liberal p
Death 23 (5%) 41 (9%) 0.02
Death –bleeding 3 (0.7%) 14
(3.1%)
0.01
Further bleeding 45 (10%) 71 (16) 0.01
No transfusion 225 (51%) 61 (14%) <
0.001
Transfusion reaction 14 (3%) 38 (9%) 0.001
Cardiac
complication
49 (11%) 70 (16%) 0.04
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Case 4
37
5 months later, the patient is admitted with ascites and
hepatic encephalopathy. There is no evidence of
bleeding. INR = 7.0 and platelet count is 60K/µL.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
The INR
• Only standardized for stable patients on warfarin
• Unreliable in liver disease
− VII falls more than II and XI
− Also if fibrinogen is low will falsely raise INR
• Not a predictor of bleeding
38© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
TEG in Liver Disease
• Normal R
• High normal α angle
• High normal MA
• Normal LY30
• Overall – Normal
• INR 2.21
• Platelets – 128,000
39© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Case 5
• 73 year old man presents with a ruptured abdominal aortic
aneurysm.
• The patient is Rh(D) negative with a negative antibody
screen.
40© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Rh(D): Basic points
41
A. Unlike ABO antibodies, Rh(D) negative
individuals do not have naturally occurring
anti-D.
B. Even if the patient has anti-D, intravascular
hemolysis is unlikely to occur.
C. Group O Rh(D) negative blood constitutes
only 7-9% of the community supply.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Frequency in Caucasian Population
O + 36% O- 9%
A+ 34% A- 8%
B+ 8% B- 2%
AB+ 2.5% AB- 0.5%
42© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Extravascular
hemolysis
Much less symptomatic than
intravascular hemolysis. Decreased
hematocrit may be the main finding.
43© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Laboratory results are not yet available
1. Is it appropriate to transfuse at a 1:1:1 ratio?
2. What does that even mean?
3. If a 1:1:1 protocol is started, for how long
should it continue?
44© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
What does a 1:1:1 ratio even mean?
Definition:
• 1 whole blood derived platelet: 1 plasma: 1
RBC
• In most systems: 1 platelet dose: 6 plasma: 6
RBC
45© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Not long. Risks:
• Respiratory compromise
• Abdominal compartment syndrome
• Suboptimal management of the coagulopathy
• eg, heparin, hemophilia, DIC
If one starts a 1:1:1 protocol, for how long should it
continue?
46© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Does a 1:1:1 ratio apply in a non-trauma
patient?
• Probably not, unless the patient has shock,
acidosis, and significant tissue injury.
• However, some replacement of coagulation
factors and (eventually) platelets is warranted.
47© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Brief history of 1:1:1 idea
• Idea first suggested in field of combat.
• Civilian trauma centers started to look at their
practice.
– This generated much retrospective data with
many variables, making a meta-analysis
difficult.
• PROMMTT trial
• PROPPR trial
48© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
49© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Prospective, Observational, Multicenter,
Major Trauma Transfusion Study
• 10 US level 1 trauma centers
• 1245 patients
• Received at least 1 RBC within 6 hrs of
admission
• Received at least 3 blood products within
24hrs
50© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
PROMMTT Objective
To relate in-hospital mortality to:
- early transfusion of plasma and/or platelets
- Time-varying plasma:RBC and platelet:RBC
ratios.
51© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
PROMMTT Results
• Increased ratios of plasma:RBC and
platelet:RBCs were independently
associated with decreased 6 hr
mortality, when hemorrhagic death
predominated.
• In the first 6 hrs, patients with ratios
less than 1:2 were 3-4 times more likely
to die compared to 1:1.
52© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
From: The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study: Comparative
Effectiveness of a Time-Varying Treatment With Competing Risks
JAMA Surg. 2013;148(2):127-136. doi:10.1001/2013.jamasurg.387
Figure 1. Blood product use in the first 6 hours in 2 Prospective, Observational, Multicenter, Major Trauma Transfusion Study patients. Patient 1 (A) had an
Injury Severity Score of 48 and died of hemorrhage at 1 hour 7 minutes after emergency department admission. Patient 2 (B) had an Injury Severity Score of 57
and was discharged to another acute care hospital at 27 days. Note the constantly changing ratios over time. For example, patient 1 received cumulative
plasma:platelet:red blood cell (RBC) ratios of 0:0:1, 0:0:3, 0:0:6, 4:6:6, and 5:6:6 at 15, 30, 45, 60, and 75 minutes, respectively, while patient 2 received
cumulative plasma:platelet:RBC ratios of 0:0:1, 0:0:4, 0:0:4, 2:0:6, and 2:0:10 at those same times.
Figure Legend:
53© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
From: The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study: Comparative
Effectiveness of a Time-Varying Treatment With Competing Risks
JAMA Surg. 2013;148(2):127-136. doi:10.1001/2013.jamasurg.387
Figure 2. The bars represent cumulative ratios at the start of each time interval. Most patients received a plasma:red blood cell
(RBC) ratio of 1:2 or higher by 3 hours (A) and a platelet:RBC ratio of 1:2 or higher by 6 hours (B). In the last time interval (24
hours), the percentage of patients receiving 0 units of platelets or plasma increases, reflecting the dynamic cohort with newly
eligible patients entering and others exiting owing to death in the previous interval.
Figure Legend:
54© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Holcomb JB et al. JAMA 2015; 313(5):471-482.
55© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
PROPPR Trial
• RCT involving 680 patients with severe trauma.
• 1:1:1 vs 1:1:2 ratio. Blood products were
administered in a pre-specified order to maintain
assigned ratios.
• Primary outcomes: 24 hr and 30 day mortality.
• Secondary outcomes: time to hemostasis, ICU
free days, functional status at discharge.
56© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Survival 1:1 vs 1:2
57
Holcomb et al JAMA 2015;313:471 – 482.
Less exsanguination at 24 hours with 1:1
NO increase in complications with 1:1
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
PROPPR Trial- results
• No significant difference in primary or
secondary outcome >> no significant
difference in mortality with either strategy.
• But a post-hoc analysis indicated that death
by exsanguination was significantly
decreased in the intervention group.
58© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Are guidelines appropriate for severe trauma
patients applicable to non-trauma patients?
2011 Consensus conference indicates
no, unless the patient has shock,
acidosis, and significant tissue injury.
.
59
Dzik et al. Critical Care 2011;15:242
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
60© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Literature is emerging about MTP use in
non-trauma patients
• Retrospective, with relatively small numbers.
• Patients are typically older and sicker at baseline than
trauma patients.
• Similar to initial retrospective trauma literature, significant
variability exists.
61© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Association Between Ratio of FFP to RBC
during Massive Transfusion and Survival
Among Patients Without Traumatic Injury
62
• Retrospective review of all massive transfusions
at Massachusetts General Hospital from 2009-
2012.
• Main measure was the examination of FFP:RBC
transfusion ratios for patients without trauma.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Findings
63
Almost 90% of massive transfusions took place in
patients without trauma:
• Higher numbers of cardiac and liver transplant
surgery, with trauma 3rd highest patient
population.
Overall, there was no difference in 30 day mortality
between the high FFP:RBC ratio and the low FFP:RBC
ratio.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Findings, cont’d
64
However, significant differences in 30 day mortality
rates were observed within individual services.
For vascular surgery, a high ratio was associated with
decreased mortality (p = .045).
But for general surgery, orthopedic surgery, and
medicine, a high ratio was associated with increased
mortality.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Massive transfusion in patients without trauma
65© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
For rAAA patients, there are other rare
retrospective studies indicating that increased
plasma: RBC ratio improves outcome.
Mell et al Surgery 2010;148:955-62.
66© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Coagulopathy in rAAA patients
• Most do not start out with a coagulation
disorder unless on anti-platelet therapy,etc.
• Dilutional coagulopathy can develop if only
RBCs administered.
• A rare patient will have/develop DIC.
67© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Consensus committee recommendations
1. For patients with critical bleeding, immediate
application of a ‘foundation ratio’ of blood components.
Example, 6 RBCs and 3 FFP for the initial treatment.
2. Adjustments to the foundation ratio based on the
clinical course and results of laboratory tests using goal
directed therapy.
68© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Better patient outcomes with massive transfusion
may be more due to:
• Improved communication.
• Decreased time of delivery of blood products.
• Clearly defined roles, responsibilities, and resource
allocation.
69© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Thromboelastrography
• Point of care test using fresh whole blood.
• Measures tensile strength of forming clot.
70© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Thromboelastrography, cont’d
71© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Thromboelastrography, cont’d
• Drawbacks
− Lack of familiarity
• TEG based protocols
− Need to run sample in 4 minutes
− Who runs samples and QA machines?
72© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Patient with Liver Disease
• Normal R
• High normal α angle
• High normal MA
• Normal LY30
• Overall – Normal
• INR 2.21
• Platelets – 128,000
73© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
TEG Based Transfusion Protocol
TEG Parameter Interpretation Action
R Time Time to fibrin formation Increased - FFP
K time Kinetics (2-20mm ) Increased - Cryo
Alpha Angle r/k slope of tracing Decreased - Cryo
Maximal
Amplitude
Strength and stability of
thrombusDecreased - plts
Whole blood
Lysis IndexFibrinolysis
Increased -
antifibrinolytic
74© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
75© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
76
Sounds good, but…
Many of the values actually reflect a mixture of things.
For example:
- the angle represents a combination of coagulation
factors, platelets, and fibrinogen.
- the R value represents a combination of coagulation
factors and platelets.
Thombin is the platelet activator in TEG. It is a very
powerful activator, so TEG will miss platelet dysfunction.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
77© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
78
Studies done often compare TEG or ROTEM to
traditional lab testing that takes 45-60 minutes. What
is needed is a comparison of TEG or ROTEM to
traditional testing that takes 20 minutes.
If we cannot achieve a 20 minute turn around time,
TEG will be used because it is available within the
“golden hour.”
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Goal: Reasonably accurate coagulation tests within 20
minutes for an actively bleeding patient.
• Stopped performing checks for clotting or hemolysis
>> >> 9% exceeded the 20 minute goal.
• Revised the fibrinogen assay with an expanded
calibration range.
>> 2% exceeded the 20 minute goal
79© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Hypothermia
AcidosisCoagulopathy
The Lethal Triad
What can we take away from the trauma
literature?
80© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Other Ideas we can take away:
Laboratory value turn around time must be
more rapid than traditional testing, and often
requires a special signal, such as activation of a
hemorrhage protocol.
81© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
And possibly:
Improved predictors for who will require
massive transfusion:
• Trauma patients requiring >3 units PRBCs
per hour.
• Shock index: ratio of heart rate to systolic
blood pressure.
82© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
In Summary
For patients with significant blood loss, early
plasma infusion is likely to improve outcome.
During cases of ongoing blood loss,
component therapy based on rapid laboratory
values should be pursued as soon as
possible.
83© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Case 6
84
A 30 year old Rh(D) negative woman delivers
a baby. Upon delivery of the placenta, the
patient experiences blood loss estimated at
1700mL. The clinical team begins their
hemorrhage protocol.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Remember
85
By convention:
Screening cell I is always Rh(D) positive (R1R1 = DCe/DCe)
Screening cell II is always Rh(D) positive (R2R2 = DcE/DcE)
Screening cell III is always Rh(D) negative (rr = ce/ce)
Good prenatal care will result in cells I and II
showing agglutination due to Rh immune
globulin administration at 28 weeks gestation.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Post Partum Hemorrhage (PPH)
• Rare: > 10 units of blood 6/100,000 deliveries
• Deadly: 3-11% of maternal deaths
• Incidence is increasing
• Can be truly massive “audible” bleeding
86© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
PPH - Plasma: RBC 1:1 Ratio• Recent data suggesting that a fix ratio of 1:1 RBC:FFP associated
with better outcomes in trauma
• Deemphasizes on laboratory testing for initiation hemostatic
resuscitation
• Logic extending to non-trauma massive transfusions such as PPH
but limited data
• Why early plasma?
− Takes time to run coagulation tests
− Many patients with coagulopathies at time of hemorrhage
• Placenta previa, abruptions, amniotic fluid embolism…
− Plasma may contain beneficial factors that help in massive
bleeding87© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Recommendations
• Start with 4 RBCs
• Transfuse 4 units plasma
• Transfuse 4 more RBCs
• 4 more units of plasma
• 2 cryopools and 1 dose platelets
J Thromb Haemost. 2016 Jan;14(1):205-10
88© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
89© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Why Early Plasma?
• Takes time to run coagulation tests
• Many patients with coagulopathies at time of hemorrhage
• Plasma may contain beneficial factors that help in massive
bleeding
90© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
65%
34%
20%
0
10
20
30
40
50
60
70
0:22 - 1:4 1:3.9 - 1:2.1 1:2 - 1:0.59
Mo
rtali
ty %
Chi Square
RB: p=0.006
RG: p<0.001
BG: p=0.034
Effect of FFP:RBC Ratio on Overall Mortality
n=31 n=56 n=165
FFP:RBC RatioBorgman et al. J Trauma. 2007;63:805-813.
91© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
However… in PPH
• Thrombocytopenia less common
− Unless severe bleeding or DIC
92© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Fibrinogen; the Forgotten Factor
• Crucial for forming hemostatic plug
• Crucial for INR and PTT testing
• Levels rise in normal pregnancy
• Lower levels predictors of post-partum hemorrhage
• Newer data indicate higher targets in obstetrical
bleeding
− > 200 mg/dl
93© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
94© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Fibrin
LysLys LysLys LysLys Lys Lys
Plasmin
95© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
LysLys LysLys LysLysLys Lys
Fibrin
Lysine EACA TXA
96© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Fig 2 Cumulative meta-analysis of the effect of tranexamic acid in surgery on
risk of blood transfusion in adequately concealed trials.
Katharine Ker et al. BMJ 2012;344:bmj.e3054©2012 by British Medical Journal
Publishing Group
97© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
TXA reduces bleeding in surgery
TX
A
TXA better TXA worse
0.61 (0.57-
0.66)
RR (95% CI)
0.4 0.8 1.2 1.6
Transfusion
TX
A
RR (95% CI)
TXA better TXA worse
0 0.4 0.8 1.2 1.6
0.57 (0.34-
0.98)
Mortality
65 trials (4,842 patients) 30 trials (2,917
patients)
98© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
TXA
• Small trials showed reduced blood loss in PPH
• WOMEN Trial
– Blood loss > 500 mL after vaginal birth or 1000 mL
after C-section or any blood loss
– sufficient to compromise hemodynamic stability.
– Intervention: one gram of TXA
– Patients: TXA: 10,036 Placebo: 9,985
Lancet 2017:389:2105-16
99© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
TXA: WOMEN TRIAL: RESULTS
• Death due to PPH
− TXA 1.5% (155/10,036) vs Placebo 1.9% (191/9,985)
− RR: 0.81 (CI 0.65 – 1.00, p = 0.045)
− Absolute risk reduction = 0.4%
− No increased in thrombosis
• TXA should be used if significant PPH present. A second
dose can be given if needed. Administer within 3 hours
of the onset of PPH.
100© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
TXA: WOMEN TRIAL: CONCLUSIONS
• TXA should be used if significant PPH present.
• A second dose can be given if needed.
• Administer within 3 hours of the onset of PPH.
101© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Prohemostastic Drug: rVIIa
• Decreasing use in massive transfusions with negative trial
data and increase risk of thrombosis
• Open label study in PHH showed 60 ug/kg reduced need
for procedure but not blood loss or blood product usage
• If bleeding is ongoing and labs are normal consider 60-90
ug/kg
• Remember
– Need fibrinogen > 200mg/dl
– Need pH > 7.2 102© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Prohemostastic Drugs: PCC
• Increasing use of PCC in massive bleeding in order
to give coagulation factors with decrease volume
• Increasing use in trauma: 50 units/kg if
coagulopathy persist despite ongoing hemostatic
resuscitation
− RCT ongoing
• Thrombosis is a concern
• Not recommend for PPH until there is more data
103© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
104© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
PPH: Massive Transfusion Protocols
• Key to get the right blood products fast to the right place
• Need to know
− Who can initiate (providers, transfusion service)
− Sending out the right products
• Box of blood
• “Trauma 4x4”
− Keeping track of products and labs
• Practice runs for less busy hospitals
• MTP associated with better outcomes
105© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Case 7
106
A 39 year old man requires a renal biopsy. The patient
is oliguric and rapidly progressive
glomerulonephritis is suspected. Platelets are
requested.
Current platelet count = 57K
PT/INR and aPTT are within normal limits.
Serum creatinine = 5.0 mg/dL
Blood urea nitrogen = 100mg/dL
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Uremia and Platelets
• Milieu of uremia inhibitors platelet function
• Transfused platelets rapidly inhibited
• Recommendations
− Dialysis to lower “toxin” level
− DDAVP improved platelet function
− Cryoprecipitate often recommend but unreliable
107© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
108© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
AABB Platelet Guidelines
• Recommendation 1: The AABB recommends transfusing
hospitalized adult patients who have therapy-induced hypoproliferative thrombocytopenia with a platelet count of 10 ×109 cells/L or less to reduce the risk for spontaneous bleeding.
• Recommendation 2: The AABB suggests prophylactic platelet
transfusion for patients having elective central venous catheter placement with a platelet count less than 20 ×109 cells/L.
• Recommendation 3: The AABB suggests prophylactic platelet
transfusion for patients having elective diagnostic lumbar
puncture with a platelet count less than 50 ×109 cells/L.
109© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
AABB Platelet Guidelines, cont’d
• Recommendation 4: The AABB suggests prophylactic platelet
transfusion for patients having major elective nonneuraxialsurgery with a platelet count less than 50 ×109 cells/L.
• Recommendation 5: The AABB recommends against routine
prophylactic platelet transfusion for patients who are
nonthrombocytopenic and have cardiac surgery with
cardiopulmonary bypass (CPB).
• Recommendation 6: The AABB cannot recommend for or
against platelet transfusion for patients receiving antiplatelet
therapy who have intracranial hemorrhage (traumatic or
spontaneous).
110© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
- Helps to show the strength of the evidence
behind the recommendations.
111
Kumar et al. Platelet
transfusion: a systematic
review of the clinical
evidence. Transfusion 2015;55:
1116-1127.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
PATCH Trial-
112
Platelet transfusion Versus Standard Care After Acute Stroke due to
Spontaneous Cerebral Haemorrhage Associated with Antiplatelet
Therapy Lancet 2016.
• Multicenter, open-label, masked endpoint, Randomized trial.
• 60 hospitals in Netherlands, UK, and France
• Enrolled adult patients with non-traumatic ICH on anti-platelet
therapy. Glasgow Coma Scale of at least 8-15. Platelet
transfusion available within 6 hours of onset of symptoms.
• Randomized to standard care or standard care with platelet
transfusion within 90 minutes of allocation.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Patients
113
Platelets Control
Age 74.2 73.5
Men % 55 57
Aspirin 73 84
Asprin/dipyridamole 19 14
ADP inhibitors 4 1
ICH volume 13.1 8.0
ICH score 1 1
GCS 5-12 19 12
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
PATCH- Outcome measures
• Primary: Shift toward death or difference in functional
outcome at 3 months after randomization rated on a modified
Rankin Scale (mRS).
• Secondary:
− Survival at 3 months
− Poor outcome defined as mRS 4-6
− Growth in hemorrhage after 24 hrs
− Serious adverse events such as complications of the
hemorrhage
114© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
PATCH- Results
115
posted in Clinical Neurology
by Salim Rezaie
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
PATCH conclusions
116
Platelet transfusion increases the risk of death or
dependence in patients with an acute intracerebral
hemorrhage while taking antiplatelet therapy.
Avoid making this part of standard care.
Baharoglu MI et al. Lancet 2016 June 25;387 (10038): 2605-13.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
The evidence for adequate platelet count and
neuraxial anesthesia in pregnancy exists in
small studies; no RCT available. Standard of
care is often 80K despite this lack of data.
No RCT exist for platelet count and central
venous catheter placement. One relatively
small trial is being done in patients with
chronic liver disease. Risk appears to be low if
an ultrasound-guided technique is used.
Stanworth, SJ. Cochrane database of Systematic Reviews 2015 and 2016.
117© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Summary
118
TM Consultation:
1. Evaluate available data prior to calling clinical
team. History, drugs, coagulation results,
products given so far.
2. Determine causes for bleeding and the most
appropriate treatment.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Pearls
119
1. Subcutaneous vitamin K is not effective.
2. KCentra is FDA approved to reverse warfarin
effect in the face of life-threatening bleeding.
3. 3-factor PCCs still require plasma for the factor VII.
4. Know which type of crossmatch is being done and
whether the clinical situation calls for something
faster.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Pearls, cont’d
120
5. ESLD patients have relatively normal thrombin
generation, despite the abnormal PT/INR.
6. The indications for plasma infusion are few; the
indication for prophylactic infusion are non-
existent.
7. Plasma is needed early to prevent irreversible
coagulopathy in the setting of massive transfusion.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Pearls, cont’d
121
8. Fibrinogen less than 200mg/dL is a predictor of
severe post-partum hemorrhage.
9. TXA should be used early in post-partum
hemorrhage.
10. Cryoprecipitate is much more effective at
increasing serum fibrinogen level quickly,
compared to plasma.
11. Infusing new platelets into a uremic environment is
ineffective.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
References
122
Abdelfattah, Cripps International Journal of Surgery 2015; 1- 6
Abdul-Kadir et al Transfusion 2014;54:1756 - 1768
Carson et al Annals of Internal Medicine 2012;157:49 - 60
Chandler et al Transfusion Practice 2010;50:2547 – 2552
Collins et al, Management of coagulopathy associated with PPH, In press.
Desborough et al Transfusion 2012;52:20 - 29
Dzik et al. Critical Care 2011;15:242.
Holcomb et al JAMA 2015;313:471 – 482.
Holcomb et al JAMA 2013;148:127 – 136.
Kaufman et al Annals of Internal Medicine 2015;162:205 - 213
Kreuziger et al British Blood Transfusion Society 2013;24:162 - 168
Lockhart ASH 2015;132 - 137
Mell et al Surgery 2010;148:955 – 962
Nester et al AABB Technical Manual 2014;18:499 - 543
Nester T, ed. Transfusion Management of the Obstetrical patient. Springer Nature 2018.
Tripodi et al NEJM 2011;365:147 – 156
Mesar et al JAMA Surg. 2017;152(6): 574-580.
Baharoglu MI et al Lancet 2016; 387(10038): 2605-13
WOMAN TRIAL collaborators Lancet, online April 26, 2017
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
Complete the online course evaluation!
Be an active participant in shaping the CAP’s Annual Meeting by sharing your feedback.
Thanks for attending!
123© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
© 2018 College of American Pathologists. Materials are used with the permission of the faculty.
top related