1. BLOOD COMPONENTS AND BLOOD DERIVATIVES
Marisa B. Marques, MD
Transfusion Services Medical Director
University of Alabama at Birmingham (UAB)

2. Nothing to disclose

3. Learning Objectives
After participating in this activity, the learner will be able to: (1) Recall when to order modified blood components such as packed red blood cells (PRBCs) and platelets (2) Understand the rationale why plasma is no longer indicated for emergent warfarin reversal (3) Describe why activated coagulation factor concentrates are necessary to reverse the new oral anticoagulants in the absence of a specific antidote

4. Blood components Cellular: Packed red blood cells (PRBCS)
Platelets, random (from whole blood)
Platelets, apheresis
Possible modifications (specifications):
CMV-negative
Leukoreduced
Irradiated
Washed (only PRBCs)
Non-cellular:
Plasma (FFP, FP24, thawed plasma, etc)
Cryoprecipitate
Above specifications do not apply

5. CMV negative PRBCs or platelets
From donors who are negative for IgG anti-CMV
When should we give it?
Neonates/Intrauterine Transfusions
CMV-Negative Pregnant Women
Bone Marrow Transplant Patients
In some states, blood centers do not test donors for anti-CMV IgG in donors – leukoreduced units are considered “CMV- safe”

6. Leukoreduction (LR)
Filtration with specialized filters that bind 99.9% of WBC from donor unit
LR essentially eliminates risk of:
Febrile non-hemolytic transfusion reaction
CMV, HLTV I-II
Herpesviruses, EBV
Trypanosoma cruzi
Decreases risk of TRALI
Universal LR is common practice

7. Irradiation
Purpose
To prevent lymphocyte proliferation in recipient and transfusion-associated graft-versus-host disease (TA-GVHD)
Indications
Stem cell transplant patients
Must give at least 30 days before, and indefinitely after
Recipients of blood products from 1st degree relatives
Intrauterine transfusions & babies up to 4 months
Congenital Immunodeficiency Syndromes
Recipients of Fludarabine/Nelarabine/Clofarabine
Some hospitals irradiate for all cancer patients – not an absolute indication

8. Washed PRBCs
Purpose
To remove supernatant (plasma proteins, K, additive solution, etc)
Indications
Severe IgA deficiency to prevent anaphylaxis
Significant hyperkalemia
Ongoing hemolysis from anti-A or anti-B
History of repetitive allergic reactions
Risk
Contamination in the process of opening bag and adding saline multiple times - 24 hours of shelf-life

9. Special precaution re: ABO and Rh Storage and shelf-life Composition
Blood comp.
Special precaution re: ABO and Rh
Storage and shelf-life
Composition
Usual dose
PRBCs
Must be ABO-compatible; Rh negative to Rh negative patients to prevent anti-D formation or when anti-D detected in antibody screen
1-6 C for 42 d in additive solution (AS-1, AS-3, AS-5); 1-6 C for 35 d in CPDA-1; if washed, expires in 24 h; irradiated, expires in 28 d
Red blood cells with hematocrit ~55% (in AS) or ~80% in CPDA-1
One unit at a time unless ongoing bleeding to increase hemoglobin by 1 g/dL

10. Special precaution re: ABO and Rh Storage and shelf-life Composition
Blood comp.
Special precaution re: ABO and Rh
Storage and shelf-life
Composition
Usual dose
Plasma, thawed
(from FFP or PF24)
Must be ABO-compatible;
Rh not important
2-6 C for 5 d (frozen, kept at -18 C for 12 months)
All coagulation factors at 1 unit/mL; mostly water
10-15 mL/Kg of body weight to increase factor levels by 10-15%

11. Special precaution re: ABO and Rh Storage and shelf-life Composition
Blood comp.
Special precaution re: ABO and Rh
Storage and shelf-life
Composition
Usual dose
CRYO
May not have to be ABO-compatible;
Rh not important
Room temperature for 4-6 h (frozen, kept at -18 C for 12 months)
Fibrinogen ( mg/single unit), Factor XIII, von Willebrand factor, Factor VIII, fibronectin
10 single units or 2 pooled units for adult with hypofibrinogenemia; may repeat if needed

12. Special precaution re: ABO and Rh Storage and shelf-life Composition
Blood comp.
Special precaution re: ABO and Rh
Storage and shelf-life
Composition
Usual dose
Platelets
May be ABO-incompatible (preferably, low titer anti-A or anti-B); Rh identical to prevent anti-D; if anti-D detected in antibody screen, safe to give Rh positive unit
20-14 C with continuous gentle agitation for 5 d; same for irradiated units
5.5 x 1010 platelets per random unit (from whole blood);
3.0 x 1011 platelets per apheresis unit
4-6 random units or 1 apheresis unit to increase platelet count by 30,000-50,000/microliter

13. Anticoagulation Reversal
(2) Understand the rationale why plasma is no longer indicated for emergent warfarin reversal
(3) Describe why activated coagulation factor concentrates are necessary to reverse the new oral anticoagulants in the absence of a specific antidote

14. Warfarin Antagonizes Vitamin KII
VII
IX, X
Protein C
Protein S
Warfarin antagonizes
Vitamin K
Warfarin acts as an anticoagulant by blocking the ability of Vitamin K to carboxylate the Vitamin K dependent clotting factors, thereby reducing their coagulant activity.
Synthesis of non-functional coagulation factors = Deficiencies of all Vitamin-K dependent factors (procoagulants and anticoagulants)

15. Prothrombin Time to monitor warfarin
(TF-VIIa)
Prothrombin activation
Thrombin
Factor X activation
Fibrin clot
(time in s) Va
Factors XII,
PK/HMWK
XI, VIII, IX
PT starts
here!

16. INR allows PT comparison between labs
PT ratio corresponding to WHO International Reference Preparation thromboplastin
Created solely to test patients on stable doses of warfarin
Most patients target: INR 2-3 (few exceptions)
NOT for pre-op evaluation, early oral anticoagulation, acquired vitamin K deficiency or hereditary factor deficiencies ( )
Patient’s PT in Seconds
Mean Normal PT in Seconds
INR =
ISI

17. ACCP 2012 Chest Guidelines

18. ACCP 2012 Chest Guidelines

19. Four-factor PCC = Kcentra®
Factors II, VII, IX, X, PC, and PS
Labeled with number of factor IX units
520 (20 mL) or 1050 units (40 mL)
Dose depends on INR and body weight:
INR 2-4 – 25 units/Kg
INR 4-6 – 35 units/Kg
INR > 6 – 50 units/Kg
Example: 80 Kg x 50 = 4,000 units
of Kcentra® in 160 mL by slow IV push
Maximum weight for calculation: 100Kg
Inside the box:

20. Why not use plasma
Contains all vitamin K-dependent factors, but highly diluted
4,000 units KCentra® = units of plasma (4L)!!!
NO LONGER INDICATED FOR ANY TYPE OF ANTICOAGULANT-INDUCED BLEEDING
Indications for plasma
Massive transfusion
DIC with bleeding
Liver failure with bleeding

21. IV Vitamin K with Kcentra ensures hepatic production of factors within hours
Low doses (1-2 mg) IV reduce INR value at 24 h
Higher doses such as mg IV (for bleeding) reduce INR faster
INR reduction begins in 2 h and correction to normal range in 24 h if normal hepatic function
Endogenous production will keep INR low when effect of Kcentra wears off several hours later
At 24 h, 5 mg of oral and 1 mg IV vitamin K produce similar effects on the INR as mg IV

22. IV Vitamin K risks
Anaphylactoid reactions may occur with large IV doses given rapidly
True frequency ≈ 3 per 10,000 doses
More likely with formulations containing polyethoxylated castor oil (to maintain vitamin K in solution)
To minimize risk of anaphylactoid reactions
Mix vitamin K in a minimum of 50 mL of IV fluid and use an infusion pump to give over 20 minutes or more

23. Newer Oral Anticoagulants (since 2010)
Direct thrombin Inhibitor
Dabigatran
Direct Xa inhibitors
Apixaban
Edoxaban
Rivaroxaban
All block coagulation activation instead of causing factor deficiencies
Reason why replacing factors not indicated
Reversal requires restoration of ability to form clot in presence of drug

24. Dabigatran (Pradaxa®)
Elimination half-life: hours; significantly longer in patients with decreased renal function – 80% excreted by kidneys
Thrombin Time very sensitive (prolonged) when dabigatran in circulation (not quantitative); PT and PTT not useful
If ingested in last 1-2 hours, consider activated charcoal; for emergent reversal, order the monoclonal antibody idarucizumab (Praxbind®) specific for dabigatran, 5 g IV once (2 x 2.5 g vials); for refractory bleeding, consider hemodialysis or a second dose of idarucizumab

25. Rivaroxaban (Xarelto®)
Elimination half-life:
Healthy: 5-9 hours
Elderly: hours
Longer in patients with decreased renal function - 67% renal elimination
Anti-Xa test useful to confirm drug in plasma (not quantitative)
PT and PTT not useful because drug effect is quite variable on the different assays used in hospital laboratories
Same patient’s blood sample may yield a normal and an abnormal result if tested in 2 laboratories using different methodologies and reagents

26. Apixaban (Eliquis®) Elimination half-life:
12 hours, range from 7 to 15
Longer in patients with decreased renal function - 33% renal elimination
Anti-Xa test useful to confirm drug in plasma (not quantitative)
PT and PTT not useful because drug effect is quite variable on the different assays used in hospital laboratories
Same patient’s blood sample may yield a normal and an abnormal result if tested in 2 laboratories using different methodologies and reagents

27. Edoxaban (Savaysa®) Elimination half-life: 10-14 hours
Longer in patients with decreased renal function - 50% renal elimination
Anti-Xa test useful to confirm drug in plasma (not quantitative)
PT and PTT not useful because drug effect is quite variable on the different assays used in hospital laboratories
Same patient’s blood sample may yield a normal and an abnormal result if tested in 2 laboratories using different methodologies and reagents

28. Strategy to reverse direct Xa-inhibitors’ effect
No specific inhibitor such as that available for dabigatran (see above)
Reversal peptide being evaluated by FDA but not yet approved (Andexanet alfa: FXa Inhibitor Antidote)
No evidence-based guidelines for reversal in emergencies; consider activated prothrombin complex concentrate (aPCC or FEIBA®) at 50 units/Kg (used in author’s institution)
Others use PCC (Kcentra®) at 50 units/Kg
Activated charcoal may be useful to inactivate apixaban if ingested in last 2-6 hours

29. Andexanet alfa: FXa Inhibitor Antidote
A recombinant protein specifically designed to reverse the anticoagulant activity of both direct and indirect Factor Xa inhibitors
Being developed as a universal reversal agent for patients anticoagulated with an oral or injectable Factor Xa inhibitor who experience a serious uncontrolled bleeding event or who require urgent or emergent surgery
Designated a Breakthrough Therapy by the U.S. Food and Drug Administration
Portola has commercial rights to andexanet alfa outside of Japan
Clinical Development - Phase 3b/4
Currently being studied in ANNEXA-4, a Phase 3b/4 single-arm, open-label confirmatory study in patients receiving apixaban, rivaroxaban, edoxaban or enoxaparin (a low molecular weight heparin and indirect Factor Xa inhibitor) who present with an acute major bleed.
On August 17, 2016, we received a Complete Response Letter, or CRL, regarding our BLA for andexanet alfa from the FDA, which raised questions regarding manufacturing and clinical data. We continue to have discussions with the FDA and plan to submit the BLA after we have addressed the deficiencies identified in the CRL.

30. Activated Prothrombin Complex Concentrate (aPCC)
FEIBA® – Factor Eight Inhibitor Bypass Activity
Approved for treatment of bleeding due to hemophilia A with inhibitor
Combination of activated and inactive factors II, VII, IX, and X
Risk of thrombosis
No test to monitor FEIBA; patient’s clinical response only guide
Maximum infusion/injection rate must not exceed 2 units/kg of body weight/minute
For a 75-kg patient, approximately
ml/minute, depending on the
number of units/vial (see package insert)

31. Overanticoagulation with oral agents
Drug PT
PTT
Anti-Xa
Thrombin Time
Warfarin
Prolonged
<0.1 units/ml
Normal
ApiXaban
(Eliquis) NA
> 1.8 units/ml
EdoXaban
(Savaysa)
RivaroXaban
(Xarelto)
Dabigatran
(Pradaxa)
>60 s

32. Hemostatic options from the Blood Bank
Plasma
When you need all factors AND volume (massive bleeding)
Cryoprecipitate
For low fibrinogen
Prothrombin Complex Concentrate (PCC) – Kcentra
All vit K-dependent factors for prolonged PT (PTT) due to warfarin
Activated Prothrombin Complex Concentrate (aPCC) - FEIBA
Off-label use for anticoagulation reversal from direct Xa inhibitors
Activated factor VII – NovoSeven
Off-label use for massive bleeding