Transfusion Medicine

Author: Sam Du, PGY-3

PRBC:

Preparation
- Obtained through apheresis of whole donated blood
- Can be refrigerated up to 42 days
  - Can last at room temperature for up to 30-60 min
  - Usually need to be returned to supply (depending on blood bank policy)
- Each unit can have up to 7 mEq potassium (2/2 leakage of intracellular stores)
  - Can be a problem with massive transfusion
  - Consider giving calcium to stabilize the cardiac membrane
- Preserved in citrate (chelates calcium) to prevent clotting.
  - Can cause hypocalcemia in massive transfusion
  - Consider giving calcium as prophylaxis
Blood product modifications
- Leukoreduction: Special filters to remove leukocytes.
  - Standard at Monte.
  - Leukocytes cause transfusion reactions and antibody formation.
  - Particularly important in chronically transfused patients
- Irradiation: Kills leukocytes
  - Prevent graft vs host disease in severely immunodeficient patients
  - Important in stem cell transplant recipients or congenital immune deficiencies
- CMV negative
  - Majority of patients are CMV positive.
  - New CMV infection can be a problem in CMV negative immunocompromised patients
- Washed: wash old preservative off
  - Prevent transfusion reactions or hyperkalemia
- Volume reduced: Preservative centrifuged off
  - To prevent volume overload
Transfusion thresholds:
- Hb 10:
  - Historic non-evidence based transfusion threshold
  - Consider in symptomatic anemia (but not evidence based)
  - Consider in ACS if ongoing ischemia, secondary to anemia
- Hb 8:
  - FOCUS trial 2011 randomized patients with stable CAD to Hb 8 vs Hb 10 while undergoing ortho surgery showed no mortality difference
    - Suggests Hb 8 is an acceptable transfusion threshold
  - Multiple trials in CABG patients comparing a threshold of Hb 8 vs Hb 9 showing no difference
  - There is no clear evidence on the transfusion threshold in acute coronary syndrome but at minimum, the threshold is Hb 8
- Hb 7:
  - TRICC trial 1999 randomized ICU patients to Hb 7 vs Hb 10
    - Subgroup analysis of patients with stable CAD showed trend favoring Hb 7 but was not powered to show a difference.
  - TRISS trial 2014 randomized septic patients to Hb 7 vs 9 and showed no mortality difference.
  - Villanueva et al 2013 randomized patients with upper GI bleeding with stable vitals to Hb 7 vs Hb 9 and showed outcomes favoring patients randomized to Hb 7.
    - Assumed that patients had access to emergent endoscopy if they began to massively hemorrhage
  - Roubinian et al 2018 longitudinal restrospective observational trial analyzing 450,000 patients between 2010 – 2014 as the above permissive anemia data was being released. Showed that mortality among all patients decreased, Hb levels decreased, the amount of blood transfused decreased, and the mortality in patients with permissive decreased without requiring later transfusions
- Hb 6:
  - Weiskopf 2000 observational study in healthy volunteers had isovolemic lowering of their Hb to 5, 6, and 7.
    - At Hb 6 volunteers had decreased cognitive function suggesting that Hb 7 is the lower limit of Hb.
    - No studies in chronically anemic patients and unlikely to be

Platelets

Preparation
- Random donor pooled platelets
  - Isolated by apheresis whole blood from 4-6 donors and mixed into 1 pack
  - Cheaper but exposes recipients to blood from 4 – 6 donors
- Single donor apheresis platelets
  - 4-6 units of platelets removed by apheresis from 1 donor to make 1 pack
  - Plasma and red cells are returned to the donor
  - Standard at Monte and Jacobi
- Must be stored at room temperature
  - Cooling causes platelet clumping and rapid destruction upon transfusion
- Can only be stored for 5 days to prevent bacterial contamination
- Short storage time makes platelets scarce
Transfusion thresholds
- Platelet 100:
  - Historic non-evidence based transfusion threshold
  - Threshold for pre-neurosurgery/CNS bleeding since there is no evidence to suggest a lower threshold
- Platelet 50:
  - Threshold for general surgery/equivalent invasive procedures
  - Threshold if bleeding (petechiae do not count)
  - TTP/HIT/DIC/severe preeclampsia
    - Goel et al 2015 retrospective cohort study of patients with TTP and HIT comparing those who received platelets vs those that did not.
      - Patients that received platelets were overall sicker.
      - Adjusted OR showed only a small increased in mortality among patients that received platelets primarily driven by arterial thrombus such as acute MI or stroke.
      - No increased in venous thrombus.
    - This data suggests that in the setting of life threatening bleeding in TTP and HIT, the benefits of platelets outweigh the risks
    - Recommendations for DIC and severe preeclampsia are extrapolated from this data
  - Lumbar puncture has been addressed in multiple poor quality studies.
    - Joost et al 2010 meta analysis suggests that Plt 40 – 50 is sufficient to prevent bleeding complications
- Platelet 20:
  - Zeidler et al 2011 retrospective cohort study of leukemia patients who underwent central line placement
    - Plt < 20 had significantly more bleeding than Plt > 20
    - Suggesting a threshold for Plt 20 for central line placement
  - Sepsis has not been studied
    - Prophylactic transfusion threshold of Plt 10 to prevent spontaneous bleeding in the general population.
    - Sepsis pts have a consumptive and metabolic coagulopathy suggesting that they may need a higher transfusion threshold.
    - The exact number is not known
- Platelet 10:
  - Chance of spontaneous bleeding increases
  - Paola et al 1997 showed in leukemia patients that a threshold of Plt 10 vs Plt 20 had no difference.
    - Suggests that among the general population, a prophylactic transfusion threshold of Plt 10 to prevent spontaneous bleeding is adequate
  - More recent studies have tried to do away with prophylactic transfusion entirely and go towards only transfusing with bleeding.
    - However, this data is still inconclusive and have not led to any firm recommendations

Plasma and plasma derived products

Preparation
- One of any of three produces depending on blood bank’s supply:
  - Fresh frozen plasma (FFP): frozen within 8 hours of collection
  - Frozen within 24 hours (FF24): frozen between 8 – 24 hours of collection
  - Thawed plasma: thawed and left at room temperature for several days
- At room temperature, Factor V and Factor 8 (needed for hemophilia A) break down so you are not getting a reliable amount of these
- Plasma has all coagulation factors (including fibrinogen) but diluted in preservative
  - Studies that transfused volunteers with plasma could not lower their INR < 1.7
- Plasma derived products are separated from plasma using Cohn fractionation
  - Cryoprecipitate separated first
    - Contains Factor VIII, XIII, vWF, Fibrinogen
  - Prothrombin complex concentrate (PCC) is separated next
    - Contains Factor II, VII, IX, X, Protein C/S
    - 3-factor PCC does not contain Factor VII
  - IVIG and albumin are separated after
  - Each individual factor can also be further purified using antibodies
  - Factor VIII (hemophilia A), IX (hemophilia B), XIII are available as recombinant forms produced in culture
Transfusion Indications
- Multiple coagulation factor deficiency:
  - Consumptive coagulopathy
    - DIC
      - Can give cryoprecipitate of fibrinogen concentrate for fibrinogen levels < 100 (but limited evidence to support this)
    - TTP
      - Patient’s plasma with the ADAMST antibodies are removed by apheresis
      - Donor plasma replete of coagulation factors is given back
    - Liver disease
      - Liver produces all coagulation factors not just those affecting INR
      - INR is followed because most rapidly changing lab value, since Factor VII has the shortest life
    - Bleeding
- Coumadin reversal
  - PCC is now the standard of care over plasma (despite limited data)
  - PCC normalizes INR faster and with less volume of blood product
  - Caveat of small increase in thrombosis.
  - No studies showing benefit in patient oriented outcomes.
  - Unlikely that these studies will be performed given that PCC is now the standard
- In rare coagulation factor deficiency (Factor II, VII, X deficiency where there is no factor concentrate or recombinant available), we are forced to use plasma
- For Factor VIII (hemophilia A) and IX (hemophilia B), XIII factor concentrate or recombinant is preferred.
  - In resource poor settings, you may be forced to use plasma
- Cryoprecipitate contains Factor VIII and XIII
  - But greater risk for viral transmission since it is not screened
- In acquired or hereditary angioedema, C1 inhibitor concentrate or icatibant bradykinin inhibitor are preferred.
  - When not available, plasma contains C1 inhibitor and can be used

Massive transfusion protocol

Transfuse in 1 : 1 : 1 ratio of FFP : Platelets : PRBC
Remember platelets are 6 units per pack so on shift, the ratio becomes is 6 : 1 : 6
If you do 1 : 1 : 1 ratio, the transfused product will have a final concentration of Hb 8.7, Plt 55 and 65% of coagulation factor.
- Therefore, if the ratio is not kept or the blood is diluted by crystalloid, the product will not have sufficient concentration to keep the patient alive.
- 30% of coagulation factor is needed to provide any hemostasis
PROPPR trial 2015 compared traditional ratio 1 : 1 : 1 vs platelet and plasma sparing ratio 1 : 1 : 2
- Showed a greater rate of death by bleeding in the platelet and plasma sparing ratio 1 : 1 : 2.
- However, was not sufficiently powered to show a difference in 30 day mortality
For more reading on MTP, check out our prior post

Urticaria:

Pause transfusion for 15 – 30 minutes
Monitor for additional allergic symptoms
Benadryl if needed
If case is mild and hives/pruritus resolves quickly, the transfusion can be resumed
Antigen-antibody interaction between Pt and the product secondary to donor serum proteins

Transfusion-related acute lung injury (TRALI):

Presentation and pathophysiology:
- New ALI/ARDS during or within six hours after blood product administration
- Leading cause of transfusion-related mortality in USA
- Mortality rates of 13 to 21% (35 to 58% in critically ill)
- May occur with all blood products
- Greater risk with high-plasma-volume components such as plasma, apheresis platelet concentrates, and whole blood
- Possible mechanism is “two-hit”
  - First hit: neutrophil sequestration and priming in the pulmonary capillaries
  - Second hit: activation of recipient neutrophils by some factor(s) in the blood product
- Result is pulmonary capillary endothelial damage (Non-cardiogenic pulmonary edema)
- Dyspnea and hypoxia usually within 1-2 hours
  - Onset is within minutes in most
- Fever and hypotension in ⅓
- Cyanosis in ¼
- May have acute drop in neutrophils (due to sequestration)
Diagnosis
- Dx requires absence of ARDS risk factors (pneumonia, sepsis, toxic inhalation, trauma, pancreatitis, etc.)
- DDx:
  - TACO (but Pt may have both TRALI and TACO and more common in the ICU);
  - Hemolytic Rxns (more fever and chills- ABO incompatibility, intravascular hemolysis with positive direct Coombs);
  - Anaphylaxis;
  - Septic shock (platelets contaminated with bacteria).
Management
- Stop transfusion;
- Labs: CBC, bili, haptoglobin, Coombs, BNP and HLA Ag typing
- Supportive care; supplemental O2; majority require intubation
- Patient may still receive blood products but from a different donor (report case to blood bank)

Anaphylactic transfusion reaction

Proceed as you would for standard anaphylaxis treatment
Test for IgA levels and anti-IgA
- IgA will be absent in IgA deficiency

Acute hemolytic reaction

ABO incompatibility
Symptoms:
- Flank pain,
- Hypotension,
- DIC
Labs:
- Serum haptoglobin,
- LDH and
- Unconjugated bilirubin levels
Treatment
- IV fluids to decrease complications of free hemoglobin (AKI, DIC, vasospasm)
Contact blood bank

Non-hemolytic febrile reaction

Mild but have to exclude acute hemolytic reaction (AHTR), sepsis or TRALI
Cytokines are generated and accumulate during product storage
- Cytokines from WBCs in a product that was not leukoreduced
Tylenol for fever
- Avoid ASA
Similar reaction in platelet transfusions but without fever

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