Blood Transfusion and Coagulopathy

Allogenic Blood Products

1. Whole Blood
Limited indications and rarely used.
- mainly used in military setting and field emergencies.
Stored in 500mL bags, last only 35d
Does not expose donors to multiple sources.

2. Packed RBCs
Provides oxygen carrying capacity to tissues
Indicated for shock, ongoing haemorrhage, marked anaemia
- loss of 30% of blood volume generally requires transfusion.
- symptoms of anaemia unlikely to manifest until Hb <70-80.
- restrictive transfusion at trigger of 70, with goal of maintaining 70-90, reduces mortality in critically ill (TRIGG trial)
--> and does not worsen outcomes in patients with cardiac comorbidities
Use depends on volume status, age, comorbidities
Increase Hb 10 or Hcrit by 3%
Safety and immunity
Data on transfusion safety is variable
- some studies show increases in infections, stroke and death from transfusion
- transfusion has an immunosuppressive effect
- essentially post-operative patients should have same cutoff of about 70, based on evidence from thoracic surgery / cardiac patients.
Leukocyte reduction in the blood reduces some bad effects of transfusions; immunological, fevers, reactions
--> but added cost means that removing leukocytes not often done.
Washing RBCs removes plasma proteins and is indicated in patients with allergic reactions.
Radiation eliminates T lymphocytes and reduces graft v host in bone marrow pts.

3. Plasma
Provides coagulation factors, including fibrinogen, vWF, vit K-dependent coagulation factors-II, VII, IX, X, and VIII and XIII.
Frozen at -18o and stored up to 1y
- 1u is 250ml and provides factors for a 70kg pt.
FFP indicated for coagulated defects and rapid reversal of anticoagulants.
- e.g. if INR >1.6
Guidance by clinical bleeding assessment and quantitative coagulation tests, including point-of-care tests (thromboelastograph)

4. Cryoprecipitate
Certain factors precipitate out of plasma in the cold, these provided by cryo
Fibrinogen, fibronectin, factors VIII, XIII and vWF
Indicated for pts with fibrinogen deficit, factor XIII deficit, massive transfusion and platelet dysfx due to renal disease
10u of cryo contain 2g of fibrinogen and raise fibrinogen by 60g/L
Give when fibrinogen drops below 100g/L in setting of bleeding or ongoing transfusion.

Coagulation cascade
image
http://www.frca.co.uk/article.aspx?articleid=100096
Balanced by endogenous antithrombotic proteins - C, S, antithrombin III and thrombomodulin, negative feedback.
- fibrinolytic system also plays a role in limiting the extent of clot formation.

5. Platelets
Collected from whole blood donation or apheresis (platelet donation)
50mL suspension; typically six pooled concentrates given in one administration.
Indicated for bleeding with platelets <50,000.
Also operations at <50,000, invasive procedures at <20,000 and <10,000 if stable without bleeding.
Should increase 5000-10000

6.  Autologous Blood
Viable option for patients scheduled for OT who very likely will need transfusion.
Particularly for rare blood types or antibodies
Prevents cross infection, transfusion reactions and immune effects.
Typically, donors give 1U every 8 weeks; donation here is weekly at 3-5w before surgery, with a gap to surgery.
- give iron, need starting Hb > 110.

Massive Transfusion

>1 blood volume in 24h OR >50% blood volume in 4hr

Many arrive coagulopathic
- hypothermia <35, coagulopathy and acidosis is classic lethal triad.
- hypothermia impairs platelet and coag factor function
- acidosis impairs coagulation factor function
- and dilutional coagulopathy results from excessive crystalloid administration.

Parameters that must be monitored
- temperature (>35)
- acid-base status (>7.2;  base excess <-6, or lactate <4)
- ionized calcium >1.1
- Hb = not a transfusion trigger alone; used in combination with other parameters
- platelets >50
- PT/APTT <1.5x normal
- fibrinogen >1 g/L

Standard tests
- PT and APTT do not detect all abnormalities;
Point of care testing is activated clotting time, TEG and bedside tests
- but regulatory and training burden make this difficult to widely implement

Military experience shows that survival improved with high ratio of blood:plasma:platelets
- exact ratio not established but moving toward 1:1:1
- currently 1:1.5 FFP to blood is associated with improved outcome

Institutional massive transfusion protocols serve to deliver aggressive component therapy to at risk pts needing massive transfusions.
- initated on criteria such as arrival systolic <90, HR >120, unstable pelvic #, pH <7.25, penetrating mechanism and +ve fast
- components delivered in packs, eg with 6u blood and 6u FFP, next one will be same with platelets.
- variable protocols includes use of cryo and recombinant factorVII
- cryo often given with a third package after 12u of packed cells.
- plasma is a priority; some EDs will have frozen plasma for very rapid availability.

Factor VII
?
Initiator of thrombin generation and rFVIIa complexes with TF.
Military work shows when given with 8u transfusion, reduces transfusion requirements, but very expensive and cost-effectiveness not established.

Coagulopathy of Trauma

Classic lethal triad
image
Synergise to create a spiral of worsening bleeding.
Genetic factors in fibronolysis proteins may help develop more severe bleeding in some pts.
Calcium is a critical cofactor in the cascade
- hypocalcemia can follow physiologic response to shock, hemodilution.

Endothelial cell trauma
Endothelial cell damage over a large trauma area triggers widespread activation of platelets and coagulation factors
May activate hemostatic system such that coag factors are consumed and platelets exceed production capabilities of liver and marrow
--> consumptive coagulopathy.
Can get paradoxical over-activation of anti-clotting pathways by this same mechanism, worsening bleeding without coagulation product depletion.

Other factors discussed in above section also contribute

Diagnostic Testing

Baseline coags on all pts: PT, APTT and prothombin, platelet count (may not define function)
- independent predictors of death when abnormal.
Point of care testing can be done with thromboelastography
 - specialist knowledge but can predict fibrin and clotting factor levels / function using output plots.

Management
1. PRBCs
- O2 transport, ADP/ATP for platets, and displace platelets to periphery of bloodstream
- balance use vs risks below but also dilution of clotting factors
- reduce need by hypotensive management, cell-savers intraoperatively, <70 limits on transfusion in ICU

2. FFP and platelets
- military ratio 1:1; civilian ratio 1:1.5 blood to plasma.
- 1:1:1 with platelets now becoming more prominent theory for optimal adminstrations.

Complications of Transfusion

1. Infectious diseases
- now very uncommon risk; 1:>2million per unit blood for HIV, 1-3M for HCV, 3M for HTLV
- but much higher for HBV; risk is 1:30,000 to 205,000
- risk of CMV is 1% (only if getting non leukocyte depleted blood); higher if immunocompromised, hence leukodeplete prior.
- EBV rare transmission as >90% adults have antibodies anyway
- plasma products can pool many donors; screened for rarer problems like parvovirus B19 (ubiquitous but can cause viraemia)
- blood also screened for west nile virus infection although v. rare
Emerging concern for vCJD
- no reported cases of transfer by transfusion; but filtration under investigation.
Decreased by donor screening, screening of serological markers and nucleic acid testing

2. Transfusion -associated sepsis
Top three causes of transfusion associated mortality
Bacterial contamination from skin, break in sterile technique or to blood storage.
- much bigger problem in room temp platelet storage
Evidenced by onset of febrile symptoms, rigors then sepsis, rapidly progressive.
- case products, administer ABx and treat as reqd.

3. Febrile nonhemolytic transfusion reaction
- common to get cytokin release from recipient antibodies against donor leukocytes or platelets
- temp increase >1o after transfusion, no other cause
- hemolysis, TAS and anaphylaxis must be ruled out.

4. Heamolytic reactions
Immune mediated lysis of RBCs
- can be early or delayed, intra or extracascular
- acute = incompatible ABO; also kidd or duffy systems
- complement and cytokine activation can also occur - imediate emergency
- send component to blood bank with new cross matching
IV fluids to maintain renal erfusion; prevent tubular necrosis
Diuretics
Lab evaluation for hemoglobinuria; monitor for DIC
Direct Coombs test positive / diagnostic
Extravasacular = no complement activation; antibody coated cells cleared in spleen or liver
- no red cell lysis; increased bilirubin, not an emergency, but low grade fever and symptoms

5. Transfusion-Related Acute Lung Injury
TRALI
Leading cause of transfusion-associated death
Same manifestations as ARDS within 6h of transfusion with no other risk fx for ARDS
- but may be delayed
Mechanism may be antibody mediated related to leukocyte antigens; and / or underlying endothelial activation in lungs in these pts; primed
Prevent by no unnecessary transfusions.
Supportive care.

Immunomodulation

Transfusions improve renal allograft success rate; are immunosuppresive
- suppression effect on leukocyte function
Also has proinflammatory effects
May activate latent viruses eg CMV
Immunomodulation extends to reducing Crohn's risk and spontaneous abortion.

Peri-op infx
Consistently shown that infectious complications increased when blood transfusion required.
Cause effect relationship unclear
Effect of leukocyte depletion variable on this.

Cancer Recurrence
Immunosuppresion reduces natural cancer surveillance
Increased cancer recurrence in all areas studied except cervix.
- independent prognostic factor.

Multiple Organ Failure
Increase in SIRS and MOF in trauma; dose response relationship with amount of transfused blood

Red Cell Storage Duration
Accumulation of degradation products may be harmfull; worse outcome iwth old blood.
Exact effects need more research

Leukocyte reduction
Several RCTs on benefits of leukocyte reduction.
Significant heterogenity = unceratin overall benefit; not recommendd beyond immunocompromised or prevention of febrile reactions

Blood substitutes

Hemoglobin-based oxygen carriers
Several advantages including availability, supply, saftey.
Commercially available products but uncertain safety prevents FDA approval.
- toxicity of hemoglobin oxygenation and reactiv eO2 species.