Massive Transfusion-Associated Coagulopathy

Massive transfusion associated coagulopathy is a bleeding disorder that develops during or after replacement of a large volume of blood (over 10 units of red cells in 24 hours, or more than half of the blood volume in 3 hours). It is a mixture of dilution, consumption, hypothermia, acidosis, hypocalcemia and hyperfibrinolysis, added to pre-existing trauma-induced coagulopathy.

Mechanisms

• Dilution of clotting factors and platelets by red cells and crystalloid that contain none (stored red cell units have almost no platelets and low factor V and VIII)
• Consumption of platelets and fibrinogen at the injury site
• Hypothermia (below 34 degrees Celsius), which slows enzyme reactions and impairs platelet function
• Acidosis (pH under 7.2), which reduces factor Xa and thrombin generation by half or more
• Citrate toxicity, causing hypocalcemia (citrate in blood products binds calcium) and impairing clotting and cardiac function
• Hyperfibrinolysis: raised tissue plasminogen activator from hypoperfusion

Fibrinogen is the first factor to fall to critical levels in trauma and obstetric bleeding. Established coagulopathy increases mortality several-fold. Complications: refractory bleeding, transfusion reactions, hypocalcemia with arrhythmia, hyperkalemia, acute respiratory distress syndrome, thrombotic events later and multiorgan failure.

• Diffuse oozing from wounds, surgical sites, cannulae and mucosa, and non-clotting blood
• Bruising, hematuria, hematemesis and bleeding from drain sites
• Hypothermia and hypotension that persist despite replacement
• Prolonged tremor, arrhythmia and low blood pressure from hypocalcemia
• Red flags: bleeding at several sites, temperature under 35 degrees Celsius, pH under 7.2, and ionized calcium under 0.9 mmol/L

1. Laboratory tests repeated every 30 to 60 minutes during active bleeding: prothrombin time and INR, activated partial thromboplastin time, fibrinogen (Clauss method), platelet count, hemoglobin, ionized calcium, potassium, lactate and blood gases.
2. Viscoelastic testing (thromboelastography or rotational thromboelastometry) gives rapid results at the bedside. Thresholds that guide therapy:
   • Prolonged clotting time or reaction time suggests factor deficiency.
   • Low clot amplitude (A5 under 35 mm or maximum amplitude under 50 mm) suggests low fibrinogen or platelets.
   • Clot lysis (LY30 over 3 to 7.5%) shows hyperfibrinolysis.
3. Temperature and pH monitoring.
4. Search for surgical bleeding, since coagulopathy does not explain bleeding from a large vessel.

Differentials: surgical bleeding, disseminated intravascular coagulation, anticoagulant effect, platelet dysfunction from drugs, uremia, transfusion reaction and liver disease.

Treat early and by ratio, and aim for targets.

1. Stop bleeding by surgery, packing or embolization. Coagulopathy cannot be corrected while a vessel bleeds.
2. Balanced resuscitation: red cells, plasma and platelets in a 1:1:1 ratio (for example, 6 units of red cells, 6 of plasma and 1 adult dose of apheresis platelets), with early plasma. Low-titer whole blood is an option.
3. Tranexamic acid: 1 g IV over 10 minutes, then 1 g IV over 8 hours (children 15 mg/kg bolus, maximum 1 g, then 2 mg/kg/h for 8 hours), ideally within 3 hours of injury.
4. Calcium: calcium chloride 1 g IV (10 mL of 10%, through a central or large vein) after every 4 units of blood, to maintain ionized calcium over 1.1 mmol/L.
5. Fibrinogen: cryoprecipitate 10 units (2 pools) or fibrinogen concentrate 3 to 4 g IV when fibrinogen is under 1.5 to 2.0 g/L (under 2.0 g/L in obstetric hemorrhage), and repeat by level.
6. Platelets: transfuse to keep over 50 × 10^9/L (over 100 × 10^9/L with brain injury or ongoing severe bleeding).
7. Prothrombin complex concentrate 25 units/kg IV (four-factor) for a persistently prolonged INR over 1.5 after plasma, and for anticoagulant-related bleeding.
8. Recombinant activated factor VII 90 micrograms/kg IV only as a last resort after other measures, with a thrombotic risk.
9. Prevent the lethal triad:
   • Warm all blood and fluid (blood warmer), forced-air warming, and room temperature over 25 degrees Celsius, with a target above 36 degrees Celsius.
   • Correct acidosis by restoring perfusion, and use sodium bicarbonate 50 mmol IV only for pH under 7.1 with ongoing resuscitation.
10. Hyperkalemia from stored red cells: calcium chloride 1 g IV, and insulin 10 units IV with 50 mL of 50% dextrose.
11. Cell salvage where safe, and avoid hypotonic crystalloid.
12. Desmopressin 0.3 micrograms/kg IV over 20 minutes for uremic or antiplatelet-related bleeding only.

Targets: hemoglobin over 80 g/L, platelets over 50, fibrinogen over 1.5 to 2 g/L, INR under 1.5, ionized calcium over 1.1 mmol/L, pH over 7.2 and temperature over 36 degrees Celsius.

Once bleeding stops, start thromboprophylaxis (enoxaparin 40 mg SC daily) within 24 to 48 hours. Monitor for transfusion-related lung injury and circulatory overload, and follow up renal function and counts.