Massive haemorrhage and transfusion

Contents

Definition

Massive haemorrhage is variably defined, but clinical consensus criteria include:

  • Loss of ≥1 blood volume (approximately 5L in a 70 kg adult) within 24 hours
  • Loss of >50% blood volume within 3 hours
  • Requirement for ≥10 units of packed red blood cells (pRBC) within 24 hours
  • Ongoing haemorrhage requiring activation of a massive haemorrhage protocol

The massive haemorrhage protocol (MHP) should be activated early — waiting for all criteria to be met before activation risks arriving too late with blood products.

Coagulopathy of trauma arises from tissue injury, hypoperfusion, haemodilution, acidosis, and hypothermia — often present before large-volume transfusion begins (the "lethal triad" of coagulopathy, hypothermia, and acidosis are mutually exacerbating).

Damage Control Resuscitation

Damage control resuscitation (DCR) is a philosophy shift from traditional crystalloid-heavy resuscitation to haemostasis-first management:

1. Permissive Hypotension

  • Target SBP 80–90 mmHg (MAP ~50 mmHg) until surgical haemostasis is achieved
  • Rationale: higher BP drives ongoing haemorrhage and washes out formed clot; low BP is tolerated briefly in otherwise healthy trauma patients
  • Exceptions:
    • TBI: cerebral perfusion must be maintained — permissive hypotension is contraindicated; target SBP ≥110 mmHg
    • Spinal cord injury: maintain spinal cord perfusion pressure — target MAP ≥85 mmHg
    • Elderly or pre-existing hypertension: less physiological reserve; use caution

2. Haemostatic Resuscitation

  • Prioritise blood products over crystalloid; minimise saline (dilutes clotting factors, worsens acidosis)
  • Target 1:1:1 ratio of pRBC : FFP : platelets (see below)

3. Early Surgical Control

  • "Damage control surgery": haemostasis first (pack, ligate), definitive repair later after physiological stabilisation
  • Interventional radiology (embolisation) for solid organ and pelvic arterial haemorrhage

4. Calcium

  • Massive transfusion depletes ionised calcium (citrate anticoagulant in blood products chelates Ca²⁺)
  • Target ionised calcium >1.1 mmol/L throughout resuscitation
  • Give 10 mL 10% CaCl₂ per 4 units of pRBC as empirical replacement (or guided by point-of-care measurement)
  • Calcium is an essential cofactor for the coagulation cascade and myocardial contractility; hypocalcaemia causes cardiac depression

5. Hypothermia Prevention

  • Transfuse through a fluid warmer
  • Warm environment in trauma bay and theatre
  • Target core temp >35°C; hypothermia impairs enzyme-mediated coagulation

Haemostatic Resuscitation

1:1:1 Ratio

PROPPR Trial (Holcomb et al, JAMA 2015): 680 severely injured trauma patients randomised to pRBC:FFP:platelet ratio of 1:1:1 vs 1:1:2. The 1:1:1 group achieved haemostasis more frequently (86% vs 78%) and had improved 24-hour survival. No significant difference in 30-day mortality overall, but the 1:1:1 ratio is now standard.

Practical points:

  • FFP: 10–15 mL/kg repletes all clotting factors; requires thawing (30 min); one unit ≈ 250 mL
  • Platelets: target >50 ×10⁹/L during active haemorrhage (>100 ×10⁹/L for TBI or ophthalmic surgery)
  • Cryoprecipitate: concentrated fibrinogen, vWF, factor VIII, factor XIII; give when fibrinogen <1.5–2 g/L; fibrinogen is the first factor to deplete

Fibrinogen

  • The coagulation factor that depletes earliest in haemorrhage
  • Target fibrinogen >1.5–2 g/L during active bleeding
  • Replace with cryoprecipitate (10 units raises fibrinogen by ~1 g/L in an adult) or fibrinogen concentrate (Haemocomplettan/RiaSTAP — dose-calculated)
  • FIBTEM (ROTEM parameter) measures fibrin contribution to clot strength — guides targeted replacement

Prothrombin Complex Concentrates (4F-PCC)

  • Contains factors II, VII, IX, X and proteins C and S
  • Rapid reversal of warfarin or factor deficiency
  • Use in warfarin-related haemorrhage or when FFP cannot be given rapidly enough (requires large volumes, ABO-compatibility)
  • Increasingly used in DCR alongside FFP

Tranexamic Acid (TXA)

Mechanism: competitive inhibitor of lysine binding sites on plasminogen → prevents fibrinolysis (inhibits breakdown of formed clot)

Dose: 1g IV over 10 minutes, then 1g over 8 hours

CRASH-2 Trial (Roberts et al, Lancet 2010)

  • 20,211 trauma patients with significant haemorrhage or at risk of haemorrhage
  • TXA within 3 hours vs placebo
  • Significant reduction in all-cause mortality and death from haemorrhage
  • If given after 3 hours: increased risk of death from haemorrhage (fibrinolysis may be protective at this stage)
  • Conclusion: give TXA as soon as possible, within 3 hours; do not give after 3 hours

MATTERs study (Morrison et al, Archives of Surgery 2012): observational study in combat casualties; TXA associated with significantly lower mortality, particularly in those requiring massive transfusion.

TXA in obstetric haemorrhage (WOMAN trial, Roberts et al, Lancet 2017): TXA reduced death from postpartum haemorrhage when given within 3 hours; no increase in thromboembolic complications.

Viscoelastic Testing — ROTEM and TEG

Standard coagulation tests (PT, APTT, fibrinogen) take 45–90 minutes and assess isolated elements of coagulation. Viscoelastic testing (ROTEM or TEG) provides whole blood coagulation assessment at the point of care within 10–15 minutes.

ROTEM Parameters

Test Measures
EXTEM Extrinsic pathway (PT equivalent); overall clot quality
INTEM Intrinsic pathway (APTT equivalent)
FIBTEM Fibrin contribution to clot (EXTEM with platelet inhibition); guides fibrinogen replacement
APTEM EXTEM + aprotinin; confirms hyperfibrinolysis if EXTEM improves
HEPTEM INTEM + heparinase; detects heparin effect

Key parameters:

  • CT (clot time): time to clot formation; prolonged = factor deficiency
  • CFT (clot formation time): rate of clot strengthening; prolonged = fibrinogen/platelet deficiency
  • MCF (maximum clot firmness): clot strength; low = platelet deficiency (EXTEM) or fibrinogen deficiency (FIBTEM)
  • ML (maximum lysis): clot breakdown; >15% ML = hyperfibrinolysis → give TXA

Clinical benefit

ROTEM/TEG guidance allows targeted blood product replacement rather than empirical FFP/platelet giving, reducing transfusion volumes and waste. Multiple RCTs in cardiac surgery show reduced transfusion with viscoelastic-guided algorithms; trauma evidence is strong observationally and increasingly supported by trials.

Transfusion Thresholds (Outside Active Haemorrhage)

TRICC Trial (Hébert et al, NEJM 1999): 838 critically ill patients; Hb threshold 70 g/L vs 100 g/L → no mortality difference; restrictive strategy (Hb 70) non-inferior and associated with reduced cardiac events in non-cardiac patients.

Clinical context Hb threshold to transfuse
General ICU patients 70 g/L
Acute coronary syndrome / cardiac surgery 80 g/L
Symptomatic anaemia (regardless of Hb) Consider transfusion
Active haemorrhage Not threshold-based — resuscitate with 1:1:1 ratio

Single-unit transfusion followed by reassessment is preferred over multi-unit empirical transfusion.

Complications of Massive Transfusion

TACO (Transfusion-Associated Circulatory Overload)

  • Most common cause of serious transfusion-related morbidity and mortality
  • Cardiogenic pulmonary oedema from volume overload
  • Risk factors: pre-existing cardiac/renal disease, rapid infusion rate, elderly
  • Presentation: dyspnoea, hypertension, pulmonary oedema within 6h of transfusion
  • Management: diuretics, slow infusion, treat underlying condition

TRALI (Transfusion-Related Acute Lung Injury)

  • Non-cardiogenic pulmonary oedema (ARDS pattern) within 6h of transfusion
  • Mechanism: donor anti-HLA or anti-neutrophil antibodies activate recipient neutrophils in pulmonary vasculature → inflammatory cascade
  • Presentation: acute hypoxaemia, bilateral infiltrates, fever; PCWP normal (unlike TACO)
  • Management: supportive; usually resolves in 24–96h; report to blood bank; implicated product withdrawn
  • Prevention: male-only or never-pregnant-female donors for FFP reduces risk

Other Complications

Complication Mechanism
Hypocalcaemia Citrate chelation of Ca²⁺
Hyperkalaemia Potassium leaks from stored red cells (older blood)
Hypothermia Cold blood products without warming
Dilutional coagulopathy Large-volume pRBC without FFP/platelets
Transfusion reactions ABO incompatibility (clerical error), febrile non-haemolytic, allergic
Transfusion-transmitted infection Bacterial, viral — very rare with modern testing

Key Trials

Trial Year Question Finding
CRASH-2 (Roberts, Lancet) 2010 TXA vs placebo in trauma haemorrhage TXA within 3h reduces mortality; harmful after 3h
PROPPR (Holcomb, JAMA) 2015 1:1:1 vs 1:1:2 pRBC:FFP:platelet ratio 1:1:1 improved haemostasis and 24h survival
TRICC (Hébert, NEJM) 1999 Hb 70 vs 100 g/L transfusion threshold in ICU Restrictive (70 g/L) non-inferior to liberal strategy
WOMAN (Roberts, Lancet) 2017 TXA in postpartum haemorrhage TXA within 3h reduced haemorrhage death; safe

Viva Questions

1. What is damage control resuscitation and how does it differ from traditional fluid resuscitation in trauma?

Traditional trauma resuscitation used large volumes of crystalloid to restore blood pressure, which diluted clotting factors, worsened hypothermia, and disrupted forming clots — perpetuating coagulopathy and haemorrhage. Damage control resuscitation replaces this with three principles: permissive hypotension (targeting SBP 80–90 mmHg until surgical haemostasis, accepting temporary underperfusion to reduce hydraulic pressure on bleeding vessels and preserve clot); haemostatic resuscitation (blood products in a 1:1:1 ratio of pRBC:FFP:platelets rather than crystalloid, replacing like-for-like and preventing dilutional coagulopathy); and early surgical source control. TXA is given within 3 hours to preserve clot integrity. Calcium replacement is essential throughout. The goal is to restore the three elements of Virchow's triad in favour of haemostasis: warm, non-acidotic, coagulation-competent blood in the vasculature, rather than maximising blood pressure at the cost of exsanguination.

2. Explain the mechanism and evidence for tranexamic acid in trauma.

Tranexamic acid (TXA) competitively inhibits the binding of plasminogen to fibrin, preventing its conversion to plasmin and thereby blocking fibrinolysis. This preserves formed clots rather than promoting new clot formation. In trauma, activation of the fibrinolytic system occurs early after major injury, contributing to what is now termed "acute traumatic coagulopathy." TXA prevents the premature breakdown of clots at injury sites. The CRASH-2 trial (2010) randomised over 20,000 trauma patients to TXA or placebo within 8 hours — TXA within 3 hours significantly reduced all-cause mortality and death from haemorrhage with no increase in thromboembolic events. Critically, TXA given after 3 hours from injury was associated with increased haemorrhage death, suggesting that at later time points, fibrinolysis is no longer pathological (or may be protective). The implication is clear: give TXA as early as possible, within 3 hours of injury, and never if more than 3 hours have elapsed.

3. What are the differences between TACO and TRALI, and how do you distinguish them?

Both present with acute hypoxaemia and bilateral pulmonary infiltrates during or within 6 hours of blood product transfusion, but their mechanisms and management differ. TACO is cardiogenic pulmonary oedema from fluid overload: excess volume raises PCWP, forcing fluid into the alveoli. It is more common in patients with pre-existing cardiac or renal disease or when transfusion is rapid. Clinical features include hypertension, elevated JVP, and a BNP rise; PCWP is elevated on invasive monitoring; CXR shows cardiomegaly and bilateral infiltrates. Management: diuretics, fluid restriction, slow transfusion rate. TRALI is non-cardiogenic acute lung injury caused by donor anti-HLA or anti-neutrophil antibodies activating recipient neutrophils in the pulmonary microvasculature, causing capillary leak and bilateral infiltrates that clinically resemble ARDS. PCWP is normal; there is often fever; the patient may be hypotensive rather than hypertensive. Management is supportive — most cases resolve in 24–96 hours. The implicated blood product should be reported to the blood bank.

4. How would you manage a patient with major haemorrhage on warfarin (INR 5.2)?

Anticoagulant reversal is urgent. Four-factor prothrombin complex concentrate (4F-PCC; Beriplex or Octaplex) is first-line: it immediately replaces factors II, VII, IX, and X and provides faster, more complete INR correction than FFP. The dose is weight-based and INR-guided (typically 25–50 units/kg for an INR >5). Give 10 mg vitamin K IV concurrently for sustained reversal (FFP and PCC are temporary without endogenous factor regeneration). FFP (15 mL/kg) is an alternative if PCC is unavailable but is slower, requires volume loading, and takes time to thaw. Continue with haemostatic resuscitation principles (1:1:1 blood products, TXA if trauma, calcium replacement, warming). Monitor the INR and repeat PCC if haemostasis is not achieved. Simultaneously: surgical or interventional radiology control of the bleeding source; concurrent activation of the massive haemorrhage protocol; clear communication with haematology and blood bank.