Submitting InstitutionQueen Mary, University of London
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences, Neurosciences
Summary of the impact
The discovery of an early Acute Traumatic Coagulopathy (ATC, a syndrome
of abnormal clotting after trauma) by Professor Brohi's team in 2000, and
subsequent work building on that pivotal discovery, has led to [A] a new
understanding of why patients bleed to death after severe injury and
resulted in [B] a fundamental change in resuscitation strategy for acute
bleeding patients (`Damage Control Resuscitation') that has led to [C] a
250-300 per cent improved survival in massively bleeding trauma patients.
Discovering the character and mechanism of ATC has led to [D] new research
in diagnostics and therapeutic opportunities to further improve outcomes.
These rapid changes have led to [E] new forums for professional education
and [F] improved public understanding of science and medicine.
Trauma remains one of the world's biggest contributors to the global
burden of disease. The increasing burden is highest in young adults and
children, with 90,000 deaths each year in the EC in people under 30, half
of which are due to bleeding. The UK mortality for bleeding trauma
patients requiring a massive transfusion approaches 50 per cent.
Loss of clotting function in severe bleeding was known about before 2003.
But up to this point it was thought to be a late phenomenon, primarily due
to loss or dilution of coagulation factors. Bleeding patients initially
received intravenous volume resuscitation with packed red cells or
crystalloid solutions. Later (usually only after a massive transfusion),
the volume of fluid would lead to a dilutional coagulopathy which would be
identified using standard laboratory tests of coagulopathy and usually
treated with a small dose of fresh frozen plasma. We now know that this is
too little, too late — and Brohi's research has been the main driver for
this dramatic shift in the management of bleeding trauma patients.
Discovery of Acute Traumatic Coagulopathy (ATC)
In 2000, Brohi performed a retrospective study analysing blood samples
from trauma patients brought in by the Helicopter Emergency Medical
Service at Barts Hospital. He identified that one in four patients already
had an established coagulopathy on arrival and that, if present, it was
associated with a four-fold increase in mortality. This study was
submitted for publication in 2001. It took two years for Journal of
Trauma to accept it, primarily because reviewers could not believe
the results. Eventually published in 2003 , this work was subsequently
replicated in studies in the USA, Europe and Australia. Brohi's team at
Queen Mary have since focused on understanding the mechanisms underlying
coagulopathy in trauma, characterisation of ATC, developing diagnostic
tests for its identification and new therapies, and management strategies
for its treatment. This work has been supported in part by a £2m NIHR
Programme Grant for Applied Research.
Characterisation of ATC
The Centre for Trauma Sciences, led by Brohi, showed that ATC is an
endogenous coagulopathy caused by a maladaptive response to severe trauma
and blood loss . They have discovered that ATC is a unique coagulopathy
in that it is characterised by a systemic activation of anticoagulation
and fibrinolysis . Blood clots are therefore poorly formed and rapidly
broken down. With collaborators, Brohi's team have identified a novel
mechanism for coagulopathy — activation of the anticoagulant protein C
pathway, which is a new target for drug discovery .
Diagnosis of ATC
Standard tests of coagulation in trauma are the laboratory tests of
clotting activation, such as the prothrombin time (INR). Brohi's team have
shown that these tests are not available in a timeframe that is able to
effectively guide management in these rapidly bleeding patients . They
have also shown that it is impossible reliably to clinically predict who
will get ATC and need a massive transfusion . Since ATC is primarily a
problem of clot strength and clot breakdown, standard laboratory clotting
times are insensitive to its presence. Brohi's group have shown that a
newer diagnostic device — thromboelastography — can identify patients with
ATC within five minutes of arrival in the A&E department and have
determined a diagnostic threshold for this condition. They have also
discovered, however, that these devices are insensitive to the clot
breakdown component of ATC and that new diagnostics will be needed in this
Treatment of ATC
Discovery of the underlying mechanisms of ATC has led to new therapeutic
approaches. Research by the Brohi group has shown that fibrinogen
deficiency is a key early component of ATC. They have shown that this loss
can be identified rapidly on thromboelastography and has the potential to
improve clotting function and survival if replaced early .
References to the research
1. Brohi K, Singh J, Heron M, et al. Acute traumatic
coagulopathy. The Journal of Trauma and Acute Care Surgery 2003;
54:1127-30. PMID: 12813333.
2. Frith D, Goslings JC, Gaarder C, Maegele M, Cohen MJ, Allard
S, Johansson PI, Stanworth S, Thiemermann C, Brohi K. Definition
and drivers of acute traumatic coagulopathy: clinical and experimental
investigations. Journal of Thrombolysis and Haemostasis 2010; 8:
1919-25. PMID: 20553376.
3. Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet
JF. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated
through the protein C pathway? Annals of Surgery 2007; 245: 812-8.
4. Davenport R, Manson J, De'Ath H, Platton S, Coates A, Allard
S, Hart D, Pearse R, Pasi KJ, MacCallum P, Stanworth S, Brohi
K. Functional definition and characterization of acute traumatic
coagulopathy. Critical Care Medicine 2011; 39: 2652-8. PMID:
5. Stanworth SJ, Morris TP, Gaarder C, Goslings JC, Maegele M, Cohen MJ,
König TC, Davenport RA, Pittet JF, Johansson PI, Allard S, Johnson T, Brohi
K. Reappraising the concept of massive transfusion in trauma. Critical
Care 2010; 14: R239. PMID: 21192812.
6. Raza I, Davenport R, Rourke C, Platton S, Stanworth S, MacCallum
P, Brohi K. The Incidence and Magnitude of Fibrinolytic Activation
in Trauma Patients. Journal of Thrombolysis and Haemostasis 2013;
11: 307-314. PMID: 23176206.
7. Rourke C, Curry N, Khan S, Taylor R, Raza I,
Davenport R, Stanworth S, Brohi K. Fibrinogen levels during
trauma hemorrhage, response to replacement therapy, and association with
patient outcomes. Journal of Thrombosis and Haemostasis 2012; 10:
1342-51. PMID: 22519961.
Details of the impact
4a: Change in management paradigm
The discovery of ATC has led to the development of a new management
strategy for patients with trauma-related bleeding — `Damage Control
Resuscitation'. A central tenet of this paradigm is `Haemostatic
Resuscitation' that targets ATC. Management has shifted dramatically from
awaiting and managing late coagulopathy to correcting ATC immediately with
rapid early administration of clotting factor therapies and avoiding
haemodilution. This resuscitation strategy has been widely adopted
internationally, in military and civilian arenas. See for example [8,9].
4b: Change in survival
Brohi's findings were first taken up by the British military, who saw
potential dramatically to reduce mortality rates if treatment was targeted
at ATC. Studies in the wars in Iraq and Afghanistan, for example, showed
that this approach appears to reduce mortality in severely bleeding
patients from 65 per cent to 19 per cent . These are retrospective
studies but have prompted prospective clinical trials, which are now
ongoing . Mortality rates for critical trauma patients in shock were
nearly three times lower at our own (Barts) Major Trauma Centre than
nationally (20 vs 55 per cent) when using a DCR approach to treatment
. These findings have been replicated internationally [eg 13].
4c: Change in policy / guidance
Based on the evidence above, both the USA and UK Surgeon Generals issued
`general standing orders' during the wars in Iran and Afghanistan that the
management of severe haemorrhage should target ATC with high-dose
coagulation therapies. The US Air Force General subsequently testified to
the US Senate that this resuscitation approach had saved lives . Our
work in developing a DCR transfusion protocol — called `Code Red' has now
been adopted by all major trauma centres in London and is being adopted
nationally and internationally. This coagulation- centric approach has
been incorporated into UK national transfusion guidelines from the
Association of Anaesthetists of Great Britain and Ireland  and new
European Guidelines on the management of major haemorrhage . The
global Advanced Trauma Life Support Manual updated in 2012 includes
ATC-targeted therapy in its protocols . This approach to bleeding in
trauma is now also being applied to other forms of bleeding, most notably
post-partum haemorrhage, another of the world's major causes of death due
to haemorrhage .
4d: New research directions
New diagnostic tools
The work of Brohi's team has shown that ATC cannot be reliably predicted
from clinical signs and existing tests. There has been renewed interested
in emergency use of thromboelastography; many hospitals now have these
devices in their resuscitation rooms. But the current generation of
thromboelastography devices were not designed for the emergency
environment. Manufacturers are developing a new generation of devices for
this purpose and also for pre-hospital care. In particular, one
manufacturer has developed a `ruggedized' version of their device that has
been deployed in Camp Bastion in Afghanistan as well as in other conflict
zones around the world . Major manufacturers have joined a consortium
with Brohi to develop the next generation of machines and interfaces in
the EU FP7 programme "TACTIC" .
New treatments are being developed and evaluated specifically to treat
ATC. In simplest form, many hospitals have now put protocols in place to
have pre-thawed FFP in the trauma receiving room, and this is deployed on
some helicopters including emergency teams in Afghanistan. Several
clinical trials of blood-derived coagulation therapies directed at ATC are
underway. We are conducting the pilot CRYOSTAT trial of early
cryoprecipitate — the first joint military-civilian randomised controlled
trial. A large RCT of high-dose platelet therapy is underway in the USA,
and a trial of fibrinogen therapy delivered en-route in a helicopter is
underway in Austria. A large international trial of the antifibrinolytic
tranexamic acid has shown improved survival in bleeding trauma patients
and is being widely adopted worldwide . Several pharmaceutical
companies are developing new anti-ATC therapeutics, including Octapharma,
Astra-Zeneca and CSL-Behring.
The name `Acute Traumatic Coagulopathy' was ratified in a consensus
conference held on this coagulopathy in Chicago in 2008 . A further
consensus conference on coagulopathy in trauma was subsequently held
jointly by the US National Institutes for Health (NHLBI) and the
Department of Defence in Washington DC in 2010 , and again in Toronto
in 2012. This led to several specific grant calls for research into trauma
haemorrhage, including a large-scale programme from the US Army Combat
Casualty Care programme. Through such funding, Brohi and others have
developed experimental models of ATC to determine underlying mechanisms,
identify new targets for drug discovery and evaluate new treatments.
Large-scale human studies to elucidate mechanisms and underlying
propensities for ATC are underway in Europe and USA, and renewed interest
in bleeding in trauma has led to the development of research networks and
a general upswing in the volume and quality of trauma research.
4e: Professional education
New educational initiatives have been formed for dissemination of these
findings, including the `PerioperativeBleeding.org' (Austria, Germany),
the `International Symposium on Critical Bleeding' (Europe and North
America), `Educational Initiative for Critical Bleeding in Trauma'
(international) , and a `Trauma Coagulopathy & Transfusion
Masterclass' at the London Trauma Conference.
4f: Improved public understanding of science
Brohi's work on ATC and new resuscitation protocols was featured in New
Scientist "Code Red"  and in television programmes in the
Netherlands and Australia. The team have showcased their work to the
public at the Royal Society's Summer Science event 2011  and the Big
Bang Fair in Birmingham 2012.
Sources to corroborate the impact
- Holcomb JB, Jenkins D, Rhee P et al. Damage control
resuscitation: directly addressing the early coagulopathy of trauma. Journal
of Trauma & Acute Care Surgery 2007; 62: 307-10.
- Holcomb JB, Nunez TC. Damage control resuscitation. In Front Line
Surgery. Springer, 2011: 47-58.
- Borgman MA, Spinella PC, Perkins JG et al The ratio of blood
products transfused affects mortality in patients receiving massive
transfusions at a combat support hospital. J Trauma 2007; 63:
- Examples of ongoing trials that draw on this work: CRYOSTAT (http://www.controlled-trials.com/ISRCTN55509212),
FI in TIC (http://clinicaltrials.gov/show/NCT01475344).
- Davenport RA, Tai N, [...], Lecky F, Walsh MS, Brohi K. A
major trauma centre is a specialty hospital not a hospital of
specialties. British Journal of Surgery 2010; 97: 109-17.
- Duchesne JC, Islam TM, Stuke L et al. Hemostatic resuscitation
during surgery improves survival in patients with traumatic-induced
coagulopathy. J Trauma. 2009; 67: 33-7.
- Ellen Altman Milhiser, ed. Senate Appropriations Committee Defense
Subcommittee Hearing. Arlington, VA: Gray and Associates, LC,
March 18, 2009, p. 3.
- Thomas D, Wee M, Clyburn P, Walker I, Brohi K et al.
Blood transfusion and the anaesthetist: management of massive
haemorrhage. Association of Anaesthetists of Great Britain and Ireland.
Anaesthesia 2010; 65: 1153-1161.
- Spahn DR, Bouillon B, Cerny V, Coats TJ et al. Management of
bleeding and coagulopathy following major trauma: an updated European
guideline. Critical Care 2013; 17: R76.
- Advanced Trauma Life Support (ATLS). Student Course Manual 9th
Edition. Committee on Trauma of American College of Surgeons
- Onwuemene O, Green D, Keith L et al. Postpartum hemorrhage
management in 2012: predicting the future. International Journal of
Gynaecology Obstetrics 2012; 119: 3-5.
- Rugged ROTEM Delta — Role 2 Support. Available: http://rotem-aoa.com/role2.php.
- TACTIC: Targeted Action for Curing Trauma Induced Coagulopathy EU
- Shakur H, Roberts I, Bautista R et al. Effects of tranexamic
acid on death, vascular occlusive events, and blood transfusion in
trauma patients with significant haemorrhage (CRASH-2): a randomised,
placebo-controlled trial. CRASH-2 trial collaborators. Lancet
2010; 376: 23-32.
- Bouillon B, Brohi K, Hess JR, Holcomb JB, Parr MJ, Hoyt DB.
Educational initiative on critical bleeding in trauma: Chicago, July
11-13, 2008. J Trauma 2010; 68: 225-30.
- National Heart Lung & Blood Institute: Trans-Agency Coagulopathy
in Trauma Workshop Available: www.nhlbi.nih.gov/meetings/workshops/tactrauma.htm.
- Cohen D. Code Red: Repairing blood in the emergency room. New
Scientist 2835, 26th October 2011. www.newscientist.com/article/mg21228352.900-code-red-repairing-blood-in-the-emergency-room.html#.UjAo9BZurww
- Trauma: Science of the Bleeding Obvious. Royal Society Summer Science