Question 21

With respect to transfusion protocols for massive haemorrhage; discuss the advantages and disadvantages of using a protocol guided by thromboelastography (TEG guided) compared to one that uses a fixed ratio of product replacement (e.g. FFP : platelets : packed cells = 1 : 1 : 1).

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College answer

Background

Heterogeneous nature of the critically bleeding trauma patient and the spectrum of trauma induced coagulopathy may mean fixed ratio protocol (FRP) is too simplistic to apply to all patients. Although a FRP may improve survival, the optimal ratio of packed cells to other blood components is unknown. TEG-guided algorithms allow rapid identification and correction of patient-specific coagulation abnormalities. Trauma induced coagulopathy in the critically bleeding patient is complex and changes throughout time of resuscitation, therefore TEG allows repeated assessment and correction throughout resuscitation period.

TEG-guided MHP algorithms, as compared to FRP may limit unnecessary blood product transfusion and the associated complications (e.g. TRALI, volume overload) of giving high volumes of plasma and other products, while ensuring appropriate clotting factors are replaced as required (i.e. allows targeted intervention to replace coagulopathy with fewer side effects)

Advantages of TEG compared with FRP

Patient specific – therefore may limit unnecessary blood product transfusion and the associated complications (e.g. TRALI, transfusion reaction, volume overload, TACO, immunomodulation, allergy)

Patient specific – therefore ensures appropriate clotting factors are replaced when required (i.e. allows rapid targeted intervention to replace coagulopathy with fewer side effects)

Aids rapid identification of when there is an ongoing medical cause of bleeding (i.e. ongoing coagulopathy) versus purely surgical bleeding with the need to progress surgical intervention.

Detects fibrinolysis and hyperfibrinolysis which may be particularly relevant in the critically bleeding trauma patient.

TEGs have a higher sensitivity than standard laboratory tests to detect trauma induced coagulopathy and are faster than lab-based tests.

Even a 1:1:1 (plasma:platelets:packed cells) delivers dilute coagulation factors compared with whole blood; ideal ratio of blood products to packed cells in FRP remains debated.

Disadvantages of TEG compared with FRP

Machine (ROTEM or TEG) not available in all centres;

More expensive than standard laboratory coagulation testing

Ability to manage MHPs in multiple trauma patients simultaneously limited by number of machines available

Requires adequate volume of blood sample to run test and can’t be performed on intraosseous sample; therefore, may not be able to be performed on critically unwell patient with difficult iv access.

May delay lab preparation (thawing) of blood products while awaiting result; compared with fixed ratio protocol where products immediately thawed and delivered. (i.e. FRP allows rapid delivery of blood products independent of test results)

Requires interpretation of values to guide blood product use.

Not valid to assess effects of platelet function, direct thrombin inhibitors, LMWH, warfarin

Evidence

Controversial; evidence exists to support TEG in identifying trauma induced coagulopathy, but limited RCT trials on role of TEG-guided MHP algorithms

STATA trial currently ongoing (FRP vs thromboelastometry guided MHP in trauma patients)

Single centre RCT reports reduced blood transfusion rates and improved-survival with TEG-guided MHP (Gonzalez 2016) (compared with MTP guided by conventional coagulation assays)

Systematic review (2014) – 55 observational studies on use of TEG to guide blood product use in trauma:

Findings overall inconclusive
Only one cohort in one study with penetrating trauma and packed cells>10 showed improved mortality with TEG-guided MHP

FRP:

PROMMTT (2013): observational – higher ratios of plasma and platelets early → decreased mortality
PROPPR (2015): RCT severe trauma – 1:1:1 vs 1:1:2 (plasma:plts:packed cells)
- More haemostasis and less death due to exsanguination @ 24hr
- No overall difference in mortality at 24 hrs or 30 days
- better haemastasis & less death from exsanguination

Note: The level of detail in the evidence section was not expected.

Examiner Comments:

A very topical question that was generally answered in a very superficial way. Detailed reference to the weak evidence base was not required, but some recognition of this fact was expected. Better structure often ensured better marks.

Discussion

The examiners referred to TEG specifically in the question and throughout the answer, but it is clear that they were using the term interchangeably with ROTEM, and so in the discussion to follow TEG is also used as a surrogate for all forms of global testing for clotting function. Though the question asked specifically for a discussion of advantages and disadvantages, the college answer was formulated in a "critically evaluate" fashion which typically calls for a description of the rationale and supporting evidence As such, some mutant combination of the two answer formats is offered here, as a compromise which satisfies the authors' unhealthy preoccupation with tabulated answers.

Rationale for TEG-guided massive transfusion

Scenarios which call for massive transfusion are diverse in aetiology (variceal bleed, postpartum haemorrhage, ruptured AAA, anticoagulant toxicity)
Diversity of aetiology produces a diversity of transfusion requirements
Ergo, transfusion should be individually tailored wherever possible
Empirical replacement of whole-blood-like products may over-replace some products and under-replace others depending on the scenario
Individually tailored transfusion should therefore prevent wasteful use of blood products and increase the chances of correcting the coagulopathy
To tailor the transfusion process to an individual case requires the ability to monitor all aspects of clotting function including platelet function and fibrinolysis
TEG offers these capabilities in a single point of care test

A comparison of TEG and empirical massive transfusion
Advantages of TEG Rapid (10-20min) Cheaper than wasting blood products Conserves blood bank resources Rapidly becoming more common Tests fibrinolysis, which otherwise you cannot conveniently do Individualised care: compensates for intercase variability of clotting factor consumption Can be used to demonstrate that coagulopathy is fully corrected, as a means of promoting surgical management (i.e. excludes "medical bleeding")	Disadvantages of TEG Not as rapid as empirical transfusion (wastes valuable minutes) More expensive than coags if you incorporate the added recalibration and maintenance cost Rare in smaller and regional centres Assessment of fibrinolysis is often omitted in place of routinely giving (cheap, safe) tranexamic acid Requires training to use and interpret Precision is poor (UK NEQAS data) Does not account for coagulopathy of hypothermia Does not identify warfarin or most NOACs (Nielsen et al, 2013) - the findings are nonspecific (just long R time) TEG-guided algorithms do not enjoy widespread familiarity and are not universally accepted as valid
Advantages of fixed ratio massive transfusion Rapidly available (time-limited by the thawing of FFP only) Available almost everywhere Easily protocolised, i.e. easy to order and thus it does not divert focus from managing the trauma Cost of products themselves is the only expense; i.e. maintenance cost for the blood bank staff and equipment is not purely for support of MTPs. Widespread familiarity with the standard transfusion ratio Does not interfere with the use of TEG (i.e. one may simply order the MTP pack while waiting for the TEG sample to cook)	Disadvantages of fixed ratio massive transfusion The exact ration (eg. 1:1:1) is still a matter of debate The fixed ratio of products does not account for the possibility of fibrinolysis (sure, everybody gets tranexamic acid, but strictly speaking it is not part of the transfusion pack) The practice of fixed ratio massive transfusion is non-diagnostic, i.e. unlike TEG it is not an investigation of clotting function but rather a management protocol which is implemented before results are available. It does not give you any information by itself.

Evidence which compares TEG-guided protocols with fixed ratio transfusion

"Systematic review (2014)" mentioned by the college examiners is probably Da Luz et al (2014), a descriptive systematic review which used relaxed criteria to drag-net 55 studies (12,489 patients). TEG appeared to uncover all sorts of coagulopathies which would not have been discovered by conventional testing (eg. hypercoagulability, hyperfibrinolysis, platelet dysfunction) which was an interesting finding. Of the total 55 studies, only three were rated as having a low risk of bias.
Hunt et al (2015), on TEG in trauma-induced coagulopathy performed a meta-analysis using different criteria (Cochrane) and also only found the same three 3 studies worth analysing. which turned this into a narrative review. Even with the risk of bias being low, there was not enough data to make a call on this. "This evidence strongly suggests that at present these tests should only be used for research", the authors concluded.
Wikkelsø et al (2017) reviewed all the data on TEG use and found 17 trials with a total of 1493 participants; this was more favourable:
- Blood product use was demonstrably reduced
- Transition to surgery was not affected
- Mortality appeared to be lower in the TEG cohort as compared to historical controls (3.9% vs 7.4%) but it would be hard to attribute this to TEG use or to take it seriously in any other sense
- Evidence was largely of a low quality, and most of it came from trials involving cardiac surgical patients
STATA trial mentioned by the college examiners is currently in progress at the University of Sao Paulo General Hospital; interim analysis in 2015 demonstrated that the intervention group (TEG-guided) does not have any increase in their mortality or morbidity.
Gonzalez et al (2016) mentioned by the college examiners found an implausibly higher survival rate in their TEG group (19.6% vs. 36.4%) among a small cohort of trauma patients (n =111). Less plasma and platelet use was also noted, which is probably more objective and genuine.

References

Practical haemostasis - page on TEG and ROTEM

LITFL - Thromboelastogram

Sankarankutty, Ajith, et al. "TEG® and ROTEM® in trauma: similar test but different results." World J Emerg Surg 7.Suppl 1 (2012): S3.

Coakley, Margaret, et al. "Transfusion triggers in orthotopic liver transplantation: a comparison of the thromboelastometry analyzer, the thromboelastogram, and conventional coagulation tests." Journal of cardiothoracic and vascular anesthesia 20.4 (2006): 548-553.

Venema, Lieneke F., et al. "An assessment of clinical interchangeability of TEG® and ROTEM® thromboelastographic variables in cardiac surgical patients." Anesthesia & Analgesia 111.2 (2010): 339-344.

Nielsen, Vance G. "A comparison of the Thrombelastograph and the ROTEM." Blood Coagulation & Fibrinolysis 18.3 (2007): 247-252.

Wikkelsoe, A. J., et al. "Monitoring patients at risk of massive transfusion with Thrombelastography or Thromboelastometry: a systematic review." Acta Anaesthesiologica Scandinavica 55.10 (2011): 1174-1189.

Hunt, Harriet, et al. "Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma‑induced coagulopathy in adult trauma patients with bleeding." Cochrane Database of Systematic Reviews 2 (2015).

Nielsen, Jorn Dalsgaard, and Galloway Gregg. "Monitoring novel anticoagulants dabigatran, rivaroxaban and apixaban by thrombelastography. Proof of concept." (2013): 4813-4813.

Wikkelsø, A., et al. "Thromboelastography (TEG) or rotational thromboelastometry (ROTEM) to monitor haemostatic treatment in bleeding patients: a systematic review with meta‐analysis and trial sequential analysis." Anaesthesia 72.4 (2017): 519-531.

Gonzalez, Eduardo, et al. "Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays." Annals of surgery 263.6 (2016): 1051.

Da Luz, Luis Teodoro, et al. "Effect of thromboelastography (TEG®) and rotational thromboelastometry (ROTEM®) on diagnosis of coagulopathy, transfusion guidance and mortality in trauma: descriptive systematic review." Critical Care 18.5 (2014): 518.

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