Prof Beverley HuntMB ChB, FRCP, FRCPath, MD

Guy s & St Thomas Trust, LondonMedical Director of Lifeblood: the

thrombosis charity

Conflicts of interest

PI on CRASH-2 and the WOMAN study funded by NIHR/WellcomeSat on the committee writing the European bleeding in trauma guidelines, which was funded by CLS Behring, previously Novo NordiskAbout to start a trial of fibrinogen supplementation in paediatric cardiac surgery funded by CLS BehringConsultancy for Haemonetics

Divergence in practice internationally

Evidence base for current practice?

Fibrinogen

Tranexamic acid

The utility of TEG/ROTEM

A large placebo controlled trial among 20,000 trauma patients with, or at risk

of, significant haemorrhage, of the effects of antifibrinolytic treatment on death and

transfusion requirement

Lancet. 2010 Jul 3;376(9734):23-32.

Antifibrinolytics: CRASH-2 (tranexamic acid v placebo in 20,000): showed a 9% reduction in death in-hospital within 4 weeks

TXA worse

TXA better

0.8 0.9 1.0 1.1

TXA-allocated

(n= 10,060)

1,463 (14.5%)

Placebo-allocated

(n= 10,067)

1,613 (16.0%)

0.91 (0.85 0.97) 2P=0.0035

1 hour

>1 to 3 hours

>3 hours

Risk ratio (99% CI)

1.7 .8 .9 1.1 1.2

p=0.11

Risk ratio (95% CI)

Blood transfusion 5,067 5,160(50.4%) (51.3%)

TXA worseTXA better

TXA allocated(10,060)

Placebo allocated(10,067)

1.8 .9 1.1

Number Preventable trauma worldwide deaths with TA

Those presenting with massive blood loss

20,000

Those presenting with bleeding but not MBL

100,000

TOTAL 120,000

BUT North American divergence of practice

Recommendations that TA is used only if hyperfibrinolysis on the TEG and/or massive blood loss

NB entry to CRASH-2 Those with significant blood loss or AT RISK of significant blood loss

Hyperf ibrinolysis on TEG/ ROTEM =ML30 > 15%

1Associated with a high mortality Cotton et al 2012 J Trauma Acute Care Surg

Tranexamic acid safely reduced the risk of death in this study. On the basis of these results, it should be used trauma patients with, or at risk of, bleeding, as early as possible

Epilogue It is a WHO essential drugTA in every paramedics pack in EnglandEnglish health system wont pay Trauma Units unless they use TA in bleeding trauma patients ..Talking to the UK government- should we tie use of TA into foreign aid?And

Randomised Placebo Controlled Clinical Trial

The CRASH-3 trial will provide reliable evidence about the effect of tranexamic acid on mortality and disability in patients

with TBI. The effect of TXA on the risk of vascular occlusive events and seizures will also be assessed.

A randomised placebo controlled trial of tranexamic acid versus placeboin 15,000 women with post pa rtum haemorrhage

HIT 10,000 recruited last week!!!

Funded by NIHR/ WELLCOME

The WOMAN study aiming to recruit 15,000 with PPH

TREATMENT AMPOULESDOSE (TRANEXAMIC ACID OR

PLACEBO)ADMINISTRATION INSTRUCTION

DOSE 1 2 1gram

To be administered by intravenous injec tion a t an approximate ra te of

1mL/ minute to a ll randomised women as soon as possib le a fter

randomisation.

DOSE 2 2 1gram

If a fter 30 minutes b leed ing c ontinues, or if it stops and resta rts within 24

hours a fter the first dose, a sec ond dose may be g iven. To be administered

by intravenous injection at an approximate rate of 1mL/minute.

The trial treatment injections should not be mixed with blood for transfusion, or infusion solutions containing

penicillin or mannitol.

Cochrane review 2010Decreased blood loss but not enough evidence as only 2

RCTsXu et al, J Gynae Obstet 2013; 287: 463.

TA 10ml/Kg vs placebo in 174 Caesarean sections reduced blood loss in first 2 hours but total blood loss not significantly different

The EXADELI study. Ducloy-Bouthors et alCrit Care 2011; 15:117

PPH > 800ml randomised to TA 4gms vs nilIn the TA Rxed group bleeding duration was shorter & Progression to severe PPH & RBC transfusion was less (p,0.03)BUT S/E from TA

To ensure all those who would benefit from tranexamicacid .We should write guidelines about MAJOR rather than MASSIVE bleeding

ADVICE is:Give RBCs, & FFP immediately without checking coagulation or full blood countRegular checks of coagulation screen and FBC to guide blood component therapy

BUTI note PRACTICE can be:

we don t have time for FBC and coag screen, just give us more blood componentsPoor interpretation of what to give if there is a haemostatic defect

Our retrospective studies inIraq make us believe we need to use lots of early FFP

Our anecdocal data make us believe we only need to give factor concentrates and tranexamic acid

From the US Agency of Health Care Policy and Research

Apart from the use of tranexamic acid in trauma, there is no Grade A evidence base that shows the use of blood products (FFP and coagulation factors) reduce mortality

Conventional triggers for using blood productsPT/APTT > 1.5 give FFPFibrinogen < 1.5 give cryo/fibrinogenPlatelets < 50 give plateletsUsing TEG/ROTEM parameters

-These are based on Grade B and C evidence

Fibrinogen is vital!

The end point of the coagulation cascade!Soluble fibrinogen converted to insoluble fibrinogen

AND ..

Fibrinogen is the ligand for platelet aggregation

Critical haemostatic factors & blood lossHiippala S et al Anaes Analgesia 1995; 81:360.

Haemostatic factor

Critical level Blood loss (%)

Platelets 50 x 109/l 230 (169-294)

Fibrinogen 1.0g/L 142 (117-169)

Prothrombin 20% 201(160-244)

Factor V 25% 229 (167-300)

Prothrombin 20% 236 (198-277)

31

Fibrinogen levels fall in massive blood loss

Fall particularly low in post partum haemorrhage-a predictor of severity of bleeding

Charbit et al, J Thaem 2007; 5: 266-73

Disproportionately lower than other haemostatic factors

The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage

Journal of Thrombosis and HaemostasisVolume 5, Issue 2, pages 266-273, 22 JAN 2007 DOI: 10.1111/j.1538-7836.2007.02297.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2007.02297.x/full#f5

Healthy pregnant woman

Normal woman

Gestational Thrombocytopenia Message: High fibrinogen of pregnancymore than compensate for low platelet counts: women can tolerate lower Plt counts when pregnant

Post partum haemorrhage & fibrinogen

New guidelines set trigger for giving fibrinogen (cryo or conc)at 1.5g/l- Based on fall from normal values of 2-4g/l

At term fibrinogen is 4-6g/lShould the trigger for supplementary fibrinogen be 2.0g/l in obstetric haemorrhage?

Currently trials of fibrinogen concentrate supplementation-Danish trial closed in spring 2013, results imminent-Cardiff trial ongoing

Use of tranexamic acid & fibrinogen are complementary? Both necessary in all?

There is a poor track recordPractice grows up from anecdocal useManaging bleeding in practice is ruled by emotional intelligencePsychological need to be using the new treatment

Registry data onlyRisk of arterial thrombosis

Conclusion Inadequate data and definite risk of harm, therefore use of rVIIa should be limited to clinical trials

No trials to test the value of FFP when introduced post WWIILess forgivable- no clinical trials of platelets when introduced in late 1960s/early 1970.These omissions led to their automatic use in certain clinical situations, accompanied by a casual approach to prescribingThe transmission of Hep C, HIV and now new variant CJD by blood transfusion makes this relaxed approach untenable

The new millenium has been characterised by concern about effectiveness & appropriate prescribingan increasing caution in prescribing biological productstheir replacement where ever possible by recombinant synthetic agents

Uterine atony

Bleeding into uterine cavity

Blood loss & hypoperfusion

Activation of coagulation

activation of fibrinolysis

Low fibrinogen( coagulation factors)

Excess thrombin

Activation of Protein CPlatelet activation

Endothelial cell activation

Activation of complement

Activation of white cells

Disseminated intravascularCoaguationMultiorgan failure

Obstetric haemorrhage

Rational for using any blood products is unclearThere is more data and familiarity with FFP i.e the standard of careLack of data on factor concentrates notably on:

EfficacySafety (prothrombotic effects) Cost efficacyWe should not change current clinical practice until there

are RCTs comparing new agents with the standard of care

!

We need the results of the WOMAN study to inform use of tranexamic acid in obstetric haemorrhage

We need results of trials of fibrinogen concentrate to inform use of fibrinogen- Does it improve survival in a prospective study?- fibrinogen is a risk factor for VTE- if fibrinogen is increased when bleeding,

are we increasing risk of hospital-acquired venous thromboembolism later?

- what dose/what target to attain?-risk benefit analysis & cost effectiveness

Will the future management of Ob Haem be 1) All receive tranexamic acid2) Give fibrinogen concentrate (not FFP) if significant losses???

Thank you!