Prof Beverley Hunt MB ChB, FRCP, FRCPath, MD Guy s & St Thomas Trust, London Medical Director of Lifeblood: the thrombosis charity Conflicts of interest

PI on CRASH-2 and the WOMAN study funded by NIHR/Wellcome Sat on the committee writing the European bleeding in trauma guidelines, which was funded by CLS Behring, previously Novo Nordisk About to start a trial of fibrinogen supplementation in paediatric cardiac surgery funded by CLS Behring Consultancy 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-allocated Placebo-allocated (n= 10,060) (n= 10,067) 1,463 (14.5%) 1,613 (16.0%)

0.91 (0.85 0.97) 2P=0.0035

0.8 0.9 1.0 1.1 TXA TXA better worse Risk ratio (99% p=0.11 CI)

1 hour

>1 to 3 hours

>3 hours

.7 .8 .9 1 1.1 1.2 TXA Placebo Risk ratio (95% CI) allocated allocated (10,060) (10,067)

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

.8 .9 1 1.1 TXA better TXA worse Number Preventable trauma worldwide deaths with TA Those presenting with 20,000 massive blood loss Those presenting with 100,000 bleeding but not MBL 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 Hyperfibrinolysis on TEG/ ROTEM =ML30 > 15%

Associated with a high mortality Cotton et al 2012 J Trauma Acute Care Surg 1 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 drug TA in every paramedics pack in England English 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 placebo in 15,000 women with post partum haemorrhage

HIT 10,000 recruited last week!!!

Fund ed by NIHR/ WELLCOME The WOMAN study aiming to recruit 15,000 with PPH DOSE (TRANEXAMIC ACID OR TREATMENT AMPOULES ADMINISTRATION INSTRUCTION PLACEBO)

To be ad ministered by intravenous injec tion at an approximate rate of DOSE 1 2 1gram 1mL/ minute to all rand omised women a s soon as possible after randomisation.

If after 30 minutes bleeding c ontinues, or if it stops and resta rts within 24 DOSE 2 2 1gram hours a fter the first d ose, a sec ond d ose ma y b e given. To b e ad ministered 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 2010 Decreased blood loss but not enough evidence as only 2 RCTs Xu 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 al Crit Care 2011; 15:117

PPH > 800ml randomised to TA 4gms vs nil In 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 tranexamic acid . We should write guidelines about MAJOR rather than MASSIVE bleeding ADVICE is: Give RBCs, & FFP immediately without checking coagulation or full blood count Regular checks of coagulation screen and FBC to guide blood component therapy BUT I note PRACTICE can be: we don t have time for FBC and coag screen, just give us more blood components Poor interpretation of what to give if there is a haemostatic defect

Our retrospective studies in Iraq 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 products PT/APTT > 1.5 give FFP Fibrinogen < 1.5 give cryo/fibrinogen Platelets < 50 give platelets Using 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 loss Hiippala S et al Anaes Analgesia 1995; 81:360.

Haemostatic Critical level Blood loss (%) factor 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

Disproportionately lower than other haemostatic factors

Fall particularly low in post partum haemorrhage -a predictor of severity of bleeding Charbit et al, J Thaem 2007; 5: 266-73 The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage

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

Healthy pregnant woman

Gestational Thrombocytopenia Message: High fibrinogen of pregnancy more 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/l Should 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 record Practice grows up from anecdocal use Managing bleeding in practice is ruled by emotional intelligence Psychological need to be using the new treatment Registry data only Risk 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 WWII Less 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 prescribing The 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 prescribing an increasing caution in prescribing biological products their replacement where ever possible by recombinant synthetic agents

Obstetric haemorrhage

Uterine atony Blood loss & hypoperfusion

Bleeding into uterine cavity activation of fibrinolysis

Activation of coagulation

Low fibrinogen ( coagulation factors)

Excess thrombin

Endothelial cell Activation of white cells activation Platelet activation Activation of Protein C

Activation of complement Disseminated intravascular Coaguation Multiorgan failure Rational for using any blood products is unclear There is more data and familiarity with FFP i.e the standard of care Lack of data on factor concentrates notably on: Efficacy Safety (prothrombotic effects) Cost efficacy We 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 acid 2) Give fibrinogen concentrate (not FFP) if significant losses ??? Thank you!