4. Tranexamic Acid

Question 1

Chemistry

Answer 1

tranexamic acid is a synthetic derivative of the amino acid lysine
(chemically it is a stereoisomer, trans 4-[aminomethyl] cyclohexane-carboxylic acid,

Question 2

Haemostatic homeostasis

Answer 2

The balance between coagulation and vascular patency is maintained by fibrinolysis,

which is the process by which fibrin clots are degraded.

Plasminogen circulates in what is described as a closed conformation,
but when binding to clots or to cell surfaces it changes to an open form which
makes it susceptible to activation.

This occurs under the influence of a number of different enzymes,

particularly tissue plasminogen activator (tPA),
which cleaves a simple peptide bond in plasminogen
to form the serine protease enzyme plasmin.

This catalyzes fibrinolysis (with the formation of fibrin degradation
products, FDPs).

Question 3

Fibrinolyis.

Answer 3

Under normal circumstances fibrinolysis is a benign process that keeps
the circulation patent.

In the context of major trauma, however, with hypoperfusion,
hypoxia and the up-regulation of tPA, the balance between coagulation and fibrinolysis
can be lost such that accelerated fibrinolysis is initiated with the subsequent
development of a coagulopathy.

Almost 25% of major trauma patients in the UK are
coagulopathic on arrival in the emergency department.

Question 4

Actions

Answer 4

Tranexamic acid has a strong affinity for the five separate lysine binding
sites on the plasminogen molecule.

This binding both displaces plasminogen from the cell surface
and fibrin clot and inhibits its conversion to plasmin.

As plasmin is also thought to be a mediator of the inflammatory response via complement and neutrophil activation,

its inhibition means that in addition to stabilizing the fibrin
clot, tranexamic acid also has an anti-inflammatory action.

Question 5

CRASH-2.

Answer 5

The CRASH-2 study, which was published in 2010, randomized more
than 20,000 trauma patients to receive either tranexamic acid (1,000 mg stat and a
further 1,000 mg over 8 hours) or placebo

The risk of death was
significantly reduced in the tranexamic group (mortality was 1.5% lower). It is not
clear if the results of CRASH-2 can legitimately be extrapolated to non-trauma
surgery, as these are very different populations. Nonetheless a subsequent metaanalysis
assessing the effect of tranexamic acid in surgical patients (129 trials
involving 10,488 patients) also reported a 37% reduction in blood transfusion
(Br Med J 2012, 344: e3054) There are also numerous individual studies from
sub-specialty surgical areas, in particular major orthopaedic surgery, which have
demonstrated its potential benefit in reducing perioperative bleeding

Question 6

WOMAN trial.

Answer 6

WOMAN trial.
The World Maternal Antifibrinolytic Trial was an international randomised double-blind placebo-controlled study of tranexamic acid in the management of postpartum haemorrhage.
It recruited more than 20,000 women in 21 countries in the developing world and concluded that tranexamic acid reduces death in women with post-partum haemorrhage with no adverse effects

Question 7

Thromboembolic complications

Answer 7

. An increase in thrombotic events has remained a theoretical concern, although the evidence is not robust.

It seems likely that in the general population there is no increased risk, although more caution may be needed in patients with pre-existing risk factors for venous thromboembolism