Antifibrinolytic drugs and haemostatics

Haemostatic agents act to conserve blood but have differing sites of action in the complex pathways determining coagulation and fibrinolysis. Antifibrinolytics inhibit the activation of plasminogen to plasmin, prevent the break-up of fibrin and maintain clot stability. They are used to prevent excessive bleeding.

• Tranexamic acid is the best known and is used where the risk of haemorrhage is high due to increased fibrinolysis (for example, women with menorrhagia have increased levels of endometrial plasminogen activators compared with those with normal menstrual loss), or short-term following acute haemorrhage.

• Aprotinin is a proteolytic enzyme inhibitor. It acts on plasmin and kallikrein.

• Etamsylate is an haemostatic agent and probably works by correcting abnormal adhesion of platelets.

Blood products (antithrombin III, recombinant activated protein C, recombinant factor VIIa, dried factor VIII, IX and XIII fractions, protein C concentrate and fresh frozen plasma) can also be considered haemostatic agents but are beyond the scope of this article. They are either derived from human plasma (carrying a potential risk of unidentified infection) or manufactured using recombinant technology. They are used to correct congenital or acquired clotting abnormalities and are specialist drugs, usually administered under the supervision of a haematologist.

Indications¹

Menorrhagia²

Tranexamic acid is widely used to treat menorrhagia and is recommended by current National Institute for Health and Care Excellence guidelines as medical treatment where:³

• There are no structural or histological abnormalities causing the bleeding pattern.

• Fibroids are less than 3 cm in diameter with no distortion of the uterine cavity.

• Women are not wishing for a contraceptive or hormonal method (such as the intrauterine system (IUS) or combined oral contraceptive (COC) pill.

It is an effective treatment, reducing blood loss on average by 40-50% but should be discontinued if a woman's menstrual symptoms are not improving after three cycles. Non-steroidal anti-inflammatory drugs may be preferred if dysmenorrhoea is also predominant. It appears to be less effective and with greater side-effects than the intrauterine system (IUS) or endometrial resection, although pharmaceutical treatments for menorrhagia are preferred by a minority of women.⁴ Etamsylate is only occasionally used to treat menorrhagia.

Primary and secondary prevention of haemorrhage

• Tranexamic acid is used to treat epistaxis, thrombolytic overdose, surgery (eg, prostatectomy and bladder surgery) and to cover the risk of haemorrhage over dental extractions in haemophiliacs. It is also increasingly being used early in civilian and military trauma.^{5 6}

• Etamsylate is used to treat periventricular haemorrhage in neonates.

• Antifibrinolytics are used to conserve blood in patients at high risk of haemorrhage during or after open heart surgery, operative repair of scoliosis,⁷ in acute promyelocytic leukaemia (where high production of plasmin can cause life-threatening haemorrhage) and in liver transplantation (unlicensed). A Cochrane review found evidence that aprotinin reduced the need for red cell transfusion and re-operation due to bleeding following major surgery.⁸ Similar trends were seen for tranexamic acid. However, there have been concerns that aprotinin is associated with higher risk of death compared with lysine analogues and this led to its temporary suspension. Tranexamic acid is currently preferred after cardiac surgery.⁹ Their usefulness in orthopaedic surgery has also been shown with no increase in risk of venous thromboembolism .¹⁰

Evidence for use of antifibrinolytics in subarachnoid haemorrhage and bleeding in patients with liver disease is lacking.^{11 12}

Management of bleeding disorders

Desmopressin is used in the management of mild-to-moderate haemophilia and von Willebrand's disease (vWD), as it boosts factor VIII concentration. The treatment of haemophilia should be under the direction of a haematologist.¹³

A Cochrane systematic review concluded there was not yet enough evidence supporting the use of antifibrinolytics in patients with haemophilia or vWD undergoing minor oral surgery or dental extractions.¹⁴

Treatment of hereditary angio-oedema

Tranexamic acid can be used in the treatment of hereditary angio-oedema, although danazol or stanozolol (unlicensed indication and on named patient use only) are the usual preferred options.

Fibrinolytic response testing

Desmopressin is given as a spray (150-microgram spray into each nostril) and blood is sampled after one hour for fibrinolytic activity.

Contra-indications¹

Contra-indications to tranexamic acid include:

• Severe renal impairment.

• Thromboembolic disease (although the rate of incidence of thrombosis whilst taking the drug appears comparable to the rate within the general population).

• Massive haematuria - avoid if there is a risk of ureteric obstruction.

• Disseminated intravascular coagulation.

• Pregnancy.

Contra-indications to etamsylate include:

• Porphyria.

Contra-indications to desmopressin include:

• Cardiac insufficiency.

• Severe renal impairment.

Initiation of treatment¹

Tranexamic acid:

• For menorrhagia - 1 g tds for up to four days, starting with commencement of menstruation. Maximum dose of 4 g daily.

• For hereditary angio-oedema - 1-1.5 g bd-tds daily.

Monitoring¹

Regular eye examinations and LFTs are recommended during long-term treatment with tranexamic acid for hereditary angio-oedema.

Complications and reasons to discontinue drug¹

• Stop tranexamic acid if disturbances in colour vision occur.

• Reduce the dose of tranexamic acid if there is gastrointestinal upset (nausea, vomiting, diarrhoea). These side-effects occur in about 15% of the population and improve with dose reduction.