Fibrinolytic and antifibrinolytic agents

This chapter is relevant to Section Q2(i) of the 2023 CICM Primary Syllabus, which expects the exam candidates to "understanding of the pharmacology of anti-coagulants, anti-platelet drugs, thrombolytic drugs and anti-fibrinolytic drugs". It has relevance for several questions where tranexamic acid and fibrinolytic drugs were mentioned:

Tranexamic acid has also received some minimal attention in the Second Part exam, where a revision chapter is waiting ready with the answer to a question the examiners haven't asked yet. Thrombolysis for pulmonary embolism and early ischaemic stroke also often draw the attention of examiners, though the thrombolytic agents themselves seldom do. So, here these agents are, side by side.

Name Tranexamic acid Alteplase
Class Serine protease inhibitor Thrombolytic agent
Chemistry Monocarboxylic acid (a synthetic derivative of the amino acid lysine) Recombinant protein
Routes of administration IV, nebulised, topical, oral IV or intraarterial
Absorption 50% absorbed from the GI tract; bioavailability is about 30-35%. Most of it is not metabolised. Zero oral bioavailability
Solubility pKa of 10.22; highly water soluble, but minimally fat-soluble pKa 6.25; good water solubility
Distribution VOD = 0.18 L/kg; minimally protein bound (3%, all of which is accounted for by its binding to plasminogen). After some loading (eg. several doses over 24-36 hrs), enough of it distributes to the tissues to continue having a sustained antifibrinolytic effect for many hours. VOD = 0.07L/kg (effectively confined to the circulating volume); minimally protein bound
Target receptor Plasminogen Plasminogen-fibrin complex
Metabolism Minimally metabolised Metabolised by the liver, most likely by the reticuloendothelial system
Elimination 95% of the dose is excreted unchanged in the kidneys; half-life is 2 hours Minimal renal excretion
Time course of action Relatively short-acting, very rapid onset of effect Initial half life ~ 5 minutes; eliminaton half life 72 minutes
Mechanism of action Competitive inhibitor of plasminogen activation (by binding to the 5-lysine site on plasminogen). This inhibts the formation of plasmin and displaces plasminogen from the surface of fibrin. Serum protease which has specific affinity for plasminogen in the presence of fibrin. Catalyses the conversion of plasminogen to plasmin, which degrades fibrin strands
Clinical effects Prevents the breakdown of fibrin, thus maintaing clot integrity. Numerous other effects (as it also inhibits other proteases), as well as indirect effects via plasminogen inhibition (eg. on complement activation, where by reducing plasmin activity it reduces the consumption of C1 esterase inhibitor) Thrombolytic effect extends into bleeding complications, which can be very serious. Anaphylaxis is not unknown, given that this is a recombinant protein
Single best reference for further information Data sheet from medsafe.govt.nz TGA PI document

Tranexamic acid

This drug is older than many of your consultants but no single publication seems to contain every necessary detail, which meant that papers from Wellington & Wagstaff (2003), McCormack (2012) and  Dunn (1999 had to be fused to produce this summary. In short, tranexamic acid is a synthetic lysine derivative, designed in the 1950s when it was observed that the amino acid lysine had some weak antiplasmin activity. In an effort to improve its activity, numerous mercaptocarbonic and aminocarbonic acids were tested, which resulted in the discovery of trans-4-aminomethylcyclohexanecarboxylic acid (only the trans-isomer was effective as an antifibrinolytic). Trans-AMCHA then somehow got pidginised into tranexamic for what we can only assume was some kind of  marketing decision by Kabi.

This substance is poorly absorbed orally, but has a bioavailability good enough for oral administration to be an option, which opens the possibility of outpatient and prehospital administration. It undergoes no metabolism and is excreted renally, which means its dose needs to be adjusted for renal failure. The volume of distribution from a single dose is reasonably small, but with multiple doses or a loading dose, there appears to be some tissue distribution, which means that its effect is sustained for many hours. Otherwise, the half life is very short (2 hours) as it is rapidly eliminated renally.

mechanism of tranexamic acid action

The mechanism of effect is fairly easy to explain, though admittedly looking at the diagram here one might conclude that it would have been better to express it in point form. So:

  • Tranexamic acid resembles lysine.
  • It competitively binds to the lysine-binding sites on the plasminogen molecule.
  • Thes are the same sites plasminogen uses to bind to specific lysine residues on the fibrin molecule.
  • The plasminogen-fibrin complex is the thing that gets activated by tissue plasminogen activator (tPA).
  • This means, in the presence of tranexamic acid, there should be less plasminogen available to form these complexes.
  • Thus, there should be less substrate for tissue plasminogen activator to act on, and therefore less fibrin degradation.

Side effects are very few. It appears that with enough tranexamic acid you can cause seizures, because tranexamic acid structurally resembles GABA, but does nothing to excite its receptors. It appears one requires insanely large doses, in the order of 7-10g. There is also a theoretical possibility of increased risk of thrombosis, which is still listed among other possible side effects of tranexamic acid. However, there is little evidence to support this. None of the large-scale trials of tranexamic acid had any sort of clinically significant increase their rates of VTE, which is encouraging.

Alteplase, as a representative of its group

The list of available thrombolytic agents includes streptokinase, urokinase, alteplase and tenecteplase, to name just a few. Realistically, it is not essential to know every detail about each of these alternatives. Alteplase, as a common enough agent, is described here in some minimal exam-oriented detail; for the others, the reader is invited to review "Thrombolytic agents" by Colleen & Lijnen (2005) or Jerjes-Sánchez &  Rodriguez (2015)

Alteplase is a recombinant version of tissue plasminogen activator (tPA). It is a 70 kDa protein produced by

transgenic Chinese hamster ovary cells, and therefore obviously ill-suited for oral administration. When given intravenously, its half-life is only five minutes, though some molecules can still be hanging around in some kind of deep compartment after about 40 minutes. 

The mechanism of the thrombolytic effect of alteplase can be summarised in point form to facilitate an answer to Question 3 from the first paper of 2010:

  • The  available thrombolytic agents are recombinant analogs of the tissue plasminogen activator (tPa)
  • This is a protease that has a specific affinity for plasminogen
  • Specifically, its affinity is massively increased by the presence of fibrin (otherwise, the affinity for plasminogen alone would be rather low)
  • Plasminogen binds to fibrin by attaching to its lysine residues 
  • When tPa binds to the plasminogen-fibrin complex, it activates plasminogen into plasmin
  • Plasmin is a protease that then cleaves fibrin into soluble peptide fragments
  • This degrades clot stability and ultimately causes its disintegration

These soluble peptide fragments are often referred to as "D-dimers" as they all tend to react with the D-dimer assay, but they are actually rather different (Wilde et al, 1989).

References

Pilbrant, Å., M. Schannong, and J. Vessman. "Pharmacokinetics and bioavailability of tranexamic acid." European journal of clinical pharmacology 20.1 (1981): 65-72.

Dunn, Christopher J., and Karen L. Goa. "Tranexamic acid." Drugs 57.6 (1999): 1005-1032.

McCormack, Paul L. "Tranexamic acid." Drugs 72.5 (2012): 585-617.

Wellington, Keri, and Antona J. Wagstaff. "Tranexamic acid." Drugs 63.13 (2003): 1417-1433.

Tengborn, Lilian, Margareta Blombäck, and Erik Berntorp. "Tranexamic acid–an old drug still going strong and making a revival." Thrombosis research 135.2 (2015): 231-242.

Griffin, James D., and Leonard Ellman. "Epsilon-aminocaproic acid (EACA).Seminars in thrombosis and hemostasis. Vol. 5. No. 1. 1978.

Collen, Désiré, and Roger H. Lijnen. "Thrombolytic agents." Thrombosis and haemostasis 93.04 (2005): 627-630.

Jerjes-Sánchez, Carlos, and H. David Rodriguez. "Pharmacokinetics and pharmacodynamics of fibrinolytic agents." Thrombolysis in Pulmonary Embolism. Springer, Cham, 2015. 19-39.

Vassalli, Jean-Dominique, A. P. Sappino, and Dominique Belin. "The plasminogen activator/plasmin system." The Journal of clinical investigation 88.4 (1991): 1067-1072.

Wilde, J. T., et al. "Plasma D‐dimer levels and their relationship to serum fibrinogen/fibrin degradation products in hypercoagulable states." British journal of haematology 71.1 (1989): 65-70.