Question 7

Last updated 28/08/2021 - 00:46
 Topic: Haematology and Oncology
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A 61-year-old male is diagnosed with a large haemothorax after a fall. He has a history of atrial fibrillation and takes rivaroxaban. He becomes increasingly hypoxic and hypotensive and a decision is made to urgently correct the coagulopathy and insert a chest drain.

His first set of coagulation tests are as follows:

Parameter

Patient Value

Adult Normal Range

International normalised ratio (INR)

2.0*

0.9 – 1.3

Activated partial thromboplastin time (APTT)   

37.0 sec

27.0 – 38.5

Fibrinogen

5.4 g/L*

2.0 – 4.0

a) What is the mechanism of action of rivaroxaban? (10% marks)

b) What other information do you need from history and investigations to make an assessment of his coagulation status? (40% marks)

c) What steps will you take to correct his coagulopathy? (50% marks)

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College answer

Not available.

Discussion

a) Mechanism of action

  • Factor Xa inhibitor is the short version.
  • Factor Xa is the active form of Factor X (activated by either the intrinsic or extrinsic pathway); its job is to cleave prothrombin into thrombin.
  • Rivaroxaban inhibits free factor Xa as well as  prothrombinase-bound and clot-associated factor Xa, in contrast to drugs like fondaparinux which only act on free Xa.
  • Thus, rivaroxaban  prevents thrombin generation.


b)

Additional history:

  • Medication compliance (has he taken the rivaroxaban?)
  • Accidental overdose (has he taken it twice, accidentally?)
  • Timing of the last dose
  • Concomitant use of drugs which are known to interact with rivaroxaban: eg. amiodaone and quinidine can increase its level by competing for the P-glycoprotein efflux transporter in the gut

Additional investigations:

  • Liver function tests (66% is metabolised in the liver)
  • Renal function tests (33% renal excretion of unchanged drug)
  • Albumin level (95% protein bound; more free fraction available)
  • Anti-Factor Xa activity may be the best method of detecting excessive rivaroxaban activity
  • Special PT assay with a rivaroxaban-sensitive thromboplastin may be the most sensitive test (i.e. a normal "special" PT suggests that the activity of rivaroxaban is within a normal therapeutic range)

c)

Correction of coagulopathy:

  • Too heavily protein-bound to be susceptible to dialysis.
  • Prothrombinex and probably Factor VIIa are valid reversal agents, but the reversal effect reaches a plateau with a maximal effect of approximately 50%.
  • Andexanet alfa is a specific reversal agent which binds to Xa with approximately the same or slightly higher activity as the Xa inhibitors, and therefore is a possible reversal agent for rivaroxaban and apixaban as well as enoxaparin and fondaparinux (Siegal et al, 2015). Chemically, it is a recombinant derivative of Xa which acts as a decoy receptor.

References

Kreutz, Reinhold. "Pharmacodynamic and pharmacokinetic basics of rivaroxaban." Fundamental & clinical pharmacology 26.1 (2012): 27-32.

Almegren, Mosaad. "Reversal of direct oral anticoagulants." Vascular health and risk management 13 (2017): 287.

Cohen, Oliver, Lucy-Anne Frank, and Susan Bradley. "Reversal of direct oral anticoagulants." British Journal of Hospital Medicine 79.5 (2018): C70-C73.

Siegal, Deborah M., et al. "Andexanet alfa for the reversal of factor Xa inhibitor activity." New England Journal of Medicine373.25 (2015): 2413-2424.

Galliazzo, S., M. P. Donadini, and W. Ageno. "Antidotes for the direct oral anticoagulants: What news?." Thrombosis research164 (2018): S119-S123.

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