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Year : 2020  |  Volume : 6  |  Issue : 3  |  Page : 228-231

Shivering Due to Repeat Dose of Tranexamic Acid: A Peculiar Case Series

Department of Pharmacology, Maulana Azad Medical College, New Delhi, India

Date of Submission15-Jul-2020
Date of Decision09-Sep-2020
Date of Acceptance21-Sep-2020
Date of Web Publication16-Dec-2020

Correspondence Address:
Dr. Vandana Roy
Room Number 169, First Floor, Pathology Block, Department of Pharmacology, Maulana Azad Medical College (MAMC), Delhi - 110002
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mamcjms.mamcjms_81_20

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Tranexamic acid (TXA) is a well-tolerated hemostatic agent that has been in clinical use for nearly 60 years. In this report, we describe for the first time 10 patients who experienced adverse reactions to repeat dose of TXA, which were not seen with the first dose. Shivering was found to be the most common adverse reaction. In half of the cases, shivering was associated with low-grade fever. On dechallenge and subsequent administration of steroids and antihistaminic agents, the reactions were controlled. On assessment with the World Health Organization–Uppsala Monitoring Centre scale, the causality was ascertained to be “Probable”.There is no clear postulated mechanism for shivering with TXA. We have postulated that hypersensitivity, fever, and shivering in these patients may be interlinked. In the light of this report, the physicians should take into account that repeated challenge with TXA may lead to adverse reactions in some patients and withdrawing the drug in such patients may be required.

Keywords: Hypersensitivity, pharmacovigilance, repeat dosing, shivering, tranexamic acid

How to cite this article:
Kumar S, Tayal V, Swachia K, Roy V. Shivering Due to Repeat Dose of Tranexamic Acid: A Peculiar Case Series. MAMC J Med Sci 2020;6:228-31

How to cite this URL:
Kumar S, Tayal V, Swachia K, Roy V. Shivering Due to Repeat Dose of Tranexamic Acid: A Peculiar Case Series. MAMC J Med Sci [serial online] 2020 [cited 2021 Apr 13];6:228-31. Available from: https://www.mamcjms.in/text.asp?2020/6/3/228/303600

  Introduction Top

Tranexamic acid (TXA, trans-4-aminomethyl-cyclohexane-carbonic acid) is an antifibrinolytic agent that has been utilized in clinical practice for nearly six decades. It is derived synthetically from amino acid lysine and therefore blocks lysine binding sites on plasminogen molecules reversibly. This results in displacement of plasminogen from fibrin and thus fibrin dissolution gets inhibited.[1] It is included in the World Health Organization (WHO) Model List of Essential Medicines because of a plethora of evidence for its efficacy in menorrhagia, postpartum hemorrhage, hereditary bleeding disorders, and reduction of perioperative blood loss.

TXA is well tolerated and considered safe at the usual dosage (10 mg/kg i.v. 3–4 times a day, 10–20 mg/kg orally 3–4 times a day).[1] Intravenous administration of TXA has been routinely used since the 1960s. Adverse effects such as nausea, vomiting, and diarrhea are commonly observed with it. Occasional reports of allergic dermatitis, giddiness, and hypotension, thromboembolic events, convulsions, chromatopsia, and visual impairment have also been reported worldwide in postmarketing studies. Hypersensitivity reactions too have seldom been reported characterized by different immunological and nonimmunological pathogenetic mechanisms. [2] Compared to other drugs used to reduce bleeding (such as aprotinin), the risk of serious immunogenic response after primary or repeated exposure to TXA is significantly lower.[3]

In the light of these evidences, we report cases of 10 patients who experienced adverse reactions to TXA.

  Case Reports Top

The patients were all females admitted to the Gynecology Ward of a tertiary care teaching hospital in New Delhi from January to June 2019. They were in the range of 28–60 years of age and mostly presented with the complaint of heavy postmenopausal bleeding or heavy menstrual bleeding. They were all prescribed injection TXA (brand name: Texid) in a dose of 500–1000 mg intravenously three times a day. None of these patients had any known previous history of hypersensitivity to TXA or any other medication. Five patients were reported to have reaction to the second dose and five to the third dose, but none with the first dose. The reactions occurred after 10–15 minutes of drug administration. Shivering was found to be the most common adverse reaction, reported in 8 of 10 patients. In four of these eight cases, shivering was associated with low-grade fever (99–100°F). Other reactions seen in some patients were localized rash and vomiting. Association of these reactions with concomitant medications was ruled out. Injection TXA was stopped and patients were treated with single intravenous injection of hydrocortisone (Efcorlin) 100 mg and pheniramine maleate (Avil) 25 mg, after which shivering and other reactions were controlled [Table 1]. The possibility of batch contamination was thought of. However, on enquiring the nursing staff about the same, we were informed that shivering reaction was seen with more than one batch.
Table 1 Details of adverse reaction cases to TXA

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  Discussion Top

TXA, although generally well tolerated, can cause hypersensitivity reactions through different mechanisms either immunological or nonimmunological. According to a few previous reports, hypersensitivity to TXA has been reported in patients (both male and female) with ages ranging from 27 to 80 years. These patients had presented with postoperative bleeding, menorrhagia, or other conditions for which TXA was administered in varying regimens. The hypersensitivity reactions reported to TXA were fixed drug eruption, bullous eruption, anaphylactic shock, facial edema, angioedema, urticarial, and toxic epidermal necrolysis [Table 2].
Table 2 Previously reported hypersensitivity reactions to TXA

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To the best of our knowledge, this is the first time when a series of cases with shivering reaction only to repeat dose (second or third) of TXA have been reported. There is no postulated mechanism in the literature for such reactions with TXA, but the fact that most patients presented with fever, rash, and intense shivering may point toward an acute hypersensitivity reaction to TXA. Development of this reaction after multiple infusions suggests some role of sensitization. We hypothesize that, in certain patients, TXA was able to elicit an immune response at the first dose, which on subsequent dosing led to frank hypersensitivity. That it occurred in only some women and not in others may also point toward a pharmacogenomic relationship.

In half of the patients presenting with shivering, an associated fever was observed. Usually shivering or shaking is associated with rapid changes in body temperature. They result from involuntary muscle contractions that occur in response to a sudden lowering of body temperature below the prevailing set point. Febrile states are often due to the release of endogenous pyrogens (EP), such as interleukin-1, tumor necrosis factor (cachetin), and interferon alpha,[11] which act on receptors in the thermoregulatory hypothalamus to cause fever. Hypersensitivity reactions to drugs may stimulate EP release from monocytes indirectly via lymphokines secreted after interaction with sensitized lymphocytes.

Several other mechanisms of drug-induced fevers are known, such as administration-related mechanisms, alteration of thermoregulation, and idiosyncratic susceptibility. However, the exact mechanism by which fever and shivering occurred in some patients (four of eight) in our setup remains enigmatic.

There was no reaction observed with the oral preparations of TXA that the same patients received. So, we proposed that the excipients involved in the injectable preparation may be responsible for immunogenicity; however, on exploration the listed excipient was only water for injection and no such reactions to it are reported in the literature.

Two cases reported by us were prescribed TXA in the dose of 1 gram. In a review by Ferrer et al. (2009),[12] trials of TXA for the prevention of obstetric haemorrhage used TXA at a dose of 1 gram without major complications. There was no mortality and no thrombotic event was reported.[3]

On the basis of the similarities of the chemical structures and potential common epitope(s) between TXA and other lysine derivatives such as aminocaproic acid, it has been suggested that they should also be avoided.[2] Thus, the structural configuration of lysine may have a role in eliciting immunological responses. In fact, intratracheal administration of synthetic cationic proteins such as poly-l-lysine and polyl-arginine has been used to create bronchial hyperresponsiveness in a number of animal species, including nonhuman primates. Moreover, it is important to outline that lysine is the amino acid involved in immunoglobulin E binding in many allergens.

If a hemostatic drug is needed, a chemically distinct agent ethamsylate (systemic, nonthrombogenic hemostatic) has been used successfully in previous reports.[2]

For the investigation of a suspected hypersensitivity or anaphylactic reaction to TXA, a standardized protocol has been proposed that entails relevant medical and drug records review and intradermal test with TXA at 0.01 and 0.1 mg/mL.

Causality assessment

We determined the causality using the WHO–Upsala Monitoring Centre scale. The causality assessment of these reactions was found to be “Probable” as a rechallenge was not performed in any reported patient. These cases were reported to the adverse drug reaction monitoring center under the Pharmacovigilance Programme of India.

  Conclusion Top

TXA is used widely in clinical practice but, although generally well tolerated, we believe it is important to be aware of a potential hypersensitivity to this drug, especially in patients with multidrug hypersensitivity and needing antihemorrhagic therapy. The findings of our report suggest that before the assignment of a TXA treatment, physicians should take into account the potential appearance of hypersensitivity reactions and should consider withdrawal of TXA when reactions appear on repeat dosing. Pharmacologically and structurally distinct agent Ethamsylate could be a useful alternative in such cases.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Food and Drug Administration (FDA). Full prescribing information (tranexamic acid); 2019. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212020lbl.pdf. Accessed September 11, 2019.  Back to cited text no. 1
Li PH, Trigg C, Rutkowski R, Rutkowski K. Anaphylaxis to tranexamic acid-a rare reaction to a common drug. J Allergy Clin Immunol Pract 2017;5:839-41.  Back to cited text no. 2
Vagyannavar R, Devi R, Bharti V. Urticarial rash after tranexamic acid infusion. Indian J Drugs Dermatol 2017;3:43-4.  Back to cited text no. 3
  [Full text]  
Kavanagh GM, Sansom JE, Harrison P, Warwick JA, Peachey RD. Tranexamic acid (Cyklokapron)-induced fixed-drug eruption. Br J Dermatol 1993;128:229-30.  Back to cited text no. 4
Carrión-Carrión C, del Pozo-Losada J, Gutierrez-Ramos R, de Lucas-Laguna R, García-Diaz B, Casado-Jiménez M et al. Bullous eruption induced by tranexamic acid. Ann Pharmacother 1994;28:1305-6.  Back to cited text no. 5
Lucas-Polomeni MM, Delaval Y, Menestret P, Delaval P, Ecoffey C. A case of anaphylactic shock with tranexamique acid (Exacyl). Ann Fr Anesth Reanim 2004;23:607-9 (in French).  Back to cited text no. 6
Imbesi S, Nettis E, Minciullo PL, Di Leo E, Saija A, Vacca A et al. Hyper-sensitivity to tranexamic acid: a wide spectrum of adverse reactions. Pharm World Sci 2010;32:416-9.  Back to cited text no. 7
Pretel Irazabal M, Marques Martin L, Aguado Gil L, Idoate Gastearena MA. Tranexamic acid-induced toxic epidermal necrolysis. Ann Pharmacother 2013;47:e16  Back to cited text no. 8
Matsumura N, Hanami Y, Yamamoto T. Tranexamic acid-induced fixed drug eruption. Indian J Dermatol 2015;60:421.  Back to cited text no. 9
[PUBMED]  [Full text]  
Bansal RA, Nicholas A, Bansal AS. Tranexamic acid: an exceedingly rare cause of anaphylaxis during anaesthesia. Case Reports Immunol 2016; 2016:7828351.  Back to cited text no. 10
Walter EJ, Hanna-Jumma S, Carraretto M, Forni L. The pathophysiological basis and consequences of fever. Crit Care. 2016; 20:200. doi: 10.1186/s13054-016- 1375-5.  Back to cited text no. 11
Ferrer P, Roberts I, Sydenham E, Blackhall K, Shakur H. Anti-fibrinolytic agents in post partum haemorrhage: a systematic review. BMC Pregnancy Childbirth 2009;9:29.  Back to cited text no. 12


  [Table 1], [Table 2]


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