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Culprits of Medication-Induced Telogen Effluvium, Part 2
Author(s)
Donglin Zhang, BA
Charlotte Lasenna, MD
Bridget E. Shields, MD

Medication-induced telogen effluvium (TE) is a nonscarring alopecia that typically is reversible. Appropriate management requires identification of the underlying trigger and cessation of potential culprit medications. In part 2 of this series, we review anticoagulant and antihypertensive medications as potential contributors to TE.

Anticoagulants

Anticoagulants target various parts of the coagulation cascade to prevent clot formation in patients with conditions that increase their risk for thromboembolic events. Common indications for initiating anticoagulant therapy include atrial fibrillation,1 venous thromboembolism,2 acute myocardial infarction,3 malignancy,4 and hypercoagulable states.5 Traditional anticoagulants include heparin and warfarin. Heparin is a glycosaminoglycan that exerts its anticoagulant effects through binding with antithrombin, greatly increasing its inactivation of thrombin and factor Xa of the coagulation cascade.6 Warfarin is a coumarin derivative that inhibits activation of vitamin K, subsequently limiting the function of vitamin K–dependent factors II, VII, IX, and X.7,8 Watras et al9 noted that heparin and warfarin were implicated in alopecia as their clinical use became widespread throughout the mid-20th century. Onset of alopecia following the use of heparin or warfarin was reported at 3 weeks to 3 months following medication initiation, with most cases clinically consistent with TE.9 Heparin and warfarin both have alopecia reported as a potential adverse effect in their structured product labeling documents.10,11

Heparin is further classified into unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH); the latter is a heterogeneous group of medications derived from chemical or enzymatic depolymerization of UFH.12 In contrast to UFH, LMWH exerts its anticoagulant effects through inactivation of factor Xa without the ability to bind thrombin.12 An animal study using anagen-induced mice demonstrated that intraperitoneal administration of heparin inhibited the development of anagen follicles, while in vitro studies showed that the addition of heparin inhibited mouse dermal papilla cell proliferation.13 Other animal and in vitro studies have examined the inhibitory effects of heparin on signaling pathways in tumor lymphangiogenesis, including the vascular endothelial growth factor C/vascular endothelial growth factor receptor 3 axis.14,15 Clinically, it has been demonstrated that heparin, especially LMWHs, may be associated with a survival benefit among certain cancer patients,16,17 with the impact of LMWHs attributed to antimitotic and antimetastatic effects of heparin on tumor growth.14 It is hypothesized that such antiangiogenic and antimitotic effects also are involved in the pathomechanisms of heparin-induced alopecia.18

More recently, the use of direct oral anticoagulants (DOACs) such as dabigatran, rivaroxaban, and apixaban has increased due to their more favorable adverse-effect profile and minimal monitoring requirements. Bonaldo et al19 conducted an analysis of reports submitted to the World Health Organization’s VigiBase database of alopecia associated with DOACs until May 2, 2018. They found 1316 nonduplicate DOAC-induced cases of alopecia, with rivaroxaban as the most reported drug associated with alopecia development (58.8% [774/1316]). Only 4 cases demonstrated alopecia with DOAC rechallenge, suggesting onset of alopecia may have been unrelated to DOAC use or caused by a different trigger. Among 243 cases with a documented time to onset of alopecia, the median was 28 days, with an interquartile range of 63 days. Because TE most commonly occurs 3 to 4 months after the inciting event or medication trigger, there is little evidence to suggest DOACs as the cause of TE, and the observed cases of alopecia may be attributable to another preceding medical event and/or medication exposure.19 More studies are needed to examine the impact of anticoagulant medications on the hair cycle.

Antihypertensives

Hypertension is a modifiable risk factor for several ­cardiovascular diseases.20 According to the 2019 American College of Cardiology/American Heart Association Guideline on the Primary Prevention of Cardiovascular Disease,21 first-line medications include thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor ­blockers (ARBs).

Angiotensin-converting enzyme inhibitors exert their antihypertensive effects by reducing conversion of angiotensin I to angiotensin II, thereby limiting the downstream effects of vasoconstriction as well as sodium and water retention. Given the proven mortality benefit of ACE inhibition in patients with congestive heart failure, ACE inhibitors are used as first-line therapy in these patients.22,23 Alopecia associated with ACE inhibitors is rare and limited to case reports following their introduction and approval in 1981.24-28 In one case, a woman in her 60s with congestive heart failure initiated captopril with development of an erythematous pruritic rash on the extremities and diffuse scalp hair loss 2 months later; spontaneous hair growth resumed 1 month following captopril discontinuation.25 In this case, the hair loss may be secondary to the drug eruption rather than true medication-induced TE. Initiation of enalapril in a woman in her 30s with hypertension was associated with diffuse scalp alopecia 4 weeks later that resolved with cessation of the suspected culprit, enalapril; rechallenge with enalapril several months later reproduced the hair loss.27 Given limited reports of ACE inhibitor–associated hair loss relative to their pervasive use, a direct causal role between ACE inhibition and TE is unlikely, or it has not been rigorously identified. The structured product labeling for captopril includes alopecia in its list of adverse effects reported in approximately 0.5% to 2% of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials.29 Alternative inciting causes of alopecia in patients prescribed ACE inhibitors may include use of other medications, hospitalization, or metabolic derangements related to their underlying cardiac disease.

Although not indicated as a primary treatment for hypertension, β-blockers have US Food and Drug Administration approval for the treatment of certain arrhythmias, hypertension, heart failure, myocardial infarction, hyperthyroidism, and other conditions.30β-Blockers are competitive antagonists of β-adrenergic receptors that limit the production of intracellular cyclic adenosine monophosphate, but the mechanism of β-blockers as antihypertensives is unclear.31 Evidence supporting the role of β-adrenergic antagonists in TE is limited to case reports. Widespread alopecia across the scalp and arms was noted in a man in his 30s several months after starting propranolol.32 Biopsy of an affected area of the scalp demonstrated an increased number of telogen follicles with no other abnormalities. Near-complete resolution of alopecia was seen 4 months following cessation of propranolol, which recurred within 4 weeks of rechallenge.32 Although the histopathologic features are compatible with TE, the loss of body hair and rapid recurrence within 4 weeks of rechallenge are atypical for TE. As such, the use of propranolol and the reported alopecia may be coincidental or evidence of an atypical drug reaction distinct from medication-induced TE. Only a handful of other case reports have been published describing TE in patients treated with β-blockers, including metoprolol and propranolol.33,34 Alopecia has been reported with the use of carvedilol in up to 0.1% of participants.35 Although cases have been reported, TE appears to be an uncommon occurrence following β-blocker therapy.

Minoxidil—Oral minoxidil originally was approved for use in patients with resistant hypertension, defined as blood pressure elevated above goal despite concurrent use of the maximum dose of 3 classes of antihypertensives.36 Unlike other antihypertensive medications, minoxidil appears to cause reversible hypertrichosis that affects nearly all patients using oral minoxidil for longer than 1 month.37 This common adverse effect was a desired outcome in patients affected by hair loss, and a topical formulation of minoxidil was approved for androgenetic alopecia in men and women in 1988 and 1991, respectively.38 Since its approval, topical minoxidil has been commonly prescribed in the treatment of several types of alopecia, though evidence of its efficacy in the treatment of TE is limited.39,40 Low-dose oral minoxidil also has been reported to aid hair growth in androgenetic alopecia and TE.41 Taken orally, minoxidil is converted by sulfotransferases in the liver to minoxidil sulfate, which causes opening of plasma membrane adenosine ­triphosphate–sensitive potassium channels.42-44 The subsequent membrane hyperpolarization reduces calcium ion influx, which also reduces cell excitability, and inhibits contraction in vascular smooth muscle cells, which results in the arteriolar vasodilatory and antihypertensive effects of minoxidil.43,45 The potassium channel–opening effects of minoxidil may underly its hair growth stimulatory action. Unrelated potassium channel openers such as diazoxide and pinacidil also cause hypertrichosis.46-48 An animal study showed that topical minoxidil, cromakalim (potassium channel opener), and P1075 (pinacidil analog) applied daily to the scalps of balding stump-tailed macaques led to significant increases in hair weight over a 20-week treatment period compared with the vehicle control group (P<.05 for minoxidil 100 mM and 250 mM, cromakalim 100 mM, and P1075 100 mM and 250 mM).50 For minoxidil, this effect on hair growth appears to be dose dependent, as cumulative hair weights for the study period were significantly greater in the 250-mM concentration compared with 100-mM minoxidil (P<.05).49 The potassium channel–opening activity of minoxidil may induce stimulation of microcirculation around hair follicles conducive to hair growth.50 Other proposed mechanisms for hair growth with minoxidil include effects on keratinocyte and fibroblast cell proliferation,51-53 collagen synthesis,52,54 and prostaglandin activity.44,55

Final Thoughts

Medication-induced TE is an undesired adverse effect of many commonly used medications, including retinoids, azole antifungals, mood stabilizers, anticoagulants, and antihypertensives. In part 156 of this 2-part series, we reviewed the existing literature on hair loss from retinoids, antifungals, and psychotropic medications. Herein, we focused on anticoagulant and antihypertensive medications as potential culprits of TE. Heparin and its derivatives have been associated with development of diffuse alopecia weeks to months after the start of treatment. Alopecia associated with ACE inhibitors and β-blockers has been described only in case reports, suggesting that they may be unlikely causes of TE. In contrast, minoxidil is an antihypertensive that can result in hypertrichosis and is used in the treatment of androgenetic alopecia. It should not be assumed that medications that share an indication or are part of the same medication class would similarly induce TE. The development of diffuse nonscarring alopecia should prompt suspicion for TE and thorough investigation of medications initiated 1 to 6 months prior to onset of clinically apparent alopecia. Suspected culprit medications should be carefully assessed for their likelihood of inducing TE.

References
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  2. Kearon C, Kahn SR. Long-term treatment of venous thromboembolism. Blood. 2020;135:317-325. doi:10.1182/blood.2019002364
  3. Frishman WH, Ribner HS. Anticoagulation in myocardial infarction: modern approach to an old problem. Am J Cardiol. 1979;43:1207-1213. doi:10.1016/0002-9149(79)90155-3
  4. Khorana AA, Mackman N, Falanga A, et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers. 2022;8:11. doi:10.1038 /s41572-022-00336-y
  5. Umerah CO, Momodu, II. Anticoagulation. StatPearls [Internet]. StatPearls Publishing; 2023. Accessed December 11, 2023. https://www.ncbi.nlm.nih.gov/books/NBK560651/
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  7. Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001;119(1 suppl):8S-21S. doi:10.1378/chest.119.1_suppl.8s
  8. Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165:1095-1106. doi:10.1001/archinte.165.10.1095
  9. Watras MM, Patel JP, Arya R. Traditional anticoagulants and hair loss: a role for direct oral anticoagulants? a review of the literature. Drugs Real World Outcomes. 2016;3:1-6. doi:10.1007/s40801-015-0056-z
  10. Heparin sodium. Product information. Hepalink USA Inc; January 2022. Accessed December 11, 2023. https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/c4c6bc1f-e0c7-fd0d-e053-2995a90abdef/spl-doc?hl=heparin
  11. Warfarin sodium. Product information. Bryant Ranch Prepack; April 2023. Accessed December 11, 2023. https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/c41b7c23-8053-428a-ac1d-8395e714c2f1/spl-doc?hl=alopecia%7Cwarfarin#section-6
  12. Hirsh J. Low-molecular-weight heparin. Circulation. 1998;98:1575-1582. doi:10.1161/01.CIR.98.15.1575
  13. Paus R. Hair growth inhibition by heparin in mice: a model system for studying the modulation of epithelial cell growth by glycosaminoglycans? Br J Dermatol. 1991;124:415-422. doi:10.1111/j.1365-2133.1991.tb00618.x
  14. Ma SN, Mao ZX, Wu Y, et al. The anti-cancer properties of heparin and its derivatives: a review and prospect. Cell Adh Migr. 2020;14:118-128. doi:10.1080/19336918.2020.1767489
  15. Choi JU, Chung SW, Al-Hilal TA, et al. A heparin conjugate, LHbisD4, inhibits lymphangiogenesis and attenuates lymph node metastasis by blocking VEGF-C signaling pathway. Biomaterials. 2017;139:56-66. doi:0.1016/j.biomaterials.2017.05.026
  16. Klerk CP, Smorenburg SM, Otten HM, et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005;23:2130-2135. doi:10.1200/jco.2005.03.134
  17. Altinbas M, Coskun HS, Er O, et al. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost. 2004;2:1266-1271. doi:10.1111/j.1538-7836.2004.00871.x
  18. Weyand AC, Shavit JA. Agent specific effects of anticoagulant induced alopecia. Res Pract Thromb Haemost. 2017;1:90-92. doi:10.1002 /rth2.12001
  19. Bonaldo G, Vaccheri A, Motola D. Direct-acting oral anticoagulants and alopecia: the valuable support of postmarketing data. Br J Clin Pharmacol. 2020;86:1654-1660. doi:10.1111/bcp.14221
  20. Fuchs FD, Whelton PK. High blood pressure and cardiovascular disease. Hypertension. 2020;75:285-292. doi:10.1161 /HYPERTENSIONAHA.119.14240
  21. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140:E596-E646. doi:10.1161/CIR.0000000000000678
  22. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128:E240-E327. doi:10.1161 /CIR.0b013e31829e8776
  23. Effects of enalapril on mortality in severe congestive heart failure. results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429-1435. doi:10.1056 /nejm198706043162301
  24. Kataria V, Wang H, Wald JW, et al. Lisinopril-induced alopecia: a case report. J Pharm Pract. 2017;30:562-566. doi:10.1177/0897190016652554
  25. Motel PJ. Captopril and alopecia: a case report and review of known cutaneous reactions in captopril use. J Am Acad Dermatol. 1990;23:124-125. doi:10.1016/s0190-9622(08)81205-4
  26. Leaker B, Whitworth JA. Alopecia associated with captopril treatment. Aust N Z J Med. 1984;14:866. doi:10.1111/j.1445-5994.1984.tb03797.x
  27. Ahmad S. Enalapril and reversible alopecia. Arch Intern Med. 1991;151:404.
  28. Bicket DP. Using ACE inhibitors appropriately. Am Fam Physician. 2002;66:461-468.
  29. Captopril. Product information. Bryant Ranch Prepack; May 2023. Accessed December 11, 2023. https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/563737c5-4d63-4957-8022-e3bc3112dfac/spl-doc?hl=captopril
  30. Farzam K, Jan A. Beta blockers. StatPearls Publishing; 2023. https://www.ncbi.nlm.nih.gov/books/NBK532906/
  31. Mason RP, Giles TD, Sowers JR. Evolving mechanisms of action of beta blockers: focus on nebivolol. J Cardiovasc Pharmacol. 2009; 54:123-128.
  32. Martin CM, Southwick EG, Maibach HI. Propranolol induced alopecia. Am Heart J. 1973;86:236-237. doi:10.1016/0002-8703(73)90250-0
  33. Graeber CW, Lapkin RA. Metoprolol and alopecia. Cutis. 1981; 28:633-634.
  34. Hilder RJ. Propranolol and alopecia. Cutis. 1979;24:63-64.
  35. Coreg. Prescribing information. Woodward Pharma Services LLC; 2023. Accessed December 11, 2023. https://www.accessdata.fda.gov/spl/data/34aa881a-3df4-460b-acad-fb9975ca3a06/34aa881a-3df4-460b-acad-fb9975ca3a06.xml
  36. Carey RM, Calhoun DA, Bakris GL, et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension. 2018;72:E53-E90. doi:10.1161/hyp.0000000000000084
  37. Campese VM. Minoxidil: a review of its pharmacological properties and therapeutic use. Drugs. 1981;22:257-278. doi:10.2165/00003495-198122040-00001
  38. Heymann WR. Coming full circle (almost): low dose oral minoxidil for alopecia. J Am Acad Dermatol. 2021;84:613-614. doi:10.1016/j .jaad.2020.12.053
  39. Yin S, Zhang B, Lin J, et al. Development of purification process for dual-function recombinant human heavy-chain ferritin by the investigation of genetic modification impact on conformation. Eng Life Sci. 2021;21:630-642. doi:10.1002/elsc.202000105
  40. Mysore V, Parthasaradhi A, Kharkar RD, et al. Expert consensus on the management of telogen effluvium in India. Int J Trichology. 2019;11:107-112.
  41. Gupta AK, Talukder M, Shemar A, et al. Low-dose oral minoxidil for alopecia: a comprehensive review [published online September 27, 2023]. Skin Appendage Disord. doi:10.1159/000531890
  42. Meisheri KD, Cipkus LA, Taylor CJ. Mechanism of action of minoxidil sulfate-induced vasodilation: a role for increased K+ permeability. J Pharmacol Exp Ther. 1988;245:751-760.
  43. Winquist RJ, Heaney LA, Wallace AA, et al. Glyburide blocks the relaxation response to BRL 34915 (cromakalim), minoxidil sulfate and diazoxide in vascular smooth muscle. J Pharmacol Exp Ther. 1989;248:149-56.
  44. Messenger AG, Rundegren J. Minoxidil: mechanisms of action on hair growth. Br J Dermatol. 2004;150:186-194. doi:10.1111/j .1365-2133.2004.05785.x
  45. Alijotas-Reig J, García GV, Velthuis PJ, et al. Inflammatory immunemediated adverse reactions induced by COVID-19 vaccines in previously injected patients with soft tissue fillers: a case series of 20 patients. J Cosmet Dermatol. 2022;21:3181-3187. doi: 10.1111/jocd.15117
  46. Boskabadi SJ, Ramezaninejad S, Sohrab M, et al. Diazoxideinduced hypertrichosis in a neonate with transient hyperinsulinism. Clin Med Insights Case Rep. 2023;16:11795476231151330. doi:10.1177/11795476231151330
  47. Burton JL, Schutt WH, Caldwell IW. Hypertrichosis due to diazoxide. Br J Dermatol. 1975;93:707-711. doi:10.1111/j.1365-2133.1975.tb05123.x
  48. Goldberg MR. Clinical pharmacology of pinacidil, a prototype for drugs that affect potassium channels. J Cardiovasc Pharmacol. 1988;12 suppl 2:S41-S47. doi: 10.1097/00005344-198812002-00008
  49. Buhl AE, Waldon DJ, Conrad SJ, et al. Potassium channel conductance: a mechanism affecting hair growth both in vitro and in vivo. J Invest Dermatol. 1992;98:315-319. doi:10.1111/1523-1747.ep12499788
  50. Patel P, Nessel TA, Kumar DD. Minoxidil. StatPearls [Internet]. StatPearls Publishing; 2023. Accessed December 11, 2023. https://www.ncbi.nlm.nih.gov/books/NBK482378/
  51. O’Keefe E, Payne RE Jr. Minoxidil: inhibition of proliferation of keratinocytes in vitro. J Invest Dermatol. 1991;97:534-536. doi:10.1111/1523-1747.ep12481560
  52. Murad S, Pinnell SR. Suppression of fibroblast proliferation and lysyl hydroxylase activity by minoxidil. J Biol Chem. 1987;262:11973-11978.
  53. Baden HP, Kubilus J. Effect of minoxidil on cultured keratinocytes. J Invest Dermatol. 1983;81:558-560. doi:10.1111/1523-1747.ep12523220
  54. Murad S, Walker LC, Tajima S, et al. Minimum structural requirements for minoxidil inhibition of lysyl hydroxylase in cultured fibroblasts. Arch Biochem Biophys. 1994;308:42-47. doi:10.1006/abbi.1994.1006
  55. Kvedar JC, Baden HP, Levine L. Selective inhibition by minoxidil of prostacyclin production by cells in culture. Biochem Pharmacol. 1988;37:867-874. doi:0.1016/0006-2952(88)90174-8
  56. Zhang D, LaSenna C, Shields BE. Culprits of medication-induced telogen effluvium, part 1. Cutis. 2023;112:267-271.
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Author and Disclosure Information

From the Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison.

Donglin Zhang and Dr. LaSenna report no conflict of interest. Dr. Shields received a grant from the Dermatology Foundation.

This article is the second of a 2-part series. The first part appeared in December 2023. doi:10.12788/cutis.0910

Correspondence: Bridget E. Shields, MD, Department of Dermatology, University of Wisconsin, 1 S Park St, Madison, WI 53715 ([email protected]).

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Author(s)
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Charlotte Lasenna, MD
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Author(s)
Donglin Zhang, BA
Charlotte Lasenna, MD
Bridget E. Shields, MD
Author and Disclosure Information

From the Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison.

Donglin Zhang and Dr. LaSenna report no conflict of interest. Dr. Shields received a grant from the Dermatology Foundation.

This article is the second of a 2-part series. The first part appeared in December 2023. doi:10.12788/cutis.0910

Correspondence: Bridget E. Shields, MD, Department of Dermatology, University of Wisconsin, 1 S Park St, Madison, WI 53715 ([email protected]).

Author and Disclosure Information

From the Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison.

Donglin Zhang and Dr. LaSenna report no conflict of interest. Dr. Shields received a grant from the Dermatology Foundation.

This article is the second of a 2-part series. The first part appeared in December 2023. doi:10.12788/cutis.0910

Correspondence: Bridget E. Shields, MD, Department of Dermatology, University of Wisconsin, 1 S Park St, Madison, WI 53715 ([email protected]).

Article PDF
CT113001011.pdf
Article PDF
CT113001011.pdf

Medication-induced telogen effluvium (TE) is a nonscarring alopecia that typically is reversible. Appropriate management requires identification of the underlying trigger and cessation of potential culprit medications. In part 2 of this series, we review anticoagulant and antihypertensive medications as potential contributors to TE.

Anticoagulants

Anticoagulants target various parts of the coagulation cascade to prevent clot formation in patients with conditions that increase their risk for thromboembolic events. Common indications for initiating anticoagulant therapy include atrial fibrillation,1 venous thromboembolism,2 acute myocardial infarction,3 malignancy,4 and hypercoagulable states.5 Traditional anticoagulants include heparin and warfarin. Heparin is a glycosaminoglycan that exerts its anticoagulant effects through binding with antithrombin, greatly increasing its inactivation of thrombin and factor Xa of the coagulation cascade.6 Warfarin is a coumarin derivative that inhibits activation of vitamin K, subsequently limiting the function of vitamin K–dependent factors II, VII, IX, and X.7,8 Watras et al9 noted that heparin and warfarin were implicated in alopecia as their clinical use became widespread throughout the mid-20th century. Onset of alopecia following the use of heparin or warfarin was reported at 3 weeks to 3 months following medication initiation, with most cases clinically consistent with TE.9 Heparin and warfarin both have alopecia reported as a potential adverse effect in their structured product labeling documents.10,11

Heparin is further classified into unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH); the latter is a heterogeneous group of medications derived from chemical or enzymatic depolymerization of UFH.12 In contrast to UFH, LMWH exerts its anticoagulant effects through inactivation of factor Xa without the ability to bind thrombin.12 An animal study using anagen-induced mice demonstrated that intraperitoneal administration of heparin inhibited the development of anagen follicles, while in vitro studies showed that the addition of heparin inhibited mouse dermal papilla cell proliferation.13 Other animal and in vitro studies have examined the inhibitory effects of heparin on signaling pathways in tumor lymphangiogenesis, including the vascular endothelial growth factor C/vascular endothelial growth factor receptor 3 axis.14,15 Clinically, it has been demonstrated that heparin, especially LMWHs, may be associated with a survival benefit among certain cancer patients,16,17 with the impact of LMWHs attributed to antimitotic and antimetastatic effects of heparin on tumor growth.14 It is hypothesized that such antiangiogenic and antimitotic effects also are involved in the pathomechanisms of heparin-induced alopecia.18

More recently, the use of direct oral anticoagulants (DOACs) such as dabigatran, rivaroxaban, and apixaban has increased due to their more favorable adverse-effect profile and minimal monitoring requirements. Bonaldo et al19 conducted an analysis of reports submitted to the World Health Organization’s VigiBase database of alopecia associated with DOACs until May 2, 2018. They found 1316 nonduplicate DOAC-induced cases of alopecia, with rivaroxaban as the most reported drug associated with alopecia development (58.8% [774/1316]). Only 4 cases demonstrated alopecia with DOAC rechallenge, suggesting onset of alopecia may have been unrelated to DOAC use or caused by a different trigger. Among 243 cases with a documented time to onset of alopecia, the median was 28 days, with an interquartile range of 63 days. Because TE most commonly occurs 3 to 4 months after the inciting event or medication trigger, there is little evidence to suggest DOACs as the cause of TE, and the observed cases of alopecia may be attributable to another preceding medical event and/or medication exposure.19 More studies are needed to examine the impact of anticoagulant medications on the hair cycle.

Antihypertensives

Hypertension is a modifiable risk factor for several ­cardiovascular diseases.20 According to the 2019 American College of Cardiology/American Heart Association Guideline on the Primary Prevention of Cardiovascular Disease,21 first-line medications include thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor ­blockers (ARBs).

Angiotensin-converting enzyme inhibitors exert their antihypertensive effects by reducing conversion of angiotensin I to angiotensin II, thereby limiting the downstream effects of vasoconstriction as well as sodium and water retention. Given the proven mortality benefit of ACE inhibition in patients with congestive heart failure, ACE inhibitors are used as first-line therapy in these patients.22,23 Alopecia associated with ACE inhibitors is rare and limited to case reports following their introduction and approval in 1981.24-28 In one case, a woman in her 60s with congestive heart failure initiated captopril with development of an erythematous pruritic rash on the extremities and diffuse scalp hair loss 2 months later; spontaneous hair growth resumed 1 month following captopril discontinuation.25 In this case, the hair loss may be secondary to the drug eruption rather than true medication-induced TE. Initiation of enalapril in a woman in her 30s with hypertension was associated with diffuse scalp alopecia 4 weeks later that resolved with cessation of the suspected culprit, enalapril; rechallenge with enalapril several months later reproduced the hair loss.27 Given limited reports of ACE inhibitor–associated hair loss relative to their pervasive use, a direct causal role between ACE inhibition and TE is unlikely, or it has not been rigorously identified. The structured product labeling for captopril includes alopecia in its list of adverse effects reported in approximately 0.5% to 2% of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials.29 Alternative inciting causes of alopecia in patients prescribed ACE inhibitors may include use of other medications, hospitalization, or metabolic derangements related to their underlying cardiac disease.

Although not indicated as a primary treatment for hypertension, β-blockers have US Food and Drug Administration approval for the treatment of certain arrhythmias, hypertension, heart failure, myocardial infarction, hyperthyroidism, and other conditions.30β-Blockers are competitive antagonists of β-adrenergic receptors that limit the production of intracellular cyclic adenosine monophosphate, but the mechanism of β-blockers as antihypertensives is unclear.31 Evidence supporting the role of β-adrenergic antagonists in TE is limited to case reports. Widespread alopecia across the scalp and arms was noted in a man in his 30s several months after starting propranolol.32 Biopsy of an affected area of the scalp demonstrated an increased number of telogen follicles with no other abnormalities. Near-complete resolution of alopecia was seen 4 months following cessation of propranolol, which recurred within 4 weeks of rechallenge.32 Although the histopathologic features are compatible with TE, the loss of body hair and rapid recurrence within 4 weeks of rechallenge are atypical for TE. As such, the use of propranolol and the reported alopecia may be coincidental or evidence of an atypical drug reaction distinct from medication-induced TE. Only a handful of other case reports have been published describing TE in patients treated with β-blockers, including metoprolol and propranolol.33,34 Alopecia has been reported with the use of carvedilol in up to 0.1% of participants.35 Although cases have been reported, TE appears to be an uncommon occurrence following β-blocker therapy.

Minoxidil—Oral minoxidil originally was approved for use in patients with resistant hypertension, defined as blood pressure elevated above goal despite concurrent use of the maximum dose of 3 classes of antihypertensives.36 Unlike other antihypertensive medications, minoxidil appears to cause reversible hypertrichosis that affects nearly all patients using oral minoxidil for longer than 1 month.37 This common adverse effect was a desired outcome in patients affected by hair loss, and a topical formulation of minoxidil was approved for androgenetic alopecia in men and women in 1988 and 1991, respectively.38 Since its approval, topical minoxidil has been commonly prescribed in the treatment of several types of alopecia, though evidence of its efficacy in the treatment of TE is limited.39,40 Low-dose oral minoxidil also has been reported to aid hair growth in androgenetic alopecia and TE.41 Taken orally, minoxidil is converted by sulfotransferases in the liver to minoxidil sulfate, which causes opening of plasma membrane adenosine ­triphosphate–sensitive potassium channels.42-44 The subsequent membrane hyperpolarization reduces calcium ion influx, which also reduces cell excitability, and inhibits contraction in vascular smooth muscle cells, which results in the arteriolar vasodilatory and antihypertensive effects of minoxidil.43,45 The potassium channel–opening effects of minoxidil may underly its hair growth stimulatory action. Unrelated potassium channel openers such as diazoxide and pinacidil also cause hypertrichosis.46-48 An animal study showed that topical minoxidil, cromakalim (potassium channel opener), and P1075 (pinacidil analog) applied daily to the scalps of balding stump-tailed macaques led to significant increases in hair weight over a 20-week treatment period compared with the vehicle control group (P<.05 for minoxidil 100 mM and 250 mM, cromakalim 100 mM, and P1075 100 mM and 250 mM).50 For minoxidil, this effect on hair growth appears to be dose dependent, as cumulative hair weights for the study period were significantly greater in the 250-mM concentration compared with 100-mM minoxidil (P<.05).49 The potassium channel–opening activity of minoxidil may induce stimulation of microcirculation around hair follicles conducive to hair growth.50 Other proposed mechanisms for hair growth with minoxidil include effects on keratinocyte and fibroblast cell proliferation,51-53 collagen synthesis,52,54 and prostaglandin activity.44,55

Final Thoughts

Medication-induced TE is an undesired adverse effect of many commonly used medications, including retinoids, azole antifungals, mood stabilizers, anticoagulants, and antihypertensives. In part 156 of this 2-part series, we reviewed the existing literature on hair loss from retinoids, antifungals, and psychotropic medications. Herein, we focused on anticoagulant and antihypertensive medications as potential culprits of TE. Heparin and its derivatives have been associated with development of diffuse alopecia weeks to months after the start of treatment. Alopecia associated with ACE inhibitors and β-blockers has been described only in case reports, suggesting that they may be unlikely causes of TE. In contrast, minoxidil is an antihypertensive that can result in hypertrichosis and is used in the treatment of androgenetic alopecia. It should not be assumed that medications that share an indication or are part of the same medication class would similarly induce TE. The development of diffuse nonscarring alopecia should prompt suspicion for TE and thorough investigation of medications initiated 1 to 6 months prior to onset of clinically apparent alopecia. Suspected culprit medications should be carefully assessed for their likelihood of inducing TE.

Medication-induced telogen effluvium (TE) is a nonscarring alopecia that typically is reversible. Appropriate management requires identification of the underlying trigger and cessation of potential culprit medications. In part 2 of this series, we review anticoagulant and antihypertensive medications as potential contributors to TE.

Anticoagulants

Anticoagulants target various parts of the coagulation cascade to prevent clot formation in patients with conditions that increase their risk for thromboembolic events. Common indications for initiating anticoagulant therapy include atrial fibrillation,1 venous thromboembolism,2 acute myocardial infarction,3 malignancy,4 and hypercoagulable states.5 Traditional anticoagulants include heparin and warfarin. Heparin is a glycosaminoglycan that exerts its anticoagulant effects through binding with antithrombin, greatly increasing its inactivation of thrombin and factor Xa of the coagulation cascade.6 Warfarin is a coumarin derivative that inhibits activation of vitamin K, subsequently limiting the function of vitamin K–dependent factors II, VII, IX, and X.7,8 Watras et al9 noted that heparin and warfarin were implicated in alopecia as their clinical use became widespread throughout the mid-20th century. Onset of alopecia following the use of heparin or warfarin was reported at 3 weeks to 3 months following medication initiation, with most cases clinically consistent with TE.9 Heparin and warfarin both have alopecia reported as a potential adverse effect in their structured product labeling documents.10,11

Heparin is further classified into unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH); the latter is a heterogeneous group of medications derived from chemical or enzymatic depolymerization of UFH.12 In contrast to UFH, LMWH exerts its anticoagulant effects through inactivation of factor Xa without the ability to bind thrombin.12 An animal study using anagen-induced mice demonstrated that intraperitoneal administration of heparin inhibited the development of anagen follicles, while in vitro studies showed that the addition of heparin inhibited mouse dermal papilla cell proliferation.13 Other animal and in vitro studies have examined the inhibitory effects of heparin on signaling pathways in tumor lymphangiogenesis, including the vascular endothelial growth factor C/vascular endothelial growth factor receptor 3 axis.14,15 Clinically, it has been demonstrated that heparin, especially LMWHs, may be associated with a survival benefit among certain cancer patients,16,17 with the impact of LMWHs attributed to antimitotic and antimetastatic effects of heparin on tumor growth.14 It is hypothesized that such antiangiogenic and antimitotic effects also are involved in the pathomechanisms of heparin-induced alopecia.18

More recently, the use of direct oral anticoagulants (DOACs) such as dabigatran, rivaroxaban, and apixaban has increased due to their more favorable adverse-effect profile and minimal monitoring requirements. Bonaldo et al19 conducted an analysis of reports submitted to the World Health Organization’s VigiBase database of alopecia associated with DOACs until May 2, 2018. They found 1316 nonduplicate DOAC-induced cases of alopecia, with rivaroxaban as the most reported drug associated with alopecia development (58.8% [774/1316]). Only 4 cases demonstrated alopecia with DOAC rechallenge, suggesting onset of alopecia may have been unrelated to DOAC use or caused by a different trigger. Among 243 cases with a documented time to onset of alopecia, the median was 28 days, with an interquartile range of 63 days. Because TE most commonly occurs 3 to 4 months after the inciting event or medication trigger, there is little evidence to suggest DOACs as the cause of TE, and the observed cases of alopecia may be attributable to another preceding medical event and/or medication exposure.19 More studies are needed to examine the impact of anticoagulant medications on the hair cycle.

Antihypertensives

Hypertension is a modifiable risk factor for several ­cardiovascular diseases.20 According to the 2019 American College of Cardiology/American Heart Association Guideline on the Primary Prevention of Cardiovascular Disease,21 first-line medications include thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor ­blockers (ARBs).

Angiotensin-converting enzyme inhibitors exert their antihypertensive effects by reducing conversion of angiotensin I to angiotensin II, thereby limiting the downstream effects of vasoconstriction as well as sodium and water retention. Given the proven mortality benefit of ACE inhibition in patients with congestive heart failure, ACE inhibitors are used as first-line therapy in these patients.22,23 Alopecia associated with ACE inhibitors is rare and limited to case reports following their introduction and approval in 1981.24-28 In one case, a woman in her 60s with congestive heart failure initiated captopril with development of an erythematous pruritic rash on the extremities and diffuse scalp hair loss 2 months later; spontaneous hair growth resumed 1 month following captopril discontinuation.25 In this case, the hair loss may be secondary to the drug eruption rather than true medication-induced TE. Initiation of enalapril in a woman in her 30s with hypertension was associated with diffuse scalp alopecia 4 weeks later that resolved with cessation of the suspected culprit, enalapril; rechallenge with enalapril several months later reproduced the hair loss.27 Given limited reports of ACE inhibitor–associated hair loss relative to their pervasive use, a direct causal role between ACE inhibition and TE is unlikely, or it has not been rigorously identified. The structured product labeling for captopril includes alopecia in its list of adverse effects reported in approximately 0.5% to 2% of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials.29 Alternative inciting causes of alopecia in patients prescribed ACE inhibitors may include use of other medications, hospitalization, or metabolic derangements related to their underlying cardiac disease.

Although not indicated as a primary treatment for hypertension, β-blockers have US Food and Drug Administration approval for the treatment of certain arrhythmias, hypertension, heart failure, myocardial infarction, hyperthyroidism, and other conditions.30β-Blockers are competitive antagonists of β-adrenergic receptors that limit the production of intracellular cyclic adenosine monophosphate, but the mechanism of β-blockers as antihypertensives is unclear.31 Evidence supporting the role of β-adrenergic antagonists in TE is limited to case reports. Widespread alopecia across the scalp and arms was noted in a man in his 30s several months after starting propranolol.32 Biopsy of an affected area of the scalp demonstrated an increased number of telogen follicles with no other abnormalities. Near-complete resolution of alopecia was seen 4 months following cessation of propranolol, which recurred within 4 weeks of rechallenge.32 Although the histopathologic features are compatible with TE, the loss of body hair and rapid recurrence within 4 weeks of rechallenge are atypical for TE. As such, the use of propranolol and the reported alopecia may be coincidental or evidence of an atypical drug reaction distinct from medication-induced TE. Only a handful of other case reports have been published describing TE in patients treated with β-blockers, including metoprolol and propranolol.33,34 Alopecia has been reported with the use of carvedilol in up to 0.1% of participants.35 Although cases have been reported, TE appears to be an uncommon occurrence following β-blocker therapy.

Minoxidil—Oral minoxidil originally was approved for use in patients with resistant hypertension, defined as blood pressure elevated above goal despite concurrent use of the maximum dose of 3 classes of antihypertensives.36 Unlike other antihypertensive medications, minoxidil appears to cause reversible hypertrichosis that affects nearly all patients using oral minoxidil for longer than 1 month.37 This common adverse effect was a desired outcome in patients affected by hair loss, and a topical formulation of minoxidil was approved for androgenetic alopecia in men and women in 1988 and 1991, respectively.38 Since its approval, topical minoxidil has been commonly prescribed in the treatment of several types of alopecia, though evidence of its efficacy in the treatment of TE is limited.39,40 Low-dose oral minoxidil also has been reported to aid hair growth in androgenetic alopecia and TE.41 Taken orally, minoxidil is converted by sulfotransferases in the liver to minoxidil sulfate, which causes opening of plasma membrane adenosine ­triphosphate–sensitive potassium channels.42-44 The subsequent membrane hyperpolarization reduces calcium ion influx, which also reduces cell excitability, and inhibits contraction in vascular smooth muscle cells, which results in the arteriolar vasodilatory and antihypertensive effects of minoxidil.43,45 The potassium channel–opening effects of minoxidil may underly its hair growth stimulatory action. Unrelated potassium channel openers such as diazoxide and pinacidil also cause hypertrichosis.46-48 An animal study showed that topical minoxidil, cromakalim (potassium channel opener), and P1075 (pinacidil analog) applied daily to the scalps of balding stump-tailed macaques led to significant increases in hair weight over a 20-week treatment period compared with the vehicle control group (P<.05 for minoxidil 100 mM and 250 mM, cromakalim 100 mM, and P1075 100 mM and 250 mM).50 For minoxidil, this effect on hair growth appears to be dose dependent, as cumulative hair weights for the study period were significantly greater in the 250-mM concentration compared with 100-mM minoxidil (P<.05).49 The potassium channel–opening activity of minoxidil may induce stimulation of microcirculation around hair follicles conducive to hair growth.50 Other proposed mechanisms for hair growth with minoxidil include effects on keratinocyte and fibroblast cell proliferation,51-53 collagen synthesis,52,54 and prostaglandin activity.44,55

Final Thoughts

Medication-induced TE is an undesired adverse effect of many commonly used medications, including retinoids, azole antifungals, mood stabilizers, anticoagulants, and antihypertensives. In part 156 of this 2-part series, we reviewed the existing literature on hair loss from retinoids, antifungals, and psychotropic medications. Herein, we focused on anticoagulant and antihypertensive medications as potential culprits of TE. Heparin and its derivatives have been associated with development of diffuse alopecia weeks to months after the start of treatment. Alopecia associated with ACE inhibitors and β-blockers has been described only in case reports, suggesting that they may be unlikely causes of TE. In contrast, minoxidil is an antihypertensive that can result in hypertrichosis and is used in the treatment of androgenetic alopecia. It should not be assumed that medications that share an indication or are part of the same medication class would similarly induce TE. The development of diffuse nonscarring alopecia should prompt suspicion for TE and thorough investigation of medications initiated 1 to 6 months prior to onset of clinically apparent alopecia. Suspected culprit medications should be carefully assessed for their likelihood of inducing TE.

References
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  2. Kearon C, Kahn SR. Long-term treatment of venous thromboembolism. Blood. 2020;135:317-325. doi:10.1182/blood.2019002364
  3. Frishman WH, Ribner HS. Anticoagulation in myocardial infarction: modern approach to an old problem. Am J Cardiol. 1979;43:1207-1213. doi:10.1016/0002-9149(79)90155-3
  4. Khorana AA, Mackman N, Falanga A, et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers. 2022;8:11. doi:10.1038 /s41572-022-00336-y
  5. Umerah CO, Momodu, II. Anticoagulation. StatPearls [Internet]. StatPearls Publishing; 2023. Accessed December 11, 2023. https://www.ncbi.nlm.nih.gov/books/NBK560651/
  6. Beurskens DMH, Huckriede JP, Schrijver R, et al. The anticoagulant and nonanticoagulant properties of heparin. Thromb Haemost. 2020;120:1371-1383. doi:10.1055/s-0040-1715460
  7. Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001;119(1 suppl):8S-21S. doi:10.1378/chest.119.1_suppl.8s
  8. Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165:1095-1106. doi:10.1001/archinte.165.10.1095
  9. Watras MM, Patel JP, Arya R. Traditional anticoagulants and hair loss: a role for direct oral anticoagulants? a review of the literature. Drugs Real World Outcomes. 2016;3:1-6. doi:10.1007/s40801-015-0056-z
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  24. Kataria V, Wang H, Wald JW, et al. Lisinopril-induced alopecia: a case report. J Pharm Pract. 2017;30:562-566. doi:10.1177/0897190016652554
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  30. Farzam K, Jan A. Beta blockers. StatPearls Publishing; 2023. https://www.ncbi.nlm.nih.gov/books/NBK532906/
  31. Mason RP, Giles TD, Sowers JR. Evolving mechanisms of action of beta blockers: focus on nebivolol. J Cardiovasc Pharmacol. 2009; 54:123-128.
  32. Martin CM, Southwick EG, Maibach HI. Propranolol induced alopecia. Am Heart J. 1973;86:236-237. doi:10.1016/0002-8703(73)90250-0
  33. Graeber CW, Lapkin RA. Metoprolol and alopecia. Cutis. 1981; 28:633-634.
  34. Hilder RJ. Propranolol and alopecia. Cutis. 1979;24:63-64.
  35. Coreg. Prescribing information. Woodward Pharma Services LLC; 2023. Accessed December 11, 2023. https://www.accessdata.fda.gov/spl/data/34aa881a-3df4-460b-acad-fb9975ca3a06/34aa881a-3df4-460b-acad-fb9975ca3a06.xml
  36. Carey RM, Calhoun DA, Bakris GL, et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension. 2018;72:E53-E90. doi:10.1161/hyp.0000000000000084
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  38. Heymann WR. Coming full circle (almost): low dose oral minoxidil for alopecia. J Am Acad Dermatol. 2021;84:613-614. doi:10.1016/j .jaad.2020.12.053
  39. Yin S, Zhang B, Lin J, et al. Development of purification process for dual-function recombinant human heavy-chain ferritin by the investigation of genetic modification impact on conformation. Eng Life Sci. 2021;21:630-642. doi:10.1002/elsc.202000105
  40. Mysore V, Parthasaradhi A, Kharkar RD, et al. Expert consensus on the management of telogen effluvium in India. Int J Trichology. 2019;11:107-112.
  41. Gupta AK, Talukder M, Shemar A, et al. Low-dose oral minoxidil for alopecia: a comprehensive review [published online September 27, 2023]. Skin Appendage Disord. doi:10.1159/000531890
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References
  1. Angiolillo DJ, Bhatt DL, Cannon CP, et al. Antithrombotic therapy in patients with atrial fibrillation treated with oral anticoagulation undergoing percutaneous coronary intervention: a North American perspective: 2021 update. Circulation. 2021;143:583-596. doi:10.1161 /circulationaha.120.050438
  2. Kearon C, Kahn SR. Long-term treatment of venous thromboembolism. Blood. 2020;135:317-325. doi:10.1182/blood.2019002364
  3. Frishman WH, Ribner HS. Anticoagulation in myocardial infarction: modern approach to an old problem. Am J Cardiol. 1979;43:1207-1213. doi:10.1016/0002-9149(79)90155-3
  4. Khorana AA, Mackman N, Falanga A, et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers. 2022;8:11. doi:10.1038 /s41572-022-00336-y
  5. Umerah CO, Momodu, II. Anticoagulation. StatPearls [Internet]. StatPearls Publishing; 2023. Accessed December 11, 2023. https://www.ncbi.nlm.nih.gov/books/NBK560651/
  6. Beurskens DMH, Huckriede JP, Schrijver R, et al. The anticoagulant and nonanticoagulant properties of heparin. Thromb Haemost. 2020;120:1371-1383. doi:10.1055/s-0040-1715460
  7. Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001;119(1 suppl):8S-21S. doi:10.1378/chest.119.1_suppl.8s
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Culprits of Medication-Induced Telogen Effluvium, Part 2
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Culprits of Medication-Induced Telogen Effluvium, Part 2
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Practice Points

  • Medications are a common culprit of telogen effluvium (TE), and medication-induced TE should be suspected in patients presenting with diffuse nonscarring alopecia who are taking systemic medication(s) such as heparin and its derivatives.
  • Infection, illness, or hospitalization around the time of initiation of the suspected culprit medication may complicate identification of the inciting cause and may contribute to TE.
  • Angiotensin-converting enzyme inhibitors and β-blockers are unlikely culprits of medication-induced TE, and the benefits of discontinuing a suspected culprit medication should be weighed carefully against the risks of medication cessation.
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