Resolution of warfarin-induced alopecia with conversion to apixaban
- 1 Cardiovascular Sciences, University of Leicester, Leicester, UK
- 2 John Walls Renal Unit, University Hospitals of Leicester NHS Trust, Leicester, UK
- 3 Haematology, University Hospitals of Leicester NHS Trust, Leicester, UK
- 4 School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
- Correspondence to Dr Katherine Leigh Hull; katherine.hull@nhs.net
Abstract
Warfarin is frequently prescribed as a long-term anticoagulant in patients with end-stage kidney disease as direct oral anticoagulants undergo renal excretion. Anticoagulation is a rare cause of alopecia in adults and is thought to be due to the promotion of the ‘resting phase’ of hair follicles. In this case report, a prevalent haemodialysis female patient required long-term anticoagulation following a complex pulmonary embolus and dialysis access complications. After commencing warfarin therapy, the patient reported generalised loss and thinning of her hair. All other potential causes were excluded. Cessation of warfarin therapy and conversion to apixaban with close monitoring alleviated the hair loss. Warfarin therapy is a rare cause of alopecia but should be considered in patients on long-term anticoagulation when other diagnoses have been excluded. Hair loss has a profoundly negative impact on patient quality of life and should prompt investigation to determine the underlying cause.
Background
Anticoagulation in people with chronic kidney disease (CKD) and end-stage kidney disease (ESKD) is challenging. Renal impairment increases the risk of thromboembolism1 with thrombosis related to dialysis access (venous catheters, arteriovenous fistulae and arteriovenous grafts) being particularly problematic, resulting in poor quality of dialysis and ultimately dialysis access failure. Conversely, patients with CKD and ESKD also have a bleeding diathesis due to a number of mechanisms, including but not limited to uraemia, platelet dysfunction and anaemia.1 Until recently, warfarin has been the preferred long-term anticoagulant due to concerns regarding the safety of direct oral anticoagulants, which are renally cleared to varying extents.2 In this case report, a prevalent haemodialysis patient with a complex vascular access and thrombosis history requiring long-term anticoagulation experiences a rare side effect of warfarin which resolves on conversion to apixaban.
Case presentation
A 49-year-old woman with ESKD secondary to IgA nephropathy commenced three times per week in-centre haemodialysis via a tunnelled venous catheter in August 2019. Four weeks later, there were poor flows during haemodialysis with difficulty aspirating and flushing the catheter lumens despite thrombolytic locks and infusions. During an episode of dialysis, she reported experiencing pleuritic chest pain and breathlessness. Cross-sectional imaging performed at the time confirmed the presence of a large volume clot (4.2 cm in length) at the tip of the catheter and extending distally, causing significant stenosis of the superior vena cava, as well as a filling defect in medial basal segmental artery of the right lower lobe consistent with a pulmonary embolus. Treatment dose heparin was commenced while the internal jugular line was removed and replaced with a tunnelled right femoral catheter, after which she was commenced on warfarin (therapeutic international normalised ratio (INR) range set at 2.0–3.0).
Unfortunately, similar thrombotic complications then occurred despite warfarin therapy. In October 2019, as a result of poor flows on haemodialysis through the femoral dialysis catheter, further vascular imaging was undertaken. This identified extensive thrombus around the catheter tip, resulting in subtotal occlusion of the right common iliac vein (figure 1). Referral was made to the haematology team to investigate a potential underlying coagulation disorder, all of which was unremarkable. The target INR was increased to 3.0 (range 2.5–3.5) and repeat imaging after 6 months indicated clot resolution. Due to the recurrent nature of the thromboses and the history of pulmonary embolus, life-long anticoagulation with warfarin was recommended.
Linogram assessing the right femoral tunnelled dialysis catheter (outlined in blue). The filling defect and accumulation of contrast in the right common iliac vein, cranial to the line tip, is due to thrombus causing subtotal occlusion. Contrast is redirected to the pelvic collateral vessels.
During a routine consultation on the haemodialysis unit in March 2020, the patient reported feeling low and distressed by generalised thinning and loss of her hair, which corresponded exactly with the commencement of warfarin.
Investigations
There were no other associated symptoms, the patient’s body mass index had been stable and she underwent regular review by the specialist renal dietetics service. The patient had good adherence to dialysis and assessment of haematological and biochemical parameters demonstrated: urea clearance over the preceding 2 months averaged 68%, haemoglobin was stable at 119 g/L on a standard dose of erythropoietin with maintenance iron infusions to sustain a ferritin in the target range (serum ferritin=218 µg/L), and her thyroid function was normal (thyroid stimulating hormone 2.6 mIU/L, normal range 0.30–5.00 mIU/L). The patient’s calcium level was within normal limits at 2.33 mmol/L, with elevated phosphate (2.32 mmol/L) and parathyroid hormone levels (37.9 pmol/L), for which the patient was prescribed phosphate binders. Liver function tests were within normal limits: albumin 39 g/L, alkaline phosphatase 106 IU/L, alanine transaminase 21 IU/L and bilirubin 10 µmol/L.
Outcome and follow-up
After discussion with the patient and in consultation with haematology colleagues, her warfarin was discontinued and converted to apixaban with dosing guided by peak and trough levels. Within 3 weeks, the patient reported no further hair loss and recovery of hair growth.
Discussion
Hair loss is caused by a disorder within the hair follicle cycle (figure 2) and the stage of disruption characterises both the nature of the hair loss and the underlying aetiology.3 Anagen effluvium refers to hair shedding during the hair follicles’ growth stage due to direct toxic injury. It can occur after exposure to chemotherapy, radiotherapy and toxins (such as heavy metals). Alopecia areata is a common presentation of anagen effluvium as the hair follicle is the main target of autoimmune disease.3 Telogen effluvium refers to hair shedding during the hair follicles’ resting stage, resulting in hair loss and reduced volume of hair. It is typically reversible on removal of, or recovery from, the precipitating factor (as in this case). Acute telogen effluvium, defined as <6 months’ duration, can occur as a result of acute illness, childbirth, haemorrhage (often associated with trauma or surgery), extreme ‘crash’ dieting and severe emotional distress.3 4 The causes of chronic telogen effluvium (>6 months) are broad and include: nutritional deficits (iron, zinc, L-lysine) which can be due to restrictive diets, anorexia nervosa and malabsorption; chronic illness such as renal failure, liver failure, malignancy, HIV, systemic lupus erythematosus and connective tissue disorders; hypothyroidism and drug induced.3 4 Furthermore, hair loss can occur due to genetic factors with androgenetic alopecia occurring commonly in men and less frequently in women, and is characterised by shedding and reduced volume of hair around the scalp.4
Stages of hair follicle development and associated causes of hair loss.
During clinical assessment, the amount of hair loss can be objectively measured to assist diagnosis and response to intervention. Daily hair counts involve patients collecting all the hair lost by brushing or washing for 7 days with counts greater than 100 a day prompting further investigation5 ; the standardised wash test requires the patient to shampoo their hair 5 days after the last shampoo, with the drain covered in gauze to collect the hair shed3 5 ; the 60-second hair count involves the patient brushing their hair for 60 s prior to washing the hair on three consecutive occasions and recording the number of hairs lost on each occasion.5 Global photography requires the patient to maintain the same hair style and colour, however, it is a useful measure of response to treatment.6 Specialist techniques include dermoscopy of the scalp, trichogram to assess the quality and nature of the hair (anagen hair vs telogen hair) and scalp biopsy.5 Unfortunately, such techniques are burdensome to patients, and the use of subjective reporting and pragmatic quantification of hair loss have more widespread practical application,7 as in this case.
Alopecia is a rarely reported side effect of warfarin therapy. Although the presence of impaired renal function has been associated with an increased side effect profile of anticoagulation therapy,8 there are few reports of warfarin-induced alopecia in patients with ESKD in the literature. Although the exact mechanism resulting in hair loss with warfarin use is unknown, in their review, Watras et al explain that anticoagulants may lead to alopecia through the process of telogen effluvium, whereby the hair follicles enter their resting phase early, resulting in increased shedding and thinning of the hair.9 Data from the UK-based Yellow Card Scheme, a Medicines and Healthcare products Regulatory Agency organisation to monitor suspected adverse events from medicines and medical devices (available at https://yellowcard.mhra.gov.uk/), were collected to explore the occurrence of alopecia with anticoagulants. Interestingly, the Yellow Card Scheme reporting suggests that alopecia can occur with all types of anticoagulants and has been reported more frequently with oral agents, including warfarin, rivaroxaban and apixaban (table 1). However, there are a number of factors that will contribute to reporting bias, including changes in reporting practices over time, patient cohorts receiving treatment and frequency of enteral versus parenteral treatment. In contrast, data from the Dresden Non-vitamin K antagonist Oral Anticoagulants Registry report only a small number of patients experiencing hair loss with direct oral anticoagulants, largely limited to the use of rivaroxaban and dabigatran.10 These slightly conflicting reports simply highlight the paucity of knowledge and experience in this area.
Number of reported cases of alopecia with different types of anticoagulation via the UK Yellow Card Scheme
| Administration | Target | Anticoagulant | Reported cases of alopecia | Reporting years |
| Enteral | Factor Xa | Apixaban | 57 | 2009–2020 |
| Rivaroxaban | 82 | 2009–2020 | ||
| Edoxaban | 8 | 2016–2020 | ||
| Thrombin | Dabigatran | 9 | 2008–2020 | |
| Vitamin K antagonist | Warfarin | 75 | 1964–2020 | |
| Acenocoumarol (Sinthrome) | No data | No data | ||
| Parenteral | Thrombin and factor Xa | Dalteparin | 7 | 1991–2020 |
| Enoxaparin | 11 | 1991–2020 | ||
| Tinzaparin | 5 | 1993–2020 | ||
| Unfractionated heparin | 7 | 1965–2020 | ||
| Factor Xa | Fondaparinux | 1 | 2002–2020 | |
| Thrombin | Argatroban | 0 | 2012–2019 |
Alopecia is known to have significant psychological consequences, resulting in anxiety and depression, as well causing a loss of self-identity due to its disfiguring impact.11 Moreover, CKD and renal replacement therapy are independent negative predictors of poor body image and low self-esteem.12 13 In this case, the link between life-long warfarin use and therefore ongoing alopecia was incredibly distressing for the patient. Discontinuation of warfarin therapy and commencement of apixaban led to the prevention of further hair loss and subsequent regrowth, ultimately relieving significant anguish for the patient and enhancing their quality of life.
Learning points
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Alopecia is a rare but clinically important side effect of all anticoagulants although the reporting of side effects is inconsistent and subject to reporting bias.
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Anticoagulants cause hair loss by stimulating the resting stage of the hair follicle life cycle resulting in increased hair shedding; acute and chronic telogen effluvium.
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Direct oral anticoagulants are a potential alternative anticoagulant to warfarin for patients experiencing hair thinning and loss.
Footnotes
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Twitter @KatherineHulll, @@drjamesburton
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Contributors KLH gained consent from the patient and prepared the manuscript. JB and RG maintained clinical oversight of the case and confirmed the accuracy of the report. All authors approved the final manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Patient consent for publication Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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