Livedoid vasculopathy, calciphylaxis, and Martorell’s hypertensive ulcer: update on ischemic ulcers due to impaired microcirculation of the lower limbs<sup/>

Lacerda, Priscila Neri; Garcia, Lucas Campos; Mazeto, Izabelle Ferreira da Silva; Miot, Hélio Amante; Abbade, Luciana Patricia Fernandes

doi:10.1016/j.abd.2024.09.004

person Priscila Neri Lacerda

Design · planning of the study · bibliographic survey · drafting · editing of the manuscript · critical review of the literature · critical review of the manuscript · approval of the final version of the manuscript

schoolSanta Casa de Misericórdia da Bahia, Hospital Santa Izabel, Salvador, BA, Brazil

0000-0001-8100-5978

person Lucas Campos Garcia

Design · planning of the study · bibliographic survey · drafting · editing of the manuscript · critical review of the literature · critical review of the manuscript · approval of the final version of the manuscript

schoolHospital das Clínicas, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

0000-0002-7883-5986

person Izabelle Ferreira da Silva Mazeto

Design · planning of the study · bibliographic survey · drafting · editing of the manuscript · critical review of the literature · critical review of the manuscript · approval of the final version of the manuscript

schoolDepartment of Infectology, Dermatology, Diagnostic Imaging and Radiotherapy, Faculty of Medicine, Universidade Estadual Paulista, Botucatu, SP, Brazil

0000-0003-2325-8701

person Hélio Amante Miot

Interpretation of the histopathological tests · critical review of the manuscript · approval of the final version of the manuscript

schoolDepartment of Infectology, Dermatology, Diagnostic Imaging and Radiotherapy, Faculty of Medicine, Universidade Estadual Paulista, Botucatu, SP, Brazil

0000-0002-2596-9294

person Luciana Patricia Fernandes Abbade *

Design · planning of the study · bibliographic survey · drafting · editing of the manuscript · critical review of the literature · critical review of the manuscript · approval of the final version of the manuscript

schoolDepartment of Infectology, Dermatology, Diagnostic Imaging and Radiotherapy, Faculty of Medicine, Universidade Estadual Paulista, Botucatu, SP, Brazil

0000-0002-0334-2079

Conflicts of interest

None declared.

person*Corresponding author.
E-mail:fernandes.abbade@unesp.br (L.P. Abbade).

Comorbidities
Metabolic	Diabetes mellitus, familial
	hypertriglyceridemia,
	hyperthyroidism, obesity,
	hyperhomocysteinemia
Cardiocirculatory	Systemic arterial hypertension,
	peripheral venous insufficiency,
	coronary artery disease
Rheumatological	Rheumatoid arthritis, systemic
	lupus erythematosus,
	antiphospholipid antibody
	syndrome, mixed connective
	tissue disease
Hematological	Systemic lymphomas, monoclonal
	gammopathies, polycythemia
	vera, acquired thrombophilias
	(cryoglobulins, cryoagglutinins,
	cryofibrinogen), congenital
	thrombophilias (associated with
	mutations in factors V, VIII, IX,
	prothrombin gene, proteins C and
	S, antithrombin III, plasminogen
	factor inhibitor and
	methylenetetrahydrofolate
	reductase [MTHFR] gene)
Infectious	HIV, hepatitis B and C
Miscellaneous	Breast cancer, asthma, migraine,
	kidney transplant, scleroderma

Class	Medication	Dose	Main adverse events
Antiplatelet agents ^a (First line of treatment)	Acetylsalicylic Acid Clopidogrel Pentoxifylline	75-325 mg/day 75 mg/day 400 mg 3x/day	Bleeding (gastric mucosa), dyspepsia, dizziness, urticaria, angioedema Bleeding, dyspepsia, diarrhea Headache, gastrointestinal discomfort, facial flushing, risky in patients with arrhythmias Bleeding, dyspnea, nausea, increased transaminases and thrombocytosis Bleeding, dyspepsia, nausea Bleeding, fever, nausea, vomiting Bleeding, confusion, nausea, anaphylactoid reactions Hypertension, hyperglycemia, infections, insomnia, irritability Menstrual irregularity, female virilization, worsening of prostatic hyperplasia, petechiae, hepatotoxicity Tachycardia, headache, diarrhea, peripheral edema Myalgia, peripheral edema, constipation, abdominal pain Hypertension, nephrotoxicity, opportunistic infections, cytopenias, malignant neoplasms Gastrointestinal, opportunistic infections and cytopenias Gastrointestinal intolerance, headache, agranulocytosis, hepatotoxicity Retinopathy, nausea, vomiting, skin pigmentation, dizziness, headache, ototoxicity and peripheral neuropathy DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), methemoglobinemia, and agranulocytosis Diarrhea, vomiting, colic, headache, asthenia Dyspepsia, teeth pigmentation, loss of appetite Headache, nausea, vomiting, fatigue
Anticoagulants ^a (First line of treatment) Systemic steroids (Second line of treatment)	Apixaban Rivaroxaban Dabigatran Warfarin Low molecular weight heparins Prednisone Danazol	2,5 mg 2x/day 20 mg 1x/day 150 mg 2x/day Maintain INR between 2-3 Enoxaparin 1 mg/kg SC 1x or 2x/day 0.5 to 1.0 mg/kg/day 200 mg/day
Peripheral vasodilators (Second line of treatment) Classical Immunosuppressants (Third line of treatment)	Cilostazol Nifedipine Ciclosporin Azathioprine	50-100 mg 2x/day 20 mg 3x/day 3-5 mg/kg/day 2-3 mg/kg/day
	Sulfasalazine	2-3 g/day divided in three doses
Immunomodulators/ miscellaneous (Third line of treatment)	Hydroxychloroquine	4-6 mg/kg/day
	Dapsone	50-200 mg/day
	Colchicine	0.5 mg 2 to 3x/day
	Doxycycline	100-200 mg/day
	Intravenous immunoglobulin (in refractory cases)	2 g/kg divided in three to five days every four weeks

General measures	Details
Risk factor control	Discontinuation of warfarin, vitamin D and calcium phosphate Maintenance of serum parathyroid hormone (PTH) levels between 150-300ng/mL Cinacalcet for treatment of secondary hyperparathyroidism Intensification of dialysis Parathyroidectomy if refractory secondary hyperparathyroidism
Pain control	Analgesia with opioids (morphine, codeine and hydrocodone should be avoided because they have active metabolites that accumulate in renal failure and cause respiratory depression) Consider an evaluation from a specialist in analgesic therapy
Local ulcer management	Surgical debridement Enzymatic (collagenase or papain) or autolytic (hydrocolloid or hydrogel) debridement Dressings Skin grafts Hyperbaric oxygen therapy
Secondary infection treatment	Systemic antibiotics
Specific treatment	Dose: 25g in 100mL of solution administered intravenously three times a week during the last 30 to 60minutes of hemodialysis
Sodium thiosulfate	Main adverse events: nausea, vomiting, metabolic acidosis and sepsis

Diagnosis	Main risk factors	Clinical manifestations Histopathological findings	Treatment
Livedoid vasculopathy	Prothrombotic conditions	Small, deep, necrotic and Thrombi in the intensely painful ulcers dermal vessels and that affect the distal sparse region of the legs, perivascular especially the malleolar lymphocytic region and dorsum of the inflammatory foot. infiltrate. They heal slowly and Deposition of fibrinoid leave characteristic material on the vessel atrophic ivory-white walls scars. Initially: painful, Calcification of small purpuric plaques or vessels (von Kossa stain) nodules associated with livedo racemosa. Progression to intensely Intimal hyperplasia and painful, reticulated thrombotic occlusion. necrotic ulcers. Initially: erythematous Acanthosis, necrosis of plaque that develops the epidermis and into a violaceous one, dermis, stenosis of and then into a subcutaneous vessels disproportionately with alteration of the painful ulcer. wall/lumen ratio, There may be associated calcification, thrombosis necrosis, bizarre and subendothelial contour, and livedo hyalinosis racemosa.	Control of risk factors and pain, local approach with dressings and debridement.
	Collagenoses Sickle cell anemia Infections (hepatitis B and C, HIV)		Drug therapy Hyperbaric oxygen therapy (see Table 2)
Calciphylaxis Hypertensive ischemic ulcer	Chronic kidney disease Warfarin use Obesity Long-standing and difficult-to-control systemic arterial hypertension (SAH)		Control of risk factors, pain, local approach (debridement) with treatment of secondary infection, active treatment with sodium thiosulfate (see Table 3) Control of hypertension, analgesia, anticoagulation, local measures, surgical debridement and grafts
	Diabetes Mellitus

[TFN1] ^a
Antiplatelet agents and anticoagulants can be used together.

Livedoid vasculopathy, calciphylaxis, and Martorell’s hypertensive ulcer: update on ischemic ulcers due to impaired microcirculation of the lower limbs☆

Livedoid vasculopathy, calciphylaxis, and Martorell’s hypertensive ulcer: update on ischemic ulcers due to impaired microcirculation of the lower limbs^☆