Clinical Management Extra Approaches to Microthrombotic Wounds: A Review of Pathogenesis and Clinical Features Asfandyar Mufti, MD, BMSc, Dermatology Resident, Division of Dermatology, Department of Medicine, University of Toronto, Ontario, Canada Khalad Maliyar, BSc, Medical Student, Department of Medicine, University of Toronto, Ontario, Canada Maleeha Syed, BSc, Family Medicine Resident, Division of Family Medicine, Department of Medicine, University of Toronto, Ontario, Canada Christian Pagnoux, MD, MSc, MPH, Associate Professor, Vasculitis Clinic, Department of Medicine, University of Toronto, Ontario, Canada Afsaneh Alavi, MD, MSc, Assistant Professor, Division of Dermatology, Department of Medicine, University of Toronto, Ontario, Canada GENERAL PURPOSE: To discuss the pathogenesis and clinical features of wounds caused by microthrombi formation under the CME following categories of systemic diseases: cold-related and immune-complex deposition diseases, coagulopathies, abnormalities in 1 AMA PRA Category 1 CreditTM red blood cell structure, emboli, and vasospasm. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. ANCC LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant should be better able to: 1.5 Contact Hours 1. Recall the etiology, risk factors, and pathophysiology of the various types of microthrombotic wounds. 2. Describe the clinical manifestations and treatment of the various types of microthrombotic wounds. 0.5 Pharmacology Contract Hour ABSTRACT Typical wounds such as diabetic foot ulcers, INTRODUCTION venous leg ulcers, pressure ulcers, and arterial ulcers are Effective treatment of leg ulcers relies on accurate diag- responsible for more than 70% of chronic wounds. Atypical nosis. More than 70% of wounds are classified as typical wounds have broad differential diagnoses and can wounds, attributable to common etiologies such as arte- sometimes develop as a combination of different conditions. rial diabetic or venous ulcers.1 However, wounds associ- Regardless of the etiology, impaired blood circulation is ated with microvascular occlusions often have atypical characteristic of all chronic and acute wounds. Chronic presentations and are therefore difficult to diagnose and man- wounds associated with microthrombi formation are an important group of atypical wounds commonly linked to an age. Because the majority of these wounds present with pain underlying systemic disease. In this perspective article, the and inflammation as leading signs and symptoms, they can pathogenesis and clinical features of wounds caused by easily be confounded with pyoderma gangrenosum. microthrombi formation are discussed under the following Atypical leg ulcers account for approximately 20% to categories of systemic diseases: cold-related and 30% of cases of leg ulcers.2 The wounds are considered immune-complex deposition diseases, coagulopathies, atypical based on their morphologic features, incidence/ abnormalities in red blood cell structure, emboli, and prevalence, clinical presentations, unusual locations, and/ vasospasm. or their inability to respond to conventional therapy. For KEYWORDS: antiphospholipid antibody, atrial myxoma, example, it is uncommon for diabetic wounds to present cholesterol emboli, cryoglobulinemia, cryofibrinogenemia, on the thigh, and providers should therefore consider hydroxyurea-induced ulcer, livedoid vasculopathy, an atypical etiology. microthrombi, sickle cell anemia, skin necrosis, vasospasm, warfarin One atypical etiology for chronic wounds is micro- thrombi formation. Although the pathogenesis of wounds ADV SKIN WOUND CARE 2020;33:68–75. attributable to microthrombi has not been completely elu- DOI: 10.1097/01.ASW.0000617860.92050.9e cidated, it is most likely linked to tissue hypoxia that leads to cutaneous ulcerations and necrosis. These lesions are ex- tremely painful and commonly related to the occlusion of The authors, faculty, staff, and planners, including spouses/partners (if any), in any position to control the content of this CME/CNE activity have disclosed that they have no financial relationships with, or financial interests in, any commercial companies relevant to this educational activity. To earn CME credit, you must read the CME article and complete the quiz online, answering at least 13 of the 18 questions correctly. This continuing educational activity will expire for physicians on January 31, 2022, and for nurses December 3, 2021. All tests are now online only; take the test at http://cme.lww.com for physicians and www.nursingcenter.com for nurses. Complete CE/CME information is on the last page of this article. ADVANCES IN SKIN & WOUND CARE • FEBRUARY 2020 68 WWW.ASWCJOURNAL.COM Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. small blood vessels from thrombi formation and not athero- fixation lead to vascular inflammation and vasculitis, often sclerosis. Diagnosis is often made based on a thorough with microthrombi formation. In both cases, obstruction of clinical history, laboratory findings, and skin biopsy; blood vessels follows, causing ischemia, gangrene, and however, these wounds may have features that can be ulcer formation.3 mistaken for more common etiologies. Cryofibrinogenemia is a rare disease that occurs be- This review article focuses on the pathogenesis and clinical cause of the precipitation of cryoprotein in plasma.9 features of cutaneous ulcers caused by microthrombi forma- These cryoprecipitates, known as cryofibrinogen, are tion, including cold-related and immune-complex depo- characteristically composed of fibrinogen, fibrin, fibro- sition ulcers, ulcers associated with coagulopathies, emboli nectin, and fibrin degradation products and may contain or microemboli, vasospasm, and blood cell-abnormal immunoglobulins. Patients with cryofibrinogenemia may deformability. This review also discusses management be asymptomatic; therefore, the presence of nonhealing plans for these ulcers and concludes with a brief discus- ulcers in otherwise healthy patients should raise suspi- sion of the less common ulcers attributable to emboli. cion of essential cryofibrinogenemia. In terms of etiology, cryofibrinogenemia can either be primary or secondary BACKGROUND AND PATHOPHYSIOLOGY to infection, vasculitis, myeloproliferative disorders, Cold-Related Ulcers solid malignancies, or diabetes mellitus.10,11 Importantly, The two most common cold-related ulcers are ulcers asso- cryofibrinogen can be associated with the presence of ciated with cryoglobulinemia and cryofibrinogenemia. a cryoglobulin. Cryoglobulinemia is a disorder characterized by the pres- Cryofibrinogen is an insoluble protein complex that is ence of serum cryoglobulin, which is an aggregate of im- constituted from fibronectin, fibrin, fibrinogen, and, on munoglobulins that precipitate in vitro at temperatures occasion, small quantities of immunoglobulins in plasma below 37° C and resolubilize upon rewarming.3 According (not serum) that reversibly precipitate at 4° C and resolve to the Brouet classification, type I cryoglobulinemia is char- at 37° C.12 It does not precipitate in serum because acterized by monoclonal immunoglobulins (commonly ei- clotting factors, which are not found in serum, are sub- ther immunoglobulin M [IgM] or G [IgG]) often associated strates for cryofibrinogen. The exact mechanism of with immune system malignancies, including monoclonal cryofibrinogenemia remains unknown. One theory is gammopathy of undetermined significance, multiple that elevated plasma α1 antitrypsin and α2macroglobu- myeloma, Waldenström macroglobulinemia, lymphoma, lin lead to a defect in the fibrinolysis pathway.13 Both of and chronic lymphocytic leukemia.4 Types II and III cryo- these molecules are known to inhibit plasmin, which globulinemia contain both IgG and IgM and are referred to leads to impaired fibrinolysis at elevated levels. As as mixed cryoglobulinemia. Type II cryoglobulinemia has cryofibrinogen levels increase in the plasma, clot forma- monoclonal IgM, polyclonal IgG, and rheumatoid factor, tion occurs, and eventual blood vessel occlusion follows. whereas type III cryoglobulinemia has polyclonal IgG The second leading theory proposes that a heightened and IgM with rheumatoid factor.4 Both types II and III thrombin-binding capacity may be the principal cause, are strongly associated with the hepatitis C virus. Other as opposed to a deficiency in the fibrinolytic pathway.9 cases can be idiopathic (essential cryoglobulinemia) or In either case, there is obstruction of small and medium associated with other systemic diseases, such as Sjögren vessels, leading to hyperviscosity, vasospasm, ischemia, syndrome. Hepatitis C virus infection has been reported and vascular stasis. in 60% to 90% of patients with mixed cryoglobulinemia and is implicated in the disease process.5,6 Ulcers Commonly Associated with Coagulopathies The pathogenesis of tissue injury in cryoglobulinemia Examples of ulcers commonly associated with coagu- is complex. The mechanism by which cryoprecipitation lopathies include those associated with antiphospholipid occurs is thought to evolve from two primary factors antibody syndrome (APLS), livedoid vasculopathy (LV), working together simultaneously at different degrees.3 or the use of anticoagulants. Low temperatures also contribute to cryoprecipitation Antiphospholipid antibody syndrome is an autoimmune