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From Skin to Cytokine Storm and Clots

Advances in Skin & Wound Care: August 2022 - Volume 35 - Issue 8 - p 415
doi: 10.1097/01.ASW.0000840644.71235.44
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Although the skin is the largest organ of the body, COVID-related skin changes are often overlooked. However, the skin has several important clues to explain the devastation that COVID-19 can cause.

Early COVID-19 skin lesions can appear before or with other organ system symptoms. The first lesions are often vesicular lesions, like other direct skin viral infections including herpes simplex and herpes zoster. However, this is where the similarity ends. COVID-19 can stimulate a cytokine storm: a massive release of inflammatory mediators that can lead to tissue destruction. This process can result in upregulation of the immune system, leading to a systemic inflammatory response syndrome with the formation of small and large blood vessel clots.

Jamshidi et al1 conducted a systemic review of skin manifestations with COVID-19 to determine if these changes could be an indicator of disease severity. Their answer was generally no, but the outcomes could be dependent on the type of skin lesion, especially blood clots.

In a study by Stefely et al,2 102 patients with severe COVID-19 infection had factor V dysregulation and a high mortality (22%). If the factor V levels were high, patients had large vessel venous thromboses and pulmonary emboli. If the levels were low, patients had disseminated intervascular coagulation and an increased risk of death. In this study, 92% of patients were on ventilators, 48% had linear clots, and 23% had deep vein thromboses and/or pulmonary emboli.

The cytokine storm can stimulate a proliferation of megakaryocytes that produce excess platelets activated by the cytokines to form blood clots. Virchow classically described the triad of reduced blood flow leading to endothelial injury and thrombosis from hypercoagulability.3 It should be no surprise for clinicians to see a livedoid pattern to the medium-sized skin blood vessels because of small clots and COVID toes with reduced local blood flow.

In COVID-associated acute respiratory distress syndrome (ARDS), the cytokine storm interacts with the local/systemic inflammatory response syndrome associated with both macrothrombi and microthrombi. Gefen and Ousey4 postulated a complex pathologic process in severe COVID-19 infection. They suggested that this process starts with tissue deformation of the airways, damaging cells and leading to cell death. In addition, this process can trigger a localized inflammatory response that facilitates vascular occasion of the airways leading to hypoxia, acidosis, and ARDS.

Overall, ARDS is best treated in the prone position, but this positioning increases other risks. Trevellini5 documented a three-times-greater prevalence of hospital-acquired pressure injuries among ICU patients who were COVID-positive versus those who were negative.

COVID toes and their differential diagnoses were the subject of the July 2021 CE article, in which Sachdeva and colleagues6 outlined that this condition is a late manifestation of infection. The incidence of this complication is estimated at 2% to 20% of COVID-19 infections, but is probably underreported. The toes are often red or violaceous and itchy; they are less likely to be painful or necrotic. Wearing warm foot protection often alleviates most of the symptoms, and the condition usually lasts only a few weeks. Electron microscopic examination of skin biopsies has revealed small clots, and patients may have the spike protein deposited in the skin. Because the changes present late in the course of the disease, the nasal swab test for COVID-19 is usually negative.

These disease complications, along with an array of novel COVID-19 variants, have created new societal challenges. With new protective vaccines and a better comprehension of the disease process, we will be whole again, travel safely, and facilitate the resocialization of society.


R. Gary Sibbald, MD, DSc (Hons), MEd, BSc, FRCPC (Med Derm), FAAD, MAPWCA, JM


Elizabeth A. Ayello, PhD, MS, BSN, RN, CWON, ETN, MAPWCA, FAAN


1. Jamshidi P, Hajikhani B, Mirsaeidi M, et al. Skin manifestations of COVID-19 patients: are they indicators for disease severity? A systemic review. Front Med (Lausanne) 2021;8:634208.
2. Stefely JA, Christensen BB, Gogakos T, et al. Marked factor V activity elevation in severe COVID-19 is associated with venous thromboembolism. Am J Hematol 2020;95:1522–30.
3. Bagot CN, Arya R. Virchow and his triad: a question of attribution. Br J Haematol. 2008 Oct;143(2):180–90.
4. Gefen A, Ousey K. COVID-19: pressure ulcers, pain and the cytokine storm. J Wound Care 2020;29:540–2.
5. Trevellini C. Challenges faced with morbidity obese patients during COVID-19. The 2020 Virtual Meeting of the European Pressure Ulcer Advisory Panel (EPUAP). Last accessed June 10, 2022.
6. Sachdeva M, Mufti A, Maliyar K, Lara-Corrales I, Salcido R, Sibbald C. A review of COVID-19 chilblains-like lesions and their differential diagnoses. Adv Skin Wound Care 2021;34:348–54.
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