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      Unilateral linear purpuric rash heralding SARS‐CoV‐2 vaccine‐induced immune thrombotic thrombocytopenia

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          Abstract

          Conflicts of interest None. Funding source None. Author contributions Concept and design: All authors. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: YTH and WTC. Critical revision of the manuscript for important intellectual content: All authors. Administrative, technical, or material support: WTC. Supervision: WTC. All four authors have reviewed the final version of the manuscript. Dear Editor, Vaccine‐induced immune thrombotic thrombocytopenia (VITT) has been a life‐threatening complication since adenovirus‐vectored vaccines, including ChAdOx1 nCoV‐19 (AstraZeneca) and Ad26.COV2.S (Johnson & Johnson/Janssen), were used against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). 1 VITT is characterized by thrombocytopenia, thrombosis, and presence of anti‐platelet factor 4 (anti‐PF4) antibodies. 1 Common reported symptoms include headache, abdominal pain, or swelling/pain of extremities, depending on the location of thrombosis. 1 Cutaneous manifestations in VITT have not yet been explored, but purpuric lesions may be observed in VITT cases with severe thrombocytopenia. 2 A 29‐year‐old otherwise healthy male presented with linear purpuric rashes on the right leg for one week, followed by acute onset of painful swelling and weakness on the same leg within recent 2 days. Meanwhile, he also complained headache, nausea, and vomiting. The patient had received ChAdOx1 nCoV‐19 vaccination 10 days before presentation. Physical examination showed linear erythematous‐to‐purplish palpable purpura along the right lower extremity (Fig. 1a,b). Duplex ultrasound examination revealed deep vein thrombosis (DVT), corresponding to the location of linear purpura from the level above right common femoral vein to right anterior/posterior tibial vein (Fig. 1c). Histopathology of linear purpura showed lymphocytic vasculitis and erythrocyte extravasation in the dermis and subcutaneous fat tissue (Fig. 1d,e). Magnetic resonance angiography study was arranged due to the neurologic symptoms and revealed dural sinus thrombosis at superior sagittal sinus (Fig. 1f), resulting in left parietal lobar hematoma, brain edema, and midline shift. Figure 1 (a–b) Clinical manifestation of the 29‐year‐old male. Unilateral linear palpable purpura along the right lower extremity (a), extending from the middle part of the posterior thigh to the whole calf (b). (c) Thrombosis developing from the level above right common femoral vein to right anterior/posterior tibial vein in Duplex ultrasound examination (thrombus indicated by arrow). (d) Histopathology of linear purpura showing lymphocytic vasculitis in the dermis (H&E stain, original magnification ×100). (e) Erythrocyte extravasation in the subcutaneous fat tissue (H&E stain, original magnification ×200). (f) Dural sinus thrombosis at superior sagittal sinus in magnetic resonance angiography (irregular filling defect indicated by arrow, contrast‐enhanced three‐dimensional fast spoiled gradient‐echo sequences). Laboratory testing showed thrombocytopenia (platelet count 42 × 109/L), elevated D‐dimer level (>10 000 FEU ng/mL), and positive anti‐PF4 IgG antibody ELISA tests [658.3 ng/mL (normal, 42.1–313.4 ng/mL)]. VITT was diagnosed, and the patient was treated with intravenous immunoglobulin (2 g/kg/day) for 2 days, intravenous methylprednisolone (80 mg/day) and apixaban (10 mg/day). Linear purpura diminished gradually after one‐month VITT treatment. Since global mass COVID‐19 vaccination is in progress, the surveillance system by the Vaccine Adverse Events Reporting System (VAERS) had reported, despite a low incidence of VITT, several hundred patients developing this catastrophic adverse event. 1 , 3 Adenovirus‐vectored COVID‐19 vaccines induce the production of anti‐PF4 antibodies which form immune complexes, triggering platelet activation and subsequent thrombotic events in VITT. 1 Venous thrombosis often occurs at multiple sites, such as cerebral venous sinus thrombosis, DVT, pulmonary embolism, splanchnic vein thrombosis, arterial thrombosis, and concomitant or secondary bleeding and/or intracerebral hemorrhage. 1 Various cutaneous manifestations have been observed following COVID‐19 vaccinations, including purpuric/petechial rashes. 2 Vasculitis is not the only etiology for COVID‐19 vaccine‐induced purpura. 2 In addition to COVID‐19 vaccines, immune thrombocytopenic purpura also occurred in other vaccinations, manifesting with bleeding events and diffuse purpura due to severe thrombocytopenia. 2 However, purpura in this case developed in a unilateral linear pattern, which was a rare presenting sign of DVT. 4 , 5 In addition to activating platelets and coagulation reactions, anti‐PF4 antibodies can cause a pancellular activation, including monocytes, neutrophils, endothelial cells, and other inflammatory cells, further posing a thrombosis risk. 1 , 3 Consequently, linear purpura may not only be associated with increased venous pressure due to stasis in DVT on a background of thrombocytopenia and coagulopathy, but also associated with vasculitis induced by maladaptive immune complex activation and deposition on the vessel walls following vaccination. 3 , 4 , 5 The area of rashes in correspondence to the extent of thrombosis shown in angiography and the therapeutic response to VITT treatments reinforce a relationship between unilateral purpura and DVT. During the era of COVID‐19 pandemic, clinicians should be alert to a linear purpuric rash developing on the unilateral lower extremity after COVID‐19 vaccination, especially accompanying with leg swelling or tenderness, which warrants further investigation for VITT.

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          Vaccine-induced immune thrombotic thrombocytopenia

          In response to the COVID-19 pandemic, vaccines for SARS-CoV-2 were developed, tested, and introduced at a remarkable speed. Although the vaccine introduction had a major impact on the evolution of COVID-19, some potential rare side-effects of the vaccines were observed. Within a short period, three scientific groups from Norway, Germany, and the UK reported cerebral venous sinus thrombosis with thrombocytopenia and anti-platelet factor 4 (anti-PF4) antibodies in individuals following AstraZeneca–Oxford vaccination and named this new syndrome vaccine-induced immune thrombotic thrombocytopenia (VITT). This syndrome was subsequently reported in individuals who received Johnson & Johnson vaccination. In this Viewpoint, we discuss the epidemiology, pathophysiology, and optimal diagnostic and therapeutic management of VITT. Presentation of an individual with possible VITT should raise prompt testing for anti-PF4 antibodies and initiation of treatment targeting autoimmune processes with intravenous immunoglobulin and prothrombotic processes with non-heparin anticoagulation.
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            Cutaneous findings following COVID‐19 vaccination: review of world literature and own experience

            Abstract There is growing evidence that not only the novel coronavirus disease (COVID‐19) but also the COVID‐19 vaccines can cause a variety of skin reactions. In this review article, we provide a brief overview on cutaneous findings that have been observed since the emerging mass COVID‐19 vaccination campaigns all over the world. Unspecific injection‐site reactions very early occurring after the vaccination are most frequent. Type I hypersensitivity reactions (e.g. urticaria, angio‐oedema and anaphylaxis) likely due to allergy to ingredients may rarely occur but can be severe. Type IV hypersensitivity reactions may be observed, including delayed large local skin lesions (“COVID arm”), inflammatory reactions in dermal filler or previous radiation sites or even old BCG scars, and more commonly morbilliform and erythema multiforme‐like rashes. Autoimmune‐mediated skin findings after COVID‐19 vaccination include leucocytoclastic vasculitis, lupus erythematosus and immune thrombocytopenia. Functional angiopathies (chilblain‐like lesions, erythromelalgia) may also be observed. Pityriasis rosea‐like rashes and reactivation of herpes zoster have also been reported after COVID‐19 vaccination. In conclusion, there are numerous cutaneous reaction patterns that may occur following COVID‐19 vaccination, whereby many of these skin findings are of immunological/autoimmunological nature. Importantly, molecular mimicry exists between SARS‐CoV‐2 (e.g. the spike‐protein sequences used to design the vaccines) and human components and may thus explain some COVID‐19 pathologies as well as adverse skin reactions to COVID‐19 vaccinations.
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              Vaccine-induced Immune Thrombotic Thrombocytopenia: Current Evidence, Potential Mechanisms, Clinical Implications, and Future Directions

              Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT) (also termed thrombosis with thrombocytopenia syndrome or vaccine-induced thrombotic thrombocytopenia or vaccine-induced immune thrombocytopenia) is characterized by (i) venous or arterial thrombosis; (ii) mild to severe thrombocytopenia; (iii) positive antiplatelet factor 4 (PF4)–polyanion antibodies or anti-PF4-heparin antibodies detected by the HIT (heparin-induced thrombocytopenia) ELISA assay (iv) occurring 5 to 30 days after ChAdOx1 nCoV-19 (AstraZeneca) or Ad26.COV2.S (Johnson & Johnson/Janssen) vaccination. VITT’s incidence is 1 per 100.000 vaccinated people irrespective of age and up to 1 in 50.000 for people < 50 years of age with the AstraZeneca COVID-19 vaccine. The exact mechanism by which adenovirus-vectored COVID-19 vaccines trigger this syndrome is still unclear, as for the increased risk for acute cerebral sinus venous thrombosis and splanchnic vein thrombosis as compared to other locations of venous thrombotic events. VITT is associated with the detection of anti-PF4 antibodies, unrelated to previous use of heparin therapy. PF4 antibodies are sought to activate platelets via the platelet FcγRIIA receptors leading to further platelet activation that causes thrombosis and thrombocytopenia. Graphical Abstract
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                Author and article information

                Contributors
                greatedisonchen@gmail.com
                Journal
                J Eur Acad Dermatol Venereol
                J Eur Acad Dermatol Venereol
                10.1111/(ISSN)1468-3083
                JDV
                Journal of the European Academy of Dermatology and Venereology
                John Wiley and Sons Inc. (Hoboken )
                0926-9959
                1468-3083
                23 February 2022
                June 2022
                23 February 2022
                : 36
                : 6 ( doiID: 10.1111/jdv.v36.6 )
                : e429-e431
                Affiliations
                [ 1 ] Department of Dermatology Chang Gung Memorial Hospital Linkou Taiwan
                [ 2 ] Drug Hypersensitivity Clinical and Research Center Chang Gung Memorial Hospital Linkou Taiwan
                [ 3 ] College of Medicine Chang Gung University Taoyuan Taiwan
                [ 4 ] Department of Anatomic Pathology Chang Gung Memorial Hospital Linkou Taiwan
                [ 5 ] Graduate Institute of Immunology College of Medicine National Taiwan University Taiwan
                Author notes
                [*] [* ] Correspondence: W.‐T. Chen. Email: greatedisonchen@ 123456gmail.com

                Article
                JDV18014
                10.1111/jdv.18014
                9114907
                35176191
                b632dbc3-c83c-4360-8794-36b92c8a28a0
                © 2022 European Academy of Dermatology and Venereology

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                Page count
                Figures: 1, Tables: 0, Pages: 2, Words: 984
                Product
                Categories
                Letter to the Editor
                Covid‐19 Special Forum
                Custom metadata
                2.0
                June 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.6 mode:remove_FC converted:18.05.2022

                Dermatology
                Dermatology

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