key: cord-1030529-9593nliu
authors: Perry, Warren M.; Salame, Nicole; Swerlick, Robert A.; Cheeley, Justin T.
title: The Clot Thickens with COVID-19 and Cryofibrinogenemia: A Thought-Provoking Association
date: 2022-04-04
journal: JAAD Case Rep
DOI: 10.1016/j.jdcr.2022.03.025
sha: bbb3ca08c729bfed9229260d9ff32c177438da14
doc_id: 1030529
cord_uid: 9593nliu

nan

Cryofibrinogenemia (CF) is a rare condition of the plasma characterized by cryoprecipitation of 47 abnormal protein complexes, sometimes resulting in thrombotic vasculopathy. 1 CF may be 48 essential (primary) or secondary to neoplastic, autoimmune, or infectious diseases. 1 We present a 49 case of livedoid vasculopathy (LV) due to secondary CF associated with coronavirus disease 50 2019 and recrudescence in the setting of a non-severe acute respiratory syndrome A 65-year-old female with a history of trochanteric osteoarthritis and COVID-19 presents to a 55 tertiary care facility with painful purpura. She was diagnosed with COVID-19 seven months 56 prior via nasopharyngeal polymerase chain reaction (PCR) for SARS-CoV-2. Within three days 57 of testing positive, she had manifested myalgias and purpuric macules on the nose, fingers, and 58 legs which resolved after steroid taper (Figure 1) . 59 60 Seven months after COVID-19 diagnosis she was admitted to an outside hospital with four days 61 of burning, pruritic purpura and edema of her fingers, arms, and legs associated with chills, 62 myalgias, and fever up to 38.7°C. She was given intravenous glucocorticoids due to concern for 63 IgA vasculitis and discharged the next day on a corticosteroid taper. Despite glucocorticoids, the 64 pruritus and pain worsened, prompting her current presentation to a tertiary care hospital. 65 66 Examination revealed symmetric hemorrhagic bulla of the bilateral distal fingers, racemose 67 purpura of the bilateral forearms, and dusky purpuric patches involving the nasal tip and bilateral 68 helices ( Figure 2 ). Confluent erythemato-violaceous petechiae and livedoid purpura, notably 69 sparing the intertriginous areas, were present on the abdomen, chest, and extremities ( Figure 2) . 70

Sublingual violaceous macules were evident. 71 72 A 4 mm punch biopsy revealed non-inflammatory intravascular thrombosis of superficial dermal 73 capillaries ( Figure 3 ). Pertinent laboratory findings are detailed in Table 1 . Specifically, SARS-74

CoV-2 nasopharyngeal PCR was negative, but serum IgG antibody was positive. Serum 75 cryoglobulins were negative and plasma cryofibrinogens were positive after 48 hours of 76 J o u r n a l P r e -p r o o f incubation. A repeat cryofibrinogen assay 8 days later was positive after 24 hours of incubation, 77 confirming the diagnosis of CF. 1 An autoimmune process causing secondary CF was considered 78 due to an elevation in the anti-nuclear antibody titer and rheumatoid factor. However, these 79 results lack diagnostic specificity, and no further laboratories, radiography, or clinical findings 80 supported a definitive autoimmune or neoplastic diagnosis. Due to the strikingly similar clinical 81 presentation with COVID-19 seven months prior and absence of other etiologies on diagnostic 82 studies, CF was thought to be provoked by a non-SARS-CoV-2 viral infection. It was suspected, 83

but not confirmed, that CF was etiologic of the initial racemose purpura during COVID-19 seven 84 months prior. 85 to lower steroid doses. However, there was no evidence of deep tissue ischemia or digital 98 necrosis on examination (Figure 4) . The patient was re-admitted, administered glucocorticoids, 99 and continued apixaban, which improved the petechiae. She was discharged on hospital day 100 three with apixaban and prednisone taper. Follow-up laboratories and visits extending seven 101 months post-CF diagnosis did not demonstrate any signs or symptoms of connective tissue 102 disease or cytopenia to suggest myeloid dyscrasia. 103

We describe secondary CF-induced LV associated with COVID-19 and recrudescence, likely 106 from a non-SARS-CoV-2 viral infection. Other cases of recrudescent CF related to infectious 107 diseases include a case of LV in the setting of hepatitis C with recurrence of skin lesions, 2 and a 108 case of Giardiasis with relapse of CF, without skin lesions, after cessation of metronidazole. 3 Our 109 literature review revealed no other infectious disease-associated cases of CF with recurrence. 19, e.g., relapsing LR and worsening of previously controlled LV. 6,7 Neither patient in these case 119 reports were tested for CF, thus an association with CF cannot be confirmed or refuted. Further studies are needed to delineate any association between CF and SARS-CoV-2. 135

One case series suggested that secondary CF can be treated similarly to essential CF with 137 immunosuppressants and anticoagulants. 4 This case further supports the role of anticoagulants in 138 secondary CF. Although our patient's petechiae more rapidly and durably cleared with heparin 139 compared to apixaban, the tissue pain and infarction resolved. This patient outcome along with 140 the convenience, tolerability, and lack of laboratory monitoring make direct oral anticoagulants 141 an attractive and potential alternative treatment for LV due to CF. Further studies are needed to 142 determine the role, timing, class, and duration of immunosuppressants and anticoagulants in the 143 management of essential and secondary CF. 

Cryofibrinogenaemia-a neglected 151 disease. Rheumatology (Oxford)

Cryofibrinogenaemia: a study of 49 patients

Giardiasis, cryofibrinogenemia, and cold sensitivity: a response to 158

A 5-year prospective follow-up study in 162 essential cryofibrinogenemia patients

COVID-19-related skin 165 manifestations: Update on therapy

Relapsing symmetric livedo 169 reticularis in a patient with COVID-19 infection

Recrudescence of livedoid vasculopathy induced by 173

High prevalence of 178 cryofibrinogenemia in patients with chilblains during the COVID-19 outbreak

COVID-19 Vasculopathy: Mounting Evidence for an Indirect 181

Mechanism of Endothelial Injury

Mild livedoid vasculopathy and nasal purpura with convalescing desquamation of the 219 digits in the setting of recrudescence after a non-SARS-CoV-2 viral infection while on 220

Mild 221 petechial rash on the bilateral lower extremities (B). Nose with a faded purpuric patch (C)

Secondary cryofibrinogenemia induced livedoid vasculopathy 223 recrudescence after a non-SARS-CoV-2 viral infection while on anticoagulation