Livedoid and Purpuric Skin Eruptions Associated With Coagulopathy in Severe COVID-19

Abstract

This case series describes livedo racemosa and retiform purpura as cutaneous findings in patients with COVID-19.

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection spreads globally, dermatologists are recognizing a variety of cutaneous manifestations in patients with coronavirus disease 2019 (COVID-19). A recent Spanish report¹ categorized skin findings in 375 patients with suspected and confirmed COVID-19, including livedoid and necrotic eruptions, which were noted in patients with more severe disease. The authors suggested that these skin manifestations may be associated with occlusive vascular disease.

Methods

In this case series, we describe the experience of 4 patients from 2 academic hospitals in New York City from March 13 to April 3, 2020, who presented with severe COVID-19 (confirmed by SARS-CoV-2 real-time polymerase chain reaction using Panther Fusion or Roche Cobas tests) and acute respiratory distress syndrome requiring intubation. The patients had skin findings of acral fixed livedo racemosa and retiform purpura, for which the dermatology department was consulted. This study was deemed exempt from formal institutional review board approval by NewYork-Presbyterian/Weill Cornell Medical College because it is a report of clinical care and is not considered human participants research. Written informed consent for skin biopsy was obtained from health care proxies because all patients were intubated and required sedation.

Results

Punch biopsies were performed for all 4 patients (age range, 40-80 years). The results of each biopsy demonstrated a pauci-inflammatory thrombogenic vasculopathy involving capillaries, venules, and/or arterioles or small arteries (Figure). In 3 of 4 patients, dermal arterial thrombosis was noted, reminiscent of antiphospholipid syndrome, without any diagnostic confirmation of these antibodies.

Figure. Clinical and Pathologic Findings.

A, Fixed, nonblanching livedo racemosa involving the left plantar foot and toes. B, This biopsy specimen reveals a pauci-inflammatory thrombogenic vasculopathy (hematoxylin-eosin, original magnification ×400).

All 4 patients had d-dimer levels of more than 3 μg/mL (normal range, 0-0.229 μg/mL) (to convert to nanomoles per liter, multiply by 5.476) and a suspected pulmonary embolus within 1 to 5 days of the reported skin findings (Table). All 4 patients initiated a standard prophylactic dose of anticoagulation therapy at admission, and all received therapeutic anticoagulation owing to increasing d-dimer levels and suspected thrombotic events.

Table. Summary of Cases.

Patient No.	Time from first symptom to reported rash, da	Rash description and location	Pathologic findings a,b	Peak d-dimer level, ng/mL	d-dimer level closest to reported rash, ng/mLa	Other known systemic coagulopathy (time from reported rash, d)a	Outcome (time after reported rash, d)a	Anticoagulation therapy at admission	Therapeutic anticoagulation during hospitalization	Reasons for anticoagulation escalation (time from reported rash, d)a
1	23	Livedo racemosa on hands and forearms	Arterial and venous thrombosis	40.1	32.5	Presumed PE (−1)	Died (2)	Subcutaneous enoxaparin, 40 mg, daily	Subcutaneous enoxaparin, 1 mg/kg, twice daily	Presumed PE and increasing d-dimer level (−1)
2	20	Early retiform purpura on hands and forearms	Venous thrombosis	3.3	1.0	Presumed PE (−5)	In ICU at end of study period	Subcutaneous heparin, 5000 units, 3 times daily	Intravenous heparin continuous infusion	Presumed PE and increasing d-dimer level (−5)
3	21	Livedo racemosa on hands	Arterial thrombosis	9.2	4.2	Presumed PE (−2)	In ICU at end of study period	Subcutaneous enoxaparin, 40 mg, daily	Subcutaneous enoxaparin, 1 mg/kg, twice daily and intravenous argatroban continuous infusion	Presumed PE and increasing d-dimer level (−2); switched to argatroban owing to skin biopsy showing thrombi
4	19	Livedo racemosa on forearms	Arterial thrombosis	8.0	8.0	Presumed PE (−4)	Died (4)	Subcutaneous heparin, 5000 units, twice daily	Intravenous heparin continuous infusion	Presumed PE and increasing d-dimer level (−4)

Abbreviations: ICU, intensive care unit; PE, pulmonary embolism.

SI conversion factor: To convert d-dimer to nanomoles per liter, multiply by 5.476.

^aReported rash reflects the day that skin findings were first documented, although owing to limited skin examinations (in an effort to minimize viral exposure and personal protective equipment use), it was difficult to confirm the exact day of rash onset.

^bBiopsies performed within 0 to 1 day of reported rash.

Discussion

These cases add to a growing body of literature supporting livedo racemosa and retiform purpura as cutaneous findings in patients with COVID-19.² Livedo racemosa and retiform purpura are hallmark manifestations of cutaneous thrombosis, with livedo racemosa representing partial occlusion of cutaneous blood vessels and retiform purpura representing full occlusion of cutaneous blood vessels. All patients had marked d-dimer level elevations and suspected pulmonary emboli, suggesting that these skin findings may be a clinical clue to an underlying thrombotic state. The features of the 4 patients are not consistent with other conditions predisposing to thrombosis, including typical disseminated intravascular coagulation or thrombotic microangiopathy, given the normal or increased fibrinogen level, normal haptoglobin level, lack of persistent severe thrombocytopenia, and absence of schistocytes on results of peripheral blood smear testing.

The exact pathophysiologic features of the coagulopathy in these patients was not yet clear; however, in all skin biopsy samples, there were deposits of complement including C5b-9, suggesting a critical role for complement activation in the pathogenesis of the thrombotic diathesis. Coagulopathy in the context of severe inflammation (elevated d-dimer, fibrinogen, or C-reactive protein levels) has been reported in patients with COVID-19.³ Because of the increased incidence of thrombotic events reported in severely ill patients with COVID-19⁴ and recent data suggesting a survival benefit in such patients who receive anticoagulants,⁵ treatment algorithms for severely ill patients with COVID-19 are including therapeutic anticoagulation at many institutions.⁶ Despite initiation of prophylactic anticoagulation therapy at admission for all 4 patients, all developed cutaneous thrombosis and a clinically suspected pulmonary embolism.

The limitations of this report include our inability to confirm the precise timing of rash onset owing to limited full skin examinations. In addition, we did not perform imaging for pulmonary emboli because of efforts to minimize staff exposure.

The findings suggest that clinicians caring for patients with COVID-19 should be aware of livedoid and purpuric rashes as potential manifestations of an underlying hypercoagulable state. If these skin findings are identified, a skin biopsy should be considered because the result may guide anticoagulation management. Even in the absence of other thrombotic events, consultation with hematology staff, along with escalation of anticoagulation, should be considered.