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Digital Ischemia in COVID-19 Patients: Case Report

Published:April 29, 2020DOI:https://doi.org/10.1016/j.jhsa.2020.04.024
      As coronavirus 2019 (COVID-19) continues to cause an immense burden on the global health care systems, it is crucial to understand the breadth of this disease process. Recent reports identified hypercoagulability in a subset of critically ill patients and extremity ischemia in an even smaller cohort. Because abnormal coagulation parameters and extremity ischemia have been shown to correlate with poor disease prognosis, understanding how to treat these patients is crucial. To better describe the identification and management of this phenomenon, we present 2 cases of critically ill patients with COVID-19 who developed fingertip ischemia while in the intensive care unit.

      Key words

      Coronavirus 2019 (COVID-19), the disease caused by the 2019 novel coronavirus, has placed an unprecedented strain on global health care systems. Although the disease is known predominantly for its respiratory manifestations, a subset of critically ill patients demonstrates clinically notable hypercoagulability.

      Zhang Y, Cao W, Xiao M, et al. Clinical analysis of seven cases of critical new coronavirus pneumonia complicated with extremity ischemia [published online ahead of print March 28, 2020]. Zhonghua Xue Ye Xue Za Zhi. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0006.

      • Zhang Y.
      • Xiao M.
      • Zhang S.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with Covid-19.
      • Heng M.
      • Yu H.
      Characteristics, causes, diagnosis and treatment of coagulation dysfunction in patients with COVID-19.
      This phenomenon has been noted by multiple intensive care unit (ICU) physicians and was further described at the Tongji Hospital in Wuhan, China.

      Zhang Y, Cao W, Xiao M, et al. Clinical analysis of seven cases of critical new coronavirus pneumonia complicated with extremity ischemia [published online ahead of print March 28, 2020]. Zhonghua Xue Ye Xue Za Zhi. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0006.

      ,
      • Zhang Y.
      • Xiao M.
      • Zhang S.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with Covid-19.
      Thrombotic events range from acute pulmonary embolism in patients with COVID-19 pneumonia to extremity ischemia, and the precise incidence of thrombotic events has yet to be determined.
      • Heng M.
      • Yu H.
      Characteristics, causes, diagnosis and treatment of coagulation dysfunction in patients with COVID-19.
      • Xie Y.
      • Wang X.
      • Yang P.
      • Zhang S.
      COVID-19 Complicated by acute pulmonary embolism.

      Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19 [published online ahead of print April 10, 2020]. Thromb Res. https://doi.org/10.1016/j.thromres.2020.04.013.

      Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association? [published online ahead of print March 30, 2020]. Eur Heart J. https://doi.org/10.1093/eurheartj/ehaa254.

      As our understanding of this disease grows, it is crucial to investigate this trend further because hypercoagulability may worsen disease prognosis in critically ill COVID-19 patients.
      • Heng M.
      • Yu H.
      Characteristics, causes, diagnosis and treatment of coagulation dysfunction in patients with COVID-19.
      ,

      Guan W, Ni Z, Hu Y, et al. Clinical characteristics of 2019 novel coronavirus infection in China. [published online ahead of print February 28, 2020]. Respir Med. https://doi.org/10.1056/NEJMoa2002032.

      Few studies to date have focused exclusively on patients with signs of hypercoagulability. An early analysis from Wuhan, China described 7 cases of extremity ischemia in critically ill patients with COVID pneumonia.

      Zhang Y, Cao W, Xiao M, et al. Clinical analysis of seven cases of critical new coronavirus pneumonia complicated with extremity ischemia [published online ahead of print March 28, 2020]. Zhonghua Xue Ye Xue Za Zhi. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0006.

      All 7 of these patients, who did not meet criteria for shock and were not undergoing active therapy with vasopressors, demonstrated varying degrees of acral ischemia; the most common manifestations of such ischemia included plantar plaques and acrophytic bruises.

      Zhang Y, Cao W, Xiao M, et al. Clinical analysis of seven cases of critical new coronavirus pneumonia complicated with extremity ischemia [published online ahead of print March 28, 2020]. Zhonghua Xue Ye Xue Za Zhi. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0006.

      Notably, the authors identified a relationship between disease aggravation and the presence of ischemia.

      Zhang Y, Cao W, Xiao M, et al. Clinical analysis of seven cases of critical new coronavirus pneumonia complicated with extremity ischemia [published online ahead of print March 28, 2020]. Zhonghua Xue Ye Xue Za Zhi. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0006.

      Five of the 7 patients died of disease complications. Ultimately, the authors concluded that extremity ischemia portends a poor prognosis in critically ill COVID-19 patients.

      Zhang Y, Cao W, Xiao M, et al. Clinical analysis of seven cases of critical new coronavirus pneumonia complicated with extremity ischemia [published online ahead of print March 28, 2020]. Zhonghua Xue Ye Xue Za Zhi. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0006.

      A recent correspondence published in the New England Journal of Medicine
      • Zhang Y.
      • Xiao M.
      • Zhang S.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with Covid-19.
      proposed antiphospholipid antibodies as the source of the coagulopathies in COVID-19 patients. The authors described the cases of 3 ICU patients, all of whom developed extremity ischemia and cerebral infarcts in the setting of a positive serologic test for phospholipid antibodies.
      • Zhang Y.
      • Xiao M.
      • Zhang S.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with Covid-19.
      We present the cases of 2 similar ICU patients with confirmed COVID-19, who developed fingertip ischemia during admission, which further suggests that extremity ischemia correlates with poor prognosis in this patient population.

      Case Report

      We obtained institutional review board approval for deidentified presentation of patient data and images.

      Patient A

      A 70-year-old woman with no known medical history presented to the emergency department (ED) with a 1-week history of fevers, chills, worsening shortness of breath, headache, and malaise. Several days earlier, she had tested negative for COVID-19 at an outside hospital but presented to our facility because of worsening symptoms. Upon arrival to the ED, her vital signs included a temperature of 36.7° C, pulse of 101 beats/min, respiratory rate of 26 breaths/min, and oxygen saturation of 88% on room air. While in the emergency department, she required oxygen at 6 L/min via a nasal cannula. The initial chest x-ray demonstrated perihilar opacification. She tested polymerase chain reaction positive for COVID-19 and was subsequently admitted to the ICU for management of acute hypoxemic respiratory failure owing to acute respiratory distress syndrome and COVID-19. The patient was intubated shortly thereafter owing to an increasing oxygen requirement. Of note, testing showed antibodies to hepatitis C, indicating likely chronic asymptomatic disease.
      Approximately 12 days after presentation to the ED, the patient developed gradually worsening duskiness of the right second, third, and fourth fingertips while in the ICU. Notably, the patient had had 3 arterial line placements on the left side (1 radial and 2 brachial) but none on the right side. The hand service was consulted and the physical examination showed a mottled, dusky appearance to the distal phalanges and nail beds of the index, middle, and ring fingers. The fingers were also noted to be cool to palpation, and Doppler signals were absent at the superficial palmar arch as well as the radial and ulnar divisions of the digital arteries to the index, middle, and ring fingers. The remainder of the vascular examination of the right upper extremity was normal on the Doppler studies. Laboratory values recorded before this encounter included hemoglobin of 7.3 g/dL, C-reactive protein of 25 mg/L, prothrombin time/international normalized ratio of 18.2/1.5, and a partial prothrombin time of 80.9. D-dimer, a measure of fibrin degradation and thus coagulopathy, was 6.89 μg/mL (reference level, 0.4 μg/mL). The D-dimer had been elevated to greater than 20 μg/mL several days prior. The patient’s fibrinogen (486 mg/dL) was also elevated 3 days before consultation.
      Based on this presentation, the hand service recommended continuation of the patient’s 25,000-unit heparin drip at 11 U/kg per hour (previously prescribed empirically because of an elevated D-dimer and then continued for a right femoral deep vein thrombosis [DVT]) in addition to duplex studies and thermal warming of the affected limb. Application of topical nitroglycerin to the affected area was also recommended.
      • Hughes M.
      • Moore T.
      • Manning J.
      • et al.
      Reduced perfusion in systemic sclerosis digital ulcers (both fingertip and extensor) can be increased by topical application of glyceryl trinitrate.
      Results of the arterial duplex ultrasound demonstrated patent brachial, radial, and ulnar arteries without evidence of hemodynamically consequential stenosis, although distal occlusion could not be ruled out.
      Throughout the hospital course, the digital ischemia remained stable. Other notable events include septic shock, severe acute respiratory distress syndrome, acute kidney injury, and obstructive shock resulting from mechanical ventilation and intermittent vasopressor use. Other medical therapies included tocilizumab, lopinavir–ritonavir/ribavirin, cefepime, vancomycin, hydroxychloroquine, azithromycin, cefdinir, ceftriaxone, oral vancomycin, and metronidazole. Owing to the patient’s worsening clinical status, the decision was made to pursue comfort care; the patient ultimately died.

      Patient B

      A 43-year-old man with a medical history of obesity, hypertension, and hyperlipidemia presented to the ED with shortness of breath, cough, and chest pain that had been progressively worsening over the past week. The patient also reported fatigue, diarrhea, and decreased urine output. Vital signs upon arrival were notable for a blood pressure of 86/60 mm Hg, a respiratory rate of 20 breaths/min, and an oxygen saturation of 91% on room air; respiratory status deteriorated while he was in the ED and he required oxygen 5 L/min via a nasal cannula. Chest x-ray showed a patchy right perihilar infiltrate concerning for infection. Within the next 24 hours, he tested positive for COVID-19 and demonstrated a worsening respiratory status requiring transfer to the ICU with intubation upon arrival.
      While in the ICU, the patient experienced several complications, most notably a retroperitoneal hematoma occurring in the setting of anticoagulation for a right popliteal DVT requiring transfusion and vasopressor support. D-dimer was elevated throughout this period, ranging from 0.86 to 8.22 μg/mL. The patient was extubated 12 days after ICU admission.
      Shortly after extubation, the patient reported right hand pain. The hand service was consulted, with physical examination showing ischemic changes with pulp necrosis of the thumb and index fingers and duskiness of the middle finger and little fingertips with sluggish but present capillary refill. Arterial duplex ultrasound demonstrated 100% occlusion of the distal radial artery at the site of a prior arterial line.
      Digital ischemia, likely of subacute duration, was diagnosed (Figs. 1, 2). The hand surgery service recommended forearm and hand warming in addition to topical nitroglycerin application.
      • Hughes M.
      • Moore T.
      • Manning J.
      • et al.
      Reduced perfusion in systemic sclerosis digital ulcers (both fingertip and extensor) can be increased by topical application of glyceryl trinitrate.
      Given the recent hemorrhage, anticoagulation was relatively contraindicated; however, given stable hemoglobin measurements, volar pulp discoloration, and a concern for embolic phenomena, low-dose heparin was recommended and was initiated 1 day after the consult recommendation.
      Figure thumbnail gr1
      Figure 1Photograph of the volar hand showing subacute digital ischemia.
      Figure thumbnail gr2
      Figure 2Photograph of the dorsoradial hand showing subacute digital ischemia.
      The patient’s digital ischemia improved throughout the hospital stay with the heparin infusion; dosing was eventually increased to a high dose as hemoglobin stabilized for a longer time. The patient was eventually transitioned to apixaban 5 mg twice daily. Arterial inflow improved and the discoloration lessened with eventual eschar formation on the thumb and index fingers and recovery of flow to the middle and little fingertips.
      Other notable in-hospital events included acute kidney failure requiring continuous venovenous hemodialysis as well as hemorrhagic shock. A head computed tomography scan, taken after sedation had been weaned, demonstrated age-indeterminate cerebral infarcts. Other medical therapies included tocilizumab, lopinavir–ritonavir/ribavirin, cefepime, vancomycin, hydroxychloroquine, azithromycin, tobramycin, ceftriaxone, piperacillin–tazobactam, fluconazole, oral vancomycin, and metronidazole. Ultimately, the patient was discharged to an acute care rehabilitation facility after sufficient clinical recovery.

      Discussion

      The existing literature strongly supports a link between severe COVID-19 and coagulopathy.

      Zhang Y, Cao W, Xiao M, et al. Clinical analysis of seven cases of critical new coronavirus pneumonia complicated with extremity ischemia [published online ahead of print March 28, 2020]. Zhonghua Xue Ye Xue Za Zhi. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0006.

      • Zhang Y.
      • Xiao M.
      • Zhang S.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with Covid-19.
      • Heng M.
      • Yu H.
      Characteristics, causes, diagnosis and treatment of coagulation dysfunction in patients with COVID-19.
      These 2 cases contribute to an evolving understanding of underlying hypercoagulability in patients with COVID-19 and identify extremity ischemia as a possible manifestation of this condition. Although previous reports also identified COVID-19 patients with limb ischemia, there are limited data on the clinical course and treatment.

      Zhang Y, Cao W, Xiao M, et al. Clinical analysis of seven cases of critical new coronavirus pneumonia complicated with extremity ischemia [published online ahead of print March 28, 2020]. Zhonghua Xue Ye Xue Za Zhi. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0006.

      ,
      • Zhang Y.
      • Xiao M.
      • Zhang S.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with Covid-19.
      The patients featured in this report demonstrated noteworthy similarities with those already described in the literature. In 2 studies from Wuhan, China, all patients with extremity ischemia demonstrated elevated D-dimer

      Zhang Y, Cao W, Xiao M, et al. Clinical analysis of seven cases of critical new coronavirus pneumonia complicated with extremity ischemia [published online ahead of print March 28, 2020]. Zhonghua Xue Ye Xue Za Zhi. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0006.

      ,
      • Zhang Y.
      • Xiao M.
      • Zhang S.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with Covid-19.
      ; both patients described here also had D-dimer elevations, with peaks of greater than 20 and 8.22 μg/mL respectively. In addition, 6 of the 7 patients in the study by Zhang et al

      Zhang Y, Cao W, Xiao M, et al. Clinical analysis of seven cases of critical new coronavirus pneumonia complicated with extremity ischemia [published online ahead of print March 28, 2020]. Zhonghua Xue Ye Xue Za Zhi. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0006.

      ,
      • Zhang Y.
      • Xiao M.
      • Zhang S.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with Covid-19.
      were treated with anticoagulation; 2 patients survived to the end point in that study, one of whom demonstrated improvement of plantar ischemia. The other patient, who had lower-extremity ischemia, progressed to gangrene.

      Zhang Y, Cao W, Xiao M, et al. Clinical analysis of seven cases of critical new coronavirus pneumonia complicated with extremity ischemia [published online ahead of print March 28, 2020]. Zhonghua Xue Ye Xue Za Zhi. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0006.

      Similarly, both patients in the current report were eventually treated with anticoagulation; patient B demonstrated improvement in skin changes, whereas patient A had persistent upper-extremity ischemia until death (Table 1). Notably, however, patient A only had 5 days between ischemia and death, whereas patient B demonstrated tissue improvement over 2 weeks. Therefore, we recommend the rapid institution of an appropriate anticoagulation regimen for the treatment of this phenomenon, with consideration for prophylactic anticoagulation given the observed incidence of DVTs in these patients and others.
      • Landry G.J.
      • Mostul C.J.
      • Ahn D.S.
      • et al.
      Causes and outcomes of finger ischemia in hospitalized patients in the intensive care unit.
      Another possible explanation for the ischemic phenomenon is vasopressor use; however, it is unlikely that vasopressors would cause unilateral ischemia. Another possibility is embolic phenomena. Thrombosis resulting from radial arterial line placement could explain some of patient B’s clinical picture, but the small finger ischemia does not fit with this hypothesis.
      Table 1Comparative Characteristics of 2 COVID-19 Patients
      Patient CharacteristicsPatient APatient B
      Age, y7043
      SexFemaleMale
      Medical historyHepatitis CObesity, hypertension, hyperlipidemia
      Presenting symptomsFevers, chills, shortness of breath, headache, malaiseShortness of breath, cough, chest pain, fatigue, diarrhea, decreased urine output
      Reasons for ICU admissionRespiratory failureRespiratory failure
      Vasopressor useYesYes
      Arterial linesLeft brachial; left radial × 2Left radial, right radial
      Thrombotic manifestation(s)Ischemia of index, middle, and ring fingers on right hand; right femoral DVTRight distal radial artery occlusion; right popliteal DVT, ischemia of thumb and index, middle, and little fingers
      AnticoagulationYesYes
      Days from ICU admission to upper-extremity thrombotic event1214
      Days from thrombotic event to death5
      Zhang and colleagues
      • Zhang Y.
      • Xiao M.
      • Zhang S.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with Covid-19.
      recently suggested antiphospholipid antibodies as a contributor to, or perhaps cause of, thrombotic events such as those described in this report. Although we were unable to test these patients for such antibodies, we acknowledge this hypothesis as a potential explanation for these ischemic events.
      The relationship between coagulopathy and poor disease prognosis in COVID-19 patients merits discussion. Several studies have demonstrated that patients with abnormal coagulation markers and those with acral ischemia are at an increased risk for a poor prognosis.

      Zhang Y, Cao W, Xiao M, et al. Clinical analysis of seven cases of critical new coronavirus pneumonia complicated with extremity ischemia [published online ahead of print March 28, 2020]. Zhonghua Xue Ye Xue Za Zhi. https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0006.

      ,

      Guan W, Ni Z, Hu Y, et al. Clinical characteristics of 2019 novel coronavirus infection in China. [published online ahead of print February 28, 2020]. Respir Med. https://doi.org/10.1056/NEJMoa2002032.

      ,
      • Landry G.J.
      • Mostul C.J.
      • Ahn D.S.
      • et al.
      Causes and outcomes of finger ischemia in hospitalized patients in the intensive care unit.
      ,
      • Tang N.
      • Li D.
      • Wang X.
      • Sun Z.
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      For instance, Guan and colleagues

      Guan W, Ni Z, Hu Y, et al. Clinical characteristics of 2019 novel coronavirus infection in China. [published online ahead of print February 28, 2020]. Respir Med. https://doi.org/10.1056/NEJMoa2002032.

      showed that patients with elevated D-dimer were more likely to have severe disease requiring ICU admission and mechanical ventilation, or to die. In addition, Tang et al
      • Tang N.
      • Li D.
      • Wang X.
      • Sun Z.
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      noted that patients with COVID-19 pneumonia who had significantly higher D-dimers and fibrinogen degradation products as well as longer prothrombin times at admission were more likely to die than were those without these abnormal parameters. Interestingly, although both patients in the current report demonstrated elevated D-dimer levels, patient A’s first D-dimer after admission was only 0.60 μg/mL whereas that of patient B, who survived, was higher at 0.92 μg/mL.
      Based on the clinical course of these 2 COVID-19 patients, we hypothesize that coagulopathies, especially those of the hand, are a marker of severe illness and merit close monitoring and early hand service consultation for appropriate intervention. It is critical to monitor for thromboembolic events in the extremities of critically ill patients to avoid permanent damage and/or limb loss.

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        Coagulopathy and antiphospholipid antibodies in patients with Covid-19.
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        • Yu H.
        Characteristics, causes, diagnosis and treatment of coagulation dysfunction in patients with COVID-19.
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      3. Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association? [published online ahead of print March 30, 2020]. Eur Heart J. https://doi.org/10.1093/eurheartj/ehaa254.

      4. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of 2019 novel coronavirus infection in China. [published online ahead of print February 28, 2020]. Respir Med. https://doi.org/10.1056/NEJMoa2002032.

        • Hughes M.
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        • Manning J.
        • et al.
        Reduced perfusion in systemic sclerosis digital ulcers (both fingertip and extensor) can be increased by topical application of glyceryl trinitrate.
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