Evans syndrome and immune thrombocytopenia in two patients with COVID-19.

Dear Editor,

The COVID‐19 pandemic caused by the SARS‐CoV‐2 virus has enveloped the globe with 83 million cases and 1,831,703 deaths worldwide, at the time of writing. Among the hematological manifestations described, severe and symptomatic thrombocytopenia has been rare. A meta‐analysis of 7613 patients found platelet counts to be much lower in patients with severe COVID‐19. Here, we report on two patients with COVID‐19, one with Evans syndrome and one with immune thrombocytopenia to highlight the rarer hematological manifestations of the disease. As there is an association between thrombocytopenia and higher mortality, early identification and treatment could potentially improve outcomes.

Patient 1: A 33‐year‐old man presented to the emergency department with a 3‐week history of gum bleeding, black tarry stools, and reddish spots on the skin. He had no fever, cough, or dyspnea. On examination, he had petechial lesions over the chest, legs, and oral mucosa. Laboratory investigations revealed severe thrombocytopenia with initial platelet counts of 6 × 109/L. The peripheral smear showed 11 nucleated RBCs per 100 WBCs, poikilocytosis, ovalocytes, and polychromatic cells with no schistocytes. He had leucocytosis (12 × 109/L), anemia (7.5 g/dl), and elevated lactate dehydrogenase 1953 U/L (normal range, 225–460 U/L). Total and direct bilirubin were 1.23 and 0.46, mean corpuscular volume was 86.8 pl, mean corpuscular hemoglobin 28.3 pg, mean corpuscular hemoglobin concentration 32.6%, and reticulocyte count was 13.73% (corrected 6.87%). Direct Coombs test was positive (2+), suggesting immune hemolytic anemia. Within a few hours of admission, the patient complained of sudden‐onset headache and developed a generalized tonic–clonic seizure. Computed tomography of the brain showed intracerebral hemorrhage in the right capsuloganglionic region with edema and midline shift. The patient's sensorium worsened rapidly with anisocoria, and he was shifted to the intensive care unit. Serology for dengue and scrub typhus (common regional causes of thrombocytopenia) were negative. Nasopharyngeal swab reverse‐transcription polymerase chain reaction (RT‐PCR) for SARS‐CoV‐2 was positive. Immune destruction being the likely cause, he was treated with pulse dexamethasone 40 mg daily with platelet transfusions (intravenous immunoglobulin [IVIG] was not feasible). Bone marrow aspiration was not done. Despite the above measures, there was no improvement in the patient's platelet counts (Figure 1) nor sensorium, and he died on the third day of admission. He had not received anticoagulation.

Figure 1

Thrombocytopenia trend during admission

Patient 2: A 54‐year‐old man presented to the emergency department with low‐grade intermittent fever and sore throat for a week. He tested positive for COVID‐19 by nasopharyngeal swab RT‐PCR. His initial platelet count was 80 × 109/L, with hemoglobin 15 g/dl and a total leukocyte count of 2.8 × 109/L. Dengue and scrub typhus serology were negative. During the admission, his platelet count dropped to 30 × 109/L. He did not have any bleeding manifestations. He was treated with dexamethasone 6 mg daily from admission, for COVID‐19, based on existing hospital protocol at the time. Platelet counts recovered to 105 × 109/L over a week (Figure 1). His symptoms subsided by Day 3, and he was discharged on Day 8. He received no anticoagulation.

These cases suggest an association between COVID‐19, Evans syndrome, and immune thrombocytopenia, based on temporal profile and other etiologies having been ruled out to a reasonable extent. They also highlight heterogeneity in the hematological manifestations of COVID‐19 ranging from asymptomatic thrombocytopenia to life‐threatening disease. This is the second case of Evans syndrome with COVID‐19 described in the literature to the best of our knowledge. Li et al. have reported immune thrombocytopenia and hemolytic anemia in a 39‐year‐old man with COVID‐19. Following IVIG treatment, he improved.

Zulfiqar et al. have described a patient with COVID‐19 and immune thrombocytopenia, who developed a subarachnoid hemorrhage. The patient was initiated on IVIG at admission, and the hemorrhage occurred on Day 9. Bomhof et al. described a patient like ours with immune thrombocytopenia associated with COVID‐19 who died following intracerebral hemorrhage.

The largest series of seven patients with autoimmune hemolytic anemia, without thrombocytopenia, has been described by Lazarian et al. Nearly all patients were treated with steroids, and two required rituximab.

The mechanisms suggested for thrombocytopenia include SARS‐CoV‐2 entering hematopoietic cells via the CD13 receptors causing aberrant hematopoiesis, immune destruction due to molecular mimicry between platelet membrane components (especially glycoprotein) and virus antigens, and increased consumption due to endothelial injury and microangiopathy. The commonest mechanism described in the literature so far has been immune‐mediated destruction (Table 1), which was likely the cause in both of our patients as well. It is imperative to anticipate this complication for early diagnosis and initiation of therapy, as mortality is high.

Table 1

Case reports and series of patients with COVID‐19 and severe thrombocytopenia

Author	Number of patients	Month	Country	Nadir platelet count	Clinical bleeding	Treatment	Outcome	Possible mechanism
Zulfiqar et al. 4	1	April 2020	France	8 × 109/L	Petechiae, subarachnoid hemorrhage	Prednisolone (high dose)	Alive	Immune destruction
Deruelle et al. 9	1	May 2020	France	19 × 109/L	Tracheal bleed	Intravenous methylprednisolone	Alive	Immune destruction
Bomhof et al. 5	3	July 2020	Netherlands	2 × 109/L	P1‐skin, mucosal petechiae; P2‐ petechiae, epistaxis; P3‐ intracerebral bleed	IVIG, dexamethasone	P1‐alive; P2‐alive; P3‐died	Immune destruction
Humbert et al. 8	1	August 2020	France	4 × 109/L	Hematuria, epistaxis	Prednisolone, IVIG	Not mentioned	Immune destruction
Ahmed et al. 10	3	June 2020	United Kingdom	0 × 109/L	P1‐epistaxis, petechiae; P2‐ petechiae, epistaxis; P3‐ intracerebral bleed	IVIG	P1‐alive; P2‐alive; P3‐died	Immune destruction
Lingamaneni et al. 11	1	Jan 2020	USA	96 × 109/L	Nil	Heparin withheld	Died	Heparin‐induced thrombocytopenia
Li et al. 3	1	June 2020	USA	3 × 109/L	Hematemesis, melena, hematochezia	IVIG	Alive	Immune destruction (Evans syndrome)
Mahevas et al. 12	14	Aug 2020	France	<1 × 109/L	Purpura, mucosal, GI bleeding, epistaxis	IVIG/steroids	Alive	Immune thrombocytopenia
Current study	2	July 2020	India	4 × 109/L 30 × 109/L	P1‐intracerebral bleed P2‐no bleed	Dexamethasone	Died Alive	P1‐immune destruction (Evans syndrome) P2‐immune destruction

Abbreviation: IVIG, intravenous immunoglobulin.

CONFLICT OF INTERESTS

The authors declare that there are no conflict of interests.

AUTHOR CONTRIBUTIONS

Josh T. Georgy: Conceptualization; methodology; formal analysis; investigation; writing—original draft; visualization. Jonathan A. J. Jayakaran: Conceptualization; methodology; formal analysis; investigation; writing—review, and editing; visualization. Anju S. Jacob: Conceptualization; methodology; formal analysis; investigation; writing—review, and editing; visualization. Karthik Gunasekaran: Conceptualization; methodology; formal analysis; investigation; writing—review and editing, visualization. Pritish J. Korula: Methodology; formal analysis; writing—review, and editing; visualization. Anup J. Devasia: Formal analysis; investigation; writing—review, and editing; visualization. Ramya Iyadurai: Writing—review, and editing; visualization; supervision; project administration; resources.