COVID-19 related immune hemolysis and thrombocytopenia.

The current pandemic due to coronavirus disease 2019 (COVID-19) has posed an unprecedented challenge for the medical communities, various countries worldwide, and their citizens. Severe acute respiratory syndrome coronavirus 2 has been studied for its various pathophysiological pathways and mechanisms through which it causes COVID-19. In this study, we discussed the immunological impact of COVID-19 on the hematological system, platelets, and red blood cells.

INTRODUCTION

Currently, the world is trampled by the coronavirus disease 2019 (COVID‐19) with more than 18 million cases and 695 129 deaths already reported (till 8th August 2020). Due to the novelty of COVID‐19 disease, there is an ongoing effort by basic science researchers and clinicians worldwide to learn more about this disease. Complement activation, immune dysregulation, and coagulation cascade perturbations have been studied as the most potential pathophysiological mechanisms for COVID‐19 disease. Recent reports of immune effects of COVID‐19, such as immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA), suggest the pathological interaction between coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2]) and various immune and tissue cells of our body. We hereby aim to summarize the collection of reported cases of ITP and AIHA secondary to COVID‐19 reported to date. , , , , , , , ,

METHODOLOGY AND RESULTS

In our literature search, we found 20 patients with COVID‐19 who were reported to have immune dysregulation with the development of ITP, AIHA, and/or Evan's syndrome. In total, there were 10 (50%) patients with ITP, 9 (45%) patients with AIHA, and 1 (5%) patient had Evan's syndrome. The average age of the patients was 61 (17‐89 years) years with the majority (55%) being males (11 out of 20). Four out of 20 (20%) patients also had a previous history of autoimmune disease (one each with polymyalgia rheumatica and autoimmune hypothyroidism, and two with chronic ITP). To note, one (5%) patient also had congenital thrombocytopenia. Regarding the underlying malignancies, eight (40%) patients were found to have history of cancers, six with lymphoproliferative disorders (CLL‐2, MZL‐2, MGUS‐1, and ALPS‐1) and the remaining two with solid malignancies. The largest case series of AIHA with COVID‐19 (7 cases) to date has been reported by Lazarian et al.

Our review showed that most patients who had bleeding symptoms only reported of superficial bruising, petechial spots, or hemorrhages. Only 2 patients out of 20 (10%) suffered from intracranial bleeding, one out of which died. Reported nadir platelet counts in ITP cases were extremely variable with as high as 338 000 cells/μL to as low as 0 cell/μL. Similarly, the lowest reported hemoglobin (2.5 gm/dL) in AIHA with COVID‐19 was reported by Wahlster et al. All patients were laboratory‐confirmed COVID‐19 positive with a positive nasopharyngeal swab. With regard to the management, drugs attempted were steroids (dexamethasone, methylprednisone, and prednisone), intravenous immunoglobulin (IVIG), eltrombopag, and rituximab (Table 1). Most of the patients (four out of seven) with AIHA reported by Lazarian et al were receiving treatment at the time of publication. Two patients had a partial response and one patient failed to respond to steroids. All nine patients (100%) with AIHA and 9 of 10 patients (90%) with ITP recovered from the acute crisis and were discharged.

Table 1

Reported cases of ITP and AIHA in association with COVID‐19

Author et al	Age	Sex	Previous comorbidities	Underlying malignancy	Diagnosis	Symptoms	Bleeding signs/sites	Zenith WBC, cells/µL	Lymphocyte count, 109/L	Nadir Hb, g/dL	Nadir platelet count, cells/µL	Reticulocyte count, 109/L	LDH	Other laboratory workup	Chest imaging	ITP/Evans's treatment
Li et al 13	39	Male	None	None	Evan's syndrome (new onset)	Hemoptysis and epistaxis ×1 d, sore throat, productive cough, fevers, chills, and dyspnea ×7 d	Oropharynx, nares, and mouth	11 000		15.6	3000	NA	947	Hemolytic panel negative, no schistocytes	Normal	IVIG
Lazarian et al 10	61	Male	HTN, CRF	Chronic lymphocytic leukemia	AIHA (warm type)	NM	NM	NM	250	6	NM	477	1000	Coombs test positive (IgG + C3d)	Moderate	Steroids
Lazarian et al 10	89	Female	HTN, CRF, AFIB	MGUS	AIHA (warm type)	NM	NM	NM	1.7	8.4	NM	103	598	Coombs test positive (IgG + C3d)	Mild	Steroids
Lazarian et al 10	62	Female	HTN, cirrhosis	MZL	AIHA (cold type)	NM	NM	NM	1.3	10.8	NM	101	357	Coombs test positive (C3d)	Severe	Steroids, rituximab
Lazarian et al 10	69	Female	Obesity, HTN	MZL	AIHA (cold type)	NM	NM	NM	5.9	3.8	NM	215	2610	Coombs test positive (IgG + C3d)	Moderate	Steroids
Lazarian et al 10	61	Male	CRF, HLD, type 2 DM	Prostate cancer	AIHA (cold type)	NM	NM	NM	3	7.2	NM	145	807	Coombs test positive (C3d)	Mild	RBC infusion
Lazarian et al 10	61	Male	Type 2 DM, HLD	None	AIHA (warm type)	NM	NM	NM	1.2	7	NM	155	1800	Coombs test positive (IgG)	Severe	Steroids, rituximab
Lazarian et al 10	75	Male	Cardiomyopathy, obesity, COPD	CLL	AIHA (warm type)	NM	NM	NM	108	7.1	NM	98	2000	Coombs test positive (IgG)	Moderate	RBC infusion
Bomhof et al 3	59	Male	NA	Stage IV NET of the small bowel	New onset ITP	Coughing and fever 10 d, contact with a positive case	Oral mucosal petechiae and spontaneous skin hematomas	3900	400	8.3	3000	NM	Not mentioned	Platelet autoantibodies positive for GP1b, GPIIBIIa, and GPV. Viral serology for HIV, Hepatitis B and C, EBV, Parvo B19 virus, CMV virus were negative	NM	SDAP, IVIG, dexamethasone
Bomhof et al 3	66	Female	HTN		New onset ITP	Fever, dyspnea, and coughing during a week, followed by diarrhea and vomiting for several days	Petechiae, spontaneous epistaxis, and increased blood loss from hemorrhoids for 3 wk	5800	700	8	2000	NM	NM	Platelet autoantibodies negative. Viral serology for HIV, hepatitis B and C, EBV were negative	NM	Dexamethasone, IVIG
Bomhof et al 3	67	Male	HTN, type 2 DM		ITP	Fever, coughing, and dyspnea ×9 d		11 200	860	9.3	338 000	NM	NM	Platelet autoantibodies testing and viral serology testing not done	Bilateral infiltrates
Lopez et al 11	46	Female	Congenital thrombocytopenia	None	AIHA (warm)	Dyspnea and cough	None	9850	680	9.7	43 000	206	553	Coombs test positive (IgG + C3d), ANA was negative	Dense left upper lobe consolidation with minimal surrounding ground‐glass opacities and no evidence of pulmonary embolism	IVIG
Tang et al 8	NA	Female	41 wk pregnant woman	None	New onset ITP	Sore throat	No bleeding	NM	NM	NM	16 000	NM	NM	Monoclonal antibody immobilization of platelet antigens (MAIPA) showed platelet autoantibodies against glycoprotein V	Left lower lobe with ground‐glass opacities	IVIG, platelet transfusion
Zulfiqar et al 9	65	Female	HTN, autoimmune hypothyroidism	None	New onset ITP	Fatigue, fever, dry cough, and abdominal discomfort of 4 d	Lower‐extremity purpura, subarachnoid microhemorrhage	Normal	NM	14.2	1000	NM	NM	Antiplatelet antibodies and antinuclear antibodies were not detected	Ground‐glass opacities in the lower zones	IVIG, prednisone, eltrombopag
Hu et al 5	72	Female	Chronic ITP (in remission with prednisone [10 mg/d] and cyclosporine [50 mg/d])	None	Relapse of chronic ITP	Productive cough ×4 d and fever ×1 d	None	None	2550	NM	18 000	NM	LDH	None	Peripheral ground‐glass opacity in the right lower lobe	IVIG, platelet transfusion, methylprednisolone
Murt et al 7	41	Male	None	None	New onset ITP	Cough and runny nose 15 d ago	Petechiae and nasal bleeding				9000			NM	Bilateral ground‐glass opacities	High‐dose dexamethasone, IVIG
Humbert et al 6	84	Male	Polymyalgia rheumatica, essential tremor	None	New onset ITP	Cough and progressive dyspnea ×10 d	Spontaneous macroscopic hematuria and bilateral epistaxis	9200	330	12.2	4000	NM	NM	ANA negative, platelet antibodies negative, lupus anticoagulant antibody	Diffuse ground‐glass opacities and condensations involving more than 50% of pulmonary parenchyma	Prednisone, IVIG
Wahlster et al 12	17	Male	Chronic ITP (in remission with eltrombopag and mycophenolate)	ALPS	AIHA	Worsening jaundice and fatigue in the setting of 4 d of emesis, diarrhea, and fevers	None	4370	440	2.5	94 000	NM	1280	IgG 3+, C3 1+	Mild prominence of perihilar markings	Steroids
Ahmed et al 2	50	Male	None	None	New onset ITP	Asymptomatic, close contact with COVID‐19 positive	Epistaxis, oral blisters, and a generalized petechial rash	4000	NM	13.2	Not detected	NM	NM	NM	Normal	IVIG, tranexamic acid
Ahmed et al 2	49	Female	None	None	New onset ITP	Asymptomatic, close contact with COVID‐19 positive	Generalized bruises and gum bleed	5300	None	13.4	4000	NM	NM	Negative	Revealed bilateral patchy consolidation	IVIG

Abbreviations: AFIB, atrial fibrillation; AIHA, autoimmune hemolytic anemia; ALPS, autoimmune lymphoproliferative syndrome; ANA, antinuclear antibody; CLL, chronic lymphocytic leukemia; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; COVID‐19, coronavirus disease 2019; CRF, cardiorespiratory fitness; EBV, Epstein‐Barr virus; Hb, hemoglobin; HIV, human immunodeficiency; HLD, hyperlipidemia; HTN, hypertension; ITP, immune thrombocytopenia; IVIG, intravenous immunoglobulin; LDH, lactate dehydrogenase; MGUS, monoclonal gammopathy of undetermined significance; MZL, marginal zone lymphoma; NA, not applicable; NET, neuroendocrine tumor; NM, not mentioned; Parvo B19, parvovirus B19; RBC, red blood cell; type 2 DM, type 2 diabetes mellitus; WBC, white blood cell.

DISCUSSION

Thrombocytopenia is one of the challenging disease entities faced by clinicians in day‐to‐day clinical practice. , Immune‐mediated hematologic conditions, characterized by ITP, AIHA, or Evan's syndrome, are known to be associated with previous exposure to various viral infections. Platelet‐virus interplay could represent a combination of multiple pathways that may include complement activation, antigen mimicry of platelet surface glycoproteins, consumptive coagulopathy, and direct bone marrow suppression. Similarly, AIHA is a common association with indolent lymphoproliferative disorders, and the coinfection of SARS‐CoV‐2 could potentially trigger hemolysis (Figure 1). Treatment of autoimmune disorders is always challenging in the presence of active infection. Hematologists and other physicians often prefer IVIG as an initial therapy when the concerns of worsening of active infection or risk of acquiring a superadded infection are high. , Due to concerns that steroids may worsen the SARS‐CoV‐2 infection and could lead to acute respiratory distress syndrome, World Health Organization (WHO) recommends against using steroids in COVID‐19. In the present patient cohort, most of the patients received steroids for their autoimmune disease and not COVID‐19.

Figure 1

Mechanisms of SARS‐CoV‐2 induced thrombocytopenia. SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2

CONCLUSION

In conclusion, hematological findings such as thrombocytopenia and anemia in COVID‐19 could be due to multiple reasons and timely diagnosis of the immunological cause is essential, so that appropriate immunosuppression can be initiated in a timely fashion.

CONFLICT OF INTERESTS

The authors declare that there are no conflict of interests.