Summary
Coronavirus disease 2019 (COVID‐19) can affect the haematopoietic system. Thrombocytopenia at admission was prevalent, while late‐phase or delayed‐phase thrombocytopenia (occurred 14 days after symptom onset) is rare. This retrospective, single‐centre study screened 450 COVID‐19 patients and enrolled 271 patients at the Union Hospital, Wuhan, China, from January 25 to March 9, 2020. COVID‐19‐associated delayed‐phase thrombocytopenia occurred in 11·8% of enrolling patients. The delayed‐phase thrombocytopenia in COVID‐19 is prone to develop in elderly patients or patients with low lymphocyte count on admission. The delayed‐phase thrombocytopenia is significantly associated with increased length of hospital stay and higher mortality rate. Delayed‐phase nadir platelet counts demonstrated a significantly negative correlation with B cell percentages. We also provided and described bone marrow aspiration pathology of three patients with delayed‐phase thrombocytopenia, showing impaired maturation of megakaryocytes. We speculated that immune‐mediated platelet destruction might account for the delayed‐phase thrombocytopenia in a group of patients. In addition, clinicians need to pay attention to the delayed‐phase thrombocytopenia especially at 3–4 weeks after symptom onset.
Keywords: clinical features, COVID‐19, cytokine, lymphocyte, SARS‐CoV‐2, thrombocytopenia
Introduction
In December 2019, the outbreak of coronavirus disease 2019 (COVID‐19) was initially reported in Wuhan, China. 1 Common symptoms of COVID‐19 include fever, cough and shortness of breath, since the lung is the major target of SARS‐CoV‐2. Cardiac, digestive and neurologic complications were also found in COVID‐19 patients. These extra‐pulmonary manifestations imply diverse target organs in addition to the lung. The haematopoietic system can also be affected by COVID‐19. A multicentre study by our hospital and others demonstrated that, on admission, lymphocytopenia was present in 83·2% of the patients and thrombocytopenia in 36·2%. 2
With increased hospitalisation capacity and prolonged isolation period, we are now able to study the disease longitudinally apart from cross‐sectionally on admission. In particular, our initial observations showed there were sudden dramatic declines in platelet count in several COVID‐19 patients without evidence of other coagulation abnormalities, which happened 3 weeks or more after symptoms’ onset. COVID‐19‐related, early‐phase thrombocytopenia was prevalent, 3 while late‐phase or delayed‐phase thrombocytopenia was rare.
In the current study, we report the incidence, characteristics and outcomes of patients with delayed‐phase thrombocytopenia. We also present the bone marrow aspiration pathology of three patients with delayed‐phase thrombocytopenia.
Methods
Study design and participants
This was a retrospective, descriptive, longitudinal study, conducted from January 25 to March 9, 2020. All patients were recruited from the Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. As a routine, electronic medical data have been archived onto a local server, from which we can retrieve the data. The study was approved by the Research Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (No. 2020‐0079‐1). Written informed consent was obtained from the patients in our study.
The inclusion criteria for this study were (1) each patient was confirmed by real‐time RT‐PCR and diagnosed as having COVID‐19 according to WHO interim guidance; 4 (2) all patients underwent chest CT and a complete panel of routine laboratory tests. The exclusion criteria were (1) monitoring period less than 21 days from symptom onset; (2) autoimmune or haematological disease history; (3) previous HIV, hepatitis B or hepatitis C infection; (4) dialysis patients.
Procedures
The demographic data, clinical characteristics, laboratory data and treatment data were obtained from patients’ medical records. The clinical outcomes (i.e., discharges, mortality and hospital stay time) were monitored up to April 15, 2020, the final date of follow‐up. Any uncertain information was clarified through direct communication with patients’ families. We collected continuously monitored laboratory data, including blood routine, blood coagulation function, inflammatory cytokines, and lymphocytes subset analysis. For some patients, the SARS‐CoV‐2 IgG results were recorded when available. The date of disease onset was defined as the day when the symptom was noticed. The severity of COVID‐19 was defined according to the diagnostic criteria of the "COVID‐19 diagnosis and treatment plan (trial seventh edition)”. 5 Throat swab samples were collected for viral detection. SARS‐CoV‐2 was confirmed with nucleic acid detection kit (Shanghai Bio‐germ Medical Technology, Shanghai, China). The IgG antibody was detected with SARS‐CoV‐2 IgG antibody detection kit (YHLO biotechnology, Shenzhen, China).
Statistical analysis
Descriptive data were presented as means [± standard deviation (SD)] for normally distributed continuous variables, and as medians with interquartile range (IQR) for non‐normally distributed data. Categorical variables were presented as percentages. Proportions for categorical variables were compared using the chi‐squared test, and the Fisher exact test was used when data were limited. The quantised variables of parameters are tested by t‐test. Nonparametric variables are tested by Mann–Whitney U‐test. The Spearman rank correlation coefficient was used for correlation analysis. All statistical analysis was performed using SPSS v.19·0 (IBM Corp., Armonk, NY, USA). A two‐tailed P value < 0·05 was considered statistically significant.
Results
Patient flow and baseline characteristics
A total of 450 hospitalised COVID‐19 patients were reviewed, and 271 patients were finally enrolled according to the inclusion and exclusion criteria. Their baseline characteristics are shown in Table I. The average time from symptom onset to hospital admission was 6·65 days (SD = 2·78). After admission, there were 246 (90·8%) patients receiving antiviral treatment, 176 (64·9%) on antibiotics, 115 (42·4%) on glucocorticoids, 117 (43·2%) on inhaled interferon‐α and 65 (24·0%) on intravenous immunoglobulin. On the final day of follow‐up, 48 patients were still in hospital (17·7%), 215 (79·3%) had been discharged and 11 (3·0%) had died. Moreover, 29 patients had been transferred to the ICU (10·7%). Among the discharged patients, the average hospital isolation ward stay was 31·96 days (SD = 10·86).
Table I.
Baseline characteristics and clinical outcomes of COVID‐19 patients.
| Characteristics |
All patients (n = 271) |
Patients without delayed‐phase Thrombocytopenia (n = 239) |
Patients with delayed‐phase Thrombocytopenia (n = 32) |
P value |
|---|---|---|---|---|
| Age (y) | 57·74 ± 14·30 | 56·52 ± 13·93 | 67·00 ± 12·86 | 0·026 |
| Age groups, n (%) | ||||
| <60 y | 125 (46·1%) | 116 (48·5%) | 9 (28·1%) | 0·030 |
| ≥ 60y | 146 (53·8%) | 123 (51·5%) | 23 (71·9%) | |
| Gender (M/F), n (%) | ||||
| Male (M) | 145 (53·5%) | 124 (51·9%) | 21 (65·6%) | 0·143 |
| Female (F) | 126 (46·5%) | 115 (48·1%) | 11 (34·4%) | |
| Respiratory rate | 22·08 ± 4·51 | 21·74 ± 3·99 | 23·03 ± 5·36 | 0·157 |
| Smoking, n (%) | 14 (5·2%) | 12 (5·0%) | 2 (6·3%) | 0·896 |
| Comorbidities, n (%) | ||||
| Cardio cerebrovascular disease | 75 (27·7%) | 66 (27·6%) | 9 (3·3%) | 0·952 |
| Endocrine system disease | 35 (12·9%) | 29 (12·1%) | 6 (18·8%) | 0·295 |
| Respiratory system disease | 11 (4·1%) | 9 (3·8%) | 2 (6·3%) | 0·848 |
| Digestive system disease | 10 (3·7%) | 7 (2·9%) | 3 (9·4%) | 0·188 |
| Nervous system disease | 6 (2·2%) | 5 (2·1%) | 1 (3·1%) | 0·790 |
| Malignant tumor | 9 (3·3%) | 7 (2·9%) | 2 (6·3%) | 0·646 |
| Symptoms on admission, n (%) | ||||
| Fever | 220 (81·2%) | 195 (81·6%) | 25 (78·1%) | 0·638 |
| Cough | 190 (70·1%) | 169 (70·7%) | 21 (65·6%) | 0·555 |
| Dyspnea | 75 (27·7%) | 65 (27·2%) | 10 (31·3%) | 0·630 |
| Pharyngalgia | 16 (5·9%) | 15 (6·3%) | 1 (3·1%) | 0·756 |
| Mucocutaneous hemorrhage | 0 (0·0%) | 0 (0·0%) | 0 (0·0%) | – |
| Diarrhea | 40 (14·8%) | 37 (15·5%) | 3 (9·4%) | 0·516 |
| Anorexia | 51 (18·8%) | 46 (19·2%) | 5 (15·6%) | 0·801 |
| Abdominal pain | 4 (1·5%) | 4 (1·7%) | 0 (0·0%) | 0·957 |
| Palpitation | 17 (7·0%) | 16 (6·7%) | 1 (3·1%) | 0·694 |
| Hypodynamia | 101 (37·3%) | 89 (37·2%) | 12 (37·5%) | 0·977 |
| Paresthesia | 4 (1·5%) | 4 (1·7%) | 0 (0·0%) | 0·960 |
| Myalgia | 47 (17·3%) | 43 (18·0%) | 4 (12·5%) | 0·602 |
| Dizziness | 18 (6·6%) | 15 (6·3%) | 3 (9·4%) | 0·777 |
| Days from illness onset to admission | 6·65 ± 2·78 | 6·64 ± 2·73 | 6·84 ± 3·06 | 0·701 |
| Treatment before delayed‐phase thrombocytopenia, n (%) | ||||
| Antibiotic treatment | 176 (64·9%) | 155 (64·9%) | 21 (65·6%) | 0·932 |
| Antiviral treatment | 246 (90·8%) | 216 (90·4%) | 30 (93·8%) | 0·769 |
| Glucocorticoids | 115 (42·4%) | 101 (42·3%) | 14 (43·6%) | 0·873 |
| Inhaled Interferon‐α | 117 (43·2%) | 103 (43·1%) | 14 (43·8%) | 0·944 |
| Intravenous immunoglobulin | 65 (24·0%) | 57 (23·8%) | 11 (34·4%) | 0·197 |
| Oxygen therapy | 248 (91·5%) | 218 (91·2%) | 30 (93·8%) | 0·884 |
| Number of cases admitted to ICU | 29 (10·7%) | 21 (8·8%) | 8 (25·0%) | 0·005 |
| Clinical outcome, n (%) | ||||
| Discharged | 215 (79·3%) | 196 (82·0%) | 19 (59·4%) | 0·003 |
| Remained in hospital | 48 (17·7%) | 39 (16·3%) | 9 (28·1%) | 0·100 |
| Died | 8 (3·0%) | 4 (1·7%) | 4 (12·5%) | 0·002 |
| Hospital days | 31·96 ± 10·86 | 31·07 ± 10·74 | 35·84 ± 11·20 | 0·021 |
Incidence and outcomes of patients with delayed‐phase thrombocytopenia
Based on the dynamic of antibody response, 6 duration of the viremia phase after SARS‐CoV‐2 infection 7 and our preliminary clinical observations, we propose setting 14 days as the rough though reasonable and feasible cutoff value. Therefore, delayed‐phase thrombocytopenia is defined as thrombocytopenia beginning after 14 days post‐symptom appearance. We found 32 patients (11·8 %) developed delayed‐phase thrombocytopenia (Table I). The mean time for delayed‐phase thrombocytopenia nadir appeared at 28·3 days from illness onset. The mean duration time for delayed‐phase thrombocytopenia was 4·32 days (SD = 2·15). We also found the mean platelet count at nadir to be 86·0 × 109/l (SD = 37·48). Delayed‐phase thrombocytopenia is more prevalent in elderly persons (71·9% in ˃60‐years‐old patients). The clinical outcomes for these 32 patients with delayed‐phase thrombocytopenia were: nine patients remained in hospital, 19 were discharged and four died. Additionally, there were eight cases that were admitted to ICU (delayed‐phase thrombocytopenia patients). Notably, mortality was markedly higher in patients with delayed‐phase thrombocytopenia than in patients without delayed‐phase thrombocytopenia (four [12·5%] versus four [1·7%]) (Table I). The representative platelet count curves are shown in Supplemental Data.
Laboratory findings of patients with delayed‐phase thrombocytopenia
On admission, the delayed‐phase thrombocytopenia cases demonstrated lower lymphocyte count (0·745 [0·62–1·03], P = 0·001), compared to the group without delayed‐phase thrombocytopenia (Table II). The level of the lymphocyte subsets (CD3+ T, CD4+ T and B cells) and inflammatory cytokines (IL‐4, IL‐6 and TNF‐α) showed significant alterations from their counterpart. Furthermore, we conducted time‐correlated data analysis of the cytokines and lymphocyte subset results at around the time delayed‐phase thrombocytopenia occurred. Delayed‐phase nadir platelet counts demonstrated a significantly negative correlation with B cell percentages (rs = 0·509, P < 0·001) and serum IL‐6 levels (rs = 0·443, P < 0·001).
Table II.
Laboratory findings of patients with COVID‐19 on admission.
| Characteristics | Reference range |
All patients (n = 271) |
Patients without delayed‐phase thrombocytopenia (n = 239) |
Patients with delayed‐phase thrombocytopenia (n = 32) |
P value |
|---|---|---|---|---|---|
| Blood routine | |||||
| White blood cell count, ×109/l | 3·50–9·50 | 6·88 ± 4·03 | 6·94 ± 4·14 | 6·10 ± 3·60 | 0·275 |
| Hemoglobin, g/l | 130·00–175·00 | 127·52 ± 17·50 | 128·31 ± 16·58 | 129·92 ± 19·67 | 0·612 |
| Platelet count, ×109/l | 125·00–350·00 | 228·86 ± 87·34 | 233·75 ± 93·49 | 212·08 ± 67·79 | 0·103 |
| Neutrophil count, ×109/l | 1·80–6·30 | 3·58 (2·48–5·84) | 3·64 (2·60–5·83) | 2·92 (2·05–7·31) | 0·905 |
| Lymphocyte count, ×109/l | 1·10–3·20 | 1·10 (0·77–1·58) | 1·20 (0·87–1·61) | 0·745 (0·62–1·03) | 0·001 |
| Platelet‐to‐lymphocyte ratio (PLR) | 160·05 (125·91–291·07) | 169·06 (125·91–297·27) | 151·95 (126·82–234·55) | 0·346 | |
| Hemorrhage and coagulation indicators | |||||
| D–dimer, mg/l FE | <0·50 | 0·40 (0·22–1·27) | 0·395 (0·22–1·22) | 0·50 (0·22–1·09) | 0·270 |
| Fibrinogen degradation products, ug/ml | <5·00 | 5·47 (5·14–6·53) | 5·28 (5·10–6·44) | 5·75 (5·17–6·93) | 0·382 |
| Prothrombin time, s | 11·00–16·00 | 14·05 ± 3·56 | 14·17 ± 3·32 | 13·59 ± 2·04 | 0·150 |
| Activated partial thromboplastin time, s | 28·00–43·50 | 38·78 ± 11·30 | 38·69 ± 11·69 | 37·60 ± 5·98 | 0·362 |
| Fibrinogen, g/l | 2·00–4·00 | 4·34 ± 1·18 | 4·45 ± 1·11 | 4·20 ± 1·40 | 0·343 |
| Blood biochemistry | |||||
| Alanine aminotransferase, U/l | 21·00–72·00 | 30·50 (19·75–43·00) | 29·50 (19·25–42·75 | 32·50 (20·75–43·00) | 0·582 |
| Aspartate aminotransferase, U/l | 17·00–59·00 | 26·00 (20·00–37·25) | 24·00 (19·25–33·75) | 34·00 (26·00–44·75) | 0·041 |
| Blood urea nitrogen, mmol/l | 3·20–7·10 | 4·81 (3·49–6·16) | 4·78 (3·41–5·87) | 5·27 (4·03–7·17) | 0·273 |
| Creatinine, μmol/l | 58·00–110·00 | 71·45 (60·58–87·15) | 70·75 (59·15–84·50) | 78·15 (21·15–49·00) | 0·269 |
| Albumin, g/l | 35·00–50·00 | 34·23 ± 7·65 | 35·40 ± 7·69 | 32·96 ± 6·75 | 0·067 |
| Immunoglobulins, g/l | 23·00–32·00 | 30·66 ± 6·94 | 30·21 ± 6·90 | 31·29 ± 7·86 | 0·414 |
| Lactate dehydrogenase, U/l | 109·00–245·00 | 228·00 (188·75–308·00) | 211·50 (186·50–290·50) | 283·50 (243·75–383·00) | 0·022 |
| Infection‐related biomarkers | |||||
| C‐reactive protein, mg/l | 0·00–5·00 | 38·93 ± 37·69 | 35·18 ± 36·80 | 40·86 ± 35·08 | 0·411 |
| Inflammatory cytokines | |||||
| Interleukin‐2, pg/ml | 0·10–4·10 | 3·01 ± 0·87 | 3·08 ± 0·93 | 2·77 ± 0·77 | 0·072 |
| Interleukin‐4, pg/ml | 0·10–3·20 | 2·65 ± 1·17 | 2·74 ± 1·07 | 2·26 ± 1·21 | 0·019 |
| Interleukin‐6, pg/ml | 0·10–2·90 | 17·64 ± 40·62 | 9·11 ± 17·30 | 40·73 ± 71·84 | 0·020 |
| Interleukin‐10, pg/ml | 0·10–5·00 | 4·63 ± 2·11 | 4·82 ± 2·29 | 4·37 ± 1·87 | 0·288 |
| Tumor necrosis factor‐α, pg/ml | 0·10–23·00 | 2·56 ± 1·41 | 2·66 ± 1·62 | 2·20 ± 0·80 | 0·005 |
| Interferon‐γ, pg/ml | 0·10–18·00 | 2·64 ± 1·00 | 2·71 ± 0·84 | 2·42 ± 1·42 | 0·274 |
| Lymphocyte Subsets | |||||
| CD3 + T Lymphocytes, % | 58·17–84·22 | 72·40 ± 9·06 | 74·53 ± 7·46 | 69·43 ± 10·33 | 0·012 |
| CD4 + T Lymphocytes, % | 25·34–51·37 | 42·76 ± 10·30 | 44·34 ± 9·14 | 38·79 ± 12·45 | 0·021 |
| CD8 + T Lymphocytes, % | 14·23–38·95 | 25·14 ± 9·88 | 26·45 ± 9·07 | 24·07 ± 12·57 | 0·313 |
| B Lymphocytes, % | 4·10–18·31 | 13·95 ± 9·43 | 11·24 ± 4·97 | 17·28 ± 12·22 | 0·010 |
| NK Lymphocytes, % | 4·10–18·31 | 9·05 ± 7·09 | 8·50 ± 6·03 | 11·00 ± 8·63 | 0·126 |
Bone marrow aspiration analysis of three cases
We specifically studied three patients who underwent bone marrow aspiration in the Union Hospital. All three patients developed rapid and dramatic decline in platelet count at delayed phase, without evidence of other coagulation abnormalities. The pathology results from each of the three patients shared common features: (1) bone marrow showed no obvious abnormities in the myeloid or the erythroid cells; (2) number of atypical or reactive lymphocytes increased; (3) maturation of megakaryocyte was impaired, the mature platelet‐producing megakaryocytes were rare and most megakaryocytes were immature granular megakaryocytes. Two patients’ bone marrow smear images are presented in Supplemental Data.
Discussion
The present study was conducted by reviewing the medical records of patients with COVID‐19 from January 25 to March 9, 2020, in a heavily‐affected hospital during the initial outbreak in China. We found that COVID‐19‐associated delayed‐phase thrombocytopenia occurred in 11·8% of enrolling patients. Delayed‐phase thrombocytopenia in COVID‐19 is prone to develop in elderly patients or patients with low lymphocyte count on admission. Delayed‐phase thrombocytopenia is significantly associated with increased length of hospital stay and higher mortality rate.
Previous cross‐sectional studies have shown that, at admission time, thrombocytopenia was prevalent in acute COVID‐19‐infected patients. 3 , 8 , 9 Besides, patients infected by other coronaviruses, severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS), also frequently suffered thrombocytopenia at admission. 10 , 11 However, the acute viral infection associated with delayed‐phase thrombocytopenia has only been reported as rare case reports without enough patients for statistical analysis. 12 , 13 Our retrospective study showed that thrombocytopenia might occur at delayed phase in COVID‐19 patients and at a significant percentage in the enrolled patients.
To clarify the pathogenesis of the delayed‐phase thrombocytopenia cases, we longitudinally reviewed the results of cytokines and lymphocyte subsets. Our results suggest that IL‐6 might be an active player in the delayed‐phase platelet decline. Since antibody production by B cells is crucial in virus protection, our results imply, but do not confirm, that antibodies might play an important role in the delayed‐phase platelet decrease. We also found most of the delayed‐phase thrombocytopenia lasted less than 7 days, implying the delayed‐phase thrombocytopenia is transient.
In addition, we sought to obtain evidence from bone marrow. All bone marrow aspiration pathology showed common features, such as impeded megakaryocyte maturation, and mature platelet‐producing megakaryocytes were rare (less than five in the bone marrow smear). These bone marrow features were similar to those in immune thrombocytopenia. Based on the antibody curve after SARS‐CoV‐2 infection, 6 , 14 we speculate that the delayed‐phase platelet decrease in these three patients might be immune‐mediated.
Virus‐associated immune thrombocytopenia may include several mechanisms: 15 first, a virus‐induced change in the host's immune system by polyclonal B cell activation or release of cytokines; second, the production of autoantibodies against platelet glycoproteins induced by the modification of platelet surface proteins by virus infection; third, cross‐reaction of the virus protein‐directed antibodies with platelet glycoproteins; fourth, virus‐infected megakaryocyte sheds platelets that present viral antigens, so antiviral antibodies attack against platelets. Animal models with Rauscher virus infection developed delayed‐phase immune thrombocytopenia. 16
This study has several limitations. First, our retrospective study was based on a relatively small sample. Second, our hospital‐based study no doubt missed patients who were mild cases. Third, regression and survival analysis are recommended. Fourth, the relationship between prognosis and thrombocytopenia remains to be investigated, since a few patients were still hospitalised.
Authors’ contributions
W.C. and Z.L.: drafting or revision of the submitted article. Q.Z. and B.Y.: health care providers of the patients. P.W. and Z.Z.: constructive suggestions and data analysis. J.Z. and X.C.: data collection and analysis. H.Z. and P.Y.: design of the study and revision of the submitted article.
Written informed consent was obtained from the patients in our study.
Funding
This work was supported by the Clinical Innovation Funds of Union Hospital (No. 2019‐125).
Conflict of interest
All authors declare that they have no conflicts of interest.
Supporting information
Data S1. Dynamic changes of platelet count in COVID‐19 patients.
Data S2. Wright's stained bone marrow aspirate smears from two patients.
Acknowledgements
We acknowledge all health care workers involved in the diagnosis and treatment of patients at Union Hospital.
*Wanxin Chen and Ziping Li contributed equally to the work.
Contributor Information
Peng Yang, Email: yangpenguh@hust.edu.cn.
Hao Zhou, Email: zhouhao@hust.edu.cn.
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Associated Data
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Supplementary Materials
Data S1. Dynamic changes of platelet count in COVID‐19 patients.
Data S2. Wright's stained bone marrow aspirate smears from two patients.