The causes of secondary immune thrombocytopenia (ITP), which account for approximately
18–20% of all adult ITP cases, include some viral infections.
1
,
2
Indeed, ITP can be triggered by or associated with many viruses including hepatitis
C virus, human immunodeficiency virus, cytomegalovirus, Epstein–Barr virus and others
like severe acute respiratory syndrome coronavirus‐1 (SARS‐CoV‐1).
1
,
3
,
4
,
5
Among the suspected mechanisms, antibodies directed against virus glycoproteins may
cross‐react with platelet surface integrins like glycoprotein IIb/IIIa (GPIIb/IIIa)
or GPIb‐IX‐V.
6
Mild thrombocytopenia has been observed in approximately 5–10% of patients with symptomatic
SARS‐CoV‐2 infection.
7
Various mechanisms have been suggested, including decreased platelet production and
enhanced platelet destruction, as for other viral infections.
5
,
8
Recently, a member of our network reported the first case of severe ITP associated
with coronavirus disease 2019 (COVID‐19).
9
Three other cases have been reported subsequently.
10
,
11
These single observations limit the interpretation of data, due to possible publication
bias. To better characterise the clinical course, management and response to therapy
of de novo ITPs occurring after SARS‐CoV‐2 infection, we recorded the incident cases
that occurred up to 30 April 2020 in France in centres belonging to the French Reference
Network for Adult Autoimmune Cytopenias (Table SI. ITP was defined according to the
International Working Group definition with no evidence of any other cause of thrombocytopenia
such as disseminated intravascular coagulation.
12
We focussed on patients with profound thrombocytopenia, that is: a platelets count
nadir of <30 × 109/l during the course of the disease to reduce the potential number
of sepsis‐induced thrombocytopenia.
13
Response and complete response (CR) were defined according to standardised international
criteria: platelet count of >30 × 109/l with at least a doubling of the baseline value,
and platelet count of >100 × 109/l respectively. According to French law and European
Union general data protection regulations, all patients were informed about the study
and data collection by a written letter detailing their rights.
We included 14 patients with a reverse transcriptase‐polymerase chain reaction (RT‐PCR)‐confirmed
SARS‐CoV‐2 infection on a nasopharyngeal swab (n = 12) or a highly suggestive feature
of COVID‐19 on chest computed tomography (CT)‐scan with compatible clinical symptoms
(n = 2). Patients’ characteristics are described in Table
I
. The median (range) age was 64 (53–79) years and seven patients (50%) were women.
The median (range) time from first COVID‐19 manifestations to first ITP manifestation
was 14 (2–30) days; it was >7 days in 12 (86%) cases. In four patients (#3, #4, #10
and #12), a SARS‐CoV‐2 RT‐PCR was performed at the time of ITP onset: it was positive
in two of them, demonstrating an active viral shedding, and negative in the two others,
including one with a previous positive RT‐PCR at the time of infection (patient #12).
Seven patients (50%) had a hypoxaemic pneumonia corresponding to a World Health Organization
(WHO) progression score of ≥5. The outcome of COVID‐19 was favourable in all cases.
Only one patient was admitted to the Intensive Care Unit (ICU) due to acute respiratory
failure (patient #14). No deaths occurred.
Table I
Characteristics and outcomes of the 14 COVID‐19‐induced immune thrombocytopenia patients.
Patient
Age (years), sex
COVID‐19 symptoms
Time from 1st COVID‐19 signs to ITP, days
Time from COVID‐19 RT‐PCR to ITP, days
Severity of COVID‐19 (WHO score)
Lowest platelet count, × 109/l
Bleeding
ITP treatment
ITP outcome
COVID‐19 outcome
Follow‐up, days
#1
58, F
Fever, cough
10
8
4
2
Purpura, epistaxis, oral haemorrhagic bullae
IVIg (D1, D5) then eltrombopag until D28
Complete response
Recovery
40
#2
66, M
Fever, cough, anosmia, dyspnoea, hypoxaemia, moderate pneumonia on CT‐scan
13
3
5
1
Epistaxis
IVIg (D1, D3) then eltrombopag until D15
Complete response
Recovery
52
#3
62, F
Fever, cough, moderate pneumonia on CT‐scan
5
9
4
9
No
Prednisone 5 days
Response then relapse (D58)
Recovery
60
#4
62, M
Dyspnoea, minor pneumonia on CT‐scan
2
Concomitant
3
<10
No
Prednisone 3 days
Complete response
Recovery
60
#5
74, M
Fever, cough pneumonia on CT‐scan
12
6
5
<1
Purpura, mucosal bleeding, gastrointestinal bleeding
Prednisone 10 days
Complete response
Recovery
50
#6
63, M
Fever, cough, dyspnoea, hypoxaemia, moderate pneumonia on CT‐scan
23
12
5
10
No
Prednisone 3 weeks
Complete Response
Recovery
60
#7
65, M
Fever, minor pneumonia on CT‐scan
22
1
4
17
0
Dexamethasone (D1–D4)
Complete response then relapse (D30)
Recovery
60
#8
66, F
Fever, cough, dyspnoea, hypoxemia, moderate pneumonia on CT‐scan
8
5
5
8
Purpura, epistaxis, intracranial bleeding
Methylprednisolone + IVIg (D1–D3) + eltrombopag until D15
Complete response
Recovery
60
#9
79, F
Fever, cough, dyspnoea, hypoxaemia, moderate pneumonia on CT‐scan
16
5
5
9
Purpura
IVIg (D1–D3)
Response
Recovery
30
#10
59, F
Fever, cough, dyspnea, moderate pneumonia on CT‐scan
30
Negative RT‐PCR
4
1
Purpura, mucosal bleeding
IVIg (D1–D3)
Response
Recovery
45
#11
61, F
Fever, cough, anosmia, dysgeusia, moderate pneumonia on CT‐scan
25
12
5
21
Purpura
IVIg (D1–D3)
Response
Recovery
45
#12
69, F
Fever, cough, dyspnoea, hypoxaemia, moderate pneumonia on CT‐scan
14
8
4
<10
Purpura, epistaxis, subcutaneous haematomas, gross haematuria
IVIg (D1–D2) then
Romiplostim on D2 and D8
Complete response
Recovery
63
#13
53, M
Fever, cough, dyspnoea, Moderate pneumonia on CT‐scan
27
Negative RT‐PCR
3
19
Purpura
Prednisone 3 weeks IVIg (D1–D3)
Complete response then relapse (D35)
Recovery
50
#14
72, M
Fever, cough, dyspnoea, hypoxaemia, diarrhoea, moderate pneumonia on CT‐scan
15
13
7
8
No
IVIg (D1–D3)
Complete response
Recovery
60
Abbreviations: CT, computed tomography; D, day; ITP, immune thrombocytopenia; IVIg,
intravenous immunoglobulin; RT‐PCR, reverse transcription‐polymerase chain reaction.
John Wiley & Sons, Ltd
This article is being made freely available through PubMed Central as part of the
COVID-19 public health emergency response. It can be used for unrestricted research
re-use and analysis in any form or by any means with acknowledgement of the original
source, for the duration of the public health emergency.
Regarding ITP, all patients but one had initial a platelet count of <20 × 109/l and
11 patients had a platelet count of ≤10 × 109/l. In all cases, either a previous normal
platelet count was obtained or the patient had no previous history of bleeding. Haemorrhagic
manifestations were heterogeneous. Noteworthy, four patients had severe bleeding symptoms,
including intracranial haemorrhage, gastrointestinal, severe metrorrhagia and gross
haematuria (one of each). Of note, three other patients had mucosal bleeding. One
patient (#4) was diagnosed concomitantly with chronic lymphocytic leukaemia. First‐line
treatment consisted of corticosteroids alone (i.e. prednisone 1 mg/kg/day) for four
patients who achieved an initial response after a median (range) of 10 (5–21) days.
One patient who received 40 mg of dexamethasone for 4 days also achieved CR on Day
5. Importantly, none of these five patients had a worsening of COVID‐19 pneumonia.
Intravenous immunoglobulin (IVIg; 1–2 g/kg) was administered to nine patients, alone
in four patients, or associated with a thrombopoietin receptor agonist (romiplostim,
n = 1; eltrombopag, n = 2; eltrombopag + methylprednisolone, n = 1) or with prednisone
(n = 1). All achieved a rapid initial response. After a median (range) follow‐up of
60 (30–63) days, all patients achieved at least a response (nine CR and three response),
but three had relapsed. No thrombosis was observed.
This first multicentre series reveals that COVID‐19‐associated ITP occurs mostly during
the second phase (after 1 week of evolution) of SARS‐CoV‐2 infection, with significant
bleeding and a favourable outcome. In all patients, an immune mechanism was suspected
because of the exclusion of alternative causes, in particular no evidence of sepsis‐induced
thrombocytopenia (the only patient in ICU dramatically responded to IVIg) and disseminated
intravascular coagulation. Post‐infectious ITP has been described in many infectious
contexts after the first week of infection.
1
,
3
,
4
,
5
Importantly, we have excluded other viral causes of ITP, and the occurrence of other
viruses, such as influenzae, have been dramatically reduced during the containment
in France as in other countries.
14
Here, the causal relationship between SARS‐CoV‐2 infection and ITP was supported by
several points: 1) the time of occurrence (after the first week of infection as reported
for other virus‐induced ITPs); 2) the exclusion of alternative causes, in particular
no evidence of sepsis‐induced thrombocytopenia (the only patient in ICU dramatically
responded to IVIg) and disseminated intravascular coagulation; 3) the dramatic response
to steroids or IVIg; 4) the low rate of recurrence as usually observed in ITP triggered
by acute viral infections; 5) the very low number of newly diagnosed ITP during the
lockdown in France.
Interestingly, it has been recently shown that patients with severe COVID‐19 pneumonia
produce a very large quantity of antibody secreting cells during the second week after
first symptoms, in contrast to patients with few symptoms who did not.
15
,
16
The short time between COVID‐19 first symptoms and ITP onset in some patients of our
present series suggests the presence of extrafollicular B‐cell generating cross‐reactive
antibodies against platelets. In contrast, delayed ITP and ITP relapses evoke a germinal
centre response resulting in persistent pathogenic antibodies secretion.
17
Thus, like other viruses, COVID‐19 may be responsible for transient resolutive ITP,
but also for triggering a tolerance breakdown potentially leading to persistent or
chronic ITP. Indeed, three patients relapsed during follow‐up. The exact causative
mechanism of thrombocytopenia remains speculative, and needs further experimental
studies.
Because of the high incidence of thromboembolic events in patients with severe COVID‐19,
18
it is reassuring that we did not observe any thrombosis, including in patients receiving
corticosteroids, IVIg and thrombopoietin receptor agonists during the first 2 months
of follow‐up. Similarly, no patient treated with corticosteroids had worsening of
COVID‐19 pneumonia. Altogether, these findings sustain recent British guidance that
recommend first‐line treatment with corticosteroids for SARS‐CoV‐2‐associated ITP.
19
The present retrospective study has some limitations. Two patients had a negative
SARS‐CoV‐2 RT‐PCR. However, the sensitivity of nasopharyngeal swab RT‐PCR is only
approximately 70% and these two patients had clinical symptoms and a CT‐scan pattern
of COVID‐19.
20
Albeit using the National Reference Centre Network for Adult Immune Cytopenias that
covers the whole French territory, we cannot ensure completeness of case recording.
Moreover, because the defined platelet‐count threshold was <30 × 109/l to be included
in this series, the number of COVID‐19‐associated ITP may have been underestimated.
Nevertheless, the prevalence of COVID‐19‐associated ITP is probably rare. Indeed,
a mathematical model estimated that 3·7 million (range 2·3–6·7) people have been infected
in France.
21
Altogether, this series highlights that COVID‐19‐associated ITP can cause profound
thrombocytopenia and severe bleeding manifestations occurring mostly during the second
phase of the infection, but has a favourable outcome in most cases. Initial response
to standard ITP treatments seems very good, with no strong safety signal and especially
in regard to the risks of thrombosis and of bacterial infection.
Conflict of interest
Matthieu Mahévas received research grants from GSK, and meeting attendance grants
from GSK and Amgen. Guillaume Moulis received research grants form CSL Behring, Novartis,
Grifols, and meeting attendance grants from Amgen and Novartis. Lionel Galicier participated
to educational boards for GSK. Bertrand Godeau received research grant from Amgen,
and Bertrand Godeau served as an expert for Amgen, Novartis, LFB and Roche. Mikael
Ebbo has participated in advisory boards for Amgen, Grifols GSK and Novartis.
Supporting information
Table SI. Number of patients recorded in this series by participating centres in the
network.
Click here for additional data file.