We greatly appreciated the recent narrative commentary by Dorgalaleh reflecting on
potential bleeding complications in coronavirus disease 2019 (COVID-19).[1] This issue is probably underestimated, perhaps considering that most experts focused
on the prothrombotic risks of COVID-19. Nevertheless, the potential development of
thrombocytopenia and the widespread use of clinical anticoagulants, sometimes given
in higher doses, now require the additional attention of treating clinicians. One
potential bleeding issue—not clearly mentioned by the author—is an infrequent type
of overt bleeding represented by spontaneous soft tissue hematomas, which may be diagnosed
late in the course of COVID-19, especially in sedated, sleeping, or unconscious patients.
A prompt detection of such conditions has relevance in therapeutic decisions, including
the need for any interventional radiological procedure and also for the prognosis,
considering the development of acute compartmental syndrome.[2] Here, we wish to describe the case of a patient with severe COVID-19 pneumonia,
who developed subsequent multiple spontaneous muscular hematomas.
On March 28, 2020, an 84-year-old Caucasian man with a history of chronic obstructive
pulmonary disease, hypertension, and ischemic heart disease presented to the Emergency
Department complaining of shortness of breath and chills, symptoms that started 10
days earlier. On admission, he was mildly tachypneic, confused, dehydrated, febrile,
and hypoxic. Results of blood tests taken at that time and subsequently are shown
in [Table 1]. Real-time polymerase chain reaction analysis of a nasopharyngeal swab sample confirmed
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection (intrafamilial
transmission) and high-resolution computed tomography (CT) detected bilateral subpleural
ground-glass areas suggestive of viral interstitial pneumonia. Along with his usual
therapy (pantoprazole, fluticasone furoate/vilanterol, simvastatin, and acetylsalicylic
acid [aspirin] 100 mg once daily), hydroxychloroquine 200 mg twice daily and piperacillin/tazobactam
4.5 g every 8 hours were prescribed. After the resolution of the mild acute kidney
injury with proper rehydration, 40 mg once daily of low molecular weight heparin (LMWH)
was administered, but this was ceased early (on April 3) due to the development of
mild thrombocytopenia (70 × 109 platelet/L at nadir). Supportive therapy with continuous positive airway pressure
with an orofacial mask was needed for the initial days, until the amelioration of
pO2 allowed oxygen delivery at lower flows through nasal prongs. On the morning of April
8, a bilateral neck and upper chest subcutaneous hematoma appeared with mild painful
swelling ([Fig. 1A]). A contrast CT scan of the chest and neck region detected bilateral and asymmetric
hematoma (left > right) of the sternocleidomastoid muscles ([Fig. 1B]); no signs of pulmonary or deep venous thrombosis were present. No central venous
access positioning had been previously attempted, and no trauma had occurred. After
a few hours, the patient complained of worsening pain in the left inguinal region,
and a deep muscular hematoma was also found within adductors muscles ([Fig. 1C]), without pathological findings in the abdomen. Given that only moderate grade anemia
gradually developed in the subsequent days and thrombocytopenia completely resolved
([Table 1]), a conservative approach was taken and two units of red packed cells were transfused,
with subsequent stable hemoglobin values. Aspirin was withdrawn. Hematomas were monitored
daily with bedside color Doppler ultrasonography and remained stable. The patient
was discharged in a postacute care facility nine days after the onset of bleeding
following resolution of the hematomas, without any recurrence reported within 30-day
follow-up visit; no further CT exam was performed because of clinical improvement
and stable hemoglobin level (refer to [Fig. 2] for a complete timeline).
Table 1
Blood tests collected during the hospitalization
|
March 28
|
April 2
|
April 8
|
April 12
|
|
Arterial blood gas
|
|
pH
|
7.43
|
7.41
|
7.37
|
NA
|
|
PaO2 (mmHg)
|
61
|
73
|
73
|
NA
|
|
PaCO2 (mmHg)
|
32
|
40
|
44
|
NA
|
|
Oxygen saturation of hemoglobin (%)
|
93
|
98
|
96
|
NA
|
|
PaO2/FiO2
|
290
|
228
|
317
|
NA
|
|
Laboratory
|
|
Hemoglobin (g/L)
|
156
|
148
|
143
|
92
|
|
Platelet count (×109/L)
|
101
|
70
|
126
|
168
|
|
White cell count (×109/L)
|
4.81
|
4.23
|
5.81
|
8.72
|
|
Total lymphocytes (×109/L)
|
0.5
|
0.8
|
1.2
|
1.8
|
|
International normalized ratio
|
1.1
|
1.4
|
1.4
|
1.4
|
|
Activated partial thromboplastin time (seconds)
|
29
|
34
|
32
|
30
|
|
Fibrinogen (g/L)
|
4.16
|
4.75
|
3.10
|
NA
|
|
D-dimer (mg/L)[a]
|
1.02
|
NA
|
0.72
|
0.91
|
|
C-reactive protein (mg/L)
|
27.3
|
63.5
|
16.0
|
61.0
|
|
Procalcitonin (ng/L)
|
NA
|
0.28
|
0.07
|
0.23
|
|
Creatinine (mmol/L)
|
2.07
|
1.34
|
1.26
|
0.89
|
|
eGFR (mL/minute/1.73m2)[b]
|
30
|
50
|
54
|
>60
|
|
Alanine aminotransferase (U/L)
|
16
|
12
|
24
|
31
|
|
Aspartate aminotransferase (U/L)
|
28
|
29
|
33
|
35
|
Abbreviations: eGFR, estimated glomerular filtration rate; NA, not available.
a D-dimer HS 500 - Instrumentation Laboratory/Werfen (turbidimetric immunoassay; fibrinogen
equivalent units).
b Estimated with MDRD-4 (Modification of Diet in Renal Disease 4 variables equation).
Fig. 1 (A) Photo showing the extension of subcutaneous hematomas. Contrast-enhanced CT (computed
tomography) images showing hemorrhagic infarction (arrowheads) and tissue distortion of both sternocleidomastoid muscles, more prominent on the
left one, in the cervical region (B) and the hematoma of the left abductors district (C) with minor intralesional contrast extravasation (asterisk).
Fig. 2 A timeline of the clinical course and key laboratory features of the described case.
A recent report has described a longer hospitalization of patients with delayed-phase
thrombocytopenia associated with older age and lymphopenia,[3] as appears to have happened in this case. Many conditions might explain the appearance
of these complications. First, an overt disseminated intravascular coagulation (DIC)
can determine transient thrombocytopenia in the course of COVID-19 infection[4]; however, the DIC score (2001 International Society on Thrombosis and Hemostasis
[ISTH] Guidelines) in our patient was < 5; therefore, DIC was unlikely. Moreover,
we considered concomitant medications, in particular LMWH and aspirin, as potential
contributors to the hematoma development. Heparin-induced thrombocytopenia, for example,
could be an explanation for the platelet count reduction, but the patient had low
probability (only 3) in 4Ts score[5]; therefore, according to our hospital's protocol, serum antibodies against heparin-PF4
complexes were not assessed. Naturally, failure to perform HIT testing could be seen
as a potential study limitation, as conclusive exclusion of HIT could not be attained.
However, thrombosis, not bleeding, is the usual clinical presentation of HIT. As an
additional study limitation, antifactor Xa testing is not available in our laboratory;
therefore, plasma heparin levels were unknown. In any case, the thrombocytopenia quickly
resolved. Upon review of the patient's past history, it was identified that he had
started aspirin 12 years earlier, without any prior development of anemia or any other
bleeding event. Nevertheless, aspirin has a well-established hemorrhagic potential.[6] Another key clinical question was whether the moderate kidney failure was indirectly
responsible for the bleeding state, potentially by increasing plasma levels of LMWH,
which we could not ascertain. However, we feel this is unlikely since the temporary
worsening of the renal function was already resolved when the hemorrhage occurred.
Finally, factor inhibitors may lead to hematoma development; although not assessed
in our patient, these are unlikely given coagulation test results never became abnormal.
In conclusion, the real burden of hemorrhagic complications resulting from COVID-19
is unknown and further studies are needed, also assessing the safety of anticoagulant
therapies. As a conclusive recommendation, we also advocate assessing a patient's
tailored bleeding risk with strong clinical surveillance, mostly in patients who develop
thrombocytopenia.
