Emmental Hospital, situated in the rural town of Burgdorf in Switzerland, has treated
a low volume of inpatients with COVID-19. Of the 13 admissions prior to 30th April
2020, 4 required treatment in the intensive care unit (ICU). Here we report on 3 consecutive
inpatients with severe COVID-19, following the unexpected death of our first patient
with severe COVID-19 from pulmonary embolism.
Following our previous findings of massively elevated von Willebrand factor (VWF)
and factor VIII clotting activity (FVIII:C) in COVID-19 [1], we complemented our analyses
of VWF, FVIII:C and D-dimers during follow-up and included the assay of ADAMTS13 activity
using the modified FRETS-VWF73 assay [2].
In the previously published patient, who required intensive care including renal replacement
therapy for pneumonia with multiple organ dysfunction [1], there was a slight decrease
of VWF antigen, VWF activity and FVIII:C (Table 1
, patient 1) after one week of intravenous therapeutic-dose anticoagulation with unfractionated
heparin with an anti-FXa-activity target range of 0.6–0.8 U/mL. At this time, we measured
a normal ADAMTS13 activity. This patient, 8 weeks after the onset of symptoms, has
now been discharged for further rehabilitation while under continued therapeutic anticoagulation
with apixaban 2 × 5 mg daily.
Table 1
Haematological parameters of COVID-19 patients.
Table 1
Parameter
Normal
Patient 1
Patient 2
Patient 3
Day 31a
Day 38a
Day 11a
Day 18a
Day 14a
D-dimer, mg/L
<0.5
20.63
6.26
1.1
1.74
2.19
ESR, mm/h
0–20
135
125
>100
65
98
VWF:activity, %
42–168
520
405
374
303
352
VWF:antigen, %
42–136
555
413
329
251
396
FVIII:C, %
55–164
369
332
310
232
432
ADAMTS13 activity, %
>51
b
56
>100
83
81
ACA IgG, CU
<20.0
<2.6
<2.6
3.9
2.7
<2.6
ACA IgM, CU
<20.0
121.9
77.1
26.2
24.1
1.5
Anti-β2-GPI IgG, CU
<20.0
6.6
<6.4
<6.4
<6.4
<6.4
Anti-β2-GPI IgM, CU
<20.0
275.3
174.1
12.7
14.5
<1.1
Fibrinogen, g/L
2.00–3.93
5.11
5.82
6.45
3.48
4.33
Thrombocytes, 109/L
150–370
352
270
315
318
254
C-reactive protein, mg/L
<5
14.3
7.5
118
5.1
33.6
ESR, erythrocyte sedimentation rate; VWF, von Willebrand factor; FVIII:C, factor VIII
clotting activity; ACA, anti-cardiolipin antibody; anti-β2-GPI, anti-β2 glycoprotein
I antibodies.
a
Refers to days after onset of symptoms.
b
Not measured.
We observed a second patient with severe COVID-19 and typical radiological findings
of bilateral pneumonia, requiring intensive care with intubation and positive pressure
ventilation. She was a 60-year-old female with no previous medical history and no
regular medication. Eleven days after the onset of a dry cough, with loss of appetite
and a worsening general condition, but with no fever or dyspnoea, she suffered a syncope
and was hospitalised. Her haemostatic laboratory values at admission (day 11) and
7 days later are summarised in Table 1 (patient 2). VWF activity, VWF antigen and
FVIII:C were markedly elevated, and ADAMTS13 activity was normal. In accordance with
our local guidelines for anticoagulation in patients with COVID-19, stratified by
D-dimer levels, the patient received a double-prophylactic dose of low molecular weight
heparin, i.e. 2 × 5000 IU of dalteparin s.c. per day upon admission. Seven days later,
due to increasing D-dimers, anticoagulation was intensified to a therapeutic dose
of dalteparin, i.e. 10′000 IU in the morning and 7′500 IU at night. The patient has
since recovered and after a 15-day hospitalisation was discharged home with therapeutic
anticoagulation with apixaban, 5 mg twice daily. Of note, anti-phospholipid antibodies
were normal or near normal (Table 1).
The third patient was a 66-year-old obese female with a medical history of diabetes
mellitus type 2, hypertension and hyperlipidaemia, and her daily medication was acetylsalicylic
acid 100 mg, candesartan 32 mg, hydrochlorothiazide 25 mg, metformin 2000 mg, vildagliptin
100 mg, fenofibrate 200 mg and pravastatin 40 mg. She was admitted for inpatient monitoring
4 days after the onset of fever of 39.8 °C, a productive cough with white sputum,
no dyspnoea but loss of appetite, adynamia and diarrhoea 2 days before admission.
Radiological findings showed typical COVID-19 associated diffuse bilateral airspace
opacities. Initially her D-dimer levels were 0.53 mg/L and prophylactic dalteparin
5000 IU s.c. once daily was given. While clinically stable and with C-reactive protein
decreasing from 78 to 16 mg/L, monitoring of the haemostatic laboratory values 14 days
after the onset of symptoms showed elevated D-dimers and massively elevated levels
of VWF and FVIII:C (Table 1, patient 3). ADAMTS13 activity was normal, and no antiphospholipid
antibodies were detected. A therapeutic dose of dalteparin was started, and three
days later the patient could be discharged with apixaban 5 mg twice daily.
In all three patients, erythrocyte sedimentation rate was markedly increased and remained
substantially elevated (Table 1). Serum protein electrophoresis reflected acute inflammation
and immunofixation was inconclusive with possible traces of oligoclonal bands. Quantitative
measurements of IgM, IgG and IgA were normal.
Prior to starting therapeutic dose anticoagulation in these 3 patients, we had observed
a patient with severe COVID-19 who seemed to have almost recovered and then died suddenly
from clinically obvious pulmonary embolism (with acute right heart failure in the
clinical examination as well as on emergency echocardiography) while on prophylactic
anticoagulation. In addition, reports from China showed a coagulopathy in 50% of the
non-survivors and the prognostic value of D-dimers [3,4]. Based on these observations,
we adapted our local guidelines with increased dose heparin according to D-dimer levels.
After introducing therapeutic-dose anticoagulation into our therapeutic concept, all
patients recovered, with rapid clinical improvement but slow and protracted improvement
of D-dimers, persistently high VWF and factor VIII:C levels, and, interestingly, also
of erythrocyte sedimentation rate. No haemorrhagic complication occurred. Since then,
the findings of highly elevated VWF and factor VIII have also been reported in a small
Italian and a large French cohort [5,6]. Furthermore, in two recent autopsy series,
thromboembolic complications, including thrombi in the small to mid-sized pulmonary
arteries were a striking common finding [7,8]. Randomised trials will clarify the
utility of anticoagulation in hospitalised patients with COVID-19 (NCT04344756, NCT04345848,
NCT04359212, NCT04362085, and NCT04359277), and we await their results to further
inform our practice.
In our patients, normal ADAMTS13 activity together with normal platelet counts (Table
1) clearly excludes thrombotic thrombocytopenic purpura. Notably, there were no schistocytes
in the blood smears, which does not support a diagnosis of classic thrombotic microangiopathy.
Whereas in severe sepsis or septic shock not due to SARS-CoV-2, some 30% of patients
had mildly reduced ADAMTS13 activity of 27–50% [9], our 3 COVID-19 patients had normal
ADAMTS13 activity suggesting that ADAMTS13 does not play a major pathogenic role in
the COVID-19 coagulopathy. Moreover, the normal platelet counts and high fibrinogen
levels in all our patients (lowest value 3.48 g/L) clearly rule out classical disseminated
intravascular coagulation (DIC) in our patients, in keeping with the low prevalence
of DIC (0–2%) in other larger cohorts [6,[10], [11], [12]]. Published evidence has
shown viral particles in endothelial cells by electron microscopy, and an endotheliitis
has been postulated [13]. Considering these findings, the COVID-19 coagulopathy may
be a distinct entity of highly prothrombotic alterations and - in light of the persistently
and excessively elevated levels of VWF and FVIII - most probably an endothelial disease.