Coronavirus disease 2019 (COVID-19) is characterized by severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) needing mechanical ventilation and intensive care unit
(ICU) treatment. In addition to lung disease, clinical features of SARS-CoV-2 include
myocardial damage and ischemia-related vascular disease, which are associated with
a hypercoagulable state (e.g., high D-dimer levels) predisposing to thrombotic-related
complications and eventually death.[1]
[2]
[3] Serum albumin levels <3.5 g/dL are detectable in SARS-CoV-2 patients and associated
with death[4] and elevated D-dimer and thrombotic events,[5] which is in accordance with previous studies reporting an association between serum
albumin <3.5 g/dL and risk of venous and arterial thrombosis.[6] Thus, we tested the hypothesis that albumin supplementation could dampen hypercoagulability
in SARS-CoV-2 with serum albumin <3.5 g/dL.
This is an observational cohort study performed at a large university hospital located
in Rome and Chieti (Italy) and devoted to COVID-19 care.
We included in the study adult (≥18 years) patients with laboratory-confirmed COVID-19
and SARS-CoV-2-related pneumonia, requiring or not mechanical ventilation, consecutively
hospitalized from May to September 2020. COVID-19 was diagnosed on the basis of the
World Health Organization interim guidance.[7] A COVID-19 case was defined as a person with laboratory confirmation of COVID-19
infection, irrespective of clinical signs and symptoms. Oropharyngeal and nasopharyngeal
swabs for laboratory diagnosis of COVID-19 were performed in duplicate: SARS-CoV-2
E and S genes were detected by a reverse transcriptase polymerase chain reaction.
The study included patients having high D-dimer, i.e., plasma values >1 µg/mL, and
treated with prophylactic doses of low-molecular-weight heparin (LMWH; n = 10) plus albumin supplementation (n = 10); albumin supplementation was given intravenously at dosage of 80 g/day in the
first 3 days and 40 g/day thereafter for a maximum of 7 days. Patients with high D-dimer
treated with prophylactic doses of LMWH alone were used as controls (n = 19). Demographic and clinical characteristics were collected after receiving informed
consent. Routine analysis included coagulation tests (D-dimer, prothrombin time, activated
partial thromboplastin time, and fibrinogen), serum albumin, and high sensitivity
C-reactive protein (hs-CRP).
In both groups, D-dimer and serum albumin were measured at baseline and after 7 days
of follow-up. During the intrahospital follow-up, thrombotic events and survival were
registered as previously described.[5] Ethical approval for this study was obtained from Ethics Committee of Azienda Ospedaliero
Universitaria Policlinico Umberto I with the agreement of Chieti University.
Statistical analyses were undertaken using SPSS 18.0 software for Windows (SPSS, Chicago,
Illinois, United States). Between-group differences were analyzed by Kruskal–Wallis
tests. The Wilcoxon test was used to assess the difference of the covariates before
and after 7 days. Bivariate analysis was performed by the Spearman test. Differences
between percentages were assessed by the χ2-test. A p-value of <0.05 was considered statistically significant.
Characteristics of patients included in the study are reported in [Table 1]. No significant difference was observed at baseline between albumin-treated patients
and controls for age, gender, albumin, D-dimer, creatinine, hs-CRP levels, and clinical
characteristics ([Table 1]). Furthermore, there were no differences in the percentage of patients admitted
to the ICU and medical wards ([Table 1]).
Table 1
Clinical and laboratory characteristics of study in SARS-CoV-2 patients treated with
albumin and controls
|
Albumin group
|
Control group
|
p-Value
|
|
N
|
10
|
19
|
–
|
|
Age (y)
|
82 ± 9
|
74 ± 13
|
0.085[a]
|
|
Female/male
|
8/2
|
7/12
|
0.052[b]
|
|
Obesity
|
0
|
7
|
0.06[b]
|
|
Hypertension
|
2
|
8
|
0.419[b]
|
|
Diabetes
|
1
|
4
|
0.632[b]
|
|
Smoking habit
|
1
|
2
|
1[b]
|
|
COPD
|
0
|
1
|
1[b]
|
|
Chronic kidney disease
|
0
|
1
|
1[b]
|
|
Cardiovascular disease
|
0
|
3
|
0.532[b]
|
|
ICU hospitalization
|
5
|
14
|
0.243[b]
|
|
Medical ward hospitalization
|
5
|
5
|
0.244[b]
|
|
Length of hospital stay
|
31 ± 10
|
20 ± 11
|
0.010[b]
|
|
Cardiovascular events
|
1 hemorrhagic event
|
2 ischemia, 1 pulmonary embolism, 1 stroke
|
0.632[b]
|
|
Death
|
0/10 (0%)
|
8/19 (42%)
|
0.02
[b]
|
|
Pharmacological therapy
|
|
Tocilizumab
|
5
|
13
|
0.229[b]
|
|
Hydroxychloroquine
|
4
|
15
|
0.316[b]
|
|
Piperacillin and tazobactam
|
6
|
16
|
0.582[b]
|
|
Teicoplanin
|
5
|
15
|
0.479[b]
|
|
Lopinavir/Ritonavir
|
2
|
10
|
0.253[b]
|
|
Darunavir
|
1
|
2
|
0.968[b]
|
|
Baseline
|
After 7 days of albumin treatment
|
p-Value
|
Baseline
|
After 7 days
|
p-Value
|
|
Albumin (g/dL)
|
2.7 [2.6–3.1]
|
3.6 [2.9–4.1]
|
0.014
[c]
|
3.0 [2.6–3.3]
|
2.9 [2.6–3.3]
|
0.347[c]
|
|
Creatinine (mg/dL)
|
0.96 [0.47–1.7]
|
0.77 [0.44–1.51]
|
0.240[c]
|
1.4 [0.8–1.7]
|
1.6 [0.65–2.1]
|
0.983[c]
|
|
hs-CRP (µg/L)
|
61,295 [40,627–10,1525]
|
35,460 [18,725–80,505]
|
0.285[c]
|
100,000 [28,860–203,000]
|
61,545 [6,325–126,325]
|
0.421[c]
|
|
D-Dimer (µg/mL)
|
3.23 [1.4–4.4]
|
1.3 [0.6–2.1]
|
0.005
[c]
|
3.37 [1.8–4.7]
|
4.4 [1.1–4.4]
|
0.754[c]
|
Abbreviations: COPD, chronic obstructive pulmonary disease; hs-CRP, high sensitivity
C-reactive protein; ICU, intensive care unit.
Note: Statistically significant values are highlighted in bold.
a Comparison between patients treated with albumin and controls (by Kruskal–Wallis
tests).
b Comparison between patients treated with albumin and controls (by χ
2-test).
c Comparison between values at baseline vs. after 7 days (by Wilcoxon test).
At baseline, both groups had low values of serum albumin, approximately around 3.0 g/dL,
and high values of D-dimer, approximately 3 µg/mL. The pairwise comparisons showed
that only after albumin treatment D-dimer levels significantly decreased ([Table 1] and [Fig. 1]); at the end of treatment, D-dimer was reduced by >50% in albumin-treated patients
while no changes were detected in untreated ones. Conversely, serum albumin significantly
increased in albumin-treated patients reaching, in average, values >3.5 g/dL. Bivariate
analysis, performed by the Spearman test, showed that the absolute delta of albumin
was inversely correlated with absolute delta of D-dimer (R
s: −0.440, p = 0.006). During the hospital stay, a bleeding complication was registered in albumin-treated
patients. A nonsignificant trend was observed for the occurrence of cardiovascular
events between patients treated with albumin versus controls; a significant difference
was observed for the number of deaths ([Table 1]).
Fig. 1 Serum albumin and D-dimer levels in SARS-CoV-2 patients treated with albumin (A and B) and controls (C and D).
The study provides the first evidence that albumin supplementation dampens hypercoagulability
in patients with SARS-CoV-2.
D-Dimer is a split-off product of fibrin degradation by plasmin and is, therefore,
considered a marker of hypercoagulability.[8] Elevated levels of D-dimer are a frequent feature of SARS-CoV-2 and associated with
an increased risk of thrombosis and death.[2]
[3] Hence anticoagulant treatment became a standard therapy for SARS-CoV-2 patients
to reduce the thrombotic risk. Even if observational studies demonstrated that prophylactic
as well as full dosage of anticoagulants improved survival in a population affected
by SARS-CoV-2, the mortality was still elevated suggesting the need for identifying
novel therapeutic strategies.[9]
Albumin is an acute-phase reactant, which is usually reduced in the case of acute
and chronic inflammation, thus under normal physiologic conditions albumin exerts
an antioxidant effect via an abundant source of free thiols that are able to scavenge
reactive oxidant species (ROS).[10] In the case of oxidative stress, the Cys34 of albumin may undergo irreversible oxidation,
which impairs its antioxidant property and eventually elicits cell and tissue damage.[10] It is interesting, in this regard, that albumin oxidation triggers neutrophil extracellular
traps (NETs) via ROS accumulation within neutrophils, which eventually accumulate
within lungs;[10] of note, accumulation of leucocytes and NETs has been detected in the thrombi detected
in the lungs of SARS-CoV-2 patients.[11]
[12]
[13] Previous studies reported that albumin possesses antiplatelet and anticoagulant
properties via a mechanism possibly related to its antioxidant effect.[14] In particular, albumin inhibits fibrin polymerization, enhances the effect of antithrombin
III, and modulates the hepatic synthesis of factor V, factor VIII, and fibrinogen;[15]
[16] furthermore, albumin impairs platelet aggregation with a mechanism related to downregulation
of Nox2, a powerful producer of ROS.[14] Others and we have previously reported a close inverse relationship between serum
albumin and D-dimer suggesting hypoalbuminemia as a factor favoring hypercoagulability,
thrombosis, and death.[4]
[17]
This hypothesis has been tested in the present study including patients with elevated
D-dimer and serum albumin, in average <3.5 g/dL. We found a significant increase of
serum albumin in albumin-treated patients coincidentally with a marked reduction of
D-dimer, while no changes of D-dimer and serum albumin were detected in the control
group. This finding suggests that albumin exerts an anticoagulant activity in human,
thereby its supplementation could turn useful in SARS-CoV-2 patients, in whom anticoagulant
treatment, at least with a prophylactic dosage, seems to be unable to lower D-dimer;
the coexistent low serum albumin could, perhaps, slow down clotting inhibition by
anticoagulants. Unfortunately, however, our sample size does not permit drawing any
inference regarding albumin supplementation and clinical outcomes; of note, however,
we registered four deaths only in the control group. Even if this preliminary study
is limited by a lack of randomization and inadequate sample size, it could suggest
a novel therapeutic tool to counteract hypercoagulability in SARS-CoV-2 with elevated
D-dimer and low serum albumin and warrants, therefore, further investigation by randomized
clinical trials.
What is known about this topic?
-
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) displays low levels of
serum albumin which are associated with hypercoagulability and predict venous and
arterial thrombosis.
-
It is unclear if albumin supplementation is able to reduce hypercoagulability in SARS-CoV-2.
What does this paper add?
-
An observational prospective study performed in 29 SARS-CoV-2 patients treated with
anticoagulant alone or anticoagulant plus albumin supplementation for 7 days demonstrated
a significant decrease of D-dimer only in albumin-treated patients.
-
Albumin supplementation may represent a novel tool to dampen hypercoagulability in
SARS-CoV-2.
