Coronavirus disease 2019 (COVID-19) is associated with an increased risk of thrombotic
complications.[1] Multiple lines of evidence support the existence of a hypercoagulable state in hospitalized
COVID-19 patients. Enhanced platelet activation,[2] enhanced in vivo thrombin generation and ex vivo thrombin-generating capacity,[3]
[4] hyperfibrinogenaemia,[5] and ex vivo resistance to fibrinolysis[3]
[4]
[6]
[7] have all been demonstrated. Despite a marked ex vivo hypofibrinolytic state, erroneously
referred to as ‘fibrinolytic shutdown’ by some researchers, patients with COVID-19
demonstrate fibrinolytic activity in vivo, as evidenced by elevated plasma levels
of plasmin–antiplasmin complexes, and high plasma levels of D-dimer.[3] The hypercoagulable state in COVID-19 persists even in the presence of anticoagulant
therapy, as evidenced by elevated plasma levels of thrombin–antithrombin complexes
and by ex vivo whole blood viscoelastic tests.[3]
[5]
[8] Nevertheless, patients with COVID-19 on anticoagulant therapy may experience both
bleeding and thrombotic complications.[9]
We have recently reported on the haemostatic status in a large cohort of COVID-19
patients and showed profound hypercoagulable changes.[10] In a continuation of our systematic assessment of haemostatic changes in COVID-19
patients, we unexpectedly detected a substantial decrease in plasma factor XIII (FXIII)
activity.
Of a single-centre cohort of 102 patients with COVID-19, we had plasma of 97 patients
available for FXIII assays. The majority of patients were admitted to general wards
with ‘mild’ disease, and specifics on this cohort are described elsewhere.[10] Of the 97 patients included in this study, 54 and 23 patients received low-molecular-weight
heparin once and twice daily, respectively, at the time of blood sampling. Four patients
received oral anticoagulants, and 16 patients were not on any anticoagulation. We
also studied 28 healthy controls to establish FXIII reference values. We measured
FXIII activity as described previously.[11] Importantly, there is no interference of our FXIII activity assay by low-molecular-weight
heparin levels up to 1 U/mL (data not shown). FXIII levels were substantially decreased
in patients compared with controls. The decrease in FXIII levels was more pronounced
in patients admitted to a high care facility compared with patients admitted to general
wards. FXIII levels decreased proportionally with the level of respiratory support.
FXIII levels were numerically lower in patients who died within 30 days of hospitalization
compared with those who survived, although this difference was not statistically significant
([Table 1]).
FXIII, after activation by thrombin, stabilizes the fibrin clot by cross-linking adjacent
fibrin fibres and further increases resistance to fibrinolysis by cross-linking α-2
antiplasmin to the fibrin network.[12] In addition, FXIII mediates red blood cell retention within clots, which has been
shown to facilitate venous thrombogenesis.[13] In the general population, acquired FXIII deficiency is a rare bleeding disorder
that may be associated with life-threatening bleeding. Causes of acquired FXIII deficiency
include neutralization of FXIII by (auto)antibodies, consumption, and decreased synthesis.[14] Importantly, immune-mediated FXIII deficiency is associated with bleeding.[14] It is unclear whether FXIII deficiency associated with consumption (e.g., during
major surgery) or decreased synthesis (e.g., in liver disease) is associated with
bleeding and may benefit from FXIII replacement.[15] The mechanism underlying acquired FXIII deficiency in COVID-19 patients remains
uncertain, but a consumptive mechanism seems likely. Even in patients receiving anticoagulation,
there is continuing generation of thrombin (as evidence by elevated thrombin–antithrombin
complex levels), with subsequent breakdown by the fibrinolytic system (evidenced by
elevated plasmin–antiplasmin complexes and D-dimer levels). As D-dimers are derived
from FXIIIa-mediated cross-linked fibrin, it seems likely that FXIII is consumed in
this process of ongoing activation of coagulation. Indeed, both FXIII and D-dimer
levels are related to COVID-19 disease severity.
We have identified a profound decrease in FXIII plasma levels in patients with COVID-19.
Whether these decreased FXIII levels in part compensate for the hypofibrinolytic state
of COVID-19, and perhaps even contribute to COVID-19-related bleeding, is an intriguing
hypothesis that requires additional study.
Table 1
Factor XIII levels in COVID-19 patients related to disease severity and 30-day mortality
|
Factor XIII (%)
|
|
Healthy controls (n = 28)
|
103 [73–152]
|
|
COVID-19 patients (n = 97)
|
49 [34–78]
|
|
p-value
|
<0.0001
|
|
Based on location
|
|
General ward (n = 85)
|
54 [37–81]
|
|
High care[a] (n = 12)
|
35 [31–42]
|
|
p-value
|
0.009
|
|
Based on level of respiratory support
|
|
No respiratory support (n = 36)
|
57 [39–97]
|
|
Nasal cannula/mask ≤5 L O2 (n = 45)
|
47 [32–79]
|
|
Higher respiratory support[b] (n = 17)
|
39 [32–63]
|
|
p-value
|
0.147
|
|
Based on 30-d survival
|
|
Survivors (n = 87)
|
51 [35–79]
|
|
Non-survivors (n = 10)
|
38 [32–67]
|
|
p-value
|
0.204
|
Note: The results are presented as median [interquartile range]. Comparisons were
made using the Mann–Whitney U test or Kruskal–Wallis test, as appropriate. p-values <0.05 were considered statistically significant.
a Three patients were admitted to the intensive care unit and nine patients were admitted
to the intermediate care unit.
b Respiratory support in this group comprised >5 L O2 by nasal cannula/mask (n = 13), non-invasive ventilation (n = 2), and intubation (n = 2).
