The coronavirus disease 2019 (COVID-19) has caused a global outbreak and became a
major public health issue globally. It has been found that COVID-19 patients are commonly
complicated with coagulation abnormities, which are closely associated with the severity
and prognosis of patients. A thorough understanding of the prevalence of coagulopathy
and potential causes of abnormities of coagulation parameters in COVID-19 patients
is crucial for clinicians to standardize the diagnosis and management of COVID-19
associated coagulopathy.
Based on our frontline experience in Wuhan, we found that symptoms of COVID-19 associated
coagulopathy range from mild abnormalities of coagulation parameters to disseminated
intravascular coagulation (DIC).
Similar to severe acute respiratory syndrome (SARS), it has been shown that the elevation
of D-dimer is the most prevalent coagulation abnormality in COVID-19 patients, which
accounting for 36% to 46.4% of all cases.[1,2] The degree and persistence of elevation
are predictors of poor prognosis. Tang's[3] study of 183 confirmed cases with COVID-19
(21 deaths, 162 survivors) from the Wuhan Tongji Hospital has reported that the non-survivors
had significantly elevated values of D-dimer compared to the survivors (2.12 vs. 0.61
μg/mL, P < 0.001). In a multivariable logistic regression model based on 191 patients
(54 non-survivors and 137 survivors), a D-dimer level greater than 1.0 μg/mL at admission
was associated with increased mortality with an odds ratio of 18.42 (2.64–128.55,
P = 0.003).[4]
Different from SARS, the changes in activated partial thromboplastin time (APTT) and
prothrombin time (PT) in COVID-19 patients are inconsistent. Chen's[2] study showed
that 16% and 30% of patients exhibited shortened APTT and PT, while 6% and 5% of patients
showed prolonged APTT and PT respectively. Zhou et al
[4] reported that 50% of non-survivors expressed symptoms of coagulopathy manifested
as a 3-s PT increase or a 5-s increase in APTT. A meta-analysis[5] revealed that PT
and D-dimer levels were significantly higher in patients with severe COVID-19 than
those in mild patients. However, no significant difference in platelet count (PLT)
and APTT values between severe and mild patients were observed. The inconsistency
of coagulation parameter alterations may attribute to different courses and severity
of COVID-19 patients in different studies.
Compared to SARS patients, thrombocytopenia is less frequently observed in COVID-19
patients. A meta-analysis of nine studies identified that the PLT was significantly
lower in severe COVID-19 patients compared with that in mild ones (−31 × 109/L; 95%,
−35 to −29 × 109/L).[6]
The incidence rate of DIC in COVID-19 patients varies in different studies. It has
been reported that among the 1099 patients with COVID-19, only one patient (0.1%)
was diagnosed as DIC.[1] Deng et al
[7] found that the death group had a higher DIC incidence rate (6.4% vs. 0%, χ
2
= 7.655, P = 0.006). Tang et al
[3] reported that the overall incidence of DIC was 8.74%. But a large variation of
the incidence rate of DIC in survivors compared with non-survivors was observed. 71.4%
of the non-survivors met the International Society of Thrombosis and Hemostasis (ISTH)
diagnostic criterion of DIC, whereas only one survivor (0.6%) met this criterion.
Until now, the exact etiology and pathogenesis of COVID-19 associated coagulopathy
remain unclear. Based on the published literature and our frontline experience, we
consider that the etiology of coagulopathy is likely to be diverse and multifactorial.
Besides the direct attack by the 2019 novel coronavirus (2019-nCoV), cytokine storm
mediated inflammation-coagulation cascades, hypoxia, and other factors also contribute
to coagulation dysfunction in COVID-19 patients.
Similar to the vascular endothelial dysfunction in sepsis-induced coagulopathy (SIC),
an endothelialopathy appears to contribute to the pathophysiology of microcirculatory
changes in COVID-19 Postmortem of 2019-nCoV infection has proved viral entry into
the endothelial cells. Viral replication could cause inflammatory cell infiltration,
which could lead to cytokine storm mediated inflammation coagulation cascades and
promote endothelial cell apoptosis as well as microvascular prothrombosis, resulting
in the development of DIC eventually. Research showed that interleukin-6 levels positively
correlated with fibrinogen levels, demonstrating and confirming the link between inflammation
and procoagulant changes. Also, the main clinical characteristic of COVID-19 patients
is hypoxia. Within the hypoxic epithelial cells in type II alveoli, hypoxia-induced
factor, whose activation stimulates the coagulation cascades and leads to thrombosis
formation level, increases significantly, and this will, in turn, aggravate hypoxia
and lung injury.
At present, there exist no criteria to define the “COVID-19 associated coagulopathy.”
Usually, COVID-19 associated coagulopathy reflects abnormalities in tests but does
not meet the classic testing criterion of clinical coagulopathy where the impaired
ability to clot results in bleeding. We suggest that COVID-19 associated coagulopathy
can be diagnosed in confirmed or suspected COVID-19 patients when the following criteria
are met: PLT <100 × 109/L; the reduction of PT and APTT by more than the lower limit
of 99th percentile, the increase of PT by more than 3 s, or the increase of APTT by
more than 5 s; the increases of fibrinogen, fibrin degradation product (FDP) and D-dimer
by more than the lower limit of 99th percentile without clinical evidence of primary
blood system diseases or chronic liver diseases. We also suggest using the ISTH score
system to diagnose DIC: an ISTH score ≧5 is the diagnostic criterion of overt-DIC.
Because elevated D-dimer at admission is associated with increased mortality, and
rising D-dimer and PT, rapid dropping in fibrinogen, and PLT count after admission
are associated with overt-DIC and multiorgan failure, hospitalized COVID-19 patients
should, therefore, have coagulation testing performed on admission and during the
whole course of the disease, at least including D-dimer, PT, APTT, fibrinogen, and
platelet count tests.
COVID-19 associated coagulopathy usually lacks clinical manifestation and signs. The
most common clinical feature of coagulopathy in COVID-19 patients is thrombosis in
the deep vein or intermuscular vein of the lower extremity, which can be identified
by coagulation parameters and ultrasonic monitoring. It has been known that COVID-19
patients are at high risk of venous thromboembolism (VTE) due to blood hypercoagulability
conditions, prolonged immobilization during illness, dehydration, old age, and presence
of other comorbidities (such as hypertension, diabetes, obesity, or cardiovascular
disease).[8] Reports have been made showing that up to 31% of severe COVID-19 patients
admitted in the intensive care unit (ICU) showed the incidence of VTE or thrombotic
complications, and D-dimer >1.5 μg/mL was a good indicator for identifying high-risk
groups of VTE.[9] Therefore, VTE risk must be assessed in all COVID-19 patients admitted
to the hospital. For severe or critically ill COVID-19 patients and mild or moderate
COVID-19 patients who are evaluated to have a high risk of VTE, an early pharmacological
thromboprophylaxis with low molecular weight heparin (LMWH) is highly recommended
in absence of contraindications. If these patients are complicated with high hemorrhage
risk, intermittent pneumatic compression is recommended for mechanical prevention.
Based on the autopsy of COVID-19 patients showing extensive microthrombosis in alveolar,
myocardial, and renal tubular epithelial cells, anticoagulation treatments may be
beneficial for the management of COVID-19 patients. LMWH or unfractionated heparin
are the first choices for anticoagulation in COVID-19 patients due to their additional
anti-inflammatory properties. However, the specific dose of anticoagulation therapy
for COVID-19 patients is controversial. Tang et al
[10] have reported that anticoagulant therapy mainly with prophylaxis doses of LMWH
appears to be associated with better prognosis in severe COVID-19 patients with SIC
score ≥4 (40.0% vs. 64.2%, P = 0.029), or D-dimer >6 fold of normal upper limit (32.8%
vs. 52.4%, P = 0.017). Klok et al
[7] reported that ICU patients with severe COVID-19 had a higher incidence of thrombotic
complications, even when standard VTE prophylaxis was applied. A Delphi method consensus
document found that 31.6% of participants supported intermediate intensity dose, 5.2%
supported therapeutic dose, while the rest supported using standard VTE prophylaxis
dose for hospitalized patients with moderate to severe COVID-19 and without the complication
of DIC.[11] We suggest that a risk-adapted strategy with escalated prophylaxis dose
or therapeutic dose of anticoagulation based on levels of D-dimer, SIC score, ICU
location, the complication with VTE, and other indications for anticoagulation could
be considered during the clinical practice. Meanwhile, we further call for adequately-powered
randomized controlled studies to determine the appropriate dose and timing of anticoagulation
treatment for COVID-19-associated coagulopathy. LMWH should be used with caution in
patients with renal insufficiency due to their longer half-lives. For patients at
a high risk of bleeding, anticoagulation is not suggested, and Chinese traditional
medicine that can improve blood circulation could be considered if necessary.
It has been highlighted that concurrent DIC is a strong predictor of mortality in
COVID-19 patients. To date, as treatment of DIC has been focused on strategies to
target the primarily associated pathology, appropriate anti-viral, and organ function
supportive therapies should be strengthened. Although bleeding manifestations are
not common despite coagulopathy in COVID-19 patients, thrombosis and bleeding may
occur simultaneously during the late stages of overt-DIC, and anticoagulation and
risk of bleeding should be balanced in that case. If bleeding does develop, similar
principles to septic coagulopathy treatment pointed out by ISTH interim guidance could
be followed.[12] Blood products and coagulation factor replacement should be taken
in bleeding patients to keep platelet count above 50 × 109/L, fibrinogen above 1.5
g/L, and PT ratio <1.5. Some experimental therapies, such as recombinant human thrombomodulin
and antithrombin could be considered.
Given cytokine storm plays an important role in the development of COVID-19 associated
coagulopathy, blood purification could be tried in severely and critically ill patients
to alleviate cytokine storm and improve prognosis.
According to the available literature and our frontline experience, we formulated
an algorithm for the management of COVID-19 associated coagulopathy [Figure 1]. As
coagulopathy contributes to the rapid progression and poor prognosis of COVID-19 patients,
it is urgent to pay more attention to COVID-19 associated coagulopathy. We should
focus on monitoring coagulation indicators closely, screening VTE risk routinely,
and applying anticoagulation treatment appropriately during the management of COVID-19
patients.
Figure 1
Algorithm for the management of COVID-19 associated coagulopathy. APTT: Activated
partial thromboplastin time; COVID-19: Coronavirus disease 2019; DIC: Disseminated
intravascular coagulation; ISTH: International Society of Thrombosis and Hemostasis;
LMWH: Low molecular weight heparin PLT: Platelet; PT: Prothrombin time; VTE: Venous
thromboembolism.
Acknowledgment
The authors would like to express their appreciation for all of the health care workers
and other hospital staff as well as the local authorities for their efforts to combat
the outbreak of COVID-19.
Conflicts of interest
None.