key: cord-298654-sb9kevkb
authors: Yang, Xiang-Hong; Li, Ran-Ran; Sun, Ren-Hua; Liu, Jiao; Chen, De-Chang
title: Focus on coronavirus disease 2019 associated coagulopathy
date: 2020-09-20
journal: Chin Med J (Engl)
DOI: 10.1097/cm9.0000000000001019
sha: 
doc_id: 298654
cord_uid: sb9kevkb

nan

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 mg/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 mg/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 metaanalysis of nine studies identified that the PLT was significantly lower in severe COVID-19 patients compared with that in mild ones (À31 Â 10 9 /L; 95%, À35 to À29 Â 10 9 /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%, x 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 nonsurvivors 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 sepsisinduced 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 × 10 9 /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 mg/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 adequatelypowered 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 Chinese Medical Journal 2020;133(18) www.cmj.org 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 Â 10 9 /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.

Clinical characteristics of coronavirus disease 2019 in China

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Changes in blood coagulation in patients with severe coronavirus disease 2019 (COVID-19): a meta-analysis

Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a metaanalysis

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 in Wuhan, China: a retrospective study

Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and followup: JACC state-of-the-art review

ISTH interim guidance on recognition and management of coagulopathy in COVID-19

Focus on coronavirus disease 2019 associated coagulopathy

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.

None.