key: cord-0767538-diwqblnl authors: MclinPharm, Syed Imran Ahmed; Khan, Shahzad title: Coagulopathy and Plausible Benefits of Anticoagulation Among COVID-19 Patients date: 2020-06-27 journal: Curr Probl Cardiol DOI: 10.1016/j.cpcardiol.2020.100648 sha: 03ae6110f3325009dadca0ccef21047887d79f6a doc_id: 767538 cord_uid: diwqblnl The exceptional outbreak of COVID-19 pandemic has let the scientific community to work closely and quickly learnt things in a very short period of time. This has let us recognise that thromboembolic complications are responsible morbidity and mortality among the COVID-19 infected patients. Available data have suggested a possible multifactorial basis of this complications, and while efforts are being made to treat this infection, preventive measure with the use of systemic anticoagulation were quickly adopted to deal with this complication. Despite obvious benefits as appeared with the use of systemic anticoagulation, most of the emerged data were retrospective, and hence raise questions on the possible interplay of the confounders as well as long term benefits and safety of systemic anticoagulation. The exceptional outbreak of COVID-19 pandemic has let the scientific community to work closely and quickly learnt things in a very short period of time. This has let us recognise that thromboembolic complications are responsible morbidity and mortality among the COVID-19 infected patients. Available data have suggested a possible multifactorial basis of this complications, and while efforts are being made to treat this infection, preventive measure with the use of systemic anticoagulation were quickly adopted to deal with this complication. Despite obvious benefits as appeared with the use of systemic anticoagulation, most of the emerged data were retrospective, and hence raise questions on the possible interplay of the confounders as well as long term benefits and safety of systemic anticoagulation. Although severe viral pneumonia and its complication such as acute respiratory distress syndrome (ARDS) and sepsis are the main causes of high mortality in COVID 19 observed globally, as we are getting more data, role of coagulation abnormalities in COVID 19 are becoming more obvious. Nearly all recently conducted retrospective studies have mentioned various degrees of increased thromboembolic events among COVID 19 victims. Among the very first of the studies conducted in China found increased odds of death in hospitalized patients were associated with D-dimer levels >1 micro gm/mL (P = 0.0033). Likewise, 50% of nonsurviving patients had coagulopathies which were recorded only 7% in surviving patients (P < 0.0001) [2] . Although sepsis seems to be a most obvious link to these coagulation derangements data showed that only 70% of the non-surviving patients had sepsis which emphasis that sepsis is not the only necessary preceding condition responsible for coagulopathy in COVID-19 [2, 4] . The idea of isolated coagulopathies in COVID 19 was strengthened by the observation that disseminated intravascular coagulopathy (DIC) commonly occurs in sepsis has marked thrombocytopenia decreased fibrinogen levels and increased prothrombin time while observations show that in COVID 19 sepsis has relatively normal platelets and prothrombin time. In fact, a recent USA study has reported that significantly elevated D-dimers and fibrinogen levels but relatively normal platelet counts were observed in COVID-19 patients [4] . The mechanism of hematopathology and coagulopathy is complex and multifactorial in COVID 19. It may involve all or any of the documented common pathways seen in other viral illness and in severely ill hospitalized patients such as endothelium cell damage by viral antigens, upregulation of von Willebrand factor, Toll-like receptors, all play a role in the coagulant state of viral infections which may lead to uncontrolled coagulations similar to DIC with the formation of excess fibrin clots. When these fibrin clots are degraded by the body's own anticoagulant system fibrin degradation products (or FDP) are produced among which D-dimer (two D fragments of the fibrin protein joined by a cross-link) is the one commonly tested in laboratories. The importance of this coagulopathy and association of it with COVID 19 is so strong that a recent study has declared that a four-fold increase in D-dimer is a strong indicator of mortality COVID-19 patients [5] . Besides DIC local coagulopathies such as venous thromboembolism due to venous stasis has also been implicated in COVID 19 patients. Furthermore, generation of localized tissue factor-mediated thrombin, depression of bronchoalveolar plasminogen activator-mediated fibrinolysis via in lungs has been documented [6]. This discovery is supported by a study that showed lung microthrombi and venous thromboembolism in COVID 19 patients without documented DIC [7]. Regardless of the certainty of the mechanism involved in COVID 19 related coagulopathy, the role of coagulation related disorder in COVID 19 illness is obvious and therefore the use of anticoagulation therapy is currently practised prophylactically and therapeutically in COVID 19 patients [1] . Interestingly, besides the classical anticoagulation mechanism of heparin via binding and enhancing antithrombin III it has been reported to alleviate inflammation through binding adhesion molecules L-and P-selectin [8, 9] and downregulating interleukin-6 (IL-6) as well [10] . Additional intriguing role of heparin antiviral properties has been tested in experimental models. Heparin has shown to bind host cell surface glycoproteins and can inhibit viral attachment [6]. In Italy, such a role of heparin has been verified successfully in experiment models [11] . Another recent study has shown that heparin binds to COVID 19 surface spike protein [12] . These secondary antiviral properties need to be clinically proven but still increase the importance of heparin in COVID 19 management. On the other hand, there is an opinion which opposes the use of early or prophylactic use of anticoagulant in patients without significant coagulopathy mainly because of the fact that activation of coagulation contributes to wall-off or compartmentalize the pathogens and decreases their invasion and propagation [13] . As of now Unfractionated Heparin (UFH) and Low-molecular Weight Heparin (LWMH) is being used in the standard management of COVID-19 induced sepsis. A recent study on 449 COVID19 patients who received LMWH for 7 days or longer has shown lower 28-day mortality in heparin treated patients who had D-dimer >6-fold of the upper limit of the normal (32.8% vs 52.4%, P = .017) but the same study showed no difference in 28-day mortality between heparin users and nonusers (30.3% vs 29.7%, P = .910) when they did not have markedly elevated D-dimer. This study further revealed that D-dimer, prothrombin time, and age were positively correlated with 28-day mortality, and platelet count was negatively correlated with 28-day mortality [7]. Another recent study in the USA has investigated the association between in-patient anti-coagulant use and survival in a large cohort of COVID-19 patients. According to this study, those who received anti-coagulants were more likely to require invasive mechanical ventilation (29.8% vs 8.1%, p<0.001), and among the mechanically ventilated patients the mortality rate was 29.1% as compared to 62.7% who were not treated with anticoagulants [1] . The study also examined the risk of bleeding, which confirms 1.9% of anticoagulants treated patients had bleeding events and the risk of bleeding was more in intubated patients after anti-coagulants use [1] . Although these findings confirm the apparent benefits of systemic anti-coagulants use, however, it did not overrule the risk of bleeding, thus requiring measurement of individualized risk calculation for thrombosis as well as bleeding among COVID-19 patients. Also, the data account for systemic use of anti-coagulants, but not reflective of the specific types such as unfractionated heparin (UFH) or low-molecular-weight heparin LWMH) or fractionated low-molecular-weight derivatives like enoxaparin, dalteparin or tinzaparin, which could also be essential while choosing among high-risk patients. In summary, COVID-19 related morbidities and mortalities are possibly contributed by thromboembolic events, and based on the suggestive data use of anti-coagulants is associated with improved outcomes. However, the risk for thromboembolic events and benefits from anti-coagulants must be individualized against the risk of bleeding. Is there a requirement of higher than the prophylactic dose of anticoagulants in patients with higher D-dimers levels, or there should be a dose adjustment depending on invasive or non-invasive mechanical ventilation, can heparin be considered independently as an adjuvant therapy due to its anti-inflammatory and anti-viral properties? These and many other questions still need more clarification. Moreover, reported data are retrospective, which cannot establish the impact of potential confounders and establish causality, requiring prospective studies on the subject. We may also need to study the benefits and risks with the use of available anti-coagulants, as they vary significantly in terms of their safety profiles. Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19 Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Incidence of thrombotic complications in critically ill ICU patients with COVID-19 Anticoagulation in COVID-19 D-dimer levels on admission Characterization of the Heparin-Binding Properties of IL-6 Coronaviridae and SARS-associated Coronavirus Strain HSR1. Emerg Infect Dis. Epub ahead of print The 2019 coronavirus (SARS-CoV-2) surface protein (Spike) S1 Receptor Binding Domain undergoes conformational change upon heparin binding. bioRxiv. Epub ahead of print 2020 Reduced thrombin generation increases host susceptibility to group A streptococcal infection. Blood. Epub ahead of print The authors declare no conflict of interest.