key: cord-1001882-v5igmg3u authors: Gómez-Mesa, Juan Esteban; Galindo-Coral, Stephania; Montes, Maria Claudia; Martin, Andrés J. Muñoz title: THROMBOSIS AND COAGULOPATHY IN COVID-19 date: 2020-11-02 journal: Curr Probl Cardiol DOI: 10.1016/j.cpcardiol.2020.100742 sha: da6d797f6cd6114214dd9f439dd0042f5ecf41fe doc_id: 1001882 cord_uid: v5igmg3u Since December 2019, an outbreak of coronavirus disease 2019 (COVID-19) which initially occurred in the city of Wuhan, located in China's Hubei province, spread around the world and on 11 March 2020, the World Health Organization declared the new Coronavirus disease 2019 (COVID-19) as a pandemic. The presence of comorbidities (e.g.: cardiovascular disease, obesity), SIC score> 4, elevation of D-dimer (> 6 times the normal value), C-reactive protein, troponins and other DIC markers; is associated to a worse prognosis in hospitalized patients with severe COVD-19, reaching a hospital mortality of 42%. Initial anticoagulant treatment with LMWH has been shown to reduce mortality by 48% at 7 days and 37% at 28 days and achieve a significant improvement in the arterial oxygen pressure / inspired fraction of O2 (PaO2 / FiO2) by mitigating the formation of microthrombi and associated pulmonary coagulopathy. This respiratory viral infection produces the COVID-19, which is generally asymptomatic or with mild symptoms including fever, cough, fatigue, dyspnea, diarrhea, headache and myalgia (up to 81.4% of patients). Severe cases are characterized by respiratory rate> 30 bpm, arterial oxygen saturation <93% at rest, PaO2 / FiO2 <300 mmHg and / or infiltrates in > 50% of lung fields in 24-48 hours (up to 13.9% of patients) and can progress to critically ill patients (up to 4.7% of patients), presenting rapid deterioration and development of acute respiratory distress syndrome (ARDS), septic shock, metabolic acidosis and coagulopathy, including disseminated intravascular coagulation (DIC) and cytokine storm (2, 4 , 7, 8, 9, 10, 11, 12, 13) . These clinical manifestations, as well as the imaging and paraclinical alterations, vary as the pandemic evolves worldwide, and they also depend on the severity of the infection. A registry of 1,099 laboratory-confirmed COVID-19 patients in 552 institutions in 30 provinces of China described some of these most frequent and relevant findings, observed in the first two months of this pandemic (Table # 1) (8) . The most consistent hemostatic alterations with COVID-19 are thrombocytopenia and elevation of D-dimer, which are associated with a higher requirement for mechanical ventilation (MV), admission to intensive care, and death. It has been described that older patients and those with comorbidities have a higher risk of in-hospital mortality, and in these two groups of patients there are also higher levels of D-dimer. Taking into account the clinical implications of the elevated D-dimer value or the marked elevations during follow-up (3 -4 times) , hospital management can be considered in this setting in the absence of other severe symptoms since this indicates an increase in thrombin generation and a greater risk of complications (Table # 2 and # 3) (14 , 15, 16) . In hospitalized patients for suspected or confirmed COVID-19, a coagulation profile should be performed, including D-dimer, PT, PTT, platelet count, and fibrinogen. Alterations in these parameters can occur 7-11 days after the onset of symptoms or 4-10 days after hospitalization. Repeating these coagulopathy parameters (D-dimer, prothrombin time, and platelet count) are recommended in patients with severe COVID-19, at least every 2 -3 days (6, 15) . The combination of thrombocytopenia, prolonged PT, and elevated D-dimer suggests DIC, however, its presentation is different from the presentation seen in sepsis, where thrombocytopenia is much more profound and the elevation of D-dimer does not reach the values observed in COVID-19 cases. Current evidence suggests COVID-19 associated coagulopathy is a combination of low-grade DIC and pulmonary thrombotic microangiopathy, which could have a significant impact on organ dysfunction in most patients with severe disease (14) . The presence of coagulopathy as part of the systemic inflammatory response syndrome is a common feature of severe COVID-19. Approximately 20% to 50% of hospitalized patients with COVID-19 have hematologic changes in coagulation tests (elevated D-dimer, prolonged PT, thrombocytopenia, and / or low fibrinogen levels). This condition is characterized by more thrombotic than hemorrhagic events that are associated with coagulopathy (specifically VTE). On the other hand, endothelial dysfunction results in high levels of D-dimer, thrombin and fibrin degradation products, thrombocytopenia and prolonged clotting times, which leads to hypoxia and pulmonary congestion mediated by thrombosis and microvascular occlusion, in addition to thrombosis of central lines and catheters and vascular occlusive events (cerebrovascular events, limb ischemia, etc.) that generally occur in the intensive care units (6, 10, 15, 17, 18, 19) . Fibrin and thrombin deposition occurs mainly in the pulmonary microvasculature, being a factor that contributes to ARDS and coagulopathy in patients who die from COVID-19. Furthermore, the hypoxia that occurs in severe COVID-19 can aggravate thrombosis not only by increasing the viscosity of the blood, but also through the hypoxia -inducible transcription factor-dependent signaling pathway (10, 17, 20) . Similar to the endothelial dysfunction of SIC, in which there is excessive thrombin generation and impaired fibrinolysis, there is a type of endotheliopathy that appears to contribute to the pathophysiology of microcirculatory changes in SARS-CoV-2 infection. IL-6 induces expression of tissue factor in macrophages, which initiates the activation of coagulation and generation of thrombin. Tumor necrosis factor and IL-1 are the main mediators of the suppression of the endogenous coagulation cascade. In a group of severely compromised COVID-10 patients, a cytokine storm characterized by high concentrations of pro-inflammatory cytokines and chemokines may be found (12, 14) . The ISTH proposed a new category to identify an early stage of DIC associated with sepsis, which is called SIC. This score can be applied to COVID-19 patients, and those who meet these criteria benefit from anticoagulant management ( Table # 4 are several studies that support the increased incidence of VTE in COVID-19 patients and their risk factors (13, 21, 23, 24, 25) (Table #5 ). Other study found that the proportion of patients with VTE was higher in the ICU patients (47%; 95% CI, 36-58) than in the general ward patients (3.3%; 95% CI, 1.3-8.1) ( Table # 6 ); the risk factors for VTE that were identified include ICU hospitalization, higher leukocyte count, higher neutrophil / lymphocyte ratio, and higher D-dimer value (25) . In patients with sudden deterioration in oxygen saturation, respiratory distress, low blood pressure, or right ventricular dysfunction, the possibility of PE should be considered. Diagnosis can be difficult as COVID-19 patients may have an elevated D-dimer value even in the absence of VTE. Imaging studies cannot be done routinely due to the risk of transmission of the infection, the limitations to transfer and the clinical instability that the patient could present at any given time. In these cases, and taking into account the value of D-dimer, the use of anticoagulants at therapeutic, intermediate doses or as prophylaxis could be considered. The use of tests at the patient side, such as compression ultrasonography for the diagnosis of DVT and echocardiography to evaluate RV strain associated with PE, can be difficult in unstable, prone, or critically ill patients ; also, without having sufficient specificity and sensitivity to diagnose VTE, in certain clinical scenarios they can increase the index of clinical suspicion, and its use may be considered (1, 25) . Hospitalized patients with COVID-19 present similar intrinsic and extrinsic risk factors for VTE to the rest of the hospitalized population, such as advanced age, obesity, immobilization, neurological events, cancer, ICU management, previous thromboembolic events or thrombophilia, however, prophylactic management in this population is currently a challenge (25) . Pharmacological thromboprophylaxis should then be considered in all hospitalized COVID-19 patients who are immobilized or severely ill, unless there are contraindications (such as active bleeding or severe thrombocytopenia). Different scales can be used to assess this hospital risk (Padua, Caprini, IMPROVE). The dose should be adjusted according to renal function. Although drug selection should be guided by available institutional protocols, the World Health Organization recommends the use of unfractionated or low molecular weight heparins and, if contraindicated, mechanical thromboprophylaxis should be considered. Pharmacological thromboprophylaxis is recommended once a day, since it reduces the risk of missing additional doses and is also associated with less exposure of health personnel for its administration. If LMWH is not available, unfractionated heparin can be considered, keeping in mind that this requires more frequent injections and, therefore, greater exposure of health personnel. Fondaparinux can also be considered, but there is no evidence that this molecule has the same anti-inflammatory properties as heparins. Patients with more severe infections may require higher doses of thromboprophylaxis due to their hypercoagulable state. The use of direct anticoagulants in thromboprophylaxis is not recommended in this context due to the possible drug interactions that may occur with the different drugs and therapies available and under investigation for the treatment of COVID-19 (4, 14, 15, 25) . Some of the non-anticoagulant properties of LMWH include the potential for binding to inflammatory cytokines, inhibition of neutrophil chemotaxis and leukocyte migration, neutralization of positively charged complement factor C5a, and sequestration of acute phase proteins (12, 26) . Regarding the above, it is suggested that LMWH administered in the early stages of SARS-CoV2 infection can exert a positive effect not only in terms of preventing thrombosis but also reducing systemic and pulmonary inflammation and limiting viral invasion (7, 13) .Other non-anticoagulant actions of heparin include its antiviral role (experimental models), decreased collagen deposits and antiarrhythmic properties (animal models), as well as modulation of endothelial dysfunction, improvement of microvascular dysfunction, and mitigation of pulmonary coagulopathy (26 , 27) . In patients who remain completely immobilized, there may be an additional benefit with intermittent pneumatic compression in addition to drug thromboprophylaxis. This therapy should also be considered if there is severe thrombocytopenia (platelets <25,000 to 50,000 x 10⁹ / L) (2, 25, 28, 29) . The use of extended ambulatory thromboprophylaxis (from 14 to 45 days) should be considered in patients at high risk of venous thromboembolism, independent of COVID-19 infection, and that includes reduced mobility, previous thromboembolic events, comorbidities (e.g.: active cancer) and Elevated D-dimer (> 2 times normal value). Thromboprophylaxis for patients who are quarantined for mild COVID-19, but with significant comorbidities, or patients without COVID-19 but who are functionally severely limited by quarantine is not recommended. These patients should be advised to remain active at home (1, 2, 25). The presence of comorbidities (e.g.: cardiovascular disease, obesity), SIC score> 4, elevation of D-dimer (> 6 times the normal value), C-reactive protein, troponins and other DIC markers; (Table # 4 ) is associated to a worse prognosis in hospitalized patients with severe COVD-19, reaching a hospital mortality of 42% (25) . In this population, initial anticoagulant treatment with LMWH has been shown to reduce mortality by 48% at 7 days and 37% at 28 days and achieve a significant improvement in the arterial oxygen pressure / inspired fraction of O2 (PaO2 / FiO2) by mitigating the formation of microthrombi and associated pulmonary coagulopathy, also decreasing complementary inflammation (26, 30, 31) . The selected drug depends on kidney and liver function, platelet count, and gastrointestinal function. Parenteral anticoagulation is recommended in critically ill patients, as it can be temporarily suspended and has no interactions with drugs considered for the treatment of COVID-19. Given the exposure of health personnel with the use of unfractionated heparin by taking paraclinics and dose adjustment, the use of low molecular weight heparins is preferred in these patients. The benefits of DOACs include no need for routine monitoring and easy outpatient management, however, potential risks may include their use in the presence of clinical deterioration and the lack of availability of a reversal agent in all institutions. In patients who are going to be discharged, the use of DOACs and LMWH should be preferred, avoiding frequent tests for INRs. The potential for drug interactions with potential treatments for COVID-19 should always be evaluated (1, 5, 7, 14, 18) (Table #8) . A 30-50% decrease in platelet count from the start of heparin treatment (4 to 14 days) should suggest heparin-induced thrombocytopenia. 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