Thromboprophylaxis in Pregnant Women with COVID-19: An Unsolved Issue.

SARS-CoV-2 infection in pregnant women is of growing interest due to controversy over the use of antiplatelet and/or anticoagulant drugs during pregnancy and postpartum. Pregnant women are susceptible to develop severe forms of viral infections due to pregnancy-related immune alterations, changes in lung functions, and hypercoagulability. The association of pregnancy with SARS-CoV-2 infection can cause an increased incidence of thrombotic complications, especially in the case of patients with some genetic variants that favor inflammation and thrombosis. Compared to the general population, pregnant women may be at increased risk of thrombotic complications related to COVID-19. The lack of extensive clinical trials on thromboprophylaxis and extrapolating data from non-pregnant patients lead to major discrepancies in treating pregnant women with COVID-19. Currently, a multidisciplinary team should determine the dose and duration of prophylactic anticoagulant therapy for these patients, depending on the disease severity, the course of pregnancy, and the estimated due date. This narrative review aims to evaluate the protective effect of thromboprophylaxis in pregnant women with COVID-19. It is unknown at this time whether antiplatelet or anticoagulant therapy initiated at the beginning of pregnancy for various diseases (preeclampsia, intrauterine growth restriction, thrombophilia) offers a degree of protection. The optimal scheme for thromboprophylaxis in pregnant women with COVID-19 must be carefully established through an individualized decision concerning gestational age and the severity of the infection.

COVID-19 Coagulopathy: From Pathogenesis to Treatment.

Coronavirus disease 2019 (COVID-19) has emerged as a pandemic at the end of 2019 and continues to exert an unfavorable worldwide health impact on a large proportion of the population. A remarkable feature of COVID-19 is the precipitation of a hypercoagulable state, mainly in severe cases, leading to micro- and macrothrombosis, respiratory failure, and death. Despite the implementation of various therapeutic regimes, including anticoagulants, a large number of patients suffer from such serious complications. This review aims to describe the current knowledge on the pathophysiology of the coagulation mechanism in COVID-19. We describe the interplay between three important mediators of the disease and how this may lead to a hyperinflammatory and prothrombotic state that affects outcome, namely, the endothelium, the immune system, and the coagulation system. In line with the hypercoagulability state during COVID-19, we further review on the rare but severe vaccine-induced thrombotic thrombocytopenia. We also summarize and comment on available anticoagulant treatment options and include suggestions for some future treatment considerations for COVID-19 anticoagulation therapy.

Evaluation of COVID-19 coagulopathy; laboratory characterization using thrombin generation and nonconventional haemostasis assays.

INTRODUCTION: Patients with COVID-19 are known to have a coagulopathy with a thrombosis risk. It is unknown whether this is due to a generalized humoral prothrombotic state or endothelial factors such as inflammation and dysfunction. The aim was to further characterize thrombin generation using a novel analyser (ST Genesia, Diagnostica Stago, Asnières, France) and a panel of haematological analytes in patients with COVID-19. METHODS: Platelet poor plasma of 34 patients with noncritical COVID-19 was compared with 75 patients with critical COVID-19 (as defined by WHO criteria) in a retrospective study by calibrated automated thrombography and ELISA. Patients were matched for baseline characteristics of age and gender. RESULTS: Critical patients had significantly increased fibrinogen, CRP, interleukin-6 and D-dimer compared to noncritical patients. Thrombin generation, in critical patients, was right shifted without significant differences in peak, velocity index or endogenous thrombin potential. Tissue plasminogen activator (tPA), tissue factor pathway inhibitor (TFPI) and vascular endothelial growth factor (VEGF) were significantly increased in the critical versus noncritical patients. Critically ill patients were on haemodiafiltration (31%; heparin used in the circuit) or often received escalated prophylactic low-molecular weight heparin. CONCLUSION: These results confirm increased fibrinogen and D-dimer in critical COVID-19-infected patients. Importantly, disease severity did not increase thrombin generation (including thrombin-antithrombin complexes and prothrombin fragment 1 + 2) when comparing both cohorts; counter-intuitively critical patients were hypocoaguable. tPA, TFPI and VEGF were increased in critical patients, which are hypothesized to reflect endothelial dysfunction and/or contribution of heparin (which may cause endothelial TFPI/tPA release).

COVID-19-associated coagulopathy and disseminated intravascular coagulation.

The pathology of coronavirus disease 2019 (COVID-19) is exacerbated by the progression of thrombosis, and disseminated intravascular coagulation (DIC), and cytokine storms. The most frequently reported coagulation/fibrinolytic abnormality in COVID-19 is the increase in D-dimer, and its relationship with prognosis has been discussed. However, limits exist to the utility of evaluation by D-dimer alone. In addition, since the coagulation/fibrinolytic condition sometimes fluctuates within a short period of time, regular examinations in recognition of the significance of the examination are desirable. The pathophysiology of disseminated intravascular coagulation (DIC) associated with COVID-19 is very different from that of septic DIC, and both thrombotic and hemorrhagic pathologies should be noted. COVID-19 thrombosis includes macro- and microthrombosis, with diagnosis of the latter depending on markers of coagulation and fibrinolysis. Treatment of COVID-19 is classified into antiviral treatment, cytokine storm treatment, and thrombosis treatment. Rather than providing uniform treatment, the treatment method most suitable for the severity and stage should be selected. Combination therapy with heparin and nafamostat is expected to develop in the future. Fibrinolytic therapy and adsorption therapy require further study.

Complement activation and coagulopathy - an ominous duo in COVID19.

INTRODUCTION: COVID-19 has similarities to the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks, as severe patients and non-survivors have frequently shown abnormal coagulation profiles. Immune-mediated pathology is a key player in this disease; hence, the role of the complement system needs assessment. The complement system and the coagulation cascade share an intricate network, where multiple mediators maintain a balance between both pathways. Coagulopathy in COVID-19, showing mixed features of complement-mediated and consumption coagulopathy, creates a dilemma in diagnosis and management. AREAS COVERED: Pathophysiology of coagulopathy in COVID-19 patients, with a particular focus on D-dimer and its role in predicting the severity of COVID-19 has been discussed. A comprehensive search of the medical literature on PubMed was done till May 30th, 2020 with the keywords 'COVID-19', 'SARS-CoV-2', 'Coronavirus', 'Coagulopathy', and 'D-dimer'. Twenty-two studies were taken for weighted pooled analysis of D-dimer. EXPERT OPINION: A tailored anticoagulant regimen, including intensification of standard prophylactic regimens with low-molecular-weight heparin is advisable for COVID-19 patients. Atypical manifestations and varying D-dimer levels seen in different populations bring forth the futility of uniform recommendations for anticoagulant therapy. Further, direct thrombin inhibitors and platelet inhibitors in a patient-specific manner should also be considered.

Coronavirus-induced coagulopathy during the course of disease.

BACKGROUND: A significant proportion of patients with coronavirus disease 19 (COVID-19) suffer from excessive coagulation activation and coagulopathy which is associated with an increased risk of venous and arterial thromboembolism and adverse outcome. Our study investigates coagulation markers and the incidence of thromboembolic events in COVID-19 patients receiving recommended anticoagulation strategies. METHODS: In a retrospective single-center analysis at the University Hospital Zurich, Switzerland, we investigated 31 adult COVID-19 patients between April 6th and May 13th, 2020 and with at least one laboratory assessment of the coagulation markers prothrombin time/Quick, thrombin time, fibrinogen and D-dimers. For antithrombotic prophylaxis low-molecular-weight-heparin or unfractionated heparin was administered and two patients with heparin-induced thrombocytopenia received argatroban. RESULTS: We analyzed 31 patients (68% male, mean age 60± SD 15 years). 22 (71%) of these required intensive care unit treatment, 5 (16%) were hospitalized in a ward, and 4 (13%) were outpatients. Mean fibrinogen levels were markedly elevated to 6.4± SD 1.8g/l, with a peak in the third week of the disease and no significant decrease over time. D-dimers were elevated to a mean value of 5.1±4.4mg/l with peak levels of 6.8±5.3mg/l in the fourth week of disease, and a subsequent decrease. Platelet count (308±136G/l) and PT/Quick (85±22%) showed no significant changes over time. Sensitivity analyses for patients treated in the ICU showed that D-dimer levels were higher in this group. The results of other sensitivity analyses were comparable. Thromboembolic events were diagnosed in 4 (13%) patients and 5 (16%) patients died during the observation period. CONCLUSION: We find coagulation alterations in COVID-19 patients indicating significant hypercoagulability. These alterations are visible despite antithrombotic treatment, and peak around week 3-4 of the disease.

Clinical outcomes and risk factors for severe COVID-19 in patients with haematological disorders receiving chemo- or immunotherapy.

Haematology patients receiving chemo- or immunotherapy are considered to be at greater risk of COVID-19-related morbidity and mortality. We aimed to identify risk factors for COVID-19 severity and assess outcomes in patients where COVID-19 complicated the treatment of their haematological disorder. A retrospective cohort study was conducted in 55 patients with haematological disorders and COVID-19, including 52 with malignancy, two with bone marrow failure and one immune-mediated thrombotic thrombocytopenic purpura (TTP). COVID-19 diagnosis coincided with a new diagnosis of a haematological malignancy in four patients. Among patients, 82% were on systemic anti-cancer therapy (SACT) at the time of COVID-19 diagnosis. Of hospitalised patients, 37% (19/51) died while all four outpatients recovered. Risk factors for severe disease or mortality were similar to those in other published cohorts. Raised C-reactive protein at diagnosis predicted an aggressive clinical course. The majority of patients recovered from COVID-19, despite receiving recent SACT. This suggests that SACT, where urgent, should be administered despite intercurrent COVID-19 infection, which should be managed according to standard pathways. Delay or modification of therapy should be considered on an individual basis. Long-term follow-up studies in larger patient cohorts are required to assess the efficacy of treatment strategies employed during the pandemic.

Lower limb deep vein thrombosis in COVID-19 patients admitted to intermediate care respiratory units.

COVID-19 has been associated with an increased risk of thrombotic events; however, the reported incidence of deep vein thrombosis varies depending, at least in part, on the severity of the disease. Aim of this prospective, multicenter, observational study was to investigate the incidence of lower limb deep vein thrombosis as assessed by compression ultrasound in consecutive patients admitted to three pulmonary medicine wards designated to care for patients with COVID-19 related pneumonia, with or without respiratory failure but not requiring admission to an intensive care unit. Consecutive patients admitted between March 27 and May 6, 2020 were enrolled. Patients were excluded if they were less than 18-year-old or if compression ultrasound could not be performed for any reason. Patients were assessed at admission (t0) and after 7 days (t1). Major and non-major clinically relevant bleedings were recorded. Sixty-eight patients were enrolled. Two were excluded due to anatomical abnormalities that prevented compression ultrasound; sixty patients were retested at (t1). All patients were started on antithrombotic prophylaxis, unless therapeutic anticoagulation was required. Deep vein thrombosis as assessed by compression ultrasound was observed in 2 patients (3%); one of them was later deemed to represent a previous episode. No new episodes were detected at t1. One major and 2 non-major clinically relevant bleedings were observed. In the setting of patients with COVID-related pneumonia not requiring admission to an intensive care unit, the incidence of deep vein thrombosis is low and our data support not screening asymptomatic patients.

COVID-19-associated coagulopathy and disseminated intravascular coagulation.

The pathology of coronavirus disease 2019 (COVID-19) is exacerbated by the progression of thrombosis, and disseminated intravascular coagulation (DIC), and cytokine storms. The most frequently reported coagulation/fibrinolytic abnormality in COVID-19 is the increase in D-dimer, and its relationship with prognosis has been discussed. However, limits exist to the utility of evaluation by D-dimer alone. In addition, since the coagulation/fibrinolytic condition sometimes fluctuates within a short period of time, regular examinations in recognition of the significance of the examination are desirable. The pathophysiology of disseminated intravascular coagulation (DIC) associated with COVID-19 is very different from that of septic DIC, and both thrombotic and hemorrhagic pathologies should be noted. COVID-19 thrombosis includes macro- and microthrombosis, with diagnosis of the latter depending on markers of coagulation and fibrinolysis. Treatment of COVID-19 is classified into antiviral treatment, cytokine storm treatment, and thrombosis treatment. Rather than providing uniform treatment, the treatment method most suitable for the severity and stage should be selected. Combination therapy with heparin and nafamostat is expected to develop in the future. Fibrinolytic therapy and adsorption therapy require further study.

Management of Acute Kidney Injury in Coronavirus Disease 2019.

Acute kidney injury is a common complication in hospitalized patients with coronavirus disease 2019. Similar to acute kidney injury associated with other conditions such as sepsis and cardiac surgery, morbidity and mortality are much higher in patients with coronavirus disease 2019 who develop acute kidney injury, especially in the intensive care unit. Management of coronavirus disease 2019-associated acute kidney injury with kidney replacement therapy should follow existing recommendations regarding modality, dose, and timing of initiation. However, patients with coronavirus disease 2019 are very hypercoagulable, and close vigilance to anticoagulation strategies is necessary to prevent circuit clotting. During situations of acute surge, where demand for kidney replacement therapy outweighs supplies, conservative measures have to be implemented to safely delay kidney replacement therapy. A collaborative effort and careful planning is needed to conserve dialysis supplies, to ensure that treatment can be safely delivered to every patient who will benefit for kidney replacement therapy.

Coronavirus Disease 2019: Hematological Anomalies and Antithrombotic Therapy.

After the first cases of COVID-19 appeared in Wuhan, China at the end of 2019, the disease quickly become a pandemic that has seriously affected the economic and health systems in more than 200 countries and territories around the world. Although most patients have mild symptoms or are even asymptomatic, there are patients who can develop serious complications such as acute respiratory distress syndrome or venous thromboembolism requiring mechanical ventilation and intensive care. Hence, it is important to identify patients with a higher risk of complications in a timely manner. Thus, the objective of this paper is to review the hematological laboratory parameters that consistently are altered in COVID-19 and to identify their relationship with the severity of the disease. According to 11 selected reports, the frequency of patients aged > 65 years is higher among subjects severely affected or deceased; likewise, males predominantly suffer from comorbidities such as hypertension, diabetes or obesity. Retrospective studies have identified alterations in various hematological and inflammatory parameters as part of the host's response to infection and a secondary increased risk of different thrombotic events. Among these altered parameters, D-dimer, C-reactive protein, and interleukin-6 have been tested as prognostic biomarkers due to their close relationship with the severity of the disease. Actually, they can reliably indicate the use of antithrombotic therapy at prophylactic or therapeutic doses (mainly D-dimer), as has already been established in those patients who, after an individualized assessment, appear to be at high risk for thrombotic events.

Acute Lower Limb Ischemia as Clinical Presentation of COVID-19 Infection.

Novel 2019 coronavirus (COVID-19) infection usually causes a respiratory disease that may vary in severity from mild symptoms to severe pneumonia with multiple organ failure. Coagulation abnormalities are frequent, and reports suggest that COVID-19 may predispose to venous and arterial thrombotic complications. We report a case of acute lower limb ischemia and resistance to heparin as the onset of COVID-19 disease, preceding the development of respiratory failure. This case highlights that the shift of coagulation profile toward hypercoagulability was associated with the acute ischemic event and influenced the therapy.