COVID-19 and Venous Thromboembolism: From Pathological Mechanisms to Clinical Management

Coronavirus disease 2019 (COVID-19), which is becoming a global pandemic, is caused by SARS-CoV-2 infection. In COVID-19, thrombotic events occur frequently, mainly venous thromboembolism (VTE), which is closely related to disease severity and clinical prognosis. Compared with historical controls, the occurrence of VTE in hospitalized and critical COVID-19 patients is incredibly high. However, the pathophysiology of thrombosis and the best strategies for thrombosis prevention in COVID-19 remain unclear, thus needing further exploration. Virchow’s triad elements have been proposed as important risk factors for thrombotic diseases. Therefore, the three factors outlined by Virchow can also be applied to the formation of venous thrombosis in the COVID-19 setting. A thorough understanding of the complex interactions in these processes is important in the search for effective treatments for COVID-19. In this work, we focus on the pathological mechanisms of VTE in COVID-19 from the aspects of endothelial dysfunction, hypercoagulability, abnormal blood flow. We also discuss the treatment of VTE as well as the ongoing clinical trials of heparin anticoagulant therapy. In addition, according to the pathophysiological mechanism of COVID-19-associated thrombosis, we extended the range of antithrombotic drugs including antiplatelet drugs, antifibrinolytic drugs, and anti-inflammatory drugs, hoping to find effective drug therapy and improve the prognosis of VTE in COVID-19 patients.

Special aspects of intensive care of patients with complicated diverticulosis of the colon

This study presented examination and treatment results of 129 patients with bleeding from the lower gastrointestinal tract who were treated at the Alexandrovskaya Hospital of St. Petersburg in the period from 2012 to 2017. Examination and treatment were performed in the intensive care unit following current clinical guidelines, taking into account the identified concomitant diseases. Endoscopic examination of the colon is the main diagnostic method for the pathological processes that caused bleeding from the lower gastrointestinal tract. Conservative therapy has been demonstrated effectiveness, and urgent surgical treatment was not needed. The main drug therapy included antifibrinolytic drugs and fresh-frozen plasma preparations. Continuous parenteral administration of proteolysis inhibitors was mandatory. Intensive therapy included correction of hemodynamic disturbances and respiratory failure and restoration of the volume of the circulating blood and plasma. Such an approach was found to be 90% effective. In patients with diverticular disease, bleeding from the colonic diverticula develops in one-third of cases. However, if additional risk factors are present, their frequency reaches 50%, often causing death. Continuous or recurrent bleeding is an indication of surgery. In our study, the conservative method of stopping bleeding from the colonic diverticula was possible in all cases. In general, the disease correlated with the age of the patients. In 68 (53%) patients, bleeding occurred despite anticoagulant or antiplatelet therapy. Patients with bleeding from colonic diverticula do not require urgent surgical intervention, and these patients may require admission to the intensive care unit. Intensive care should include the provision of antifibrinolytic drugs, proteolysis inhibitors, and fresh-frozen plasma.

Haematology

This chapter describes the anaesthetic management of the patient with a haematological disorder. Topics covered include anaemia; sickle-cell disease; porphyria; coagulation disorders; haemophilia and related disorders; platelet disorders and hypercoagulability syndromes. For each topic, pre-operative investigation and optimisation, treatment, and anaesthetic management are described. There is detailed discussion about the perioperative management of the patient taking a drug which affects the coagulation system, including anticoagulants, antiplatelet drugs, fibrinolytic and antifibrinolytic drugs. Coagulation tests are discussed in detail, and the haematological management of the bleeding patient is described.

Efficacy and Safety of Antifibrinolytic Drugs in Pediatric Surgery: A Systematic Review

Antifibrinolytic drugs are used to reduce blood loss and subsequent transfusions during surgery and following trauma, but the optimal dosing regimen in the pediatric population is still unresolved. The aim of this systematic review was to evaluate efficacy and safety of antifibrinolytic drugs in pediatric surgery and trauma to determine the optimal dosing regimen. A literature search was performed in PubMed, Embase, Cochrane, and Web of Science on May 3, 2020. We included randomized controlled studies investigating the effect of tranexamic acid (TXA), aprotinin, and epsilon-aminocaproic acid, in terms of reducing blood loss, blood transfusions, reoperations, and rebleeds in pediatric patients aged 0 to 18 years undergoing cardiac surgery, noncardiac surgery, or trauma. Fifty randomized controlled trials (RCTs) were included; 28 RCTs investigated cardiac surgery and 22 investigated noncardiac surgery. No RCTs regarding trauma met the inclusion criteria. All antifibrinolytic drugs reduced postoperative blood loss and transfusions when used in pediatric surgery. The dosing regimen varied between studies, but similar effect sizes were found in terms of reduced blood loss regardless of the cumulative dose used. Few studies found adverse events, and no difference in incidence or type of adverse events was seen between the antifibrinolytic and the placebo group. In conclusion, use of antifibrinolytics is efficient and safe in children undergoing surgery. We propose TXA as the drug of choice based on its level of evidence and safety profile; we recommend a dosing regimen composed of a loading dose of 10 to 15 mg/kg prior to surgery followed by 1 to 5 mg/kg/h as continuous infusion throughout surgery.

Analysis of Ascites-Challenged Blood in Patients with Liver Cirrhosis Using Rotational Thromboelastometry: How Robust Is the Evidence on Ascites-Attributed Fibrinolysis?

Introduction: For over 30 years, ascites has been postulated to facilitate fibrinolysis in patients with liver cirrhosis. In contrast to previous research employing conventional coagulation tests, this study aimed to characterize hemostatic interactions between blood and ascites using the rotational thromboelastometry (ROTEM). Methods: Blood samples – pure or mixed with ascites in a ratio of 1:1 – from cirrhotic patients (n = 10) were subjected to ROTEM analysis. In addition, a negative control group was built with cirrhotic patients (n = 10) whose blood was mixed with physiologic sodium chloride (0.9% NaCl) solution in a ratio of 1:1. Subsequently, ROTEM measurements were subjected to statistical analysis. Results: During ascites challenge, clotting time (CT, measured in seconds) was significantly prolonged in EXTEM (blood: 70.40 ± 20.40 vs. ascites/blood: 109.8 ± 47.7) and APTEM (blood: 66.50 ± 14.55 vs. ascites/blood: 138.7 ± 105.8), likely reflecting a dilution effect. However, CT in INTEM remained unchanged, suggesting a sustained intrinsic pathway function. Maximal clot firmness (measured in millimeters) in FIBTEM decreased significantly (blood: 14.70 ± 9.55 vs. ascites/blood: 6.00 ± 5.66), thus indicating depletion of fibrinogen in ascites. Strikingly, maximum lysis (measured in %) significantly decreased in EXTEM (blood: 9.30 ± 2.79 vs. ascites/blood: 5.50 ± 2.84), APTEM (blood: 8.50 ± 3.10 vs. ascites/blood: 5.60 ± 2.88), and INTEM (blood: 7.50 ± 2.27 vs. ascites/blood: 5.10 ± 3.48). Conclusions: ROTEM provided new evidence that ascites may not primarily induce fibrinolysis in cirrhotic patients. This finding seems to be of significant importance for the clinical management of cirrhotic patients experiencing complications, for example, abdominal hemorrhage after liver biopsy or paracentesis; here, replacement of prothrombin complex concentrates and/or fibrinogen concentrates may prove more beneficial than the use of fresh frozen plasma or antifibrinolytic drugs.

Challenges and Advances in Managing Thrombocytopenic Cancer Patients

Cancer patients have varying incidence, depth and duration of thrombocytopenia. The mainstay of managing severe chemotherapy-induced thrombocytopenia (CIT) in cancer is the use of platelet transfusions. While prophylactic platelet transfusions reduce the bleeding rate, multiple unmet needs remain, such as high residual rates of bleeding, and anticancer treatment dose reductions/delays. Accordingly, the following promising results in other settings, antifibrinolytic drugs have been evaluated for prevention and treatment of bleeding in patients with hematological malignancies and solid tumors. In addition, Thrombopoeitin receptor agonists have been studied for two major implications in cancer: treatment of severe thrombocytopenia associated with myelodysplastic syndrome and acute myeloid leukemia; primary and secondary prevention of CIT in solid tumors in order to maintain dose density and intensity of anti-cancer treatment. Furthermore, thrombocytopenic cancer patients are often prescribed antithrombotic medication for indications arising prior or post cancer diagnosis. Balancing the bleeding and thrombotic risks in such patients represents a unique clinical challenge. This review focuses upon non-transfusion-based approaches to managing thrombocytopenia and the associated bleeding risk in cancer, and also addresses the management of antithrombotic therapy in thrombocytopenic cancer patients.

O1: DISCOVERING NOVEL THERAPEUTICS TO TREAT ACUTE TRAUMATIC COAGULOPATHY (ATC)

Introduction In the UK, 17,000 people die from injury each year, with uncontrolled bleeding the most significant cause of preventable mortality. Acute Traumatic Coagulopathy (ATC) exacerbates bleeding through the failure of blood-clotting with accelerated clot breakdown that mechanistically is driven by activated Protein C (aPC). No targeted therapy to treat the underlying cause of ATC exists with treatment limited to blood component resuscitation and antifibrinolytic drugs to prevent premature clot breakdown. Method Two hundred fifty-four bleeding trauma patients had Factor V and aPC measured on arrival and during resuscitation. A preclinical ATC model was used to test the novel therapeutic recombinant Factor V (rFV), which is resistant to aPC mediated cleavage. Mice underwent combined injury and pressure controlled-blood loss with intervention at 30-minutes to represent a clinically relevant model. Coagulopathy was measured by ROTEM and biomarkers of coagulation/fibrinolysis. Result Admission levels of FV were 38% lower (83 vs 134u/dL, p<0.0001), deteriorated during resuscitation to 65% of normal after transfusion of eight RBC units and were inversely related to aPC levels. Compared to vehicle, animals treated with rFV had reduced coagulopathy (Clot Strength at 5 minutes: 31 vs 24mm, p<0.01) and significantly improved survival (80% vs 44%, p≤ 0.001). Conclusion FV falls significantly during bleeding in trauma patients and in the murine model, rFV improved coagulation suggesting it may represent a potential therapeutic target for ATC. Take-home message Directly targeting the cause of ATC represents a novel therapeutic strategy in trauma and may improve survival after major haemorrhage by directly improving clot function.

In Vivo Assessment of Thermosensitive Liposomes for the Treatment of Port Wine Stains by Antifibrinolytic Site-Specific Pharmaco-Laser Therapy

Antifibrinolytic site-specific pharmaco-laser therapy (SSPLT) is an experimental treatment modality for refractory port wine stains (PWS). Conceptually, antifibrinolytic drugs encapsulated in thermosensitive liposomes are delivered to thrombi that form in semi-photocoagulated PWS blood vessels after conventional laser treatment. Local release of antifibrinolytics is induced by mild hyperthermia, resulting in hyperthrombosis and complete occlusion of the target blood vessel (clinical endpoint). In this study, 20 thermosensitive liposomal formulations containing tranexamic acid (TA) were assayed for physicochemical properties, TA:lipid ratio, encapsulation efficiency, and endovesicular TA concentration. Two candidate formulations (DPPC:DSPE-PEG, DPPC:MPPC:DSPE-PEG) were selected based on optimal properties and analyzed for heat-induced TA release at body temperature (T), phase transition temperature (Tm), and at T > Tm. The effect of plasma on liposomal stability at 37 °C was determined, and the association of liposomes with platelets was examined by flow cytometry. The accumulation of PEGylated phosphocholine liposomes in laser-induced thrombi was investigated in a hamster dorsal skinfold model and intravital fluorescence microscopy. Both formulations did not release TA at 37 °C. Near-complete TA release was achieved at Tm within 2.0–2.5 min of heating, which was accelerated at T > Tm. Plasma exerted a stabilizing effect on both formulations. Liposomes showed mild association with platelets. Despite positive in vitro results, fluorescently labeled liposomes did not sufficiently accumulate in laser-induced thrombi in hamsters to warrant their use in antifibrinolytic SSPLT, which can be solved by coupling thrombus-targeting ligands to the liposomes.