Coagulation System Activation for Targeting of COVID-19: Insights into Anticoagulants, Vaccine-Loaded Nanoparticles, and Hypercoagulability in COVID-19 Vaccines.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as COVID-19, is currently developing into a rapidly disseminating and an overwhelming worldwide pandemic. In severe COVID-19 cases, hypercoagulability and inflammation are two crucial complications responsible for poor prognosis and mortality. In addition, coagulation system activation and inflammation overlap and produce life-threatening complications, including coagulopathy and cytokine storm, which are associated with overproduction of cytokines and activation of the immune system; they might be a lead cause of organ damage. However, patients with severe COVID-19 who received anticoagulant therapy had lower mortality, especially with elevated D-dimer or fibrin degradation products (FDP). In this regard, the discovery of natural products with anticoagulant potential may help mitigate the numerous side effects of the available synthetic drugs. This review sheds light on blood coagulation and its impact on the complication associated with COVID-19. Furthermore, the sources of natural anticoagulants, the role of nanoparticle formulation in this outbreak, and the prevalence of thrombosis with thrombocytopenia syndrome (TTS) after COVID-19 vaccines are also reviewed. These combined data provide many research ideas related to the possibility of using these anticoagulant agents as a treatment to relieve acute symptoms of COVID-19 infection.

A clinical coagulopathy score concurrent with viscoelastic testing defines opportunities to improve hemostatic resuscitation and enhance blood product utilization during liver transplantation.

BACKGROUND: An NIH clinical coagulopathy score has been devised for trauma patients, but no such clinical score exists in transplantation surgery. We hypothesize that that this coagulopathy score can effectively identify laboratory defined coagulopathy during liver transplantation and correlates to blood product utilization. METHODS: TEGs were performed and coagulopathy scores (1, normal bleeding - 5, diffuse coagulopathic bleeding) were assigned by the surgeons at 5 intra-operative time points. Blood products used during the case were recorded between time points. Statistical analyses were performed to identify correlations between coagulopathy scores, TEG-detected abnormalities, and blood product utilization. RESULT: Transfusions rarely correlated with the appropriate TEG measurements of coagulation dysfunction. Coagulopathy score had significant correlation to various transfusions and TEG-detected coagulopathies at multiple points during the case. High aggregate coagulopathy scores identified patients receiving more transfusions, re-operations, and longer hospital stays CONCLUSION: The combination of viscoelastic testing and a standardized clinical coagulopathy score has the potential to optimize transfusions if used in tandem as well as standardize communication between surgery and anesthesia teams about clinically evident coagulopathy.

Manifestaciones orales de trastornos hematológicos no neoplásicos / Oral manifestations of non-neoplastic hematologic disorders

Las alteraciones hematológicas pueden tener el primer signo en la cavidad oral y los signos varían dependiendo de la línea celular que se encuentre afectada: eritrocitos, leucocitos y plaquetas. La formación de las células sanguíneas se lleva a cabo en la médula ósea a través de un proceso denominado hematopoyesis que se encarga de la formación, desarrollo y especialización de todas sus células sanguíneas funcionales, pasan de células troncales pluripotenciales a células hematopoyéticas maduras que emergen a la sangre periférica. El odontólogo debe ser capaz de identificar los distintos signos en la cavidad oral que podrían sugerir que el paciente padece un trastorno hematológico, el cual podría complicar el tratamiento dental. La identificación oportuna de estos signos a través de una minuciosa exploración física y la historia clínica completa evita que se presenten complicaciones en el paciente y que éstas puedan poner en riesgo su vida, por lo que al encontrar algún signo sugerente de un trastorno hematológico debe referirse al paciente con el hematólogo (AU)

Hematological alterations may be the first sign in the oral cavity and symptoms vary depending on the cell line that is affected: Erythrocytes, leukocytes and platelets. The formation of blood cells are held in the bone marrow through a process called hematopoiesis, which is responsible for training, development and specialization in all its functional blood cells, they move from pluripotent stem cell to hematopoietic cells mature emerging to peripheral blood. The dentist must be able to identify the different signs in the oral cavity that could suggest that the patient has a haematological disorder, which could complicate dental treatment. The timely identification of these signs through a thorough physical examination and the complete clinical history prevents complications from occurring in the patient and may put their lives at risk, so when finding any sign suggestive of a hematological disorder should refer to the patient with the hematologist (AU)

Orientació diagnòstica dels trastorns de la coagulació en pediatria / No disponible

No disponible

The International Normalized Ratio overestimates coagulopathy in stable trauma and surgical patients.

BACKGROUND: The international normalized ratio (INR) was developed to assess adequacy of Coumadin dosing. Its use has been generalized to guide fresh frozen plasma (FFP) therapy in stable patients. Thrombelastography (TEG) is a whole-blood assay measuring the viscoelastic properties of the clot in near real time. This study hypothesized that INR does not reflect coagulopathy and should not be used to guide FFP therapy in stable trauma and surgical patients. METHODS: Prospective observational data were collected from stable trauma and surgical patients (n = 106) who received FFP transfusions. Pretransfusion and posttransfusion blood samples were obtained to assess complete blood count, standard coagulation parameters (INR, partial thromboplastin time, fibrinogen and D-dimer), soluble clotting factors (II, V, VII, VIII, IX, X, XI, XII, proteins C and S) and TEG. Data were analyzed using a Mann-Whitney U-test. Significance was defined as p < 0.05. RESULTS: A total of 262 U of FFP were transfused, with 78% of 106 patients receiving two or more units. Despite a reduction in INR, median TEG values remained within normal limits, while clotting factor levels retained adequate function to produce normal clotting before and following FFP transfusion. CONCLUSION: The use of FFP in this population did not affect coagulation status in a clinically relevant manner based on TEG values and coagulation factor function. INR is not a predictor of coagulopathy and should not be used to guide coagulation factor replacement in stable trauma and surgical patients. LEVEL OF EVIDENCE: Diagnostic study, level III.

Rare bleeding disorders: worldwide efforts for classification, diagnosis, and management.

Rare bleeding disorders (RBDs) comprise the inherited deficiencies of coagulation factors such as fibrinogen, factor (F)II, FV, FV + FVIII, FVII, FX, FXI, and FXIII, and are usually transmitted as autosomal recessive disorders. RBDs are characterized by a wide variety of symptoms from mild to severe; however, due to their rarity, only little information is available on the adequate management of patients affected with these deficiencies. Moreover, the limitations of laboratory assays and the lack of a definitive consensus concerning their classification have prevented adoption of optimal approaches to their individual management. To overcome these limitations, new strategies are therefore necessary, such as the establishment of global collaborations and networks among treatment centers, as well as increasing support provided by public health organizations.

Approach to a child with bleeding in the emergency room.

A bleeding child is a cause of great concern and often, panic, for parents and pediatricians alike. Causes of bleeding could be trivial or secondary to an underlying bleeding disorder or a potentially serious systemic illness. Based on etiology, they can be categorized into disorders affecting platelets or the coagulation cascade and can be inherited or acquired. A systematic approach with relevant clinical history and examination along with appropriate laboratory investigations aid in reaching the diagnosis promptly. Indication and administration of blood products including fresh frozen plasma, cryoprecipitate, random donor and single donor apheresis platelets is elaborated. Management of hemophilia, Von Willebrand disease, disseminated intravascular coagulation and bleeding in cyanotic congenital heart disease, among other causes is outlined. Role of antifibrinolytic therapy, desmopressin and recombinant factor VIIa is briefly described. The review outlines the approach to a bleeding child in the emergency room. Practical points in history, examination, investigations and management are discussed. Management in resource constraint setting of developing countries is addressed.

[Trauma-associated bleeding in the severely injured. Relevance, risk stratification and current therapy approaches]. / Traumaassoziierte Blutung beim Schwerverletzten. Relevanz, Risikostratifizierung und aktuelle Therapieansätze.

Of all trauma-related deaths 40% are due to exsanguination. The causes for acute, hemorrhaging are uncontrolled bleeding sources and the development of acute posttraumatic coagulopathy. Clinical observations and recent research results emphasize the key role of this disorder in acute trauma care. The present synopsis summarizes the results from different analyses based on datasets from severely injured patients derived from the Trauma Register of the German Trauma Society (DGU) on frequency, potential triggers and strategies to manage acute posttraumatic coagulopathy. In an extension to this work a clinical scoring system for early identification of patients at high risk for ongoing bleeding is presented. High risk patients seem to benefit from a more balanced transfusion regimen.

Hypercoagulable state, pathophysiology, classification and epidemiology.

Hypercoagulable state is not a uniform disease. It is a complex condition with an abnormal propensity for thrombosis that may or may not lead to thrombosis, depending on complex gene-gene and gene-environment interactions. The prevalence of the hypercoagulable state depends on the ethnicity and clinical history of the population being studied. The consequences of a hypercoagulable state due to thrombosis of veins and arteries are the most important cause of sickness and death in developed countries at present. Primary hypercoagulable state is an inherited condition caused by the reduced level of natural anticoagulants due to a qualitative defect or quantitative deficiency of an antithrombotic protein, or increased concentrations or function of coagulation factors. Most of the inherited abnormalities recognized to date have little or no effect on arterial thrombosis and are associated primarily with venous thromboembolism. Arterial thrombosis usually develops as a complication of atherosclerosis and patients usually have more than one traditional risk factor. Secondary hypercoagulable states generally occur as a result of a large number of transient or permanent acquired conditions that increase the tendency for formation of blood clots. New epidemiological data and clinical trials suggest that many acquired risk factors in the pathophysiology of arterial and venous thrombosis overlap and coexist for both disorders.

Comparison of the rates of joint arthroplasty in patients with severe factor VIII and IX deficiency: an index of different clinical severity of the 2 coagulation disorders.

Data from the Italian Hemophilia Centres were collected to perform a retrospective survey of joint arthroplasty in patients with severe hemophilia. Twenty-nine of 49 hemophilia centers reported that 328 of the 347 operations were carried out in 253 patients with severe hemophilia A (HA) and 19 in 15 patients with severe hemophilia B (HB). When results were normalized to the whole Italian hemophilia population (1770 severe HA and 319 severe HB), patients with HA had a 3-fold higher risk of undergoing joint arthroplasty (odds ratio [OR], 3.38; 95% confidence interval [CI], 1.97-5.77; P < .001). These results were confirmed after adjustment for age, HIV, hepatitis C virus (HCV), and inhibitor in a Cox regression model (HR, 2.65; 95% CI, 1.62-4.33; P < .001). The survival analysis of time to joint arthroplasty in the subset of patients with severe HA was not affected by the severity of factor VIII (FVIII) gene mutations. A systematic review of literature articles reporting joint arthroplasties in HA and HB showed that the proportion of HA patients who had undergone arthroplasties was higher than that of HB patients, in agreement with the findings in our Italian cohort. These data suggest that the 2 inherited coagulation disorders have a different severity of clinical phenotype.

Pediatric otolaryngologic manifestations of bleeding disorders.

OBJECTIVE: In 1930, considering the diseases of the blood and lymphatic glands in relation to otolaryngology, Goldsmith and McGregor stated that "... the otolaryngologist has frequently to deal with bleeding from the nose and throat ...". After approximately 8 decades, in particular preoperatively, the use of universal coagulation screening in children is still controversial. Aim of the present review was to offer a concise but complete discussion of clotting disorders with pediatric otolaryngological interest recognizing: (i) vascular disorders, (ii) platelet disorders, (iii) disorders of coagulation, and (iv) thrombosis. METHODS: An exhaustive review of literature was performed to investigate available data and evidences regarding pediatric otolaryngologic manifestations of bleeding disorders. RESULTS/CONCLUSIONS: Modern otolaryngologists should be familiar with common bleeding disorders since many have head and neck manifestations. This knowledge allows the choice of appropriate pre-operative screening of surgical patients. The most important component of the preoperative assessment is the bleeding history that directs further laboratory evaluation. All otolaryngologic surgical procedures in children with bleeding disorders should be carried out with the close co-operation of the Haematology Department.

Plasminogen deficiency.

Plasminogen (plg) deficiency has been classified as (i) hypoplasminogenemia or 'true' type I plg deficiency, and (ii) dysplasminogenemia, also called type II plg deficiency. Both forms, severe hypoplasminogenemia and dysplasminogenemia, are not causally linked to venous thrombosis. Dysplasminogenemia does not lead to a specific clinical manifestation and probably represents only a polymorphic variation in the general population, mainly in Asian countries. Severe hypoplasminogenemia is associated with compromised extracellular fibrin clearance during wound healing, leading to pseudomembraneous (ligneous) lesions on affected mucous membranes (eye, middle ear, mouth, pharynx, duodenum, upper and lower respiratory tract and female genital tract). Ligneous conjunctivitis is by far the most common clinical manifestation. More than 12% of patients with severe hypoplasminogenemia exhibit congenital occlusive hydrocephalus. In milder cases of ligneous conjunctivitis, topical application of plg-containing eye drops, fresh frozen plasma, heparin, corticosteroids or certain immunosuppressive agents (such as azathioprine) may be more or less effective. Oral treatment with sex hormones was successful in two female patients with ligneous conjunctivitis. In severe cases with possibly life-threatening multi-organ involvement, true therapeutic options are not available at present. The plg-knockout mouse is a useful tool to study the many different properties of plg in a variety of settings, such as wound healing, tissue repair and tissue remodeling, virulence and invasiveness of certain bacteria in the human host, tumor growth and dissemination, as well as arteriosclerosis.

Critical care clotting catastrophies.

Coagulation problems are very common in intensive care patients. It is important to recognize potential problems, perform a rapid assessment, and start therapy. The author reviews general clinical and laboratory approaches to diagnosis and treatment of the bleeding patient and to correction of coagulopathies. This review outlines a set of often catastrophic coagulation problems, which may present both thrombotic and bleeding challenges. These include heparin induced thrombocytopenia, thrombotic thrombocytopenic purpura, and disseminated intravascular coagulation.

Inherited coagulation factor abnormalities: a pediatric review.

Clotting factor abnormalities in children provide an interesting challenge to the medical care team. Understanding the diagnostic process and the medical management of children with factor abnormalities is crucial, as life-threatening complications can occur. This article will familiarize the reader with symptoms, laboratory testing, diagnosis, and treatment of hereditary coagulation factor abnormalities.

[Haemostaseological aspects of perioperative blood management]. / Hämostaseologische Aspekte des perioperativen Blutmanagements.

Recent studies in humans have shown that tissue factor on the surface of endothelial cells, monocytes, or subendothelial structures sparks plasmatic coagulation. In vivo, there is no functional separation of an "endogenous" and "exogenous" pathway of the coagulation cascade. However, global laboratory tests run along such pathways due to preincubation with specific activators and, hence, allow localization of inherited coagulation defects. Coagulation inhibitors such as antithrombin or activated protein C are accelerated in their activity by cell surface glycoproteins and almost completely inactivate procoagulant activity in the microcirculation. Antithrombin binds to endothelial glycosaminoglycans and then significantly increases anticoagulant activity. Protein C is activated by the thrombin-thrombomodulin-complex and inactivates factors V a and VIII a, respectively. Additionally, activated protein C has a profibrinolytic effect. Both systems physiologically counteract the procoagulant transformation of endothelial and monocyte cell surfaces which occurs in critically ill patients due to induction of tissue factor, suppression of thrombomodulin, and removal of glycosaminoglycans from the cell surface. The distinction of static and dynamic coagulation disorders is useful since static disorders seldom require therapeutic interventions although global laboratory tests may continuously deteriorate. Dynamical disorders are symptoms of an underlying disease, and consumption coagulopathy with disseminated fibrin deposition and oozing occurs when coagulation turnover cannot be stopped. Antithrombin substitution is a well documented therapeutic option along with fresh frozen plasma and erythrocyte concentrate transfusion for blood substitution. Recent case reports in patients with irreversible bleeding complications favour the application of a recombinant factor VII concentrate. A rising perspective to decrease the use of heterologous blood and blood products may be intraoperative plasma retransfusion. The quality of such plasma undergoing consecutive filtration steps has to be clinically studied. The application of a synthetic platelet substitute, the "plateletsome", containing platelet glycoproteins led to significantly improved haemostasis without generating systemic procoagulant activity. In a far future, procoagulant cell surface transformation may be influenced by topic application of inhaled thrombomodulin loaded liposomes or by sense or antisense oligonucleotides inducing thrombomodulin expression or suppressing tissue factor expression, respectively.

Coagulopathies and osteonecrosis.

Intravascular coagulation of the intraosseous microcirculation (capillaries and venous sinusoids) progressing to generalized venous thrombosis, and less commonly retrograde arterial occlusion, now appears to be the cause of nontraumatic osteonecrosis. However, this coagulopathy is only an intermediary event, which is always activated by some underlying etiologic risk factor(s). Conditions capable of triggering intravascular coagulation include familial thrombophilia (resistance to activated protein C, decreased protein C, protein S, or antithrombin III), hyperlipemia and embolic lipid (alcoholism and hypercortisonism), hypersensitivity reactions (allograft organ rejection, immune complexes, and antiphospholipid antibodies), bacterial endotoxic (Shwartzman) reactions and various viral infections, proteolytic enzymes (pancreatitis), tissue factor release (inflammatory bowel disease, malignancies, neurotrauma, and pregnancy), and other prothrombotic and hypofibrinolytic conditions.