Coagulopatías por consumo en el paciente con cáncer / Consumptive Coagulopathies in the Patient with Cancer

Introducción: Los trastornos de la coagulación durante el perioperatorio de pacientes oncológicos, son eventos más frecuentes de lo que se conoce en realidad, debido a que un gran número de estos transitan de forma inadvertida. Objetivo: Describir los factores fisiopatológicos que propician la ocurrencia de las coagulopatías adquiridas por consumo durante el perioperatorio del paciente oncológico. Métodos: Se realizó una revisión narrativa, en idiomas español e inglés, se utilizaron como fuente de búsqueda las bases de datos Ebsco, SciElo, Pubmed, Cubmed, Hinary, durante el período de enero a marzo de 2022, y el referenciador Zotero versión 5.0. Resultados: Para comprender qué pasa en el paciente con cáncer en relación con las coagulopatías por consumo es necesario entender la fisiología de los mecanismos de la coagulación. En este sentido, se pueden observar tanto trastornos trombóticos como hemorrágicos, por el incremento del factor tisular que determina la formación de trombina y el fallo de los mecanismos antifibrinolíticos. También, factores como la radioterapia, la quimioterapia y la transfusión de hemocomponentes, aumentan el riesgo de padecerlas. Conclusiones: la coagulopatía por consumo en el paciente oncológico es una entidad multifactorial, compleja y dinámica, en la que se debe pensar y diagnosticar para evitar complicaciones graves en el período perioperatorio.

Introduction: Coagulation disorders during the perioperative period of cancer patients are more frequent events than is actually known, due to the fact that a large number of these go unnoticed. Objective: To describe the pathophysiological factors that favor the occurrence of consumption-acquired coagulopathies during the perioperative period of cancer patients. Methods: A narrative review was carried out, in Spanish and English, using the Ebsco, Scielo, Pubmed, Cubmed, Hinary databases as a search source, during the period from January to March 2022, and the Zotero version 5.0 referer. 96.3. Results: To understand what happens in cancer patients in relation to consumption coagulopathies, it is necessary to understand the physiology of coagulation mechanisms. In this sense, both thrombotic and hemorrhagic disorders can be observed, due to the increase in the tissue factor that determines the formation of thrombin and the failure of antifibrinolytic mechanisms. Also, factors such as radiotherapy, chemotherapy and transfusion of blood components, increase the risk of suffering from them. Conclusions: consumption coagulopathy in cancer patients is a multifactorial, complex and dynamic entity, which must be considered and diagnosed to avoid serious complications in the perioperative period.

Comprehensive Analyses of Coagulation Parameters in Patients with Vascular Anomalies.

BACKGROUND: Vascular anomalies comprise a diverse group of rare diseases with altered blood flow and are often associated with coagulation disorders. The most common example is a localized intravascular coagulopathy in venous malformations leading to elevated D-dimers. In severe cases, this may progress to a disseminated intravascular coagulopathy with subsequent consumption of fibrinogen and thrombocytes predisposing to serious bleeding. A separate coagulopathy is the Kasabach-Merritt phenomenon in kaposiform hemangioendothelioma characterized by platelet trapping leading to thrombocytopenia and eventually consumptive coagulopathy. Our previous work showed impaired von Willebrand factor and platelet aggregometry due to abnormal blood flow, i.e., in ventricular assist devices or extracorporeal membrane oxygenation. With altered blood flow also present in vascular anomalies, we hypothesized that, in particular, the von Willebrand factor parameters and the platelet function may be similarly impacted. METHODS: We prospectively recruited 73 patients with different vascular anomaly entities and analyzed their coagulation parameters. RESULTS: Acquired von Willebrand syndrome was observed in both of our patients with Kasabach-Merritt phenomenon. In six out of nine patients with complex lymphatic anomalies, both the vWF antigen and activity were upregulated. Platelet aggregometry was impaired in both patients with Kasabach-Merritt phenomenon and in seven out of eight patients with an arteriovenous malformation. CONCLUSIONS: The analysis of coagulation parameters in our patients with vascular anomalies advanced our understanding of the underlying pathophysiologies of the observed coagulopathies. This may lead to new treatment options for the, in part, life-threatening bleeding risks in these patients in the future.

Disseminated intravascular coagulation: epidemiology, biomarkers, and management.

Disseminated intravascular coagulation (DIC) is a systemic activation of the coagulation system, which results in microvascular thrombosis and, simultaneously, potentially life-threatening haemorrhage attributed to consumption of platelets and coagulation factors. Underlying conditions, e.g. infection, cancer, or obstetrical complications are responsible for the initiation and propagation of the DIC process. This review provides insights into the epidemiology of DIC and the current understanding of its pathophysiology. It details the use of diagnostic biomarkers, current diagnostic recommendations from international medical societies, and it provides an overview of emerging diagnostic and prognostic biomarkers. Last, it provides guidance on management. It is concluded that timely and accurate diagnosis of DIC and its underlying condition is essential for the prognosis. Treatment should primarily focus on the underlying cause of DIC and supportive treatment should be individualised according to the underlying aetiology, patient's symptoms and laboratory records.

Paeoniflorin alleviates lipopolysaccharide-induced disseminated intravascular coagulation by inhibiting inflammation and coagulation activation.

Lipopolysaccharide (LPS) is a toxic component of the outer membrane of gram-negative bacteria that can activate the blood coagulation system, leading to disseminated intravascular coagulation (DIC). DIC is a syndrome characterized by thromboembolism and multiple organ failure. Herein, the beneficial effect of paeoniflorin (PF) on the alleviation of LPS-induced DIC was investigated with an experimental DIC mouse model. Briefly, mice were randomly divided into the following six groups: (1) control; (2) LPS; (3) heparin; (4) low-PF treatment; (5) medium-PF treatment; and (6) high-PF treatment. The histological morphology of the liver and kidney was observed, and the coagulation indicators (such as prothrombin time), function indicators (such as alanine transferase), and inflammatory factors (such as TNF-α) were detected. Additionally, an in vitro cell inflammation model using RAW 264.7 murine macrophages was established. Activation of the nuclear factor kappa B (NF-κB) signaling pathway and tumor necrosis factor-α (TNF-α) were determined by western blotting. Based on our findings, PF could significantly improve the histological morphology of the liver and kidney, indicating that PF protects the liver and kidney against damage induced by LPS. Additionally, PF improved the function and coagulation indicators and reduced the production of inflammatory factors. In vitro, PF inhibited the expression of TNF-α by suppressing NF-κB signaling pathway activation. Collectively, our findings support the hypothesis that PF has anti-inflammatory and anticoagulation effects for the alleviation of LPS-induced DIC. PF is thus a potential co-treatment option for DIC.

Japanese Spotted Fever with Hemophagocytic Lymphohistiocytosis.

Japanese spotted fever (JSF) is an uncommon but potentially fatal infection transmitted by tick bites. We herein report a fulminant case of JSF infection that occurred in an immunocompetent adult that was complicated by disseminated intravascular coagulation and hemophagocytic lymphohistiocytosis (HLH). We discuss the difficulty in making the diagnosis and identifying the complication of HLH in our patient. HLH is a rare complication of rickettsiosis, and this is the first reported case in English of JSF complicated by HLH in an immunocompetent adult. Secondary HLH caused by rickettsiosis requires a different treatment from primary HLH. Rickettsiosis must therefore be considered in patients with HLH.

New considerations on pathways involved in acute traumatic coagulopathy: the thrombin generation paradox.

Background: An acute traumatic coagulopathy (ATC) is observed in about one third of severely traumatized patients. This early, specific, and endogenous disorder is triggered by the association of trauma and hemorrhage. The early phase of this condition is characterized by the expression of a bleeding phenotype leading to hemorrhagic shock and the late phase by a prothrombotic profile leading to multiple organ failure. The physiopathology of this phenomenon is still poorly understood. Hypotheses of disseminated intravascular coagulation, activated protein C-mediated fibrinolysis, fibrinogen consumption, and platelet functional impairment were developed by previous authors and continue to be debated. The objective of this study was to observe general hemostasis disorders in case of ATC to confront these hypotheses. Method: Four groups of 15 rats were compared: C, control; T, trauma; H, hemorrhage; and TH, trauma and hemorrhage. Blood samples were drawn at baseline and 90 min. Thrombin generation tests, platelet aggregometry, and standard hemostasis tests were performed. Results: Significant differences were observed between the baseline and TH groups for aPTT (17.9 ± 0.8 s vs 24.3 ± 1.4 s, p < 0.001, mean ± SEM), MAP (79.7 ± 1.3 mmHg vs 43.8 ± 1.3 mmHg, p < 0.001, mean ± SEM), and hemoglobin (16.5 ± 0.1 g/dL vs 14.1 ± 0.3 g/dL, p < 0.001, mean ± SEM), indicating the presence of an hemorrhagic shock due to ATC. Compared to all other groups, coagulation factor activities were decreased in the TH group, but endogenous thrombin potential was (paradoxically) higher than in group C (312 ± 17 nM/min vs. 228 ± 23 nM/min; p = 0.016; mean ± SEM). We also observed a subtle decrease in platelet count and function in case of ATC and retrieved an inversed linear relationship between fibrinogen concentration and aPTT (intercept, 26.53 ± 3.16; coefficient, - 3.40 ± 1.26; adjusted R2: 0.1878; p = 0.0123). Conclusions: The clinical-biological profile that we observed, combining normal thrombin generation, fibrinogen depletion, and a hemorrhagic phenotype, reinforced the hypothesis of activated protein C mediated-fibrinolysis. The key role of fibrinogen, but not of the platelets, was confirmed in this study. The paradoxical preservation of thrombin generation suggests a protective mechanism mediated by rhabdomyolysis in case of major trauma. Based on these results, we propose a new conception concerning the pathophysiology of ATC.

Hemostatic function in hyperfibrinolytic disseminated intravascular coagulation.

BACKGROUND: Global hemostatic mechanism(s) in patients with disseminated intravascular coagulation (DIC) are poorly understood. There are few diagnostic criteria of DIC based on overall or global hemostatic mechanisms. METHODS: We have assessed in detailed the dynamic global hemostatic changes using thrombin and plasmin generation assay (T/P-GA), clot fibrinolytic waveform analysis (CFWA) and not-activated rotational thromboelastometry (NATEM), in a young girl with DIC associated with acute myeloid leukemia (AML). The ratios of endogenous thrombin potential (T-EP) and plasmin lag time (P-LT) relative to normal plasma was sourced from pooled normal plasma from healthy volunteers on T/P-GA. RESULTS: The inverse P-LT ratio prior to tranexamic acid (TXA) treatment was greater than the T-EP ratio (1.1-2.8 and 0.83-1.2, respectively). Significant reduction in inverse P-LT ratio (0.084-1.3) was observed after TXA treatment. The interval from clotting to the initiation of fibrinolysis (fibrinolysis lag time: FLT) in CFWA was significantly shorter than the control at onset (74.2-91.6 s vs 109 s), indicating enhanced fibrinolysis. Data from an adult with acute promyelocytic leukemia-associated DIC also supportively showed a high inverse P-LT ratio (2.1) and shortened FLT (83.7 s). The clotting time in patient whole blood using NATEM-mode during an episode of severe epistaxis markedly shortened beyond control, but returned to normal after the addition of an anti-tissue factor (TF) monoclonal antibody. CONCLUSION: The release of intravascular TF contributed to sustained activation of coagulation and subsequent fibrinolytic activity in this patient with AML-associated DIC, and T/P-GA could provide better quantitative data than conventional assays in these circumstances.

Endothelial Dysfunction Is Associated with Mortality and Severity of Coagulopathy in Patients with Sepsis and Disseminated Intravascular Coagulation.

The role of the endothelium in sepsis-associated disseminated intravascular coagulation (DIC) is multifaceted and may contribute substantially to disease severity and outcome. The purpose of this study was to quantify measures of endothelial function, including markers of activation (endocan, Angiopoietin-2 [Ang-2], and von Willebrand Factor), endogenous anticoagulants (tissue factor pathway inhibitor and protein C), and damage-associated factors (High Mobility Group Box 1 [HMGB-1]) in the plasma of patients with sepsis and DIC, and to determine the relationship of these factors with severity of illness and outcome. Plasma samples were collected from 103 adult patients with sepsis within 48 hours of intensive care unit admission. Biomarker levels were measured using commercially available, standardized methods. Disseminated intravascular coagulation was diagnosed according to the International Society of Thrombosis and Hemostasis scoring algorithm. Twenty-eight-day mortality was used as the primary end point. In this study, endothelial damage and dysfunction were associated with the severity of coagulopathy and mortality in DIC patients. Loss of the endogenous anticoagulant protein C and elevation in the vascular regulator Ang-2 were associated with the development of overt DIC. In addition to Ang-2 and protein C, endocan, a biomarker of endothelial activation, and HMGB-1, a mediator of endothelial damage and activation, were significantly associated with mortality. This underscores the contribution of the endothelium to the pathogenesis of sepsis-associated DIC.

No impact of disseminated intravascular coagulation in kidney donors on long-term kidney transplantation outcome: A multicenter propensity-matched study.

The diagnosis of disseminated intravascular coagulation (DIC) is often considered to be a contraindication to organ donation. The aim of this study was to evaluate the impact of DIC+ donors on kidney recipient (KR) evolution. We identified 169 KRs with DIC+ donation after brain death donors between January 1996 and December 2012 in 6 French transplant centers. Individuals were matched using propensity scores to 338 recipients with DIC- donors according to donor age and sex, whether expanded criteria for the donor existed, graft year, and transplantation center. After kidney transplantation, delayed graft function was observed in 28.1% of DIC+ KRs and in 22.8% of DIC- KRs (NS). Renal allograft survival at 1, 5, and 10 years was 94.5%, 89.3%, and 73.9% and 96.2%, 90.8%, and 81.3% in DIC+ KRs and DIC- KRs, respectively (NS). The median estimated glomerular filtration rate (eGFR) was similar between DIC+ and DIC- KRs at 3 months, 1 year, and 10 years: 45.9 vs 48.1 mL/min, 42.1 vs 43.1 mL/min, and 33.9 vs 38.1 mL/min, respectively. Delayed calcineurin inhibitor introduction or induction had no impact on delayed graft function rate or eGFR evolution at 10 years after transplantation in DIC+ KRs. Donor DIC did not seem to affect initial outcome, long-term graft function, or allograft survival.

Anticoagulant Therapy for Disseminated Intravascular Coagulation After Gastrointestinal Surgery.

Many studies about anticoagulant therapy for disseminated intravascular coagulation (DIC) confused gastrointestinal surgery-related DIC with DIC unrelated to a prior operation. Furthermore, the potentially increased risk of bleeding by anticoagulants complicates their use. We carried out a systematic review to describe the efficacy and safety of anticoagulant agents for DIC after gastrointestinal surgery. Several studies have indicated that gabexate mesylate improves DIC score without increasing bleeding events, and that antithrombin is associated with lower mortality of DIC after gastrointestinal surgery. Recombinant thrombomodulin has been the most frequently analyzed anticoagulant agent in this field. DIC score and survival rate were better in patients treated with recombinant thrombomodulin, without increasing bleeding events. In conclusion, anticoagulant therapy may be effective and safe in DIC after gastrointestinal surgery.

Disseminated intravascular coagulation: is it fact or fancy?

: 'Disseminated intravascular coagulation (DIC)' occurs commonly in critical illnesses such as sepsis, trauma, cancer, and complications of surgery and pregnancy. Mortality is very high. The pathogenesis has been ascribed to tissue factor-initiated coagulation disorder, resulting in disseminated microblood clots that are made of platelets, plasma factors, fibrins, and blood cells. True DIC depletes coagulation factors and consumes platelets, and activates fibrinolysis. 'DIC' is assumed to orchestrate thrombocytopenia, microangiopathic hemolytic anemia and hypoxic multiorgan dysfunction syndrome, and causes hemorrhagic disorder due to depleted coagulation factors. In contrast, disseminated intravascular microthrombosis (DIT) occurs in thrombotic thrombocytopenic purpura (TTP) and TTP-like syndrome due to ADAMTS13 deficiency or insufficiency. The pathogenesis is due to formation of intravascular 'microthrombi' composed of complexes of platelets and unusually large von Willebrand factor multimers. Interestingly, DIT also occurs in the same critically ill patients as 'DIC' does. Following activation of complement system, the terminal complex C5b-9 causes endotheliopathy via channel formation to the endothelial cell membrane. Endotheliopathy activates microthrombotic pathway and initiates microthrombogenesis, leading to endotheliopathy-associated DIT. DIT results in TTP-like syndrome with hematologic phenotype of consumptive thrombocytopenia, microangiopathic hemolytic anemia, and multiorgan dysfunction syndrome. In reinterpretation of 'DIC', the true lesion is 'microthrombi' but not microblood clots. Thus, 'DIC' is endotheliopathy-associated DIT. This concept reconciles all the clinical features of 'DIC', and dramatically changes our understanding of pathophysiological mechanism in hemostasis and thrombosis. This new paradigm should assist the physician with correct diagnostic evaluation and treatment intervention.

The impact of oral arsenic and all-trans-retinoic acid on coagulopathy in acute promyelocytic leukemia.

The aim of our study was to evaluate the impact of oral arsenic (the realgar-indigo naturalis formula, RIF) and all-trans retinoic acid (ATRA) on coagulopathy in acute promyelocytic leukemia (APL) compared with intravenous arsenic trioxide (ATO) and ATRA during induction. Mitoxantrone was added to all the patients at a dose of 1.4mg/m2 per day for 5-7 days. D-dimer levels, prothrombin time (PT), fibrinogen (Fbg) levels and the platelet count were comparably analyzed among 83 newly diagnosed APL patients treated with RIF (n=45) or with ATO (n=38). Since induction therapy with RIF and ATRA, the median levels of Fbg, PT and platelets were recovered to the normal range within 4days, 10days and 28days, respectively. The last day of platelet and plasma transfusion was day 12 (range: 0-24 days) and day 3 (range: 0-27 days), respectively. Among the 42 patients with a disseminated intravascular coagulation (DIC) score=4, the consumption of transfused platelets was less in the RIF group than that in the ATO group (P=0.037). In the 17 patients with a DIC score <4, prompt recovery of Fbg levels (P=0.028) was observed in the RIF group compared with that in the ATO group (P=0.401). RIF and ATO showed similar effects on the recovery of coagulopathy in APL patients. RIF had a potential beneficial effect in accelerating the recovery of thrombocytopenia and hypofibrinogenemia for subclinical DIC patients.

Biomarker Profile of Sepsis-Associated Coagulopathy Using Biochip Assay for Inflammatory Cytokines.

Disseminated intravascular coagulation (DIC) is a major pathophysiological mechanism of sepsis and greatly increases the risk of death in septic patients. Disseminated intravascular coagulation is a complex physiological phenomenon that involves inappropriate activation of coagulation, inflammation, and endothelial processes. The purpose of this study was to analyze the levels of inflammatory cytokines in the plasma of patients with DIC in order to compare the measured levels with those from healthy individuals, draw correlations, and provide a basis for further biomarker panel development. The inflammatory biomarkers interleukin (IL) 1ß, IL-6, IL-8, IL-10, interferon (IFN) γ, vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF) α, monocyte chemoattractant protein (MCP)-1, and epidermal growth factor (EGF) showed significant ( P < .05) elevation in patients with DIC. Interestingly, while numerous correlations were present between IL-ß, IL-6, IL-8, IL-10, IFN-γ, TNF-α, MCP-1, and many of the inflammatory cytokines measured, VEGF and EGF exhibited much less extensive correlation, suggesting that their involvement in DIC may be independent of the other investigated inflammatory markers.

[Pathogenic peculiarities of disseminated intravascular coagulation of various ethiology].

DIC is a severe complication, often resulting in multi-organ failure and fatal outcome. As any syndrome, it is polyethiologic, while a big number of its causes logically leads to various mechanisms of its forming. Main manifestations of the disseminated intravascular blood coagulation syndrome are clottage and haemorrhage. A result of a massive clottage in microcirculatory bed of internal organs is development of dystrophic changes in them and organ failure. Haemorrhage in its turn, results in decreased volume of circulating blood, arterial hypotension and hemic hypoxia, in most severe cases leading to the fatal outcome. Although, development mechanisms and manifestation degree of the disorder mentioned above are not always the same. As the syndrome may result from a great number of causes (currently, over 150 diseases have been described with which it can develop), namely its initial stages are different to the greatest extent. Main triggering mechanisms of the DIC may be: blood formed element activation and increased process of their microvesiculation, activation of coagulative hemostasis in intrinsic and extrinsic pathways, lack of anticoagulants and excessive activity of fibrinolytic system. Various ethiologic factors (sepsis, obstetrical pathology, leucosis and other malignant tumours, traumas, etc) have different effect on function of hemostasis system components. Depending on the degree of the above mentioned disorders mechanisms manifestation, the DIC may develop with prevailing coagulation, with prevailing fibrinolysis or with their balanced activation. Clinical manifestations of these DIC forms, as well as duration and manifestation degree of its stages (hypercoagulation, coagulopathy of consumption with compensatory activation of fibrinolysis, defibrination of the blood and excessive activation of fibrinolysis) will be different as well. Consequently, knowing the prevailing disorder in hemostasis system during a disease that is potentially dangerous in terms of the DIC development offers to find optimal methods of its prevention, diagnosing and treatment.

Thrombotic Microangiopathies (TTP, HUS, HELLP).

Thrombocytopenia, strictly defined as a platelet count less than 150,000, is common in the emergency department. Recognition, diagnostic investigation, and proper disposition of a thrombocytopenic patient are imperative. One group of disorders leading to thrombocytopenia is the thrombotic microangiopathies, hallmarked by platelet destruction. These thrombotic microangiopathies include thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS) and hemolysis, elevated liver enzyme levels, low platelet count (HELLP), which should be distinguished from similar disease processes such as immune thrombocytopenia (ITP), disseminated intravascular coagulation (DIC) and heparin induced thrombocytopenia (HIT). In this article, clinical presentations, pathophysiology, diagnostic workup, management plans, complications, and dispositions are addressed for this complex group of platelet disorders.

Disseminated intravascular coagulation caused by moojenactivase, a procoagulant snake venom metalloprotease.

Snake venom toxins that activate coagulation factors are key players in the process of venom-induced coagulopathy, and account for severe clinical manifestations. The present study applies a variety of biochemical, hematological, and histopathological approaches to broadly investigate the intravascular and systemic effects of moojenactivase (MooA), the first described PIIId subclass metalloprotease isolated from Bothrops sp. venom that activates coagulation factors. MooA induced consumption coagulopathy with high toxic potency, characterized by prolongation of prothrombin and activated partial thromboplastin time, consumption of fibrinogen and the plasma coagulation factors X and II, and thrombocytopenia. MooA promoted leukocytosis and expression of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, accompanied by tissue factor-dependent procoagulant activity in peripheral blood mononuclear cells. This metalloprotease also caused intravascular hemolysis, elevated plasma levels of creatine kinase-MB, aspartate transaminase, and urea/creatinine, and induced morphopathological alterations in erythrocytes, heart, kidney, and lungs associated with thrombosis and hemorrhage. Diagnosis of MooA-induced disseminated intravascular coagulation represents an important approach to better understand the pathophysiology of Bothrops envenomation and develop novel therapeutic strategies targeting hemostatic disturbances.