Activation Of Intravascular Coagulation Research Articles

Sepsis-induced disseminated intravascular coagulation: an international estrangement of disease concept.

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation, which can be caused by infectious and noninfectious insults, such as trauma, postcardiac arrest syndrome, and malignant diseases. At present, diagnosis and treatment of DIC clearly differ between Japan and Western countries; in Japan, DIC has long been considered a therapeutic target, and much evidence on DIC has been published. However, there has recently been no international consensus on whether DIC should be a therapeutic target with anticoagulant therapy. This review describes the coagulofibrinolytic system abnormalities associated with sepsis and discusses related management strategies. It also explores the reasons why DIC is perceived differently in different regions. There is a major discrepancy between diagnostic and treatment options in Japan, which are based on holistic assessments of trials, as well as the results of post hoc subgroup analyses and observational studies, and those in Western countries, which are based mainly on the results of sepsis mega trials, especially randomized controlled trials. The differences might also be due to various patient factors in each region, especially racial characteristics in thrombolytic mechanisms, and differences in interpretation of evidence for candidate drugs. Hence, Japanese researchers need to distribute their high-quality clinical research data not only to Japan but also to the rest of the world.

The Role of Fibrin-Related Markers in Disseminated Intravascular Coagulation Due to Sepsis

Sepsis leads to local and systemic activation of different response systems, including coagulation and fibrinolysis. An overwhelming inflammatory response may lead to organ failure, and the coagulation and fibrinolysis involvement may lead to Disseminated Intravascular Coagulation (DIC). Special regard is given to the diagnosis of DIC by the use of scoring systems, which are, APACHE II, SAPS II, International Society of Thrombosis and Hemostasis (ISTH), and Japanese Ministry of Health and Welfare (JMHW). A large variety of fibrin compounds can be detected in plasma from septic patients with intravascular coagulation activation. Coagulation activation is indicated by elevated plasma levels of D-dimer, prothrombin fragments, and Thrombin-Antithrombin (TAT) complexes. Fibrin-Related Markers (FRMs) identified in sepsis are D-dimer, fibrinogen, Soluble Fibrin Monomer (SFM), and Fibrin Degradation Products (FDP). Hemostatic molecular markers, such as TAT, Plasmin-Plasmin Inhibitor Complex (PPIC), D-dimer, and SFM are better for the diagnosis of pre-DIC. No single biomarker of sepsis may be ideal, but many are helpful in terms of at least identifying critically ill patients who need more careful monitoring. As each biomarker has limited sensitivity and specificity, it may be interesting to combine several biomarkers. The purpose of this literature review was to increase knowledge about laboratory tests of FRMs and provide current knowledge and insight into these biomarkers related to DIC-sepsis. The method used in this literature review was a traditional review. Search, identify, and select relevant literature on PubMed–CBI and Google Scholar based on keywords, 30 journals were obtained from the two search engines.

Coagulation/fibrinolysis and circulating tumor cells in patients with advanced breast cancer

PurposeTo evaluate the relationship between circulating tumor cells (CTCs) and standard coagulation tests in both a discovery and a validation cohort of patients with advanced breast cancer.MethodsIn a retrospective (n = 77) and a prospective (n = 92) study of patients with progressive advanced breast cancer, CTC count, platelet number, fibrinogen level, D-dimers, prothrombin time, and activated partial thromboplastin time were measured. The association between these coagulation studies and CTC count was analyzed. The impact of these measurements on overall survival (OS) was assessed.ResultsIn both cohorts, results were similar; absolute CTC count was significantly associated to D-dimer level and inversely with platelet count. In the prospective cohort, quantification of tumor-derived extracellular vesicles (tdEVs) was associated with CTC count, and with coagulation abnormalities (low platelet count and increased D-dimers). tdEVs did not add to CTC count in predicting changes in platelets or D-dimers. In multivariate analysis only CTC ≥ 5 CTC/7.5 mL, ER status, HER2 status and lines of chemotherapy were associated with OS. In patients with terminally metastatic breast cancer, very high CTC counts are prevalent.ConclusionA significant association exists between increasing CTC number and increased D-dimers and decreased platelet counts, suggesting a potential role for CTCs as a direct contributor of intravascular coagulation activation. In patients with advanced and progressive breast cancer, abnormalities in routine coagulation tests is the rule. In patients with terminally advanced breast cancer a “leukemic” phase with high CTC count is prevalent.

Влияние свинцовой интоксикации на показатели крови у больных с пылевым бронхитом и бронхиальной астмой

Th e aim of the research. To study the eff ects of lead intoxication on blood parameters in battery factory workers with dust bronchitis and bronchial asthma. Material and methods. Th e study was conducted on battery factory workers (45 subjects) aged 30 to 60 years who came into contact with lead and on healthy volunteers (15 subjects). Blood parameters were evaluated in hematological analyser XT-2000i using a unique technology of fl uorescent fl ow cytometry. Results. Employees of the battery plant develop occupational diseases: dust bronchitis and bronchial asthma. In all studied groups of patients, laboratory blood parameters changed compared with the control group: anemia, leukocytosis, haemoglobinopathy, a change in the qualitative characteristics of the leukocyte formula, an increase in the percentage of micro and macrophages were observed. Activation of intravascular coagulation is characteristic to all groups of patients, which indicates a tendency to DIC syndrome. Comparative characteristics of blood parameters revealed deeper changes in BA patients who were exposed to lead in their professional activities. It has been established that the technique of fl ow cytometry for determining functional blood parameters is informative and can be used to characterise the condition of persons with occupational diseases based on lead intoxication. Conclusion. For the fi rst time, it has been revealed that the total number of platelets increases with the growth of their size in battery factory workers, which indicates a trend toward DIC syndrome. For the fi rst time, a decrease has been fi rst found in the concentration of haemoglobin, the number of red blood cells, an increase in the total number of leukocytes due to lymphocytes with a decrease in neutrophils and eosinophils in patients with dust bronchitis. Th ere is a correlation between the amount of haemoglobin and the number of leukocytes. It has been found for the fi rst time that employees of a battery factory suff ering from bronchial asthma have an increase in the amount of haemoglobin, erythrocytes, leucocytosis due to lymphocytes, but the linear associations between leukocyte parameters are very weak. Based upon this, we recommend repeating medical examination with shorter intervals in between. Th e timing of periodic inspections depends on the nature of production and types of work with lead and its compounds. When applying for a job, such contraindications as blood diseases and diseases of the respiratory and cardiovascular systems should be a principal factor.

Agreement on Overt Disseminated Intravascular Coagulation in Sepsis Patients between International Society of Thrombosis and Haemostasis Criteria and Japanese Ministry of Health and Welfare Criteria

Disseminated Intravascular Coagulation (DIC) is an acquired syndrome characterized by the activation of intravascular coagulation which is most commonly caused by sepsis. There are two types of DIC disease: overt and non-overt DICs. The International Society of Thrombosis and Haemostasis (ISTH) criteria are more frequently used in the diagnosis of overt DIC compared to Japanese Ministry of Health and Welfare (JMHW). One of the different parameters of the two criteria is the D-Dimer element in the ISTH criteria and Fibrin Degradation Products (FDP) in the JMHW criteria. The availability of fibrin-related markers is different in each health center. This study aimed to see the agreement of the DIC diagnosis based on the ISTH and JMHW criteria and to analyze the correlation between D-Dimer and FDP in sepsis patients to help clinician decide which criteria is better to use. An analytical cross-sectional study was carried out on patients with sepsis based on the clinical diagnosis from the laboratory order forms and the DIC criteria according to the ISTH and JMHW. Patients included in this study were those visiting Dr. Hasan Sadikin General Hospital Bandung from August 2019-April 2020. Data collected were analyzed statistically using Cohen's Kappa test and Spearman test, both were performed in SPSS 17.0 program.There were 35 subjects participating in this study with overt and non-overt DIC with a composition based on the ISTH and JMHW criteria of 31 and 19 vs. 4 and 16, respectively. The Kappa coefficient between ISTH and JMHW was 0.266 (p 0.021) and the correlation between the D-Dimer and the FDP was 0.88 based on the Spearman test. There is a fair agreement on the DIC diagnosis and strong correlation between the FDP and the D-Dimer in sepsis patients when assessed using the ISTH and JMHW criteria. Both criteria are equally able to assist clinicians in determining the type of DIC depending on the type of fibrin-related markers available in the health centers.

Comparative analysis of the hemostasis system of cancer patients with thrombotic complications

Surgical treatment of female genital cancer remains a rather difficult task in gynecological practice due to the possibility of thrombotic complications. It is important to study the features of hemostasis in such patients for the practical application of this knowledge. The aim of the study was to scientifically substantiate the features of hemostasis in patients with female genital cancer. Study materials: 103 patients with genital cancer who were treated.
 The purpose of the study. Coagulogram, colorimetry, others. Results of the research. As a result of a blood test, it was found that the initial level of hemoglobin in patients with thrombotic complications after surgery decreased by 12%, in patients without thrombotic complications – by 14%. The average platelet count in patients with thrombotic complications decreased by 11,50%, in patients without thrombotic complications – 8,12%. The level of leukocytes in patients with thrombotic complications – increased by 21,05%, in patients without thrombotic complications – 30,30%. In the study of hemostasis, it has been found that surgery in patients with female genital cancer causes a pronounced activation of the hemostasis system, especially in patients with thrombotic complications. In patients with thrombotic complications there is a more pronounced activation of intravascular coagulation on the background of a significant decrease in the level of antigen III than in patients without thrombotic complications. The level of fibrinogen in patients with thrombotic complications in the preoperative period was significantly higher by 16,3% than in patients without thrombotic complications; there was a decrease in fibrinogen levels in the early postoperative period; from the third day after surgery, fibrinogen levels increased in patients without thrombotic complications. There was also a significant reduction in activated partial thromboplastin time in patients with thrombotic complications. The number of soluble complexes of fibrin monomers increased to higher values in patients with thrombotic complications. Conclusion. In the study of hemostasis, it has been found that surgery in patients with female genital cancer causes marked activation of the hemostasis system, especially in patients with thrombotic complications.

Current approaches to the use of antiplatelet and anticoagulant drugs in pregnant women with thrombocytopenia caused by hemostasis activation

Introduction. At present, hemostasis disorders still hold one of the lead places in the pathogenesis of reproductive losses associated with high risk of miscarriage and remain one of the major causes for developing serious obstetric complications. Relevance, efficacy and safety of using drugs containing acetylsalicylic acid (ASA) and low molecular weight heparins (LMWH) in pregnant women with thrombocytopenia comorbid with intravascular coagulation activation remain pressing issues. The study of thrombocytopenia pathogenesis during pregnancy and search for new methods of hemostasis correction are accounted for by high risk of developing diverse perinatal complications and necessity to conduct prophylactic measures for their prevention.Aim: to study hemostasis changes and clinical outcomes in pregnant women with thrombocytopenia, to substantiate the use of antiplatelet agents and anticoagulants in pregnant women with activated intravascular blood coagulation for preventing development of thromboembolic and placenta-associated complications of pregnancy.Materials and Methods. A multicenter prospective study was conducted by enrolling 299 pregnant women at a gestational age of22.85 [22.00; 25.00] weeks, whose average age was 31.06 [27.75; 35.00] years. There were distinguished three groups: main group (n = 124) consisted of pregnant women with lowered platelet count and activated intravascular blood coagulation, who received ASA preparations and LMWH in prophylactic doses for 4 weeks; pregnant comparison groups (n = 125) received no such drugs; control group (n = 50) consisted of women with normal platelet counts during physiological pregnancy. All patients underwent clinical, anamnestic and laboratory examination, and the clinical outcomes of pregnancy were assessed.Results. It was found that use of ASA (a combined drug: ASA 75 mg + magnesium hydroxide 15.2 mg/day) and LMWH (enoxaparin sodium) in pregnant women from the main group were noted to improve hemostasis parameters: via markedly increased platelet count, decreased fibrinogen level, prothrombin index as well as normalized antithrombin III level (p < 0.01). It was also found during treatment that the D-dimer level and the rate (83.6 ± 2.3 % and 72.4 ± 2.7 %) and the degree (86.4 ± 2.7 % and 74.4 ±2.8 %) of platelet aggregation in the main group (in contrast with comparison group) were significantly decreased (p < 0.01). The frequency of detected chronic placental insufficiency was significantly higher (p < 0.01) in the comparison group (n = 50; 41.32 %) vs. the main group after receiving ASA and LMWH (n = 20; 16.52 %). The incidence of moderate (p = 0.016) and severe (p = 0.018) preeclampsia was significantly higher in the comparison group vs. the main group. While comparing the volume of blood loss during delivery, there were no differences between the main group and the comparison group (p = 0.46); it was noted only a statistically significant difference compared to the control group (p = 0.04), in which the lowest blood loss was found (337.9 [200.0; 600.0] ml) in comparison with the other two groups (p1,3 = 0.05; p2,3 = 0.04). It should be noted that the volume of blood loss in all groups remained within the physiological permissible range.Conclusion. Our clinical and laboratory study allowed to substantiate relevance of using ASA and LMWH drugs in pregnant women with thrombocytopenia comorbid with confirmed activation of intravascular blood coagulation, for prevention of thromboembolic and placenta-associated complications of pregnancy as well as proved safety of such drugs during pregnancy.

Management of Disseminated Intravascular Coagulation in Acute Leukemias.

Disseminated intravascular coagulation (DIC) is characterized by the intravascular activation of coagulation with loss of localization arising from different causes, and is diagnosed using scoring systems which rely upon the presence of an underlying disorder compatible with DIC alongside hemostatic derangements such as low platelet count, prolonged prothrombin time, and elevated fibrinogen degradation products. DIC is common in patients with acute leukemia, with prevalence ranging from 17 to 100% in acute promyelocytic leukemia (APL) and 8.5 to 25% in acute lymphoblastic leukemia (ALL) and non-APL acute myeloid leukemia (AML). The pathophysiology is complex and varies between the leukemia subtypes, and is not fully reflected by the laboratory markers currently used to classify DIC. Similarly, the clinical consequence of DIC in acute leukemia also varies across the types of leukemia. DIC is primarily associated with bleeding in APL, while thrombosis is the dominant phenotype in ALL and non-APL AML. The cornerstone of managing DIC is the treatment of the underlying disease, as exemplified by the important role of early administration of all-trans retinoic acid in APL. Other aspects of management focus on supportive care aimed at minimizing the risk of bleeding, via transfusion of blood products. The use of blood products is more liberal in APL, due to the hemorrhagic phenotype and unacceptably high rates of early hemorrhagic death. This review will focus on the pathophysiology, risk factors, clinical implications, and the management of DIC in patients across the spectrum of acute leukemias.

Accelerated Intravascular Activation of Coagulation During Cardiopulmonary Bypass.

Accelerated Intravascular Activation of Coagulation During Cardiopulmonary Bypass.

A Lipid Peroxidation Product, 4-Hydroxy-2-Nonenal, Triggers Intravascular Coagulation and Inflammation through Generation of Tissue Factor-Positive Microvesicles

Tissue factor (TF) is a cellular receptor for the clotting protease factor VIIa (FVIIa), and TF-FVIIa complex initiates activation of the coagulation cascade. TF-FVIIa also influences non-hemostatic functions via direct or indirect cell signaling. Constitutive expression of TF is primarily restricted to the surface of perivascular cells, sequestered from circulating blood clotting factors, to prevent aberrant intravascular clotting. It has been suggested that TF is also present in the blood associated with microvesicles (MVs). These circulating TF, however, do not induce any thrombotic complications as they are either cleared from the system before they could accumulate to a pathological level or lack procoagulant activity. However, various pathological conditions such as sepsis, diabetes, bacterial infection, atherosclerosis, and cancer can increase the levels of circulating TF+ MVs, which can then trigger intravascular coagulation and inflammation. We hypothesized that oxidative stress, a pathological condition, central to most of the diseases mentioned above, plays a role in the generation of TF+ MVs in vivo, which could contribute to intravascular coagulation and inflammation. We recently showed that 4-hydroxy-2-nonenal (HNE), the most abundant and stable unsaturated aldehyde produced by the oxidation of ω-6 polyunsaturated fatty acids, enhances TF activity in monocytic cells and macrophages. However, the role of HNE in activation of intravascular coagulation is unknown. To investigate this, C57Bl/6J wild-type mice were administered with HNE intraperitoneally (10 mg/kg body weight) and generation of TF+ MVs, activation of intravascular coagulation, and inflammation was assessed. HNE administration markedly increased TF activity associated with MVs. Nanoparticle tracking analysis (NTA) showed a 3-fold increase in the number of MVs in the plasma of HNE-treated mice. Measurement of thrombin-antithrombin (TAT) complexes revealed a significant increase in TAT levels in HNE treated mice. Pre-treatment of the mice with anti-murine TF antibody attenuated the HNE-induced increase in TAT levels. Measurement of plasma clotting times showed a significant reduction in HNE treated mice (118.3 ± 10.42 sec) compared to saline treated control mice (> 300 sec). Incubation of plasma with anti-TF antibody reversed the reduction observed in the plasma clotting time of HNE treated mice. Assessment of clotting in the saphenous vein injury bleeding model showed an increased number of clots, and reduced blood loss in HNE-administered mice compared to saline treated mice. Blockade of TF with 1H1 anti-TF antibody negated the HNE-mediated reduction in the clotting time. Next, we investigated whether HNE administration also induces a proinflammatory response in mice. Blood cells analysis showed approximately a 4-fold increase in circulating neutrophils in HNE-treated mice at 6 h following HNE treatment. Immunohistochemistry studies showed a robust infiltration of neutrophils into the lungs. Cytokine analysis of plasma showed a significant increase in IL-6 and CXCL1 levels in HNE-treated mice. Blockade of TF using 1H1 anti-TF antibody significantly reduced the HNE-mediated neutrophil infiltration into the lungs and completely abrogated the increase in plasma IL-6 levels. In additional studies, we attempted to identify the source of TF+ MVs. It is unlikely that they are originated from monocytes or endothelial cells as HNE did not induce TF expression in these cell types. LPS, used as a positive control, showed significant induction of TF on both PBMCs and the endothelium Immunohistochemistry revealed that HNE disrupted endothelial barrier integrity of vessel wall, raising a possibility that TF+ MVs could have come from perivascular cells. In summary, our data indicate that oxidative stress could induce the release of TF+ MVs, and this would contribute to intravascular coagulation and inflammation. Our studies also suggest that TF-positive microvesicles can be a useful therapeutic target in the treatment of thromboinflammatory diseases. Disclosures No relevant conflicts of interest to declare.

A Paraneoplastic Syndrome to Remember: A Case of Disseminated Intravascular Coagulation in Lung Cancer.

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by the widespread activation of coagulation. It can present as an acute life-threatening emergency or as a chronic process. Mortality is highly dependent on the reversibility of the aetiology and degree of coagulation impairment, so treatment of the underlying cause is vital. The authors present the case of a 57-year-old man whose inaugural presentation of lung cancer was chronic DIC, characterized by three thrombotic events, followed by acute DIC, culminating in death. Metastatic lung cancer was diagnosed only after death.LEARNING POINTSDisseminated intravascular coagulation (DIC) is an acquired syndrome characterized by systemic intravascular activation of coagulation, originating from and causing damage to the microvasculature, which can present as an acute or chronic condition, manifested by bleeding or thrombotic events.Unexplained thrombotic events should raise suspicion of chronic DIC.Treatment will fail, despite supportive measures, if the cause of the DIC is not identified.

Disseminated Intravascular Coagulation in Cancer: An Update.

Cancer often leads to the activation of coagulation, manifesting as disseminated intravascular coagulation (DIC) in its most extreme form. DIC is characterized by systemic intravascular coagulation activation (leading to deposition of intravascular platelets and fibrin) and simultaneous consumption of coagulation proteins and thrombocytes (which may cause bleeding complications). The clinical course of DIC in patients with malignancies is typically less intense compared with DIC complicating alternative clinical settings, including systemic inflammatory responses following infection or traumatic injury. A more slowly proceeding, less fulminant, and widespread hemostatic derangement can remain asymptomatic. Eventually, the ongoing consumption may result in low levels of platelets and coagulation factors, and bleeding complications (frequently localized at the site of the tumor or distant metastases) may be the first clinical manifestation of DIC. An alternative clinical scenario is dominated by thrombotic complications, ranging from clinically manifest vascular thrombosis to microvascular platelet plugs. The main principle of DIC management is adequate treatment of the precipitating disorder; however, there are clinical presentations that may require additional supportive strategies specifically aimed at the amelioration of the coagulopathy.

Neutrophil Extracellular Traps in the Development of Sepsis-Induced Disseminated Intravascular Coagulation

Introduction: Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation complicating many conditions including sepsis and traumatic injuries. Early recognition and treatment of DIC is of paramount importance. However, to date no useful markers have been identified that can differentiate “pre-DIC” (which is destined to lead to DIC) from “without-DIC” (in which the hypercoagulable state is transient and does not lead to DIC). Activation of neutrophils by inflammatory stimuli or microbes results in the release of neutrophil extracellular traps (NETs). NETs are web-like structures consisting of cell-free DNA (cfDNA), histones, myeloperoxidase (MPO), and anti-microbial proteins. Although NETs aid in the host response to infection by sequestering pathogens, excessive production of NETs can exert collateral damage to the host by activating coagulation, inhibiting fibrinolysis, and causing endothelial cell death. Recently, sepsis-induced DIC has been shown to correlate with circulating levels of DNA-associated MPO, suggesting that the release of NETs by neutrophils plays a critical role in the onset of DIC. Our objective was to attempt to identify a mechanistic role for NETosis in the development DIC in sepsis and use this information to identify ‘pre-DIC’ signatures.Methods: Clinical data and biological samples from 357 septic patients who were part of the DNA as a Prognostic Marker in ICU patient (DYNAMICS) study were used. Incidence of DIC was determined using the International Society on Thrombosis and Haemostasis (ISTH) scoring system on Day 1 and each subsequent day. We quantified levels of Citrullinated Histone H3 (H3Cit), a biomarker of NETosis, as well as levels of cfDNA. We also measured levels of Protein C (PC), a natural anticoagulant that prevents blood clotting in the microcirculation. Increased consumption of PC is a hallmark of sepsis and may lead to microvascular thrombosis and DIC.Results: Of the 357 patients included from the DYNAMICS study, 121 were classified as having DIC during the study period: 79 on Day 1 ('overt-DIC') and 42 on a subsequent day ('pre-DIC'). Baseline characteristics of patients are shown in Table 1. Those with DIC had significantly higher baseline APACHE II scores and were significantly more likely to be on vasopressors at admission or have a history of chronic liver disease. DIC was associated with significantly increased mortality (HR= 2.53; 95% CI = 1.62 - 3.93; p < 0.001) even when age and past medical history were controlled for. Levels of PC were significantly reduced in patients with DIC at all time points compared to those without DIC (p < 0.01). However, cfDNA levels did not differ between patients with and without DIC at any timepoint. As cfDNA may be released by multiple mechanisms and sources, H3 Cit was quantified on Day 1 as a marker of NETosis. Levels of H3 Cit on Day 1 were significantly higher in “pre-DIC” and “overt-DIC” patients compared to those 'without DIC' (p<0.05), non-septic, non-trauma ICU Controls (p<0.01), and healthy volunteers (p<0.001) (Figure 1). With respect to differentiating ‘pre-DIC’ from ‘overt-DIC’, using Day 1 H3 Cit provided an AUC of 0.66 (0.59-0.74). Higher H3 Cit levels were also correlated with lower PC levels in septic patients (r = -0.124; p = 0.02). In a comparison group of non-septic trauma patients also from the DYNAMICS study; (n=6) patients with DIC did not have significantly different Day 1 H3 Cit from (n=25) trauma patients without DIC (p=0.62) or ICU controls (p=0.99).Conclusion: In sepsis, DIC pathophysiology reflects a consumptive process as indicated by reduced PC levels. NETosis may contribute to this process by producing pro-coagulant stimuli and may prove useful in identifying patients who will develop DIC. As a regulated and targetable process investigations involving NETosis may yield therapies for early treatment of DIC in sepsis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

β-Thromboglobulin may not reflect platelet activation during haemodialysis with the HeprAN membrane

Background: When blood passes through the extracorporeal circuit during haemodialysis (HD) undesirable effects including platelet degranulation and coagulation activation take place. β-thromboglobulin (β-TG) is a sensitive marker of platelet activation. The aim of this study was to investigate platelet degranulation and coagulation activation during HD with the heparin-coated dialysis membrane HeprAN.Methods: Four HD sessions were evaluated in each of 12 chronic HD patients. None of the patients used oral warfarin, other anticoagulants or antiplatelet drugs. In the first session the HeprAN membrane or a conventional polyflux membrane was used in a randomized manner and thereafter alternately in a cross-over design, and 50% of the conventional dalteparin dose was given at start of HD. Prothrombin fragment 1 + 2 (PF1 + 2), β-TG and anti-factor Xa activity were measured repeatedly.Results: No dialysis sessions were terminated early due to clotting of the extracorporeal system. Activation of intravascular coagulation as assessed by change in PF1 + 2 during 4 hours of HD was the same with the two membranes. β-TG concentration decreased significantly during 4 hours of HD with the HeprAN membrane but remained stable with the polyflux membrane.Conclusion: There were no differences in clotting scores or coagulation activation with the two membranes. The decrease in β-TG during HD with the HeprAN membrane suggests β-TG to be an inferior marker of platelet degranulation when using a heparin-coated dialysis membrane. A possible mechanism for the decline in β-TG concentration may be adherence of this heparin-binding protein to the heparin-coated dialysis membrane.

Therapeutic Effect of Low Doses of Acenocoumarol in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats.

Intravascular activation of coagulation is observed in acute pancreatitis and is related to the severity of this inflammation. The aim of our study was to evaluate the impact of acenocoumarol therapy on the course of acute pancreatitis induced in male rats by pancreatic ischemia followed by reperfusion. Acenocoumarol at a dose of 50, 100, or 150 µg/kg/dose was administered intragastrically once a day, starting the first dose 24 h after the initiation of pancreatic reperfusion. Results: Histological examination showed that treatment with acenocoumarol reduces pancreatic edema, necrosis, and hemorrhages in rats with pancreatitis. Moreover, the administration of acenocoumarol decreased pancreatic inflammatory infiltration and vacuolization of pancreatic acinar cells. These findings were accompanied with a reduction in the serum activity of lipase and amylase, concentration of interleukin-1β, and plasma d-Dimer concentration. Moreover, the administration of acenocoumarol improved pancreatic blood flow and pancreatic DNA synthesis. Acenocoumarol given at a dose of 150 µg/kg/dose was the most effective in the treatment of early phase acute pancreatitis. However later, acenocoumarol given at the highest dose failed to exhibit any therapeutic effect; whereas lower doses of acenocoumarol were still effective in the treatment of acute pancreatitis. Conclusion: Treatment with acenocoumarol accelerates the recovery of ischemia/reperfusion-induced acute pancreatitis in rats.

Thrombophilia and Pregnancy

Background. Women with a predisposition to thrombosis (thrombophilia) during pregnancy develop pathological hypercoagulation, which can lead to early and late pregnancy losses. The most significant polymorphisms of thrombophilia genes include antithrombin III deficiency, protein C deficiency, Leiden mutation, hereditary hyperhomocysteinemia, and mutations of other clotting factors. In addition, several forms of thrombophilia are caused by hyperaggregation. Currently, heparin and its derivatives are considered the safest and most effective agents for the prevention and therapy of thrombosis. However, it is impossible to evaluate the efficacy of heparins using only standard methods (activated partial thromboplastin time, thrombin time, prothrombin time) and markers of intravascular coagulation activation (soluble fibrin-monomer complexes, D-dimer) due to their insufficient sensitivity. One of the new tests of qualitative and quantitative evaluation of the plasma coagulation system is thrombodynamics test, which allows to detect even minimal coagulation disturbances. Aim. The aim was to evaluate the use of the thrombodynamics test in women with first trimester pregnancy pathology. The authors aimed to show the high sensitivity of this test for the monitoring of treatment with low molecular weight heparins (LMWH). Methods. The study included 23 pregnant women with pregnancy pathology and/or history of thrombosis and threatening miscarriage in the first trimester. The women were aged 22-38 years (median age 30 years). The complex evaluation of the hemostatic system was performed using the thrombodynamics test. Results. LMWH therapy with the thrombodynamics monitoring was administered to 20 of 23 women. The statistically significant changes were observed only for thrombodynamics indices (p &lt; 0.05). The total of 14 women delivered healthy children at 38-40 weeks (all patients received LMWH in the first trimester). Conclusion. The thrombodynamics test was the most reliable method of monitoring LMWH therapy, since it allows recording even minimal coagulation disturbances.

Ischemic Colitis Complicated by Consumptive Coagulopathy

Colonic ischemia-induced reperfusion injury can lead to multisystem organ failure, regardless of ischemic colitis etiology. However, it rarely leads to consumptive coagulopathy. A review of the current literature shows that there have been limited reported cases of colonic ischemia-induced consumptive coagulopathy. Known etiologies of disseminated intravascular coagulopathy (DIC) include sepsis, malignancy, trauma, and intravascular hemolysis. Ischemic colitis is not a known cause of disseminated intravascular coagulopathy; however, we can relate it to the mechanism of sepsis-induced disseminated intravascular coagulopathy as sepsis is frequently complicated by disseminated intravascular coagulopathy. Disseminating intravascular coagulopathy is the activation of intravascular coagulation culminating in intravascular fibrin formation and deposition into the microvasculature. Secondary fibrinolysis accompanies coagulation activation. Intravascular deposition of fibrin in sepsis leads to a diffuse obstruction of the microvascular bed resulting in progressive organ dysfunction, such as in acute respiratory distress syndrome, acute kidney injury, hypotension, and shock liver. Both the coagulation activation and the consumption of coagulation inhibitors leading to anticoagulation pathways are activated in sepsis, leading to consumptive coagulopathy. Consumptive coagulopathy was an unexpected response to ischemic colitis. We present a case of a 71 year old Hispanic female with past medical history significant for hypertension presented to our facility with sudden onset diffuse abdominal pain and bright red blood per rectum. Work up revealed hematologic profile significant for DIC in addition to acute kidney injury and ischemic hepatitis, negative for schistocytes on peripheral blood smear. Colonoscopy revealed severe ischemic colitis with submucosal hemorrhage and necrosis involving descending colon. Biopsy from colonoscopy was consistent with observation, revealing acute colitis with focal ischemic changes, granulation tissue, and acute inflammatory exudate of descending colon. We believe that the intense inflammatory reaction of ischemic colitis led to this consumptive coagulopathy. While the known etiologies of disseminated intravascular coagulopathy are numerous, ischemic colitis is rarely presented as one.Table 1: Initial labsTable 2: Resolution of disseminated intravascular coagulopathy in a case of ischemic colitisFigure 1Figure 2

Disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation that can be caused by infectious insults (such as sepsis) and non-infectious insults (such as trauma). The main pathophysiological mechanisms of DIC are inflammatory cytokine-initiated activation of tissue factor-dependent coagulation, insufficient control of anticoagulant pathways and plasminogen activator inhibitor 1-mediated suppression of fibrinolysis. Together, these changes give rise to endothelial dysfunction and microvascular thrombosis, which can cause organ dysfunction and seriously affect patient prognosis. Recent observations have pointed to an important role for extracellular DNA and DNA-binding proteins, such as histones, in the pathogenesis of DIC. The International Society on Thrombosis and Haemostasis (ISTH) established a DIC diagnostic scoring system consisting of global haemostatic test parameters. This scoring system has now been well validated in diverse clinical settings. The theoretical cornerstone of DIC management is the specific and vigorous treatment of the underlying conditions, and DIC should be simultaneously managed to improve patient outcomes. The ISTH guidance for the treatment of DIC recommends treatment strategies that are based on current evidence. In this Primer, we provide an updated overview of the pathophysiology, diagnosis and management of DIC and discuss the future directions of basic and clinical research in this field.

Management of cancer-associated disseminated intravascular coagulation

Cancer may be complicated by the occurrence of disseminated intravascular coagulation (DIC). DIC is characterized by a widespread and intravascular activation of coagulation (leading to intravascular fibrin deposition) and simultaneous consumption of coagulation factors and platelets (potentially resulting in bleeding). Clinically, DIC in cancer has in general a less fulminant presentation than the types of DIC complicating sepsis and trauma. A more gradual, but also more chronic, systemic activation of coagulation can proceed subclinically. Eventually this process may lead to exhaustion of platelets and coagulation factors and bleeding (for example at the site of the tumor) may be the first clinical symptom indicating the presence of DIC. In some cases, the clinical presentation of DIC in cancer may be reminiscent of thrombotic microangiopathies, which is understandable in view of the role of endothelium in both conditions. The therapeutic cornerstone of DIC is treatment of the underlying disorder but supportive treatment, specifically aimed at the hemostatic system may be required.

Glutathione metabolism of erythrocytes in the paroxysmal nocturnal hemoglobinuria

Introduction. Oxidative stress (OS) is involved in the development of vascular inflammation and hemostasis. The aim. We hypothesized that GSH-dependent antioxidant defense system may be affected in paroxysmal nocturnal hemoglobinuria (PNH), causing exacerbation of inflammation and activation of intravascular coagulation and fibrinolysis (AIVCF). Methods. The study involved 63 patients with PNH and 75 healthy people. The concentration of GSH and the activity of glutathione peroxidase (GP), glutathione reductase (GR) and superoxide dismutase (SOD) have been determined in the erythrocytes. Results. We have demonstrated the inhibition of glutathione metabolism and signs of OS, expressed in a significant reduction in levels of GSH and decreased activity of antioxidant enzymes GP, GR and SOD in erythrocytes when compared PNH patients with healthy people. Spearman's test showed significant positive correlation between the activity of GR and GP (R = 0.376; p<0.01) in red blood cells, as well as a weak negative correlation (R = -0.338; p<0.05) between GP activity in erythrocytes and the concentration of D-dimer in the blood plasma in patients with PNH. A positive (R = 0.626; p<0.001) correlation was found between GSH in erythrocytes and plasma concentrations of CRP at CRP concentration values in the range of reference interval. Conclusion. The results are consistent with previously published data on disorders of glutathione metabolism in PNH. The indicators GSH and GP in erythrocytes can be considered as potential markers of AIVCF and vascular inflammation in PNH.