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Rheumatology (Oxford, England) Feb 2024In 2006, at a meeting in Sydney, Australia, consensus was reached by an international group of specialists to establish a number of serological criteria that identify... (Review)
Review
In 2006, at a meeting in Sydney, Australia, consensus was reached by an international group of specialists to establish a number of serological criteria that identify patients with a history of thrombosis or pregnancy complications as having antiphospholipid syndrome (APS). These criteria were originally formulated for research purposes and to compare clinical trials in different centres. However, these same criteria are now generally used and accepted for the diagnosis and treatment of patients. The practice of using these criteria for direct patient care requires that these criteria are based on sound scientific evidence. Indeed, for all the autoantibodies that are officially included in the serological criteria, it has been shown that they induce thrombosis and fetal loss when infused into mice. There are also a number of additional autoantibodies that have been identified in these patients but for these antibodies there was not enough evidence to meet the official APS criteria in 2006. Seventeen years have now passed since the consensus meeting, therefore, this review examines whether additional studies performed with these 'non-criteria' autoantibodies have provided sufficient results to suggest the inclusion of these autoantibodies in the official serological criteria of APS.
Topics: Pregnancy; Female; Humans; Animals; Mice; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Autoantibodies; Thrombosis; Prenatal Care; Prothrombin
PubMed: 38320588
DOI: 10.1093/rheumatology/kead632 -
Journal of Thrombosis and Haemostasis :... Sep 2023The acquired thrombotic risk factor known as lupus anticoagulant (LA) interferes with laboratory clotting assays and can be caused by autoantibodies against...
BACKGROUND
The acquired thrombotic risk factor known as lupus anticoagulant (LA) interferes with laboratory clotting assays and can be caused by autoantibodies against β2-glycoprotein I (β2GPI) and prothrombin. LA is associated with activated protein C (APC) resistance, which might contribute to thrombotic risk in patients with antiphospholipid syndrome. How antibodies against β2GPI and prothrombin cause APC resistance is currently unclear.
OBJECTIVES
To investigate how anti-β2GPI and antiphosphatidylserine/prothrombin (PS/PT) antibodies induce APC resistance.
METHODS
The effects of anti-β2GPI and anti-PS/PT antibodies on APC resistance were studied in plasma (of patients with antiphospholipid syndrome) and with purified coagulation factors and antibodies.
RESULTS
APC resistance was observed in LA-positive patients with anti-β2GPI or anti-PS/PT antibodies and in normal plasma spiked with monoclonal anti-β2GPI or anti-PS/PT antibodies with LA activity. Analysis of factor (F)V cleavage patterns after APC incubation indicated that anti-β2GPI antibodies attenuated APC-mediated FV cleavage at R506 and R306. APC-mediated cleavage at R506 is required for FV cofactor activity during inactivation of FVIIIa. Assays with purified coagulation factors confirmed that anti-β2GPI antibodies interfered with the cofactor function of FV during FVIIIa inactivation but not with FVa inactivation. Anti-PS/PT antibodies attenuated APC-mediated FVa and FVIIIa inactivation. Analysis of FV(a) cleavage patterns after APC incubation indicated that anti-PS/PT antibodies interfere with APC-mediated cleavage of FV at positions R506 and R306.
CONCLUSION
Anti-β2GPI antibodies with LA activity contribute to a procoagulant state by causing APC resistance via interference with the cofactor function of FV during FVIIIa inactivation. LA-causing anti-PS/PT antibodies interfere with the anticoagulant function of APC by preventing FV(a) cleavage.
Topics: Humans; Activated Protein C Resistance; Antiphospholipid Syndrome; Autoantibodies; beta 2-Glycoprotein I; Factor V; Lupus Coagulation Inhibitor; Phosphatidylserines; Protein C; Prothrombin; Thrombosis
PubMed: 37290588
DOI: 10.1016/j.jtha.2023.05.024 -
Annals of Hematology Nov 2023Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease. In the present retrospective study, we aimed to investigate coagulation disorders and...
Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease. In the present retrospective study, we aimed to investigate coagulation disorders and their outcome implications in patients with secondary HLH. We evaluated clinical characteristics and the relationship between coagulation indices and prognosis in HLH patients (n = 141). The information, including clinical symptoms, laboratory indicators, and coagulation indices, was evaluated. Coagulation disorders and bleeding events occurred in 95 (67.4%) and 60 (42.6%) patients, respectively. A coagulation index analysis primarily showed elevated levels of D-Dimer, the international standardized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT), while the prothrombin activity, fibrinogen levels, and platelet levels were significantly decreased. Dominant disseminated intravascular coagulation (DIC) occurred in 76 patients (53.9%). Patients with lymphoma-associated hemophagocytic syndrome (LAHS) frequently exhibited apparent coagulation disorders. Multivariate analysis revealed that age ≥ 29.5 years, bleeding events, APTT ≥ 47.3 s, fibrinogen ≤ 1.68 g/L, and absolute neutrophil counts (ANC) of ≤ 1.21 × 10/L were independent prognostic factors. We thereby devised a prognostic scoring system and stratified patients into low-risk (0-2 points), intermediate-risk (3-4 points), and high-risk (5-7 points) groups, and the 1-year overall survival rates in the above-mentioned groups were 66.40%, 40.00%, and 2.30%, respectively (P < 0.0001). In conclusion, coagulation dysfunctions and bleeding tendencies were common characteristics in HLH patients. We constructed a novel prognostic score model based on APTT, fibrinogen level, ANC, age, and bleeding events, which had superior prognostic value compared with these markers alone.
PubMed: 37561154
DOI: 10.1007/s00277-023-05398-w -
Seminars in Thrombosis and Hemostasis Sep 2023Factor VIII and IX inhibitors in congenital hemophilia A and B, respectively, neutralize the infused coagulation factor concentrate rendering them ineffective. Bypassing... (Review)
Review
Factor VIII and IX inhibitors in congenital hemophilia A and B, respectively, neutralize the infused coagulation factor concentrate rendering them ineffective. Bypassing agents (BPAs) that circumvent the block imposed by the inhibitors are used for the prevention and management of bleeding. Activated prothrombin complex concentrate was the original BPA, recombinant activated factor VII was then introduced, and more recently nonfactor agents that target the procoagulant and anticoagulant systems have been developed and are in clinical use (e.g., emicizumab, a bispecific antibody for hemophilia A). Other BPAs are in clinical trials (e.g., fitusiran targets antithrombin, concizumab and marstacimab target tissue factor pathway inhibitor, and SerpinPC targets activated protein C). The BPAs have a varied effect on coagulation assays, and as more patients are exposed to these agents, it is important to be aware of the effects. Herein, we present an overview of the effect of BPAs on routine and specialized coagulation assays including thrombin generation and viscoelastic assays.
Topics: Humans; Hemophilia A; Factor VIII; Hemorrhage; Hemostatics; Blood Coagulation Tests; Thrombin
PubMed: 37146647
DOI: 10.1055/s-0043-1768660 -
Annals of Emergency Medicine Sep 2023Direct oral anticoagulants (DOACs) are widely used for the prevention and treatment of venous thromboembolism and stroke. When emergency reversal of DOAC-related... (Review)
Review
Direct oral anticoagulants (DOACs) are widely used for the prevention and treatment of venous thromboembolism and stroke. When emergency reversal of DOAC-related anticoagulation is required, specific DOAC reversal agents are recommended, including idarucizumab for dabigatran reversal and andexanet alfa for apixaban and rivaroxaban reversal. However, specific reversal agents are not always available, andexanet alfa has not been approved for urgent surgery, and clinicians need to know the patient's anticoagulant medication before administering these treatments. Four-factor prothrombin complex concentrates (4F-PCCs) are recognized as nonspecific, alternative hemostatic agents for treatment of DOAC-related bleeding. Evidence from preclinical and clinical studies shows that they may reduce the anticoagulant effects of DOACs and may help control DOAC-related bleeding. However, randomized controlled trials are lacking, and most data are from retrospective or single-arm prospective studies in bleeding associated with activated factor X inhibitors. There are no clinical data showing the efficacy of 4F-PCC for the treatment of bleeding in dabigatran-treated patients. This review focuses on the current evidence of 4F-PCC use in controlling bleeding associated with DOACs and provides an expert opinion on the relevance of these data for clinical practice. The current treatment landscape, unmet needs, and future directions are also discussed.
Topics: Humans; Dabigatran; Clinical Relevance; Retrospective Studies; Prospective Studies; Anticoagulants; Hemorrhage; Administration, Oral; Recombinant Proteins
PubMed: 37204347
DOI: 10.1016/j.annemergmed.2023.04.015 -
Blood Coagulation & Fibrinolysis : An... Dec 2023The aim of this study was to define normal percentile values of coagulation parameters in preterm infants below 32 weeks of gestational age. This retrospective cohort...
The aim of this study was to define normal percentile values of coagulation parameters in preterm infants below 32 weeks of gestational age. This retrospective cohort study was conducted at Istanbul Medical Faculty. Preterm infants who were born prior to 32 weeks of gestation, between 2011 and 2021 were included and evaluated for coagulation parameters. Blood samples obtained through umbilical catheters prior to administration of heparinized flushes/fluids, vitamin K or fresh frozen plasma (FFP). Infants with a major bleeding disorder, intrapartum asphyxia or a history of familial bleeding disorders were excluded. Infants were grouped according to their gestational ages and birth weights: less than 24, 25-26, 27-28, 29-30, 31-32 weeks and <500, 500-749, 750-999, 1000-1249, 1250-1499, more than 1500 g. Third to 97th percentile values of both prothrombin time (PT) and activated partial thromboplastin time (aPTT) were defined. A total of 420 preterm infants were included. The median value and range of gestational age and birth weight of the infants were 29 (22.3-32.9) weeks and 1150 (395-2790) g, respectively. PT values were similar between subgroups according to gestational age but longer in infants with a birth weight less than 1000 g. aPTT values in infants born less than 24 weeks of gestation were found significantly longer. As maturation of the coagulation system increases by gestational age, very preterm infants (<32 gestational week (GW)) are under increased risk of bleeding. Determination of normal percentile distribution of coagulation parameters for preterm infants will shed light on the interpretation of coagulation parameters of these infants and minimize unnecessary FFP administrations.
Topics: Infant; Female; Infant, Newborn; Humans; Infant, Premature; Birth Weight; Retrospective Studies; Blood Coagulation; Blood Coagulation Tests; Gestational Age; Blood Coagulation Disorders; Fetal Growth Retardation; Infant, Premature, Diseases; Hemorrhagic Disorders
PubMed: 37823397
DOI: 10.1097/MBC.0000000000001256 -
Medicina (Kaunas, Lithuania) Sep 2023Acquired Hemophilia A (AHA) is a rare autoimmune disorder characterized by the onset of a sudden and unexpected bleeding episode in a patient with no personal or family... (Review)
Review
Acquired Hemophilia A (AHA) is a rare autoimmune disorder characterized by the onset of a sudden and unexpected bleeding episode in a patient with no personal or family history of bleeding diathesis, and with a typical laboratory feature, i.e., a prolonged activated partial thromboplastin time that is not otherwise explained. This bleeding disorder is caused by autoantibodies directed against the coagulation factor VIII (FVIII). AHA is idiopathic in 50% of cases and is secondary to well-defined diseases in the remaining 50%. AHA affects elderly patients although it has also been observed in the post-partum period. Bleeding manifestations are heterogeneous, ranging from mild to life-threatening bleeds involving limbs and organs. Severe bleeding with a significant decrease in hemoglobin levels must be promptly and adequately treated in order to avoid a worsening of the hemorrhages and their complications. According to international recommendations, the bypass agents (i.e., activated prothrombin complex concentrate and activated recombinant factor VII) and the replacement therapy with recombinant porcine FVIII are considered as the first-line therapy for bleeding control, due to their proven clinical efficacy. Plasma-derived or recombinant FVIII concentrates could be used as second-line treatments. Emicizumab may represent a valid and interesting therapeutic option for prophylaxis of bleeding recurrences.
Topics: Humans; Animals; Swine; Aged; Hemophilia A; Hemostatics; Hemorrhage; Autoimmune Diseases
PubMed: 37893457
DOI: 10.3390/medicina59101739 -
Marine Drugs Nov 2023Alginate-based materials have gained significant attention in the medical industry due to their biochemical properties. In this article, we aimed to synthesize...
Alginate-based materials have gained significant attention in the medical industry due to their biochemical properties. In this article, we aimed to synthesize Cotton-Alginate-Copper Composite Materials (COT-AlgCu). The main purpose of this study was to assess the biochemical properties of new composites in the area of blood plasma coagulation processes, including activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT). This study also involved in vitro antimicrobial activity evaluation of materials against representative colonies of Gram-positive and Gram-negative bacteria and antifungal susceptibility tests. The materials were prepared by immersing cotton fibers in an aqueous solution of sodium alginate, followed by ionic cross-linking of alginate chains within the fibers with Cu(II) ions to yield antimicrobial activity. The results showed that the obtained cotton-alginate-copper composites were promising materials to be used in biomedical applications, e.g., wound dressing.
Topics: Copper; Alginates; Anti-Bacterial Agents; Gram-Negative Bacteria; Gram-Positive Bacteria; Blood Coagulation; Prothrombin Time; Partial Thromboplastin Time; Ions
PubMed: 38132946
DOI: 10.3390/md21120625 -
Diagnostics (Basel, Switzerland) Aug 2023Juvenile autoimmune hepatitis (JAIH) is severe immune-mediated necro-inflammatory disease of the liver with spontaneous progression to cirrhosis and liver failure if... (Review)
Review
Juvenile autoimmune hepatitis (JAIH) is severe immune-mediated necro-inflammatory disease of the liver with spontaneous progression to cirrhosis and liver failure if left untreated. The diagnosis is based on the combination of clinical, laboratory and histological findings. Prothrombin ratio is a useful prognostic factor to identify patients who will most likely require a liver transplant by adolescence or early adulthood. JAIH treatment consists of immune suppression and should be started promptly at diagnosis to halt inflammatory liver damage and ultimately prevent fibrosis and progression to end-stage liver disease. The risk of relapse is high especially in the setting of poor treatment compliance. Recent evidence however suggests that treatment discontinuation is possible after a prolonged period of normal aminotransferase activity without the need for liver biopsy prior to withdrawal.
PubMed: 37685291
DOI: 10.3390/diagnostics13172753 -
Seminars in Thrombosis and Hemostasis Sep 2023Clot waveform analysis (CWA) is a recently developed global coagulation assessment, based on the continuous observation of changes in light transmittance, absorbance, or...
Clot waveform analysis (CWA) is a recently developed global coagulation assessment, based on the continuous observation of changes in light transmittance, absorbance, or light scattering that occurs as fibrin formed in a plasma sample during routine clotting tests such as activated partial thromboplastin time (aPTT) and prothrombin time (PT). CWA can utilize qualitative waveform patterns as well as sensitive quantitative parameters and can be used as a simple method to assess global hemostasis, and can be applied to various challenging clinical situations. Although not all coagulation analyzers currently in use are able to provide CWA, the number of analyzers available to do so is increasing, as the usefulness of this process has become more widely recognized. CWA can be based on the coagulation mechanism of aPTT, an intrinsic trigger, and this has been reported in many studies, including diagnosis and treatment of patients with hemophilia, disseminated intravascular coagulation, and monitoring of anticoagulants and thrombosis. CWA using trace amounts of tissue factors also has the potential to expand the applications of this technology. Recently, there have been reports of the combined evaluation of fibrinolytic dynamics. Among the existing global coagulation assays, CWA may prove to be the easiest to standardize in clinical practice. However, more extensive testing using standardized methods in various clinical settings is needed to determine the true role of CWA in the evaluation of hemostasis and thrombosis in the future.
Topics: Humans; Blood Coagulation Tests; Blood Coagulation; Hemostasis; Prothrombin Time; Partial Thromboplastin Time; Thrombosis
PubMed: 36174610
DOI: 10.1055/s-0042-1756706