ABSTRACT
Around the world, with the availability of factor concentrates, patients with haemophilia have undergone major and minor surgeries. Inhibitor development in early postoperative period leading to inadequate factor recovery and ongoing bleeding is a nightmare for both operating surgeon as well as haematologists. We describe a case of an elderly man with mild haemophilia A, who was diagnosed with pancreatic carcinoma and underwent Whipple's procedure. After an uneventful procedure, he developed high-titre inhibitors and bleeding a week after surgery posing major challenges in his management. The case highlights the importance of experienced surgeons, trained haematologists, regular monitoring of factor assay/inhibitors, adequate factor and bypassing-agent support while performing such procedures.
Subject(s)
Blood Coagulation Factors/antagonists & inhibitors , Hemophilia A/immunology , Pancreatic Neoplasms/surgery , Postoperative Hemorrhage/drug therapy , Aged , Antibody Formation/immunology , Blood Coagulation Factors/immunology , Factor VIII/administration & dosage , Factor VIII/therapeutic use , Fatal Outcome , Hematology/standards , Hemophilia A/complications , Humans , Immunoglobulin Fc Fragments/administration & dosage , Immunoglobulin Fc Fragments/therapeutic use , Intracranial Hemorrhages/complications , Male , Pancreatic Neoplasms/complications , Postoperative Complications/epidemiology , Postoperative Complications/immunology , Postoperative Hemorrhage/etiology , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/therapeutic use , Risk Factors , Surgeons/statistics & numerical data , Pancreatic NeoplasmsABSTRACT
A sulfated polysaccharide from the green alga Chaetomorpha linum, designated CLS4, was isolated by water extraction, anion-exchange and size-exclusion chromatography. Chemical and spectroscopic analyses demonstrated that CLS4 was a sulfated arabinogalactan, which was constituted by (1â6)-ß-d-galactopyranose and (1â5)-α-l-arabinofuranose residues with sulfate groups at C-2/ C-3 of (1â5)-α-l-arabinofuranose and C-2/C-4 of (1â6)-ß-d-galactopyranose. CLS4 possessed strong anticoagulant activity in vitro or in vivo as evaluated by activated partial thromboplastin time and thrombin time assays. CLS4 largely inhibited the activities of the coagulation factors XII, XI, IX and VIII. CLS4 was a potent thrombin inhibitor mediated by antithrombin III (ATIII) or heparin cofactor II, and it also effectively stimulated the factor Xa inhibition by potentiating ATIII. Moreover, CLS4 had a high thrombolytic activity in vitro as assessed by clot lytic rate assay. The results suggested that CLS4 could be a promising source of anticoagulant agent.
Subject(s)
Anticoagulants/pharmacology , Blood Coagulation Factors/antagonists & inhibitors , Chlorophyta/chemistry , Galactans/pharmacology , Sulfates/pharmacology , Anticoagulants/chemistry , Anticoagulants/isolation & purification , Carbohydrate Conformation , Galactans/chemistry , Galactans/isolation & purification , Humans , Sulfates/chemistry , Sulfates/isolation & purificationABSTRACT
The review discusses main approaches to searching for new low-molecular-weight inhibitors of coagulation factors IIa, Xa, IXa, and XIa and the results of such studies conducted from 2015 to 2018. For each of these factors, several inhibitors with IC50 < 10 nM have been found, some of which are now tested in clinical trials. However, none of the identified inhibitors meets the requirements for an "ideal" anticoagulant, so further studies are required.
Subject(s)
Anticoagulants/pharmacology , Blood Coagulation Factors/antagonists & inhibitors , Computer-Aided Design , Anticoagulants/chemistry , Blood Coagulation Factors/metabolism , Humans , Molecular WeightABSTRACT
Anticoagulant drugs directly or indirectly influence coagulation factors preventing fibrin formation, thus preventing blood clotting. They are classified into two groups according to the mode of application, namely parenteral and oral drugs. Among the latter, vitamin K antagonists (most often warfarin) were most widely used for almost a century. In recent years new oral anticoagulant drugs have become available that directly target either factor IIa or Xa (direct oral anticoagulants, DOACs). The proportion of patients to whom DOACs are prescribed is increasing because clinical studies have proved they are at least as effective and safe as vitamin K antagonists. Some of the anticoagulant drugs require regular laboratory monitoring, while others only need assessment of blood drug levels in specific clinical situations. This chapter provides an overview of appropriate laboratory tests used for either regular laboratory monitoring of therapy or occasional assessment of the anticoagulant effect of both parenteral and oral anticoagulant drugs used in clinical practice.
Subject(s)
Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Drug Monitoring , Blood Coagulation Factors/antagonists & inhibitors , Humans , Thrombin TimeABSTRACT
Activation of the intrinsic pathway of coagulation contributes to the pathogenesis of arterial and venous thrombosis. Critical insights into the involvement of intrinsic pathway factors have been derived from the study of gene-specific knockout animals and targeted inhibitors. Importantly, preclinical studies have indicated that targeting components of this pathway, including FXI (factor XI), FXII, and PKK (prekallikrein), reduces thrombosis with no significant effect on protective hemostatic pathways. This review highlights the advances made from studying the intrinsic pathway using gene-specific knockout animals and inhibitors in models of arterial and venous thrombosis. Development of inhibitors of activated FXI and FXII may reduce thrombosis with minimal increases in bleeding compared with current anticoagulant drugs.
Subject(s)
Blood Coagulation/physiology , Thrombosis/physiopathology , Animals , Anticoagulants/adverse effects , Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Bleeding Time , Blood Coagulation/drug effects , Blood Coagulation Factors/antagonists & inhibitors , Blood Coagulation Factors/genetics , Blood Coagulation Factors/physiology , Disease Models, Animal , Drug Design , Enzyme Activation , Hemorrhage/chemically induced , Humans , Mice, Knockout , Primates , Rabbits , Rats , Thrombosis/drug therapy , Thrombosis/epidemiology , Thrombosis/prevention & controlABSTRACT
Patients with haemophilia who have developed inhibitors against factor VIII (FVIII) or factor IX present a significant concern to those surgeons who operate on them. The evidence base for bypassing agents such as recombinant factor VIIa and activated prothrombin complex concentrate has amassed over several decades. The literature is open to positive interpretation on the successful use of these agents in the treatment of inhibitor-positive patients. However, there are equally persistent concerns amongst surgeons, in particular orthopaedic surgeons, regarding the high complication rate of bleeding. To explore and quantify this concern, we present a literature review spanning two decades of publications on haemophilia patients with inhibitors undergoing orthopaedic surgery. Irrespective of the progress made with haemostatic protocols, trepidation on embarking on surgery is valid. The high risk of bleeding is a function of the inherent complexity of the disease and rightfully translates into difficulties in its management. Combined with the prospect of orthopaedic surgery, those involved in the care of such patients are justified in their continued anxiety and diligence when considering the benefits in quality of life against the prevalent complications.
Subject(s)
Blood Coagulation Disorders, Inherited/pathology , Hemorrhage/etiology , Isoantibodies/blood , Orthopedic Procedures/adverse effects , Blood Coagulation Disorders, Inherited/surgery , Blood Coagulation Factors/antagonists & inhibitors , Blood Coagulation Factors/therapeutic use , Databases, Factual , Factor VIIa/therapeutic use , Hemorrhage/prevention & control , Humans , Recombinant Proteins/therapeutic useABSTRACT
Native (F2) and carboxyl-reduced (R) ulvans from Ulva fasciata were sequentially oxidized with periodate-chlorite affording the polycarboxyl ulvans C1, C2 and C3 (1.20, 1.41 and 1.81â¯mmolâ¯g-1 of COOH, respectively; 19.7, 21.3 and 21.0% of NaSO3, respectively) and R-C3 (1.86â¯mmolâ¯g-1 of COOH; NaSO3â¯=â¯22.7%), respectively. APTT assay (polysaccharide fractions at 150⯵gâ¯mL-1) showed clotting time of 45.6â¯s for F2 fraction. For polycarboxyl ulvans C1, C2, C3 and R-C3 the clotting times were 101.0, 122.2, 222.0 and 227.0â¯s, respectively. Comparison of the APTT assay results using ulvans chemically modified by carboxyl-reduction, desulfation, periodate oxidation and/or chlorite oxidation showed the anticoagulant activity of polycarboxyl ulvans is dependent of the sulfate groups present in the native polymer. In addition, the increase of the anticoagulant activity was accompanied by the increasing of the carboxyl groups and the content of this acidic substituent seems to be more important than its positioning.
Subject(s)
Anticoagulants/pharmacology , Blood Coagulation Factors/antagonists & inhibitors , Chlorides/pharmacology , Periodic Acid/pharmacology , Polysaccharides/pharmacology , Anticoagulants/chemistry , Chlorides/chemistry , Dose-Response Relationship, Drug , Molecular Conformation , Oxidation-Reduction , Periodic Acid/chemistry , Polysaccharides/chemistryABSTRACT
BACKGROUND/AIMS: The Kunitz Protease Inhibitor (KPI) domain of protease nexin 2 (PN2) potently inhibits coagulation factor XIa. Recombinant KPI has been shown to inhibit thrombosis in mouse models, but its clearance from the murine circulation remains uncharacterized. The present study explored the pharmacokinetic and pharmacodynamic effects of fusing KPI to human serum albumin (HSA) in fusion protein KPIHSA. METHODS: Hexahistidine-tagged KPI (63 amino acids) and KPIHSA (656 amino acids) were expressed in Pichia pastoris yeast and purified by nickel-chelate chromatography. Clearance profiles in mice were determined, as well as the effects of KPI or KPIHSA administration on FeCl3-induced vena cava thrombus size or carotid artery time to occlusion, respectively. RESULTS: Fusion to HSA increased the mean terminal half-life of KPI by 8-fold and eliminated its interaction with the low density lipoprotein receptor-related protein. KPI and KPIHSA similarly reduced thrombus size and occlusion in both venous and arterial thrombosis models when administered at the time of injury, but only KPI was effective when administered one hour before injury. CONCLUSIONS: Albumin fusion deflects KPI from rapid in vivo clearance without impairing its antithrombotic properties and widens its potential therapeutic window.
Subject(s)
Amyloid beta-Protein Precursor/genetics , Serum Albumin, Human/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Area Under Curve , Blood Coagulation Factors/antagonists & inhibitors , Blood Coagulation Factors/metabolism , Chlorides/toxicity , Chromatography, High Pressure Liquid , Disease Models, Animal , Ferric Compounds/toxicity , Half-Life , Histidine/genetics , Humans , Iodine Radioisotopes/chemistry , Mice , Oligopeptides/genetics , Protein Domains/genetics , ROC Curve , Receptors, LDL/chemistry , Receptors, LDL/metabolism , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/isolation & purification , Recombinant Fusion Proteins/pharmacokinetics , Recombinant Fusion Proteins/therapeutic use , Serum Albumin, Human/metabolism , Spectrometry, Mass, Electrospray Ionization , Thrombosis/chemically induced , Thrombosis/prevention & controlABSTRACT
Novel oral anticoagulants (NOACs), which include direct thrombin inhibitor (dabigatran) and direct factor Xa inhibitors (rivaroxaban, apixaban and edoxaban), are gaining popularity in the prevention of embolic stroke in non-valvular atrial fibrillation as well as in the prevention and treatment of venous thromboembolism. However, similar to traditional anticoagulants, NOACs have the side effects of bleeding, including gastrointestinal bleeding (GIB). Results from both randomized clinical trials and observations studies suggest that high-dose dabigatran (150 mg b.i.d), rivaroxaban and high-dose edoxaban (60 mg daily) are associated with a higher risk of GIB compared with warfarin. Other risk factors of NOAC-related GIB include concomitant use of ulcerogenic agents, older age, renal impairment, Helicobacter pylori infection and a past history of GIB. Prevention of NOAC-related GIB includes proper patient selection, using a lower dose of certain NOACs and in patients with renal impairment, correction of modifiable risk factors, and prescription of gastroprotective agents. Overt GIB can be managed by withholding NOACs followed by delayed endoscopic treatment. In severe bleeding, additional measures include administration of activated charcoal, use of specific reversal agents such as idarucizumab for dabigatran and andexanent alfa for factor Xa inhibitors, and urgent endoscopic management.
Subject(s)
Anticoagulants/adverse effects , Atrial Fibrillation/prevention & control , Gastrointestinal Hemorrhage/chemically induced , Gastrointestinal Hemorrhage/therapy , Stroke/prevention & control , Administration, Oral , Anticoagulants/administration & dosage , Anticoagulants/therapeutic use , Blood Coagulation Factors/agonists , Blood Coagulation Factors/antagonists & inhibitors , Clinical Trials as Topic , Endoscopy, Gastrointestinal , Gastrointestinal Hemorrhage/prevention & control , Helicobacter Infections/complications , Humans , Peptic Ulcer/chemically induced , Peptic Ulcer/complications , Risk FactorsSubject(s)
Blood Coagulation Disorders, Inherited/economics , Blood Coagulation Disorders, Inherited/immunology , Blood Coagulation Disorders, Inherited/psychology , Blood Coagulation Disorders, Inherited/therapy , Blood Coagulation Factors/antagonists & inhibitors , Adolescent , Adult , Antibodies/adverse effects , Blood Coagulation Factors/immunology , Blood Transfusion , Child , Child, Preschool , Cost of Illness , Drug Contamination/economics , Drug Contamination/prevention & control , Factor IX/therapeutic use , Factor VIII/therapeutic use , Health Expenditures , Humans , Immunoglobulin Fc Fragments/therapeutic use , Infusions, Intravenous/psychology , Mobile Applications , Quality of Life , Recombinant Fusion Proteins/therapeutic use , Recombinant Proteins/therapeutic use , United Kingdom , Video GamesABSTRACT
INTRODUCTION: For a long time, vitamin K antagonists (VKA) have been the preferred drugs for the anticoagulation management of both atrial fibrillation and venous thromboembolism. Hereby, the major purpose is to attenuate the onset of thrombosis without affecting hemostasis. Areas covered: Nowadays, non-vitamin K anticoagulants (NOAC), a new class of oral anticoagulants is available for the above-mentioned indications. NOAC are at least as effective and safer with regard to intracranial bleedings compared to VKA, but major bleedings still occur. For this reason, the search for safer anticoagulants is still ongoing. Expert commentary: There are several unmet needs in NOAC management, including selection of optimal drug and dose, uncertainty on specific conditions and lack of drug persistence. There remains to be an important need for safer anticoagulants; 'upstream' anticoagulants including inhibitors of factor XIa may provide additional benefit related to fewer bleeding complications.
Subject(s)
Anticoagulants/pharmacology , Blood Coagulation Factors/antagonists & inhibitors , Thrombin/antagonists & inhibitors , Administration, Oral , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Antithrombins/adverse effects , Antithrombins/pharmacology , Antithrombins/therapeutic use , Blood Coagulation/drug effects , Blood Coagulation/physiology , Fibrinolytic Agents/adverse effects , Fibrinolytic Agents/pharmacology , Fibrinolytic Agents/therapeutic use , Humans , Thrombin/physiology , Vitamin K/adverse effects , Vitamin K/antagonists & inhibitors , Warfarin/adverse effects , Warfarin/pharmacologyABSTRACT
BACKGROUND AND OBJECTIVES: Atrial fibrillation (AF) and the associated risk of stroke are emerging epidemics throughout the world. Suboptimal use of oral anticoagulants for stroke prevention has been widely reported from observational studies. In recent years, direct oral anticoagulants (DOACs) have been introduced for thromboprophylaxis. We conducted a systematic literature review to evaluate current practices of anticoagulation in AF, pharmacologic features and adoption patterns of DOACs, their impacts on proportion of eligible patients with AF who receive oral anticoagulants, persisting challenges and future prospects for optimal anticoagulation. LITERATURE SOURCE AND SELECTION CRITERIA: In conducting this review, we considered the results of relevant prospective and retrospective observational studies from real-world practice settings. PubMed (MEDLINE), Scopus (RIS), Google Scholar, EMBASE and Web of Science were used to source relevant literature. There were no date limitations, while language was limited to English. Selection was limited to articles from peer reviewed journals and related to our topic. RESULTS: Most studies identified in this review indicated suboptimal use of anticoagulants is a persisting challenge despite the availability of DOACs. Underuse of oral anticoagulants is apparent particularly in patients with a high risk of stroke. DOAC adoption trends are quite variable, with slow integration into clinical practice reported in most countries; there has been limited impact to date on prescribing practice. CONCLUSION: Available data from clinical practice suggest that suboptimal oral anticoagulant use in patients with AF and poor compliance with guidelines still remain commonplace despite transition to a new era of anticoagulation featuring DOACs.
Subject(s)
Antithrombins/administration & dosage , Atrial Fibrillation/drug therapy , Blood Coagulation Factors/antagonists & inhibitors , Evidence-Based Medicine , Practice Guidelines as Topic , Practice Patterns, Physicians' , Stroke/prevention & control , Administration, Oral , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Antithrombins/adverse effects , Antithrombins/therapeutic use , Atrial Fibrillation/etiology , Blood Coagulation Factors/metabolism , Dabigatran/administration & dosage , Dabigatran/adverse effects , Dabigatran/therapeutic use , Dose-Response Relationship, Drug , Factor Xa Inhibitors/administration & dosage , Factor Xa Inhibitors/adverse effects , Factor Xa Inhibitors/therapeutic use , Humans , Medication Errors/prevention & control , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Pyridines/administration & dosage , Pyridines/adverse effects , Pyridines/therapeutic use , Pyridones/administration & dosage , Pyridones/adverse effects , Pyridones/therapeutic use , Risk Assessment , Risk Factors , Rivaroxaban/administration & dosage , Rivaroxaban/adverse effects , Rivaroxaban/therapeutic use , Stroke/epidemiology , Stroke/physiopathology , Thiazoles/administration & dosage , Thiazoles/adverse effects , Thiazoles/therapeutic use , Warfarin/administration & dosage , Warfarin/adverse effects , Warfarin/therapeutic useABSTRACT
The vitamin K antagonists (VKAs) have been the standard (and only) oral anticoagulants used for the long-term treatment or prevention of venous thromboembolism or stroke in patients with atrial fibrillation. The coagulopathy induced by VKAs can be reversed with vitamin K, and in urgent situations, the vitamin K-dependent coagulation factors can be replaced by transfusion. In the last decade, a new class of oral anticoagulants has been developed, direct oral anticoagulants that bind to a specific coagulation factor and neutralize it. These compounds were shown to be effective and safe compared with the VKAs and were licensed for specific indications, but without a specific reversal agent. The absence of a reversal agent is a barrier to more widespread use of these agents. Currently, for the management of major life-threatening bleeding with the direct oral anticoagulants, most authorities recommend the use of four factor prothrombin complex concentrates. There are now three reversal agents in development and poised to enter the market. Idarucizumab is a specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran, which was recently approved for use in the USA. Andexanet alfa is an antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor enoxaparin. Ciraparantag is an antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor enoxaparin.
Subject(s)
Anticoagulants/adverse effects , Blood Coagulation Disorders/drug therapy , Blood Coagulation Factors/antagonists & inhibitors , Coagulants/therapeutic use , Practice Guidelines as Topic , Administration, Oral , Animals , Antibodies, Monoclonal, Humanized/therapeutic use , Anticoagulants/administration & dosage , Anticoagulants/chemistry , Antifibrinolytic Agents/therapeutic use , Antithrombins/administration & dosage , Antithrombins/adverse effects , Antithrombins/chemistry , Arginine/analogs & derivatives , Arginine/therapeutic use , Blood Coagulation Disorders/chemically induced , Blood Coagulation Disorders/prevention & control , Blood Coagulation Disorders/therapy , Blood Coagulation Factors/agonists , Blood Coagulation Factors/metabolism , Blood Coagulation Factors/therapeutic use , Combined Modality Therapy , Dabigatran/administration & dosage , Dabigatran/adverse effects , Dabigatran/antagonists & inhibitors , Drugs, Investigational , Enoxaparin/administration & dosage , Enoxaparin/adverse effects , Enoxaparin/antagonists & inhibitors , Factor Xa/therapeutic use , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/adverse effects , Fibrinolytic Agents/chemistry , Humans , Piperazines/therapeutic use , Recombinant Proteins/therapeutic use , Vitamin K/agonists , Vitamin K/antagonists & inhibitors , Vitamin K/metabolism , Vitamin K/therapeutic useABSTRACT
Little is known about the molecular mechanisms whereby the human blood fluke Schistosoma japonicum is able to survive in the host venous blood system. Protease inhibitors are likely released by the parasite enabling it to avoid attack by host proteolytic enzymes and coagulation factors. Interrogation of the S. japonicum genomic sequence identified a gene, SjKI-1, homologous to that encoding a single domain Kunitz protein (Sjp_0020270) which we expressed in recombinant form in Escherichia coli and purified. SjKI-1 is highly transcribed in adult worms and eggs but its expression was very low in cercariae and schistosomula. In situ immunolocalization with anti-SjKI-1 rabbit antibodies showed the protein was present in eggs trapped in the infected mouse intestinal wall. In functional assays, SjKI-1 inhibited trypsin in the picomolar range and chymotrypsin, neutrophil elastase, FXa and plasma kallikrein in the nanomolar range. Furthermore, SjKI-1, at a concentration of 7·5 µ m, prolonged 2-fold activated partial thromboplastin time of human blood coagulation. We also demonstrate that SjKI-1 has the ability to bind Ca(++). We present, therefore, characterization of the first Kunitz protein from S. japonicum which we show has an anti-coagulant properties. In addition, its inhibition of neutrophil elastase indicates SjKI-1 have an anti-inflammatory role. Having anti-thrombotic properties, SjKI-1 may point the way towards novel treatment for hemostatic disorders.
Subject(s)
Blood Coagulation Factors/antagonists & inhibitors , Protease Inhibitors/metabolism , Schistosoma japonicum/metabolism , Amino Acid Sequence , Animals , Aprotinin/genetics , Aprotinin/immunology , Aprotinin/metabolism , Calcium/metabolism , Cattle , Cluster Analysis , Female , Gene Expression Regulation, Developmental , Humans , Male , Mice , Protease Inhibitors/chemistry , Protease Inhibitors/immunology , Protein Structure, Secondary , Rabbits , Schistosoma japonicum/genetics , Sequence Alignment , SnailsABSTRACT
The humoral barrier in transplant biology is the result of preformed donor-specific antibodies (DSAs), directed either against human leukocyte antigens (HLA) or non-HLA antigens such as blood group (ABO) molecules. The term "sensitization" applies to patients carrying these antibodies. Transplantation is widely accepted as a life-saving opportunity for patients with terminal end-organ disease. However, in sensitized patients, transplant outcome is hampered by antibody-mediated rejection (AMR) as a consequence of DSA exposure. Furthermore, sensitized patients have limited access to "matched" organs from the both living and deceased donor pool.Considering the crucial role of the complement system in the pathophysiology of AMR and the availability of complement intervention therapeutics, there is a growing interest in complement-targeting strategies. This review highlights the emerging importance of monitoring and modulation of the complement system in the context of enabling transplantation across humoral incompatibility in sensitized recipients with preformed anti-HLA or natural anti-ABO antibodies. It also discusses the significance of the complement system in the induction of accommodation and further emphasizes current and future perspectives of novel complement therapeutics.
Subject(s)
Complement Activation/drug effects , Complement Inactivating Agents/therapeutic use , Graft Rejection/prevention & control , Immunity, Humoral/drug effects , Kidney Transplantation , ABO Blood-Group System/genetics , ABO Blood-Group System/immunology , Antibodies, Monoclonal, Humanized/therapeutic use , Antibody Formation/drug effects , Blood Coagulation Factors/antagonists & inhibitors , Blood Coagulation Factors/genetics , Blood Coagulation Factors/immunology , Complement C1 Inhibitor Protein/therapeutic use , Complement System Proteins/drug effects , Complement System Proteins/genetics , Complement System Proteins/immunology , Desensitization, Immunologic/methods , Gene Expression , Graft Rejection/immunology , Graft Rejection/pathology , HLA Antigens/genetics , HLA Antigens/immunology , Histocompatibility Testing , Humans , Unrelated DonorsABSTRACT
The proper performance and interpretation of factor inhibitor assays is a critical role for the hemostasis laboratory. Both false-positive and false-negative inhibitor assays may be reported, leading to serious patient mismanagement. Knowledge and recognition of common causes of both false-positive and negative-results can aid in the identification of these potential pitfalls. Safeguards to reporting accurate factor inhibitor assays include initial characterization of the sample, using the Nijmegen modification, properly performing and interpreting an incubated mixing test in conjunction, and performing two dilutions for each dependent dilution in the factor inhibitor assay.
Subject(s)
Blood Coagulation Factor Inhibitors/therapeutic use , Blood Coagulation Factors/antagonists & inhibitors , Blood Coagulation Tests/methods , Blood Coagulation Tests/standards , False Negative Reactions , False Positive Reactions , Humans , Quality Assurance, Health Care/methods , Quality Assurance, Health Care/standards , Reproducibility of ResultsABSTRACT
One important complication of patients with severe haemophilia A is the formation of inhibitory antibodies to factor VIII (FVIII). Immune tolerance induction (ITI) is the treatment of choice for patients with inhibitors, but this approach is successful in about 60% of patients. Treatment of acute bleeding in patients with inhibitors is one of the greatest challenges in haemophilia management and is costly. Bypassing agents are the mainstay of treatment in these patients. The aims of this study were to review the most recent publications concerning the costs of inhibitor treatment. We conducted a literature review using PubMed which yielded 63 papers analysing the costs of inhibitor management of which 12 were suitable for our study. Four of eight studies supported the use of activated prothrombin complex concentrate (aPCC) with lower costs, but the remaining four studies showed that recombinant factor VIIa (rFVIIa) had a lower average treatment cost. Of four ITI studies, two supported lifelong cost-effectiveness of ITI vs. bypassing agents and the remaining two papers showed a high cost of inhibitor treatment. Dosages, time between onset of bleeding and treatment, patient characteristics and the price of drugs are some of the important issues that should be considered for further studies.
Subject(s)
Antibodies/blood , Blood Coagulation Factors/economics , Factor VIII/economics , Health Care Costs , Hemophilia A/economics , Hemorrhage/economics , Blood Coagulation Factors/antagonists & inhibitors , Blood Coagulation Factors/immunology , Blood Coagulation Factors/therapeutic use , Clinical Trials as Topic , Factor VIII/antagonists & inhibitors , Factor VIII/immunology , Factor VIII/therapeutic use , Hemophilia A/blood , Hemophilia A/drug therapy , Hemophilia A/immunology , Hemorrhage/blood , Hemorrhage/drug therapy , Hemorrhage/immunology , Humans , Immune Tolerance , Severity of Illness Index , Time FactorsABSTRACT
Viper bites cause high morbidity and mortality especially in tropical and subtropical regions, affecting a large number of the rural population in these areas. Even though anti-venoms are available, in most cases they fail to tackle viper venom-induced local manifestations that persist even after anti-venom administration. Several studies have been reported the use of plant products and approved drugs along side anti-venom therapy for efficient management of local tissue damage. In this regard, the present study focuses on the protective efficacy of Cassia auriculata L. (Leguminosae) against Echis carinatus venom (ECV) induced toxicity. C. auriculata is a traditional medicinal plant, much valued in alternative medicine for its wide usage in ayurveda, naturopathy, and herbal therapy. Further, it has been used widely by traditional healers for treatment of snake and scorpion bites in the Western Ghats of Karnataka, India. In the present study, C. auriculata leaf methanol extract (CAME) significantly inhibited enzymatic activities of ECV proteases (96 ± 1 %; P = 0.001), PLA2 (45 ± 5 %; P = 0.01) and hyaluronidases (100 %; P = 0.0003) in vitro and hemorrhage, edema and myotoxicity in vivo. Further, CAME effectively reduced the lethal potency of ECV and increased the survival time of mice by ~6 times (17 vs 3 h). These inhibitory potentials of CAME towards hydrolytic enzymes, mortal and morbid symptoms of ECV toxins clearly substantiates the use by traditional healers of C. auriculata as a folk medicinal remedy for snakebite.
Subject(s)
Antivenins/therapeutic use , Cassia/chemistry , Phytotherapy , Viper Venoms/antagonists & inhibitors , Animals , Antivenins/chemistry , Blood Coagulation Factors/antagonists & inhibitors , Edema/chemically induced , Edema/prevention & control , Hemorrhage/chemically induced , Hemorrhage/prevention & control , Humans , Hyaluronoglucosaminidase/antagonists & inhibitors , Male , Methanol , Mice , Phenols/isolation & purification , Phytochemicals/chemistry , Plant Extracts/chemistry , Plant Leaves/chemistry , Viper Venoms/toxicityABSTRACT
The main purpose of anticoagulants is to diminish fibrin formation, thereby decreasing the risk of venous or arterial thrombosis. Vitamin K antagonist have been used for many decades in order to achieve reduced thrombotic risk, despite major drawbacks of this class of drugs such as cumbersome dossing and monitoring of anticoagulant status. To overcome these drawbacks of VKA, new classes of anticoagulants have been developed including oral anticoagulants for direct inhibition of either thrombin or factor Xa, which can be administrated in a fixed dose without monitoring. Coagulation factors can activate cellular protease-activated receptors, thereby inducing cellular processes as inflammation, apoptosis, migration, and fibrosis. Therefore, inhibition of coagulation proteases not only attenuates fibrin formation, but may also influence pathophysiological processes like vascular calcification and atherosclerosis. Animal models revealed that VKA therapy induced both intima and media calcification and accelerated plaque vulnerability, whereas specific and direct inhibition of thrombin or factor Xa attenuated atherosclerosis. In this review we provide an overview of old and new oral anticoagulants, as well discuss potential pleiotropic effects with regard to calcification and atherosclerosis. Although translation from animal model to clinical patients seems difficult at first sight, effort should be made to fully understand the clinical implications of long-term oral anticoagulant therapy on vascular side effects.