BACKGROUND AND PURPOSE: The ANNEXA-4 trial measured hemostatic efficacy of andexanet alfa in patients with major bleeding taking factor Xa inhibitors. A proportion of this was traumatic and nontraumatic intracranial bleeding. Different measurements were applied in the trial including volumetrics to assess for intracranial bleeding depending on the compartment involved. We aimed to determine the most reliable way to measure intracranial hemorrhage (ICrH) volume by comparing individual brain compartment and total ICrH volume. METHODS: Thirty patients were randomly selected from the ANNEXA-4 database to assess measurement of ICrH volume by compartment and in total. Total and compartmental hemorrhage volumes were measured by five readers using Quantomo software. Each reader measured baseline hemorrhage volumes twice separated by 1 week. Twenty-eight different ANNEXA-4 subjects were also randomly selected to assess intra-rater reliability of total ICrH volume measurement change at baseline and 12-h follow up, performed by three readers twice to assess hemostatic efficacy categories used in ANNEXA-4. RESULTS: Compartmental minimal detectable change percentages (MDC%) ranged between 9.72 and 224.13, with the greatest measurement error occurring in patients with a subdural hemorrhage. Total ICrH volume measurements had the lowest MDC%, which ranged between 6.57 and 33.52 depending on the reader. CONCLUSION: Measurement of total ICrH volumes is more accurate than volume by compartment with less measurement error. Determination of hemostatic efficacy was consistent across readers, and within the same reader, as well as when compared to consensus read. Volumetric analysis of intracranial hemostatic efficacy is feasible and reliable when using total ICrH volumes.

• MeSH
• Adult MeSH
• Factor Xa * MeSH
• Factor Xa Inhibitors administration & dosage   therapeutic use   MeSH
• Intracranial Hemorrhages * MeSH
• Middle Aged MeSH
• Humans MeSH
• Brain diagnostic imaging   MeSH
• Recombinant Proteins administration & dosage   MeSH
• Reproducibility of Results MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

• MeSH
• Acute Disease MeSH
• Cerebral Hemorrhage * drug therapy   chemically induced   MeSH
• Factor Xa * therapeutic use   adverse effects   MeSH
• Atrial Fibrillation drug therapy   complications   MeSH
• Hematoma * chemically induced   drug therapy   MeSH
• Factor Xa Inhibitors * adverse effects   therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Recombinant Proteins * therapeutic use   adverse effects   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

The treatment of hemophilia A has progressed amazingly in recent years. Emicizumab, a bispecific-humanized monoclonal antibody, is able to improve coagulation by bridging activated factor IX and factor X. Emicizumab is administered subcutaneously and much less often compared to factor VIII products. It has low immunogenicity, does not require dose adjustment, and can be administered regardless of the presence of factor VIII inhibitors. Thrombin generation assays but not factor VIII activity are indicated to guide and monitor the treatment. Emicizumab has enabled the conversion of patients with severe forms into patients with milder forms of hemophilia A. It has reduced the number of bleeding episodes compared to both on-demand and prophylactic substitution therapy and has an excellent safety profile. Gene therapy can elevate factor VIII plasma levels for many years after a single treatment course, could offer long-term protection from bleeding episodes, and minimize or eliminate the need for substitutive treatment with factor VIII concentrates. Gene therapy can provoke an immune response, manifested by an increase in common liver enzymes, that require immunotherapy. Long term monitoring is necessary to identify possible adverse effects. Future objectives are: the development of an ideal viral vector, the possibility of its re-administration, the use of gene therapy in hemophiliac children, and determining whether it can be successfully used to induce immune tolerance to factor VIII ceteri paribus. The future will determine the place of each type of treatment and group of patients for which it is indicated.

• MeSH
• Child MeSH
• Factor X therapeutic use   MeSH
• Genetic Therapy MeSH
• Hemophilia A * drug therapy   MeSH
• Humans MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

INTRODUCTION: Critically ill patients are exposed to a high risk of developing thromboembolism. Moreover, standard prophylaxis with subcutaneous (SC) heparin is less efficient in patients requiring vasopressors. The aim is a comparison of pharmacokinetics between SC and intravenous (IV) applied nadroparin. METHODS: Thirty-eight ventilated ICU patients requiring vasopressor support were randomized into a single dose of nadroparin 3,800 IU (0.4 mL) subcutaneously (SC group) or 1,900 IU (0.2 mL) intravenously (IV group). Anti-factor Xa activity (anti-Xa) was observed over 24 h; data are stated as median (IQR). RESULTS: Peak anti-Xa was significantly higher in the IV group 0.42 (0.39-0.43) IU/mL than in the SC group 0.16 (0.09-0.18) IU/mL (p < 0.001). There was a trend towards higher area under the curve (AUC) of anti-Xa in the SC group 1.41 (0.41-1.80) IU/mL × h than in the IV group 1.04 (0.93-1.13) IU/mL × h (p = 0.08). In the SC group, there was a negative correlation between anti-Xa AUC and both capillary refill time Xa (r = -0.86) and norepinephrine dose (r = -0.68). In the IV group, anti-Xa decrease half-life was 1.6 (1.4-2.0) h. CONCLUSIONS: IV administration of 1,900 IU of nadroparin led to a predictable effective peak anti-Xa. After SC administration, anti-Xa was heterogeneous and significantly influenced by peripheral perfusion.

• MeSH
• Anticoagulants administration & dosage   pharmacokinetics   MeSH
• Factor Xa analysis   MeSH
• Injections, Subcutaneous MeSH
• Administration, Intravenous MeSH
• Critical Illness MeSH
• Middle Aged MeSH
• Humans MeSH
• Nadroparin administration & dosage   pharmacokinetics   MeSH
• Aged MeSH
• Vasoconstrictor Agents therapeutic use   MeSH
• Venous Thromboembolism prevention & control   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH

V současné době nová přímá perorální antikoagulancia (DOAC) postupně nahrazují dosavadní historicky nejčastěji užívaný warfarin. Jedná se o dvě skupiny léčiv přímo inhibující faktor Xa (Xarelto, Eliquis, Lixiana) a trombin (Pradaxa). Nabízí mnohá pozitiva, která ocení i samotní pacienti. Jedná se zejména o odpadnutí nutnosti pravidelné monitorace, minimum lékových a potravinových interakcí či příznivý bezpečnostní profil. Nicméně jako jednu z nevýhod lze vnímat nepřítomnost antidota při předávkování. Své specifické antidotum - Idarucizumab - má v současné době pouze Pradaxa. Ostatní jsou ve vývoji, stejně tak jako nové molekuly samotných antikoagulancií.

Currently, new direct oral anticoagulants (DOAC) are gradually replacing the historically most frequently used warfarin. These are two classes of drugs directly inhibiting factor Xa (Xarelto, Eliquis, Lixiana) and thrombin (Pradaxa). It offers many positives that patients themselves will appreciate. These include, in particular, no need for regular monitoring, minimal drug and food interactions, or afavorable safety profile. However, one of the drawbacks is the absence of antidotes for overdose. Only Pradaxa currently has its specific antidote - Idarucizumab. Others are in development as well as new molecules of anticoagulants themselves.

• Keywords
• betrixaban, darexaban, otamixaban, andexanet, ciraparantag,
• MeSH
• Antidotes pharmacology   therapeutic use   MeSH
• Anticoagulants * pharmacokinetics   pharmacology   therapeutic use   MeSH
• Azepines pharmacokinetics   pharmacology   therapeutic use   MeSH
• Benzamides pharmacokinetics   pharmacology   therapeutic use   MeSH
• Cyclic N-Oxides pharmacokinetics   pharmacology   therapeutic use   MeSH
• Factor Xa analogs & derivatives   therapeutic use   drug effects   MeSH
• Factor Xa Inhibitors * pharmacokinetics   pharmacology   therapeutic use   MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Thromboembolism prevention & control   MeSH
• Check Tag
• Humans MeSH

• MeSH
• Adenocarcinoma of Lung complications   MeSH
• Enoxaparin * administration & dosage   therapeutic use   MeSH
• Factor Xa MeSH
• Heparin, Low-Molecular-Weight * administration & dosage   pharmacokinetics   adverse effects   MeSH
• Carcinoma, Renal Cell complications   MeSH
• Middle Aged MeSH
• Humans MeSH
• Nadroparin administration & dosage   therapeutic use   MeSH
• Pneumonia complications   MeSH
• Thromboembolism prevention & control   MeSH
• Treatment Outcome MeSH
• Venous Thrombosis diagnosis   drug therapy   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH

V současné době nová přímá perorální antikoagulancia (DOAC) postupně nahrazují dosavadní historicky nejčastěji užívaný warfarin. Jedná se o dvě skupiny léčiv přímo inhibující faktor Xa (Xarelto, Eliquis, Lixiana) a trombin (Pradaxa). Nabízí mnohá pozitiva, která ocení i samotní pacienti. Jedná se zejména o odpadnutí nutnosti pravidelné monitorace, minimum lékových a potravinových interakcí či příznivý bezpečnostní profil. Nicméně jako jednu z nevýhod lze vnímat nepřítomnost antidota při předávkování. Své specifické antidotum - Idarucizumab - má v současné době pouze Pradaxa. Ostatní jsou ve vývoji, stejně tak jako nové molekuly samotných antikoagulancií.

Currently, new direct oral anticoagulants (DOAC) are gradually replacing the historically most frequently used warfarin. These are two classes of drugs directly inhibiting factor Xa (Xarelto, Eliquis, Lixiana) and thrombin (Pradaxa). It offers many positives that patients themselves will appreciate. These include, in particular, no need for regular monitoring, minimal drug and food interactions, or afavorable safety profile. However, one of the drawbacks is the absence of antidotes for overdose. Only Pradaxa currently has its specific antidote - Idarucizumab. Others are in development as well as new molecules of anticoagulants themselves.

• Keywords
• betrixaban, darexaban, otamixaban, andexanet, ciraparantag,
• MeSH
• Antidotes pharmacology   therapeutic use   MeSH
• Anticoagulants * pharmacokinetics   pharmacology   therapeutic use   MeSH
• Azepines pharmacokinetics   pharmacology   therapeutic use   MeSH
• Benzamides pharmacokinetics   pharmacology   therapeutic use   MeSH
• Cyclic N-Oxides pharmacokinetics   pharmacology   therapeutic use   MeSH
• Factor Xa analogs & derivatives   therapeutic use   drug effects   MeSH
• Factor Xa Inhibitors * pharmacokinetics   pharmacology   therapeutic use   MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Thromboembolism prevention & control   MeSH
• Check Tag
• Humans MeSH

Serine peptidases are involved in many physiological processes including digestion, haemostasis and complement cascade. Parasites regulate activities of host serine peptidases to their own benefit, employing various inhibitors, many of which belong to the Kunitz-type protein family. In this study, we confirmed the presence of potential anticoagulants in protein extracts of the haematophagous monogenean Eudiplozoon nipponicum which parasitizes the common carp. We then focused on a Kunitz protein (EnKT1) discovered in the E. nipponicum transcriptome, which structurally resembles textilinin-1, an antihemorrhagic snake venom factor from Pseudonaja textilis. The protein was recombinantly expressed, purified and biochemically characterised. The recombinant EnKT1 did inhibit in vitro activity of Factor Xa of the coagulation cascade, but exhibited a higher activity against plasmin and plasma kallikrein, which participate in fibrinolysis, production of kinins, and complement activation. Anti-coagulation properties of EnKT1 based on the inhibition of Factor Xa were confirmed by thromboelastography, but no effect on fibrinolysis was observed. Moreover, we discovered that EnKT1 significantly impairs the function of fish complement, possibly by inhibiting plasmin or Factor Xa which can act as a C3 and C5 convertase. We localised Enkt1 transcripts and protein within haematin digestive cells of the parasite by RNA in situ hybridisation and immunohistochemistry, respectively. Based on these results, we suggest that the secretory Kunitz protein of E. nipponicum has a dual function. In particular, it impairs both haemostasis and complement activation in vitro, and thus might facilitate digestion of a host's blood and protect a parasite's gastrodermis from damage by the complement. This study presents, to our knowledge, the first characterisation of a Kunitz protein from monogeneans and the first example of a parasite Kunitz inhibitor that impairs the function of the complement.

• MeSH
• Antifibrinolytic Agents chemistry   immunology   MeSH
• Anticoagulants chemistry   immunology   MeSH
• Factor Xa immunology   MeSH
• Hemostasis * MeSH
• Trematode Infections blood   immunology   parasitology   veterinary   MeSH
• Enzyme Inhibitors chemistry   immunology   MeSH
• Factor Xa Inhibitors chemistry   immunology   MeSH
• Host-Parasite Interactions MeSH
• Carps blood   immunology   parasitology   MeSH
• Complement System Proteins immunology   MeSH
• Fish Diseases blood   immunology   parasitology   MeSH
• Fibrinolysin immunology   MeSH
• Plasma Kallikrein antagonists & inhibitors   immunology   MeSH
• Helminth Proteins chemistry   genetics   immunology   MeSH
• Amino Acid Sequence MeSH
• Sequence Alignment MeSH
• Trematoda chemistry   genetics   immunology   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Anticoagulants therapeutic use   MeSH
• Factor Xa metabolism   MeSH
• International Normalized Ratio MeSH
• Humans MeSH
• Heart-Assist Devices * MeSH
• Reproducibility of Results MeSH
• Heart Failure blood   therapy   MeSH
• Vitamin K antagonists & inhibitors   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Letter MeSH
• Research Support, Non-U.S. Gov't MeSH

Podáváme přehled o farmakologii a klinickém použití 4F‑PCC (four‑factor prothrombin complex concentrate) přípravku Beriplex® při obnově koagulace u nemocných léčených antagonisty vitaminu K, při substituci koagulačních faktorů II, VII, IX, X a také v případě život ohrožujícího krvácení, včetně krvácení vyvolaného užíváním nových perorálních antikoagulancií apixabanu, edoxabanu a rivaroxabanu, pro něž zatím není k dispozici specifické antidotum.

We present an overview of pharmacology and clinical use of 4F‑PCC (four‑factor prothrombin complex concentrate) manufactured as Beriplex® with respect to restitution of coagulation in patients treated with vitamin K antagonists, to substitution of coagulation factors (II, VII, IX, X), and also to life‑threatening hemorrhages including those affecting patients using new oral anticoagulants such as apixaban, edoxaban, and rivaroxaban with no specific antidotes available.

• Keywords
• Beriplex, NOAC, 4F-PCC,
• MeSH
• Acute Disease MeSH
• Antidotes MeSH
• Anticoagulants adverse effects   MeSH
• Factor IX therapeutic use   MeSH
• Factor VII therapeutic use   MeSH
• Factor X therapeutic use   MeSH
• Drug Combinations MeSH
• Blood Coagulation drug effects   MeSH
• Factor Xa Inhibitors adverse effects   MeSH
• Blood Loss, Surgical prevention & control   MeSH
• Hemorrhage * drug therapy   chemically induced   prevention & control   MeSH
• Humans MeSH
• Prothrombin therapeutic use   MeSH
• Vitamin K antagonists & inhibitors   MeSH
• Drug Dosage Calculations MeSH
• Warfarin adverse effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH