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Nature Reviews. Disease Primers Jun 2021Haemophilia A and B are rare congenital, recessive X-linked disorders caused by lack or deficiency of clotting factor VIII (FVIII) or IX (FIX), respectively. The... (Review)
Review
Haemophilia A and B are rare congenital, recessive X-linked disorders caused by lack or deficiency of clotting factor VIII (FVIII) or IX (FIX), respectively. The severity of the disease depends on the reduction of levels of FVIII or FIX, which are determined by the type of the causative mutation in the genes encoding the factors (F8 and F9, respectively). The hallmark clinical characteristic, especially in untreated severe forms, is bleeding (spontaneous or after trauma) into major joints such as ankles, knees and elbows, which can result in the development of arthropathy. Intracranial bleeds and bleeds into internal organs may be life-threatening. The median life expectancy was ~30 years until the 1960s, but improved understanding of the disorder and development of efficacious therapy based on prophylactic replacement of the missing factor has caused a paradigm shift, and today individuals with haemophilia can look forward to a virtually normal life expectancy and quality of life. Nevertheless, the potential development of inhibitory antibodies to infused factor is still a major hurdle to overcome in a substantial proportion of patients. Finally, gene therapy for both types of haemophilia has progressed remarkably and could soon become a reality.
Topics: Genetic Therapy; Hemophilia A; Hemorrhage; Humans; Mutation; Quality of Life
PubMed: 34168126
DOI: 10.1038/s41572-021-00278-x -
Intensive Care Medicine Mar 2023Coagulopathy is a severe and frequent complication in critically ill patients, for which the pathogenesis and presentation may be variable depending on the underlying... (Review)
Review
Coagulopathy is a severe and frequent complication in critically ill patients, for which the pathogenesis and presentation may be variable depending on the underlying disease. Based on the dominant clinical phenotype, the current review differentiates between hemorrhagic coagulopathies, characterized by a hypocoagulable and hyperfibrinolysis state, and thrombotic coagulopathies with a systemic prothrombotic and antifibrinolytic phenotype. We discuss the differences in pathogenesis and treatment of the common coagulopathies.
Topics: Humans; Critical Illness; Blood Coagulation Disorders; Thrombosis; Phenotype; Disseminated Intravascular Coagulation
PubMed: 36808215
DOI: 10.1007/s00134-023-06980-6 -
Gaceta Medica de Mexico 2021Hemophilia is a hemorrhagic disorder with a sex-linked inherited pattern, characterized by an inability to amplify coagulation due to a deficiency in coagulation factor...
Hemophilia is a hemorrhagic disorder with a sex-linked inherited pattern, characterized by an inability to amplify coagulation due to a deficiency in coagulation factor VIII (hemophilia A or classic) or factor IX (hemophilia B). Sequencing of the genes involved in hemophilia has provided a description and record of the main mutations, as well as a correlation with the various degrees of severity. Hemorrhagic manifestations are related to levels of circulating factor, mainly affecting the musculoskeletal system and specifically the large joints (knees, ankles, and elbows). This document is a review and consensus of the main genetic aspects of hemophilia, from the inheritance pattern to the concept of women carriers, physiopathology and classification of the disorder, the basic and confirmation studies when hemophilia is suspected, the various treatment regimens based on infusion of the deficient coagulation factor as well as innovative factor-free therapies and recommendations for the management of complications associated with treatment (development of inhibitors and/or transfusion-transmitted infections), or secondary to articular hemorrhagic events (hemophilic arthropathy). Finally, relevant reviews of clinical and treatment aspects of hemorrhagic pathology characterized by acquired deficiency of FVIII secondary to neutralized antibodies named acquired hemophilia.
Topics: Algorithms; Hemophilia A; Mexico
PubMed: 33819260
DOI: 10.24875/GMM.M21000463 -
Otolaryngology--head and Neck Surgery :... Jan 2020, also known as , is a common problem that occurs at some point in at least 60% of people in the United States. While the majority of nosebleeds are limited in severity...
OBJECTIVE
, also known as , is a common problem that occurs at some point in at least 60% of people in the United States. While the majority of nosebleeds are limited in severity and duration, about 6% of people who experience nosebleeds will seek medical attention. For the purposes of this guideline, we define the target patient with a nosebleed as . Interventions for nosebleeds range from self-treatment and home remedies to more intensive procedural interventions in medical offices, emergency departments, hospitals, and operating rooms. Epistaxis has been estimated to account for 0.5% of all emergency department visits and up to one-third of all otolaryngology-related emergency department encounters. Inpatient hospitalization for aggressive treatment of severe nosebleeds has been reported in 0.2% of patients with nosebleeds.
PURPOSE
The primary purpose of this multidisciplinary guideline is to identify quality improvement opportunities in the management of nosebleeds and to create clear and actionable recommendations to implement these opportunities in clinical practice. Specific goals of this guideline are to promote best practices, reduce unjustified variations in care of patients with nosebleeds, improve health outcomes, and minimize the potential harms of nosebleeds or interventions to treat nosebleeds. The target patient for the guideline is any individual aged ≥3 years with a nosebleed or history of nosebleed who needs medical treatment or seeks medical advice. The target audience of this guideline is clinicians who evaluate and treat patients with nosebleed. This includes primary care providers such as family medicine physicians, internists, pediatricians, physician assistants, and nurse practitioners. It also includes specialists such as emergency medicine providers, otolaryngologists, interventional radiologists/neuroradiologists and neurointerventionalists, hematologists, and cardiologists. The setting for this guideline includes any site of evaluation and treatment for a patient with nosebleed, including ambulatory medical sites, the emergency department, the inpatient hospital, and even remote outpatient encounters with phone calls and telemedicine. Outcomes to be considered for patients with nosebleed include control of acute bleeding, prevention of recurrent episodes of nasal bleeding, complications of treatment modalities, and accuracy of diagnostic measures. This guideline addresses the diagnosis, treatment, and prevention of nosebleed. It focuses on nosebleeds that commonly present to clinicians via phone calls, office visits, and emergency room encounters. This guideline discusses first-line treatments such as nasal compression, application of vasoconstrictors, nasal packing, and nasal cautery. It also addresses more complex epistaxis management, which includes the use of endoscopic arterial ligation and interventional radiology procedures. Management options for 2 special groups of patients-patients with hereditary hemorrhagic telangiectasia syndrome and patients taking medications that inhibit coagulation and/or platelet function-are included in this guideline. This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the guideline development group. It is not intended to be a comprehensive, general guide for managing patients with nosebleed. In this context, the purpose is to define useful actions for clinicians, generalists, and specialists from a variety of disciplines to improve quality of care. Conversely, the statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experience and assessment of individual patients.
ACTION STATEMENTS
The guideline development group made for the following key action statements: (1) At the time of initial contact, the clinician should distinguish the nosebleed patient who requires prompt management from the patient who does not. (2) The clinician should treat active bleeding for patients in need of prompt management with firm sustained compression to the lower third of the nose, with or without the assistance of the patient or caregiver, for 5 minutes or longer. (3a) For patients in whom bleeding precludes identification of a bleeding site despite nasal compression, the clinician should treat ongoing active bleeding with nasal packing. (3b) The clinician should use resorbable packing for patients with a suspected bleeding disorder or for patients who are using anticoagulation or antiplatelet medications. (4) The clinician should educate the patient who undergoes nasal packing about the type of packing placed, timing of and plan for removal of packing (if not resorbable), postprocedure care, and any signs or symptoms that would warrant prompt reassessment. (5) The clinician should document factors that increase the frequency or severity of bleeding for any patient with a nosebleed, including personal or family history of bleeding disorders, use of anticoagulant or antiplatelet medications, or intranasal drug use. (6) The clinician should perform anterior rhinoscopy to identify a source of bleeding after removal of any blood clot (if present) for patients with nosebleeds. (7a) The clinician should perform, or should refer to a clinician who can perform, nasal endoscopy to identify the site of bleeding and guide further management in patients with recurrent nasal bleeding, despite prior treatment with packing or cautery, or with recurrent unilateral nasal bleeding. (8) The clinician should treat patients with an identified site of bleeding with an appropriate intervention, which may include one or more of the following: topical vasoconstrictors, nasal cautery, and moisturizing or lubricating agents. (9) When nasal cautery is chosen for treatment, the clinician should anesthetize the bleeding site and restrict application of cautery only to the active or suspected site(s) of bleeding. (10) The clinician should evaluate, or refer to a clinician who can evaluate, candidacy for surgical arterial ligation or endovascular embolization for patients with persistent or recurrent bleeding not controlled by packing or nasal cauterization. (11) In the absence of life-threatening bleeding, the clinician should initiate first-line treatments prior to transfusion, reversal of anticoagulation, or withdrawal of anticoagulation/antiplatelet medications for patients using these medications. (12) The clinician should assess, or refer to a specialist who can assess, the presence of nasal telangiectasias and/or oral mucosal telangiectasias in patients who have a history of recurrent bilateral nosebleeds or a family history of recurrent nosebleeds to diagnose hereditary hemorrhagic telangiectasia syndrome. (13) The clinician should educate patients with nosebleeds and their caregivers about preventive measures for nosebleeds, home treatment for nosebleeds, and indications to seek additional medical care. (14) The clinician or designee should document the outcome of intervention within 30 days or document transition of care in patients who had a nosebleed treated with nonresorbable packing, surgery, or arterial ligation/embolization. The policy level for the following recommendation, about examination of the nasal cavity and nasopharynx using nasal endoscopy, was an (7b) The clinician may perform, or may refer to a clinician who can perform, nasal endoscopy to examine the nasal cavity and nasopharynx in patients with epistaxis that is difficult to control or when there is concern for unrecognized pathology contributing to epistaxis.
Topics: Cautery; Endoscopy; Epistaxis; Hemostatics; Humans; Ligation; Nasal Surgical Procedures; Patient Acuity; Patient Education as Topic; Quality Improvement; Risk Factors; Tampons, Surgical; Telangiectasia, Hereditary Hemorrhagic; Vasoconstrictor Agents
PubMed: 31910111
DOI: 10.1177/0194599819890327 -
Hamostaseologie Apr 2021Disseminated intravascular coagulation (DIC) is characterized by the intravascular activation of coagulation with loss of localization arising from different causes, and... (Review)
Review
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.
Topics: Acute Disease; Disseminated Intravascular Coagulation; Humans; Leukemia
PubMed: 33860520
DOI: 10.1055/a-1393-8302 -
Haematologica Aug 2020The acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder with laboratory findings similar to those of inherited von Willebrand disease. However, unlike... (Review)
Review
The acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder with laboratory findings similar to those of inherited von Willebrand disease. However, unlike the inherited disease, AvWS occurs in persons with no personal and family history of bleeding and is often associated with a variety of underlying diseases, most frequently lymphoproliferative, myeloproliferative and cardiovascular disorders. After the presentation of a typical case, in this narrative review we discuss the more recent data on the pathophysiology, clinical, laboratory and therapeutic aspects of this acquired bleeding syndrome. We chose to focus particularly on those aspects of greater interest for the hematologist.
Topics: Cardiovascular Diseases; Hemorrhage; Hemorrhagic Disorders; Humans; Syndrome; von Willebrand Diseases; von Willebrand Factor
PubMed: 32554559
DOI: 10.3324/haematol.2020.255117 -
Blood Advances Jan 2021von Willebrand disease (VWD) is a common inherited bleeding disorder. Significant variability exists in management options offered to patients.
BACKGROUND
von Willebrand disease (VWD) is a common inherited bleeding disorder. Significant variability exists in management options offered to patients.
OBJECTIVE
These evidence-based guidelines from the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and health care professionals in their decisions about management of VWD.
METHODS
ASH, ISTH, NHF, and WFH formed a multidisciplinary guideline panel. Three patient representatives were included. The panel was balanced to minimize potential bias from conflicts of interest. The University of Kansas Outcomes and Implementation Research Unit and the McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing and updating systematic evidence reviews (through November 2019). The panel prioritized clinical questions and outcomes according to their importance to clinicians and patients. The panel used the GRADE approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment.
RESULTS
The panel agreed on 12 recommendations and outlined future research priorities.
CONCLUSIONS
These guidelines make key recommendations regarding prophylaxis for frequent recurrent bleeding, desmopressin trials to determine therapy, use of antiplatelet agents and anticoagulant therapy, target VWF and factor VIII activity levels for major surgery, strategies to reduce bleeding during minor surgery or invasive procedures, management options for heavy menstrual bleeding, management of VWD in the context of neuraxial anesthesia during labor and delivery, and management in the postpartum setting.
Topics: Female; Hemophilia A; Hemostasis; Humans; Thrombosis; Venous Thromboembolism; von Willebrand Diseases
PubMed: 33570647
DOI: 10.1182/bloodadvances.2020003264 -
Blood Advances Jan 2021von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Accurate and timely diagnosis presents numerous challenges.
BACKGROUND
von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Accurate and timely diagnosis presents numerous challenges.
OBJECTIVE
These evidence-based guidelines of the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and other health care professionals in their decisions about VWD diagnosis.
METHODS
ASH, ISTH, NHF, and WFH established a multidisciplinary guideline panel that included 4 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Outcomes and Implementation Research Unit at the University of Kansas Medical Center (KUMC) supported the guideline-development process, including performing or updating systematic evidence reviews up to 8 January 2020. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subsequently subject to public comment.
RESULTS
The panel agreed on 11 recommendations.
CONCLUSIONS
Key recommendations of these guidelines include the role of bleeding-assessment tools in the assessment of patients suspected of VWD, diagnostic assays and laboratory cutoffs for type 1 and type 2 VWD, how to approach a type 1 VWD patient with normalized levels over time, and the role of genetic testing vs phenotypic assays for types 2B and 2N. Future critical research priorities are also identified.
Topics: Hemophilia A; Hemorrhage; Hemostasis; Humans; Thrombosis; von Willebrand Diseases
PubMed: 33570651
DOI: 10.1182/bloodadvances.2020003265 -
Cellular & Molecular Immunology Dec 2023Primary immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disorder in which macrophages play a critical role. Mammalian sterile-20-like kinase 4 (MST4), a...
Primary immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disorder in which macrophages play a critical role. Mammalian sterile-20-like kinase 4 (MST4), a member of the germinal-center kinase STE20 family, has been demonstrated to be a regulator of inflammation. Whether MST4 participates in the macrophage-dependent inflammation of ITP remains elusive. The expression and function of MST4 in macrophages of ITP patients and THP-1 cells, and of a macrophage-specific Mst4 (Mst4) ITP mouse model were determined. Macrophage phagocytic assays, RNA sequencing (RNA-seq) analysis, immunofluorescence analysis, coimmunoprecipitation (co-IP), mass spectrometry (MS), bioinformatics analysis, and phosphoproteomics analysis were performed to reveal the underlying mechanisms. The expression levels of the MST4 gene were elevated in the expanded M1-like macrophages of ITP patients, and this elevated expression of MST4 was restored to basal levels in patients with remission after high-dose dexamethasone treatment. The expression of the MST4 gene was significantly elevated in THP-1-derived M1 macrophages. Silencing of MST4 decreased the expression of M1 macrophage markers and cytokines, and impaired phagocytosis, which could be increased by overexpression of MST4. In a passive ITP mouse model, macrophage-specific depletion of Mst4 reduced the numbers of M1 macrophages in the spleen and peritoneal lavage fluid, attenuated the expression of M1 cytokines, and promoted the predominance of FcγRIIb in splenic macrophages, which resulted in amelioration of thrombocytopenia. Downregulation of MST4 directly inhibited STAT1 phosphorylation, which is essential for M1 polarization of macrophages. Our study elucidates a critical role for MST4 kinase in the pathology of ITP and identifies MST4 kinase as a potential therapeutic target for refractory ITP.
Topics: Animals; Mice; Humans; Purpura, Thrombocytopenic, Idiopathic; Macrophages; Thrombocytopenia; Inflammation; Cytokines; Mammals; STAT1 Transcription Factor
PubMed: 37833401
DOI: 10.1038/s41423-023-01089-8 -
Journal of Thrombosis and Haemostasis :... Dec 2023Disseminated intravascular coagulation can occur due to different causes but commonly following sepsis. Trauma-induced coagulopathy (TIC) occurs on hospital arrival in...
Disseminated intravascular coagulation can occur due to different causes but commonly following sepsis. Trauma-induced coagulopathy (TIC) occurs on hospital arrival in approximately 25% of seriously injured patients who initially presents with impaired hemostasis and a bleeding phenotype that can later progress to a prothrombotic phase. Following traumatic injury, ineffective hemostasis is driven by massive blood loss, tissue damage, and hyperfibrinolysis. This initial impaired hemostasis continues until surgical or other management strategies not only to stop the causes of hemorrhage but also progresses to a prothrombotic and hypofibrinolytic state, also termed fibrinolytic shutdown. Prothrombotic progression is also promoted by inflammatory mediator release, endothelial injury, and platelet dysregulation, which is commonly seen in sepsis with increased mortality. Unlike TIC, the early phase of sepsis is frequently complicated by multiorgan dysfunction described as sepsis-induced coagulopathy (SIC) that lacks a hemorrhagic phase. The phenotypes of SIC and TIC are different, especially in their initial presentations; however, patients who survive TIC may also develop subsequent infections and potentially sepsis and SIC. Although the pathophysiology of SIC and TIC are different, endothelial injury, dysregulated fibrinolysis, and coagulation abnormalities are common. Management includes treatment of the underlying cause, tissue injury vs infection is critical, and supportive therapies, such as hemostatic resuscitation and circulatory support are essential, and adjunct therapies are recommended in guidelines. Based on clinical studies and certain guidelines, additional therapies include tranexamic acid in the limited timing of initial traumatic injury and anticoagulants, such as antithrombin and recombinant thrombomodulin in disseminated intravascular coagulation.
Topics: Humans; Disseminated Intravascular Coagulation; Blood Coagulation Disorders; Hemostasis; Fibrinolysis; Hemorrhage; Anticoagulants; Sepsis
PubMed: 37722532
DOI: 10.1016/j.jtha.2023.05.028