1) Glanzmann thrombasthenia is a rare bleeding disorder caused by a deficiency in the platelet integrin αIIbβ3, which normally allows platelets to aggregate and form blood clots.
2) Patients experience mucocutaneous bleeding such as purpura, epistaxis, and menorrhagia. The severity of bleeding varies between patients.
3) The disorder is inherited in an autosomal recessive pattern and is caused by mutations in the genes encoding the αIIb and β3 subunits of the integrin. Over 100 mutations have been identified.
UAEU - CMHS - Hematology-Oncology Course - MMH 302 - HONC 320. Education material for medical students - It cover basic principles of hematology and oncology, including CAR-T and gene editing. It can be used for study and review. It illustrates main principles of hematology and oncology.
This document discusses hematopoiesis and leukemia, specifically chronic myeloid leukemia (CML). It defines CML as a clonal expansion of stem cells with a reciprocal translocation between chromosomes 9 and 22, forming the Philadelphia chromosome. This causes a BCR-ABL fusion gene which produces a constitutively active tyrosine kinase driving proliferation. CML accounts for 14% of leukemias and presents mainly in adults aged 40-60 with increased white blood cells. The document covers classification, signs and symptoms, progression from chronic to blast phase, and treatment with tyrosine kinase inhibitors.
UAEU - CMHS - Hematology-Oncology Course - MMH 302 - HONC 320. Education material for medical students - It cover basic principles of hematology and oncology, including CAR-T and gene editing. It can be used for study and review. It illustrates main principles of hematology and oncology.
Factor 3 (tissue factor) and Factor 7 work together in the extrinsic pathway of the coagulation cascade. Factor 3 is a cell surface glycoprotein found on tissues and leukocytes that activates Factor 7. Once bound, Factor 7 is activated to Factor 7a, which activates Factor 10 to 10a and prothrombin to thrombin, ultimately resulting in fibrin clot formation. A deficiency in either Factor 3 or Factor 7 can cause a bleeding disorder.
Procoagulant disorders in neonates (Updated)Tai Alakawy
This document discusses neonatal thrombophilia and procoagulant disorders. It begins by defining thrombophilia as a clinical tendency to thrombosis or molecular abnormalities that predispose to thromboembolic disease. It then discusses various inherited and acquired hypercoagulable states including factor V Leiden mutation, prothrombin gene mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency. It notes that thrombophilia in neonates is a significant problem often associated with predisposing disorders and triggers like sepsis.
Chronic myeloid leukemia is a cancer of the white blood cells caused by a fusion of the BCR and ABL genes, which results in uncontrolled proliferation of mature and immature white blood cells. It progresses through three phases - chronic, accelerated, and blast crisis - and is characterized by excessive neutrophils, basophils and eosinophils in the blood and bone marrow. The standard diagnostic tests are detecting the Philadelphia chromosome or BCR-ABL fusion gene via cytogenetic analysis, FISH or PCR. Targeted therapy with tyrosine kinase inhibitors such as imatinib has dramatically improved survival for most CML patients.
detailed discussion on cytogenetics in CML - Pathophysiology, treatment, TKI Resistance, Mutation analysis timing, various mutations in CML, BCR-ABL1 Variants, Significance of mutations and management.
UAEU - CMHS - Hematology-Oncology Course - MMH 302 - HONC 320. Education material for medical students - It cover basic principles of hematology and oncology, including CAR-T and gene editing. It can be used for study and review. It illustrates main principles of hematology and oncology.
This document discusses hematopoiesis and leukemia, specifically chronic myeloid leukemia (CML). It defines CML as a clonal expansion of stem cells with a reciprocal translocation between chromosomes 9 and 22, forming the Philadelphia chromosome. This causes a BCR-ABL fusion gene which produces a constitutively active tyrosine kinase driving proliferation. CML accounts for 14% of leukemias and presents mainly in adults aged 40-60 with increased white blood cells. The document covers classification, signs and symptoms, progression from chronic to blast phase, and treatment with tyrosine kinase inhibitors.
UAEU - CMHS - Hematology-Oncology Course - MMH 302 - HONC 320. Education material for medical students - It cover basic principles of hematology and oncology, including CAR-T and gene editing. It can be used for study and review. It illustrates main principles of hematology and oncology.
Factor 3 (tissue factor) and Factor 7 work together in the extrinsic pathway of the coagulation cascade. Factor 3 is a cell surface glycoprotein found on tissues and leukocytes that activates Factor 7. Once bound, Factor 7 is activated to Factor 7a, which activates Factor 10 to 10a and prothrombin to thrombin, ultimately resulting in fibrin clot formation. A deficiency in either Factor 3 or Factor 7 can cause a bleeding disorder.
Procoagulant disorders in neonates (Updated)Tai Alakawy
This document discusses neonatal thrombophilia and procoagulant disorders. It begins by defining thrombophilia as a clinical tendency to thrombosis or molecular abnormalities that predispose to thromboembolic disease. It then discusses various inherited and acquired hypercoagulable states including factor V Leiden mutation, prothrombin gene mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency. It notes that thrombophilia in neonates is a significant problem often associated with predisposing disorders and triggers like sepsis.
Chronic myeloid leukemia is a cancer of the white blood cells caused by a fusion of the BCR and ABL genes, which results in uncontrolled proliferation of mature and immature white blood cells. It progresses through three phases - chronic, accelerated, and blast crisis - and is characterized by excessive neutrophils, basophils and eosinophils in the blood and bone marrow. The standard diagnostic tests are detecting the Philadelphia chromosome or BCR-ABL fusion gene via cytogenetic analysis, FISH or PCR. Targeted therapy with tyrosine kinase inhibitors such as imatinib has dramatically improved survival for most CML patients.
detailed discussion on cytogenetics in CML - Pathophysiology, treatment, TKI Resistance, Mutation analysis timing, various mutations in CML, BCR-ABL1 Variants, Significance of mutations and management.
Somatic activating kras mutations in arteriovenous malformationDiego Mejía
The document discusses a study investigating somatic activating KRAS mutations in arteriovenous malformations. The study aimed to determine if KRAS mutation is a genetic marker for arteriovenous malformation and analyze the relationship between abnormal MAPK-EPK signaling and tissue defects. The study analyzed 72 patients and found somatic activating KRAS mutations in arteriovenous malformation tissue samples. The findings suggest KRAS mutation may be a genetic factor associated with arteriovenous malformations.
UAEU - CMHS - Hematology-Oncology Course - MMH 302 - HONC 320. Education material for medical students - It cover basic principles of hematology and oncology, including CAR-T and gene editing. It can be used for study and review. It illustrates main principles of hematology and oncology.
01.13.09: Chronic Myeloid Leukemia and other Myeloproliferative Neoplasms (MPNs)Open.Michigan
Slideshow is from the University of Michigan Medical
School's M2 Hematology / Oncology sequence
View additional course materials on Open.Michigan: openmi.ch/med-M2Hematology
This document summarizes various neoplastic abnormalities of leukocytes, including leukemia, lymphoma, myeloma, and mycosis fungoides. It describes the characteristics, diagnostic markers, classification, and clinical presentation of different types of leukemia such as acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia. Cytogenetic abnormalities, immunophenotyping, and molecular testing play an important role in the diagnosis and classification of leukemias. Chronic myeloid leukemia is characterized by the Philadelphia chromosome and BCR-ABL fusion gene. Mycosis fungoides is a cutaneous T-cell lymphoma that typically presents in patches, plaques and tumors on the skin
The document discusses hemostasis, the process by which bleeding is prevented after vascular injury. It describes the four main mechanisms: vasoconstriction, formation of a platelet plug, coagulation pathways, and fibrinolytic phase. Specifically, it details the roles of platelets, calcium ions, coagulation factors, fibrinogen and thrombin in forming a blood clot via the intrinsic and extrinsic coagulation pathways. It also discusses anticoagulants that prevent unnecessary clotting and plasmin which lyses blood clots.
Mutations in genes like BCR-ABL, JAK2, MPL, and KIT can cause myeloid neoplasms by promoting proliferation or blocking differentiation. BCR-ABL, found in chronic myeloid leukemia (CML), encodes a fusion protein with constitutive tyrosine kinase activity. The JAK2 V617F mutation is present in the majority of polycythemia vera and a significant portion of essential thrombocythemia and primary myelofibrosis cases. MPL mutations like MPLW515L can also drive essential thrombocythemia and primary myelofibrosis. These genetic abnormalities activate signaling pathways that dysregulate myeloid cell growth and maturation.
X linked macrocytic dyserythropoietic anemia in females with an alas2 mutati...qussai abbas
This document summarizes a case study of a family found to have a novel mutation in the X-linked ALAS2 gene causing sideroblastic anemia. Whole exome sequencing identified a coding mutation in ALAS2. The proband and affected female relatives were found to have skewed X-inactivation favoring the mutant ALAS2 allele, explaining their symptoms. This expands the known mutations and phenotypes caused by ALAS2 deficiencies.
Thrombin generation profiles in deep venous thrombosisMD TIEN
This document summarizes a study that used numerical modeling to simulate thrombin generation profiles based on coagulation factor levels from participants in the Leiden Thrombophilia Study. The simulations evaluated thrombin generation parameters in relation to risk of deep vein thrombosis. The study found the greatest risk association with the maximum rate of thrombin generation, with those in the highest 90th percentile having a 2.6-fold increased risk. Oral contraceptive use was also found to significantly shift thrombin generation profiles and interact with underlying prothrombotic traits, suggesting it may identify individuals at higher risk. The researchers conclude that thrombin generation profiles based on an individual's blood composition could serve as a useful predictive marker for thrombosis risk.
5-2. C3 glomerulonephritis and Dense Deposit Disease. Francesco Emma (eng)KidneyOrgRu
This document discusses C3 glomerulonephritis (C3GN) and Dense Deposit Disease (DDD). It provides background on the classification of these conditions and how they relate to membranoproliferative glomerulonephritis (MPGN). It describes the histological features and proteomic profiles of C3GN and DDD, which are very similar. Both can be caused by dysregulation of the alternative complement pathway due to genetic mutations or autoantibodies. There is no established treatment, though immunosuppressants may help in some cases and anti-C5 therapy shows promise for certain patients. The document provides detailed information on the physiology, genetics, and pathology of complement-mediated MP
Chronic myeloid leukemia (CML) is a clonal stem cell disorder caused by the BCR-ABL1 fusion gene from the Philadelphia chromosome. CML progresses through chronic, accelerated, and blast phases. It is characterized by excessive proliferation of myeloid cells. Diagnosis involves detecting the Philadelphia chromosome via cytogenetics or molecular testing. Treatment with tyrosine kinase inhibitors targets the BCR-ABL1 fusion protein and controls disease progression.
This document provides an overview of bleeding and clotting disorders, including:
- The normal mechanism of blood coagulation involving primary and secondary hemostasis.
- Types of hemorrhages such as petechiae, purpura, and ecchymosis.
- Laboratory tests used to evaluate bleeding disorders including platelet count, bleeding time, prothrombin time, and activated partial thromboplastin time.
- Inherited bleeding disorders like hemophilia A, hemophilia B, and von Willebrand disease.
- Considerations for dental treatment of patients with bleeding disorders.
The document discusses coagulation, hemostasis, and various bleeding disorders. It covers the process of coagulation including platelet adhesion, activation, and aggregation. It also discusses factors that promote coagulation as well as anticoagulant factors. Various bleeding disorders are described such as abnormalities of blood vessels, coagulation factors, platelets, and disseminated intravascular coagulation. Laboratory tests for evaluating coagulation are also mentioned.
This document discusses hypercoagulation states and thrombosis. It defines thrombosis and reviews the coagulation pathway and its relation to hypercoagulation. It describes arterial and venous thrombosis, their causes, and treatment approaches. The importance of obtaining a thorough medical history and family history is emphasized. Laboratory tests for diagnosing a hypercoagulation state are also reviewed.
This document discusses neonatal procoagulant disorders and thrombophilia. It covers inherited and acquired causes of thrombophilia including factor V Leiden mutation, prothrombin gene mutation, protein C deficiency, protein S deficiency, antithrombin deficiency, and acquired deficiencies. Clinical manifestations such as deep vein thrombosis, pulmonary embolism, and neonatal purpura fulminans are described. The epidemiology, pathophysiology, diagnosis, and management of thrombophilia in neonates are summarized.
1. Chronic myeloid leukemia (CML) is a cancer of the white blood cells characterized by the Philadelphia chromosome, which results from a reciprocal translocation between chromosomes 9 and 22.
2. CML progresses through chronic, accelerated, and blast crisis phases and presents with splenomegaly, basophilia and elevated white blood cell count.
3. Treatment has advanced significantly with tyrosine kinase inhibitors like imatinib that target the BCR-ABL1 fusion protein resulting from the Philadelphia chromosome. These drugs have improved survival rates and altered the treatment landscape for CML.
This document discusses hemostasis, which is the biological process that controls bleeding at the site of injured blood vessels. It summarizes the key components and steps of hemostasis, including:
1. Vasoconstriction of injured blood vessels to reduce blood flow and platelet plug formation via adhesion and aggregation of platelets at the injury site.
2. Activation of the coagulation cascade through intrinsic and extrinsic pathways leading to thrombin generation and fibrin clot formation to strengthen the platelet plug.
3. Fibrinolysis by the plasminogen system which acts to dissolve clots when healing is complete to restore blood flow.
Von Willebrand disease is the most common inherited bleeding disorder. It is caused by deficiencies or defects in von Willebrand factor, which plays a key role in hemostasis. The document discusses the synthesis, structure, and function of VWF, as well as its clearance mechanisms. It then covers the classification of VWD into types 1, 2, and 3 based on the nature and severity of the VWF deficiency. Diagnostic testing and evaluation algorithms are presented. Management strategies for VWD include local hemostatic measures, antifibrinolytic agents, hormonal therapies, desmopressin to increase VWF levels, and VWF/FVIII concentrates for replacement therapy.
This document provides an overview of chronic myeloid leukemia (CML), including:
- CML is characterized by the Philadelphia chromosome and BCR-ABL1 fusion gene. It has three phases: chronic, accelerated, and blast.
- In chronic phase, peripheral blood and bone marrow testing show elevated white blood cells and immature granulocytes. Cytogenetics confirm the Philadelphia chromosome.
- Accelerated phase is defined by worsening blood counts, additional genetic abnormalities, or suboptimal response to tyrosine kinase inhibitors.
- Blast phase occurs when blasts make up 20% or more of blood or bone marrow cells or there is extramedullary blast proliferation.
This lecture was the opening lecture on the ‘Physiology of Coagulation’ at the Continuing Medical Education (CME) Grand Rounds, 2011. Organised by Kuwait Anesthesia Council, Kuwait
Molecular Pathogenesis of Cerebral Cavernous Malformations NeuroAcademy
Cerebral cavernous malformations are clusters of enlarged blood vessels in the brain that lack normal vessel support structures. They are caused by mutations in three genes, CCM1, CCM2, and CCM3, which disrupt blood vessel formation and cause thin, leaky vessels. Loss of these genes leads to endothelial cell abnormalities and weak cell-cell junctions between vessels, resulting in hemorrhaging and lesion formation in the brain. Mice with induced deletion of CCM genes develop cerebral cavernous malformations similar to human lesions.
Phone Aid donates a portion of cell phone fees on World Food Day each year to help end hunger. Every 5th call or text triggers a 5 cent or 5% fee donation from phone companies to organizations working to end hunger. Making the 5th call or sending the 5th text on World Food Day allows phone companies to donate part of their fees to the cause of ending hunger worldwide.
Manejo farmacologico de la hipertension portalMEDICINE VALE´S
This document discusses the pharmacologic management of portal hypertension and summarizes several studies on this topic. It references articles on the use of terlipressin, somatostatin, and their analogues to treat acute esophageal variceal hemorrhage and portal hypertension. It also mentions studies on the effects of carvedilol, statins, renin-angiotensin-aldosterone inhibitors, obesity, and insulin resistance on cirrhosis and portal hypertension. The document repeatedly references a 2014 review on the pharmacologic management of portal hypertension published in Clinical Liver Disease.
Somatic activating kras mutations in arteriovenous malformationDiego Mejía
The document discusses a study investigating somatic activating KRAS mutations in arteriovenous malformations. The study aimed to determine if KRAS mutation is a genetic marker for arteriovenous malformation and analyze the relationship between abnormal MAPK-EPK signaling and tissue defects. The study analyzed 72 patients and found somatic activating KRAS mutations in arteriovenous malformation tissue samples. The findings suggest KRAS mutation may be a genetic factor associated with arteriovenous malformations.
UAEU - CMHS - Hematology-Oncology Course - MMH 302 - HONC 320. Education material for medical students - It cover basic principles of hematology and oncology, including CAR-T and gene editing. It can be used for study and review. It illustrates main principles of hematology and oncology.
01.13.09: Chronic Myeloid Leukemia and other Myeloproliferative Neoplasms (MPNs)Open.Michigan
Slideshow is from the University of Michigan Medical
School's M2 Hematology / Oncology sequence
View additional course materials on Open.Michigan: openmi.ch/med-M2Hematology
This document summarizes various neoplastic abnormalities of leukocytes, including leukemia, lymphoma, myeloma, and mycosis fungoides. It describes the characteristics, diagnostic markers, classification, and clinical presentation of different types of leukemia such as acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia. Cytogenetic abnormalities, immunophenotyping, and molecular testing play an important role in the diagnosis and classification of leukemias. Chronic myeloid leukemia is characterized by the Philadelphia chromosome and BCR-ABL fusion gene. Mycosis fungoides is a cutaneous T-cell lymphoma that typically presents in patches, plaques and tumors on the skin
The document discusses hemostasis, the process by which bleeding is prevented after vascular injury. It describes the four main mechanisms: vasoconstriction, formation of a platelet plug, coagulation pathways, and fibrinolytic phase. Specifically, it details the roles of platelets, calcium ions, coagulation factors, fibrinogen and thrombin in forming a blood clot via the intrinsic and extrinsic coagulation pathways. It also discusses anticoagulants that prevent unnecessary clotting and plasmin which lyses blood clots.
Mutations in genes like BCR-ABL, JAK2, MPL, and KIT can cause myeloid neoplasms by promoting proliferation or blocking differentiation. BCR-ABL, found in chronic myeloid leukemia (CML), encodes a fusion protein with constitutive tyrosine kinase activity. The JAK2 V617F mutation is present in the majority of polycythemia vera and a significant portion of essential thrombocythemia and primary myelofibrosis cases. MPL mutations like MPLW515L can also drive essential thrombocythemia and primary myelofibrosis. These genetic abnormalities activate signaling pathways that dysregulate myeloid cell growth and maturation.
X linked macrocytic dyserythropoietic anemia in females with an alas2 mutati...qussai abbas
This document summarizes a case study of a family found to have a novel mutation in the X-linked ALAS2 gene causing sideroblastic anemia. Whole exome sequencing identified a coding mutation in ALAS2. The proband and affected female relatives were found to have skewed X-inactivation favoring the mutant ALAS2 allele, explaining their symptoms. This expands the known mutations and phenotypes caused by ALAS2 deficiencies.
Thrombin generation profiles in deep venous thrombosisMD TIEN
This document summarizes a study that used numerical modeling to simulate thrombin generation profiles based on coagulation factor levels from participants in the Leiden Thrombophilia Study. The simulations evaluated thrombin generation parameters in relation to risk of deep vein thrombosis. The study found the greatest risk association with the maximum rate of thrombin generation, with those in the highest 90th percentile having a 2.6-fold increased risk. Oral contraceptive use was also found to significantly shift thrombin generation profiles and interact with underlying prothrombotic traits, suggesting it may identify individuals at higher risk. The researchers conclude that thrombin generation profiles based on an individual's blood composition could serve as a useful predictive marker for thrombosis risk.
5-2. C3 glomerulonephritis and Dense Deposit Disease. Francesco Emma (eng)KidneyOrgRu
This document discusses C3 glomerulonephritis (C3GN) and Dense Deposit Disease (DDD). It provides background on the classification of these conditions and how they relate to membranoproliferative glomerulonephritis (MPGN). It describes the histological features and proteomic profiles of C3GN and DDD, which are very similar. Both can be caused by dysregulation of the alternative complement pathway due to genetic mutations or autoantibodies. There is no established treatment, though immunosuppressants may help in some cases and anti-C5 therapy shows promise for certain patients. The document provides detailed information on the physiology, genetics, and pathology of complement-mediated MP
Chronic myeloid leukemia (CML) is a clonal stem cell disorder caused by the BCR-ABL1 fusion gene from the Philadelphia chromosome. CML progresses through chronic, accelerated, and blast phases. It is characterized by excessive proliferation of myeloid cells. Diagnosis involves detecting the Philadelphia chromosome via cytogenetics or molecular testing. Treatment with tyrosine kinase inhibitors targets the BCR-ABL1 fusion protein and controls disease progression.
This document provides an overview of bleeding and clotting disorders, including:
- The normal mechanism of blood coagulation involving primary and secondary hemostasis.
- Types of hemorrhages such as petechiae, purpura, and ecchymosis.
- Laboratory tests used to evaluate bleeding disorders including platelet count, bleeding time, prothrombin time, and activated partial thromboplastin time.
- Inherited bleeding disorders like hemophilia A, hemophilia B, and von Willebrand disease.
- Considerations for dental treatment of patients with bleeding disorders.
The document discusses coagulation, hemostasis, and various bleeding disorders. It covers the process of coagulation including platelet adhesion, activation, and aggregation. It also discusses factors that promote coagulation as well as anticoagulant factors. Various bleeding disorders are described such as abnormalities of blood vessels, coagulation factors, platelets, and disseminated intravascular coagulation. Laboratory tests for evaluating coagulation are also mentioned.
This document discusses hypercoagulation states and thrombosis. It defines thrombosis and reviews the coagulation pathway and its relation to hypercoagulation. It describes arterial and venous thrombosis, their causes, and treatment approaches. The importance of obtaining a thorough medical history and family history is emphasized. Laboratory tests for diagnosing a hypercoagulation state are also reviewed.
This document discusses neonatal procoagulant disorders and thrombophilia. It covers inherited and acquired causes of thrombophilia including factor V Leiden mutation, prothrombin gene mutation, protein C deficiency, protein S deficiency, antithrombin deficiency, and acquired deficiencies. Clinical manifestations such as deep vein thrombosis, pulmonary embolism, and neonatal purpura fulminans are described. The epidemiology, pathophysiology, diagnosis, and management of thrombophilia in neonates are summarized.
1. Chronic myeloid leukemia (CML) is a cancer of the white blood cells characterized by the Philadelphia chromosome, which results from a reciprocal translocation between chromosomes 9 and 22.
2. CML progresses through chronic, accelerated, and blast crisis phases and presents with splenomegaly, basophilia and elevated white blood cell count.
3. Treatment has advanced significantly with tyrosine kinase inhibitors like imatinib that target the BCR-ABL1 fusion protein resulting from the Philadelphia chromosome. These drugs have improved survival rates and altered the treatment landscape for CML.
This document discusses hemostasis, which is the biological process that controls bleeding at the site of injured blood vessels. It summarizes the key components and steps of hemostasis, including:
1. Vasoconstriction of injured blood vessels to reduce blood flow and platelet plug formation via adhesion and aggregation of platelets at the injury site.
2. Activation of the coagulation cascade through intrinsic and extrinsic pathways leading to thrombin generation and fibrin clot formation to strengthen the platelet plug.
3. Fibrinolysis by the plasminogen system which acts to dissolve clots when healing is complete to restore blood flow.
Von Willebrand disease is the most common inherited bleeding disorder. It is caused by deficiencies or defects in von Willebrand factor, which plays a key role in hemostasis. The document discusses the synthesis, structure, and function of VWF, as well as its clearance mechanisms. It then covers the classification of VWD into types 1, 2, and 3 based on the nature and severity of the VWF deficiency. Diagnostic testing and evaluation algorithms are presented. Management strategies for VWD include local hemostatic measures, antifibrinolytic agents, hormonal therapies, desmopressin to increase VWF levels, and VWF/FVIII concentrates for replacement therapy.
This document provides an overview of chronic myeloid leukemia (CML), including:
- CML is characterized by the Philadelphia chromosome and BCR-ABL1 fusion gene. It has three phases: chronic, accelerated, and blast.
- In chronic phase, peripheral blood and bone marrow testing show elevated white blood cells and immature granulocytes. Cytogenetics confirm the Philadelphia chromosome.
- Accelerated phase is defined by worsening blood counts, additional genetic abnormalities, or suboptimal response to tyrosine kinase inhibitors.
- Blast phase occurs when blasts make up 20% or more of blood or bone marrow cells or there is extramedullary blast proliferation.
This lecture was the opening lecture on the ‘Physiology of Coagulation’ at the Continuing Medical Education (CME) Grand Rounds, 2011. Organised by Kuwait Anesthesia Council, Kuwait
Molecular Pathogenesis of Cerebral Cavernous Malformations NeuroAcademy
Cerebral cavernous malformations are clusters of enlarged blood vessels in the brain that lack normal vessel support structures. They are caused by mutations in three genes, CCM1, CCM2, and CCM3, which disrupt blood vessel formation and cause thin, leaky vessels. Loss of these genes leads to endothelial cell abnormalities and weak cell-cell junctions between vessels, resulting in hemorrhaging and lesion formation in the brain. Mice with induced deletion of CCM genes develop cerebral cavernous malformations similar to human lesions.
Phone Aid donates a portion of cell phone fees on World Food Day each year to help end hunger. Every 5th call or text triggers a 5 cent or 5% fee donation from phone companies to organizations working to end hunger. Making the 5th call or sending the 5th text on World Food Day allows phone companies to donate part of their fees to the cause of ending hunger worldwide.
Manejo farmacologico de la hipertension portalMEDICINE VALE´S
This document discusses the pharmacologic management of portal hypertension and summarizes several studies on this topic. It references articles on the use of terlipressin, somatostatin, and their analogues to treat acute esophageal variceal hemorrhage and portal hypertension. It also mentions studies on the effects of carvedilol, statins, renin-angiotensin-aldosterone inhibitors, obesity, and insulin resistance on cirrhosis and portal hypertension. The document repeatedly references a 2014 review on the pharmacologic management of portal hypertension published in Clinical Liver Disease.
This document summarizes a case report of a patient with hepatitis C virus (HCV) infection who was also found to have epithelioid granulomas in their liver biopsy. The presence of granulomas is not typically described in patients with HCV. The patient had no history of other infections, drug use, or other risk factors that could explain the granulomas. While granulomas are often seen in infectious diseases like tuberculosis, no acid-fast bacteria were found in this patient. The morphological features of HCV are generally understood to be necroinflammatory changes, fibrosis and cirrhosis, but this case highlights that granulomas may also occasionally be seen in HCV without another known cause.
This document summarizes what was learned from several pictures, including that spirit houses were meant as homes for spirits, people lived in Thailand 2000-3000 years ago, bird nests occur naturally not by human hands, ruins were meant to welcome mythical creatures, certain plants were used to feed cows, harvesting rice is difficult and involves many steps, Phi Mai ruins were made of sandstone, and cocoons are boiled to extract silk thread.
Este documento resume la cefalea tensional. Explica que es el tipo de dolor de cabeza más común, afectando entre un 30-80% de la población. Describe la fisiopatología, los subtipos de cefalea tensional episódica y crónica, los factores desencadenantes, el diagnóstico y el tratamiento con analgésicos y terapia preventiva con antidepresivos tricíclicos u otros medicamentos. El objetivo del tratamiento es reducir la frecuencia, gravedad y duración de las cefaleas.
Every few seconds someone dies of hunger, while millions of children go hungry each year when the cost of a single missile could feed many. The document proposes that on World Hunger Day, Subway restaurants donate 10 cents from each sandwich sold to purchase food to make sandwiches for hungry children, which could raise a significant amount given Subway's size and presence around the world. It asks the reader to help convince their local Subway to donate time and funds to address starvation.
The document proposes an educational game to help solve world hunger issues. The game would teach players about hunger in a realistic way by having them experience scarcity of food and water. Players would work to establish sustainable settlements and improve living conditions in poorer areas. Profits from game sales would be donated to feed people, with the goal of making a very popular game to generate many donations.
Este documento resume las definiciones y lineamientos para el diagnóstico y tratamiento de la fiebre de origen desconocido (FUO). Describe las categorías de FUO (inmunocompetente, nosocomial, neutropénico, VIH), posibles causas infecciosas y no infecciosas, estrategias diagnósticas como exámenes físicos, pruebas de laboratorio e imágenes, y discute el papel potencial de la terapia empírica.
Over 1 billion people do not have enough food while supermarkets give away over 17.5 billion plastic bags per year. The document proposes charging for plastic bags at retail stores and selling eco-friendly bags instead, with the goal of raising money for the World Food Programme to help address world hunger.
Vitiligo is a skin depigmentation condition caused by an autoimmune process targeting melanocytes. It is characterized by achromic and hypochromic patches. It is the most common depigmentation disorder, affecting 0.38% of the global population. Vitiligo can be classified as segmental or non-segmental. Treatment involves topical corticosteroids, calcineurin inhibitors, phototherapy, or surgical interventions like skin grafting depending on the type and severity of the condition.
Estudios que evaluaron el tratamiento actual de la hepatitis C, los cuales fueron presentados en el consenso de viena en abril de 2015.
Forman parte de EASL guidelines HCV 2015.
This document contains numerous examples of racist and inflammatory language used by individuals affiliated with a faction seeking control of WBAI radio. The language demeans and insults people of color, makes light of racist violence, and promotes racist stereotypes. Some examples include referring to Black Americans as less than "real Africans," fabricating stories about Black men acting violently, using racist slurs, and referring to Black women as "attack dogs." The document aims to show that this faction promotes racism and that their efforts are negatively impacting diversity at the radio station.
This document outlines the 6 traits of effective writing that teachers evaluate: content, organization, sentence structure, vocabulary, voice, and writing conventions. For content, the writing must be focused and hold the reader's interest. Organization means the writing is in logical paragraphs. Sentence structure evaluates varied and complex sentences. Vocabulary examines word choice. Voice considers if the writer's personality comes through. Writing conventions cover spelling, grammar, and punctuation.
Clasficacion de antimicrobianos sabinston cirugiaMEDICINE VALE´S
This document summarizes various classes of penicillin and cephalosporin antibiotics including their mechanism of action, half-life, toxicity, and antibacterial spectrum. It describes how penicillins like penicillin G and methicillin work by inhibiting bacterial cell wall synthesis. It also outlines expanded spectrum penicillins like piperacillin that are effective against more gram-negative bacteria. Finally, it reviews first and second generation cephalosporins and their similarities and differences to penicillins in terms of antibacterial coverage and properties.
This document summarizes key differences between cirrhosis and hepatosplenic schistosomiasis as causes of portal hypertension. Schistosomiasis causes fibrosis restricted to the portal tract, preserving liver architecture, while cirrhosis causes complete alteration of architecture. Portal hypertension in schistosomiasis is associated with minimal hepatic dysfunction, unlike cirrhosis where dysfunction is directly correlated. Treatment of portal hypertension also differs, as higher doses of propranolol are needed for schistosomiasis compared to cirrhosis.
Este documento resume la anemia de enfermedades crónicas. Explica que es una anemia común en pacientes hospitalizados causada por factores inflamatorios. Su patogenia es multifactorial e incluye la producción de citoquinas que inhiben la proliferación de eritrocitos y la absorción de hierro. Los hallazgos de laboratorio comunes son hierro sérico bajo, ferritina normal o elevada, y recuentos normales de reticulocitos. No hay prueba definitiva para el diagnóstico pero se basa en estas anormalidades
A patient has a history of recurrent gum bleeding since childhood. While platelet counts and coagulation tests are normal, an inherited platelet disorder is suspected. The doctor's diagnostic approach would include a detailed bleeding history, physical exam looking for bruises/petechiae, and first-line screening tests like a bleeding time and platelet function analyzer. Further specific tests may include light transmission aggregometry to assess platelet aggregation in response to various agonists and help identify potential defects in adhesion, activation, secretion or aggregation. Interpreting the different waveforms is important to determine abnormalities consistent with disorders like Glanzmann's thrombasthenia or storage pool disease.
NORMAL HEMOSTASIS, PLATELET AND VASCULAR DISORDERSAmosiRichard
The document discusses normal hemostasis and bleeding disorders. It begins with an outline of topics to be covered, including normal hemostasis, platelet bleeding disorders, and vascular bleeding disorders. It then provides details on the components involved in normal hemostasis, including blood vessels, platelets, coagulation factors, and the roles they play in maintaining blood fluidity and forming clots. The document discusses platelet structure and function, as well as qualitative and quantitative platelet disorders like Bernard-Soulier disease and immune thrombocytopenia. It also covers vascular bleeding disorders.
This document from Williams Hematology discusses disseminated intravascular coagulation (DIC). It defines DIC as occurring when procoagulants overwhelm the body's natural anticoagulation mechanisms, leading to systemic thrombin generation and microthrombi formation. Common triggers of DIC include tissue factor exposure, infections, tumors, trauma, and pregnancy complications. The document outlines the pathogenesis of DIC and describes underlying conditions that can predispose patients to DIC such as various infections, cancers, liver disease, burns, and pregnancy-related disorders. Treatment involves managing the underlying cause, replacing blood components only in actively bleeding patients, and providing organ support.
This document from Williams Hematology discusses disseminated intravascular coagulation (DIC). It defines DIC as occurring when procoagulants overwhelm the body's natural anticoagulation mechanisms, leading to systemic thrombin generation and microthrombi formation. Common triggers of DIC include tissue factor exposure, infections, tumors, trauma, and pregnancy complications. The document outlines various underlying conditions that can predispose patients to DIC and discusses approaches to diagnosis and treatment.
Anti-GBM disease is a rare form of rapidly progressive glomerulonephritis caused by antibodies against the glomerular basement membrane. It presents with lung hemorrhage, renal failure, and linear IgG deposits along the glomerular basement membrane on biopsy. The disease is treated with plasma exchange and immunosuppression to remove antibodies, with the goal of preventing permanent kidney damage and failure. Prognosis depends on early diagnosis and treatment, with the most important factor being the level of anti-GBM antibodies at time of treatment.
Bernard-Soulier syndrome is a rare inherited bleeding disorder characterized by thrombocytopenia and giant platelets. It is caused by mutations in the glycoprotein Ib/IX/V complex, which binds von Willebrand factor and is essential for platelet adhesion. Patients present with bruising, epistaxis, and heavy menstrual bleeding. Diagnosis involves finding giant platelets, prolonged bleeding times, and absent ristocetin-induced platelet aggregation. Management focuses on prevention of bleeding episodes through hormonal contraceptives, antifibrinolytics, and desmopressin. Severe bleeding may require platelet transfusions or recombinant factor VIIa.
Suspect Hereditary Thrombocytopenia:Familial history of thrombocytopenia, especially parent-child or maternal uncle-nephew.
Lack of platelet response to autoimmune thrombocytopenia therapies.
Diagnostic features on smear such as abnormal size platelets, absence of platelet alpha granules, Dohle-like bodies or microcytosis.
Bleeding out of proportion to the platelet count.
Onset at birth.
Associated features such as absent radii, mental retardation, renal failure, high tone hearing loss, cataracts or the development of leukemia.
Persistence of a stable level of thrombocytopenia for years. Some patients may present with petechial purpura, cranial hematoma or recurrent rectorrhagia
This study analyzed two genetic variants, rs13277113 and rs2736340, in the C8orf13-BLK region in 220 biopsy-proven giant cell arteritis (GCA) patients and 486 controls. No significant differences were found in genotype frequencies between GCA patients and controls for these variants. However, the rs13277113 A allele was overrepresented in GCA patients with severe ischemic manifestations compared to those without, suggesting this variant may be implicated in the development of severe ischemic complications in GCA patients.
1. The document discusses laboratory investigation of hemorrhagic disorders and covers topics like primary and secondary hemostasis, inherited and acquired bleeding disorders, diagnosis of bleeding disorders through history, clinical examination and laboratory tests.
2. Key laboratory tests discussed are platelet count, bleeding time, tests for platelet function like PFA-100, screening tests for coagulation like PT, APTT and tests for specific coagulation factor deficiencies.
3. Causes, interpretation and clinical relevance of prolongation of various coagulation tests are explained. Inherited and acquired bleeding disorders of platelets, vessels and coagulation factors are summarized.
This document provides an overview of bleeding disorders and their evaluation. It discusses:
1) The normal processes of hemostasis involving platelets, coagulation factors, and endothelium.
2) Classification of bleeding disorders as issues with blood vessels, platelets, or coagulation factors.
3) A stepwise diagnostic approach to evaluating bleeding disorders, beginning with patient history, clinical examination findings, and laboratory investigations.
4) Details on using clinical features like bleeding pattern and location, family history, and physical exam findings to help differentiate between platelet disorders and coagulation factor deficiencies.
The primary function of platelets is their role in hemostasis. Briefly, under normal physiological conditions, platelets will adhere to and begin to spread over the surface of subendothelial cells exposed by damage to the vascular endothelium.(1) Adhesion is dependent on the platelet membrane glycoprotein lb complex. The von Willebrand factor (vWF) is required for both adhesion and spreading.
The primary function of platelets is their role in hemostasis. Briefly, under normal physiological conditions, platelets will adhere to and begin to spread over the surface of subendothelial cells exposed by damage to the vascular endothelium.(1) Adhesion is dependent on the platelet membrane glycoprotein lb complex. The von Willebrand factor (vWF) is required for both adhesion and spreading.
This document discusses hemostasis, surgical bleeding, and transfusion. It begins by outlining the basic biology of hemostasis, including platelet plug formation and the coagulation cascade. It then discusses various congenital and acquired hemostatic defects that can cause bleeding, such as hemophilia and von Willebrand disease. The document concludes by discussing parameters used to evaluate bleeding and examines causes of excessive bleeding in surgical patients.
This document provides an overview of bleeding and coagulation disorders. It discusses the components of hemostasis including primary hemostasis mediated by platelets and vessel walls and secondary hemostasis involving the coagulation factors. Common disorders are described such as platelet disorders, hemophilia, and von Willebrand disease. Clinical features and laboratory evaluation including screening coagulation tests are reviewed. Specific conditions like immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura are then explained in more detail covering etiology, pathogenesis, clinical presentation, and diagnosis.
This document summarizes thrombotic thrombocytopenic purpura (TTP), a rare and life-threatening blood disorder. TTP is characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia caused by platelet-rich microthrombi. It is specifically related to a severe deficiency in ADAMTS13, an enzyme that cleaves von Willebrand factor. The deficiency is usually acquired through autoantibodies against ADAMTS13, but is rarely inherited through mutations in the ADAMTS13 gene. Rapid diagnosis is crucial to initiate treatment with daily plasma exchange to replace the deficient ADAMTS13. Additional treatments target ADAMTS13 autoantibodies
This document discusses drugs used to treat thrombotic disorders. It begins by defining hemostasis and blood coagulation, noting they involve platelets, clotting factors, and a delicate balance. Drugs that modulate this balance are then discussed, including antiplatelets like aspirin, anticoagulants like warfarin and heparin, and fibrinolytics. The coagulation cascade and its initiation by tissue factor are described. Natural anticoagulants like antithrombin and the protein C pathway are also outlined. Finally, fibrinolysis and its regulation are summarized.
This document summarizes a seminar on hemostasis and bleeding disorders. It begins with an overview of hemostasis and the process of forming blood clots. It then discusses different types of bleeding disorders, including disorders of blood vessels, platelets, and coagulation factors. The document outlines an approach to diagnosing bleeding disorders, including screening tests like complete blood count, bleeding time, and clotting time tests. It also discusses specific tests used to evaluate platelet function, coagulation factors, and fibrinolysis. The seminar provided an in-depth review of hemostasis and approaches for diagnosing underlying causes of bleeding disorders.
Coagulation: In medicine, the clotting of blood. The process by which the blood clots to form solid masses, or clots.
More than 30 types of cells and substances in blood affect clotting. The process is initiated by blood platelets. Platelets produce a substance that combines with calcium ions in the blood to form thromboplastin, which in turn converts the protein prothrombin into thrombin in a complex series of reactions. Thrombin, a proteolytic enzyme, converts fibrinogen, a protein substance, into fibrin, an insoluble protein that forms an intricate network of minute threadlike structures called fibrils and causes the blood plasma to gel. The blood cells and plasma are enmeshed in the network of fibrils to form the clot.
This document summarizes several inherited platelet disorders (IPDs). It describes defects that can occur in platelet adhesion, aggregation, secretion, signal transduction and cytoskeletal regulation. Specific IPDs are discussed in more detail, including Bernard-Soulier syndrome, Glanzmann thrombasthenia, storage pool disorders, and cytoskeletal abnormalities like Wiskott-Aldrich syndrome. The document provides an overview of the genetic causes and clinical manifestations of various rare inherited bleeding disorders linked to platelet dysfunction.
La coccidiodomicosis es una micosis sistémica causada por la inhalación del hongo Coccidioides immitis. Se manifiesta principalmente como una infección pulmonar primaria o crónica, pero también puede diseminarse a otros órganos. Es endémica del suroeste de Estados Unidos y partes de México. El diagnóstico se basa en la serología, el cultivo y la microscopía, mientras que el tratamiento depende de la gravedad de la infección y el estado inmunológico del paciente.
Este documento describe el tétanos, una enfermedad causada por la toxina del Clostridium tetani que causa espasmos musculares. Se presenta más en adultos mayores y sus factores de riesgo incluyen heridas, infecciones y tejido muerto. El tratamiento involucra la neutralización de la toxina, antibióticos, control de espasmos y soporte. Con terapia adecuada, el pronóstico suele ser bueno a pesar de que la mortalidad puede alcanzar hasta el 2% en algunos casos.
Este documento resume las guías para el tratamiento de la fibrilación auricular. Describe las clasificaciones de la fibrilación auricular, las indicaciones y contraindicaciones para la cardioversión eléctrica y farmacológica. También discute las opciones de tratamiento farmacológico para el control del ritmo y la frecuencia, incluidos los betabloqueantes, verapamil, diltiazem y digoxina. Además, proporciona recomendaciones sobre el control del ritmo frente al control de la frecuencia según la edad y los síntomas del pac
El documento provee recomendaciones para la profilaxis antimicrobiana en pacientes con HIV. Describe que antes de la terapia antirretroviral, las infecciones oportunistas eran la principal causa de morbilidad y mortalidad en pacientes con HIV. Restaurar la inmunidad celular con terapia antirretroviral potente es la mejor manera de prevenir estas infecciones. Se proveen indicaciones específicas para iniciar profilaxis contra neumonía por Pneumocystis, toxoplasmosis, criptococosis, histoplasmosis y MAC dependiendo
El documento describe las encefalopatías metabólicas agudas en adultos. Se caracterizan por alteraciones de la función cerebral global sin anormalidades estructurales, causadas por enfermedades sistémicas graves pero generalmente reversibles. Los síntomas incluyen confusión, delirio, alteraciones de la conciencia y el comportamiento. El diagnóstico se basa en la historia clínica, exámenes físico y neurológico y pruebas paraclínicas. El tratamiento depende de la causa subyacente.
Este documento resume la historia del VIH/SIDA, incluyendo su descubrimiento en 1981, la identificación del virus en 1983-1984, y la controversia sobre su descubrimiento entre investigadores franceses e investigadores estadounidenses. También describe brevemente la estructura y morfología del virus, así como su ciclo de vida, desde la unión a las células huésped hasta la liberación de nuevas partículas virales.
1) El documento describe las diferentes hepatitis virales, incluyendo los virus que las causan, sus características y formas de transmisión. 2) Explica las distintas fases de la hepatitis B crónica y los marcadores serológicos asociados. 3) Incluye información sobre el diagnóstico, tratamiento y complicaciones de las hepatitis A, B, C, D y E.
El documento describe hipogonadismo, que se refiere a la disminución de la producción de espermatozoides y testosterona en los testículos. Explica que puede ser primario, debido a problemas en los propios testículos, o secundario, causado por problemas en el hipotálamo o la pituitaria. El tratamiento principal para el hipogonadismo sintomático es la sustitución de testosterona para restaurar los niveles normales.
Este documento describe la hipertiroidismo y la enfermedad de Graves-Basedow. Define la hipertiroidismo como un trastorno caracterizado por la secreción excesiva de hormonas tiroideas. Describe las causas como la enfermedad de Graves-Basedow, adenomas tóxicos y bocios multinodulares tóxicos. Detalla las manifestaciones clínicas, el diagnóstico y los tratamientos como betabloqueadores, tionamidas, ablación con yodo y cirugía.
Este documento discute el uso de omeprazol en pacientes críticamente enfermos. Define varios tipos de úlceras como la úlcera de estrés, la úlcera de Cushing y la úlcera de Curling. Explica factores de riesgo para úlceras de estrés como ventilación mecánica prolongada, coagulopatía e insuficiencia de órganos. Compara inhibidores de bomba de protones, sucralfato y antagonistas H2 como opciones para la profilaxis y encuentra que los inhibidores de
Este documento describe la nefrotoxicidad causada por fármacos. Explica que puede causar daño renal anatómico o funcional a través de mecanismos como alteración hemodinámica, toxicidad de células tubulares o inflamación. Detalla tres tipos principales de daño renal - enfermedad tubulointersticial, glomerular y vascular - así como factores de riesgo y ejemplos comunes como aminoglucósidos y litio. Finalmente, proporciona medidas para prevenir la nefrotoxicidad como ajustar dosis,
La hipertensión portal se define como una elevación del gradiente de presión venosa hepática. Puede ser prehepática, hepática o posthepática dependiendo de la ubicación de la obstrucción. Las principales manifestaciones clínicas son hemorragia gastrointestinal, ascitis y esplenomegalia. El diagnóstico se realiza mediante métodos como angiografía, elastografía, angiorresonancia, endoscopia y ultrasonido abdominal. El tratamiento incluye fármacos como vasoconstrictores y betabloqueadores, así como procedimientos para controlar hemorragias de
El documento presenta las guías para el manejo de la sepsis severa y el choque séptico. Resume las recomendaciones para la reanimación inicial con fluidoterapia y vasopresores, el diagnóstico y tratamiento antibiótico temprano de la infección subyacente, y el control de la fuente de infección dentro de las primeras 12 horas. El objetivo es reconocer y tratar agresivamente la sepsis para mejorar los resultados de los pacientes.
Este documento describe la angina de pecho estable. 1) Explica que la angina de pecho fue descrita por primera vez en 1768 y define la angina de pecho estable como un trastorno en el que parte del miocardio recibe una cantidad insuficiente de sangre y oxígeno. 2) Detalla los factores de riesgo, fisiopatología y clasificación clínica de la angina de pecho estable. 3) Explica los objetivos del tratamiento, que incluyen mejorar el pronóstico y minimizar los síntomas.
La diabetes gestacional es una elevación de la glucosa en la sangre que se reconoce por primera vez durante el embarazo. Afecta alrededor del 7% de los embarazos y puede repetirse en embarazos futuros. El diagnóstico se realiza mediante una prueba de tolerancia oral a la glucosa entre la 24 y 28 semanas de gestación, la cual mide los niveles de glucosa en la sangre una hora después de consumir 50 gramos de glucosa. El tratamiento consiste principalmente en modificaciones en el estilo de vida como dieta y ej
Este documento presenta las recomendaciones actualizadas de GeSIDA y el Plan Nacional sobre el Sida sobre el tratamiento antirretroviral en adultos infectados por el VIH. Se revisa la evaluación clínica y de laboratorio para guiar el tratamiento, las opciones de tratamiento inicial, los cambios de régimen cuando el tratamiento es eficaz, el manejo del fracaso virológico y factores que afectan el éxito del tratamiento. También se discuten situaciones especiales como la infección aguda, VIH-2, embarazo y comorb
El documento proporciona información sobre el traumatismo craneoencefálico (TCE), incluyendo la anatomía del cráneo y el encéfalo, la fisiología cerebral, los tipos de lesiones causadas por TCE como hematomas y contusiones, y el manejo y tratamiento del TCE leve y grave. Se describen procedimientos como la hiperventilación, el uso de manitol y furosemida para reducir la presión intracraneal elevada, y el uso de anticonvulsivantes. También se discuten intervenciones quirú
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
Adhd Medication Shortage Uk - trinexpharmacy.comreignlana06
The UK is currently facing a Adhd Medication Shortage Uk, which has left many patients and their families grappling with uncertainty and frustration. ADHD, or Attention Deficit Hyperactivity Disorder, is a chronic condition that requires consistent medication to manage effectively. This shortage has highlighted the critical role these medications play in the daily lives of those affected by ADHD. Contact : +1 (747) 209 – 3649 E-mail : sales@trinexpharmacy.com
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Does Over-Masturbation Contribute to Chronic Prostatitis.pptxwalterHu5
In some case, your chronic prostatitis may be related to over-masturbation. Generally, natural medicine Diuretic and Anti-inflammatory Pill can help mee get a cure.
Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
ABDOMINAL TRAUMA in pediatrics part one.drhasanrajab
Abdominal trauma in pediatrics refers to injuries or damage to the abdominal organs in children. It can occur due to various causes such as falls, motor vehicle accidents, sports-related injuries, and physical abuse. Children are more vulnerable to abdominal trauma due to their unique anatomical and physiological characteristics. Signs and symptoms include abdominal pain, tenderness, distension, vomiting, and signs of shock. Diagnosis involves physical examination, imaging studies, and laboratory tests. Management depends on the severity and may involve conservative treatment or surgical intervention. Prevention is crucial in reducing the incidence of abdominal trauma in children.
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
Histololgy of Female Reproductive System.pptxAyeshaZaid1
Dive into an in-depth exploration of the histological structure of female reproductive system with this comprehensive lecture. Presented by Dr. Ayesha Irfan, Assistant Professor of Anatomy, this presentation covers the Gross anatomy and functional histology of the female reproductive organs. Ideal for students, educators, and anyone interested in medical science, this lecture provides clear explanations, detailed diagrams, and valuable insights into female reproductive system. Enhance your knowledge and understanding of this essential aspect of human biology.
1. Glanzmann thrombasthenia
Author: Dr Alan T Nurden*
*
IFR N°4, Laboratoire d'Hématologie, Hôpital Cardiologique, 33604 Pessac, FRANCE.
Alan.Nurden@cnrshl.u-bordeaux2.fr
Scientific Editor: Doctor Sylvia Bellucci
Creation date: December 2003
Updated: September 2005
Abstract
Key Words
Disease name
Definition
History
Differential diagnosis
Etiology
Clinical manifestations
Epidemiology
Diagnostic methods
Carrier analysis, prenatal diagnosis and genetic counseling
Management including treatment
Unresolved questions
References
Abstract
Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding syndrome affecting the
megakaryocyte lineage and characterized by lack of platelet aggregation. The molecular basis is linked to
quantitative and/or qualitative abnormalities of the αIIbβ3 integrin. This receptor mediates the binding of
adhesive proteins that attach aggregating platelets and ensure thrombus formation at sites of injury in
blood vessels. GT is associated with clinical variability: some patients have only minimal bruising while
others have frequent, severe and potentially fatal hemorrhages. The site of bleeding in GT is clearly
defined: purpura, epistaxis, gingival hemorrhage, and menorrhagia are nearly constant features;
gastrointestinal bleeding and hematuria are less common. In most cases, bleeding symptoms manifest
rapidly after birth, even if GT is occasionally only diagnosed in later life. Diagnosis associates
mucocutaneous bleeding with absent platelet aggregation in response to all physiologic stimuli, a normal
platelet count and morphology. Platelet αIIbβ3 deficiency or nonfunctioning should always be confirmed,
by flow cytometry for example. In order to avoid platelet alloimmunisation, therapeutic management must
include, if possible, local hemostatic procedures and/or DDAVP (desmopressin) administration. If these
measures are ineffective, or to prevent bleeding during surgery, management often requires the
transfusion of HLA-compatible platelet concentrates. Administration of recombinant factor VIIa is an
increasingly used therapeutic alternative. GT can be a severe hemorrhagic disease, however the
prognosis is excellent with careful supportive care.
Key Words
Glanzmann thrombasthenia, bleeding disorder, platelet aggregation, αIIbβ3 integrin, αIIb gene, β3 gene,
recombinant factor VIIa
Disease name
Glanzmann thrombasthenia (GT)
Nurden A. Glanzmann thrombasthenia. Orphanet Encyclopedia, September 2005.
http://www.orpha.net/data/patho/GB/uk-Glanzmann.pdf 1
2. Definition
GT is an autosomal, recessive, bleeding syndrome affecting the megakaryocyte lineage and
characterized by a lack of platelet aggregation. It is a moderate to severe hemorrhagic disorder with
mainly mucocutaneous bleeding. The molecular basis is linked to quantitative and/or qualitative
abnormalities of the IIb 3 integrin, the receptor that mediates the incorporation of platelets into an
aggregate or thrombus at sites of vessel injury.
History
Glanzmann first described this disease in 1918 as "hereditary hemorrhagic thrombasthenia" [1]. A
prolonged bleeding time and an isolated, rather than clumped, appearance of platelets on a peripheral
blood smear were early diagnostic criteria. In 1956, Braunsteiner and Pakesch reviewed disorders of
platelet function and described thrombasthenia as an inherited disease characterized by platelets of
normal size that failed to spread onto a surface and did not support clot retraction [2]. The diagnostic
features of GT including the absence of platelet aggregation as the primary feature were clearly
established in 1964 by the classic report on 15 French patients by Caen et al [3]. Those patients with
absent platelet aggregation and absent clot retraction were subsequently termed type I disease; those
with absent aggregation but residual clot retraction, type II disease; while variant disease was first
established in 1987 (reviewed in ref [4]).
Differential diagnosis
Platelet aggregation defects specific to ADP or collagen, imply abnormalities of their primary receptors or
of signalling pathways. Defects in the second wave of aggregation to ADP or in the response to collagen
can imply storage pool disease and an absence of the secretory stores of ADP in dense granules.
Deficiencies in the platelet response to arachidonic acid can point either to an inherited abnormality in
thromboxane A2 formation or a platelet function defect temporarily acquired through aspirin ingestion. GT
is the only disease in which platelet aggregation is defective to all agonists, while absent clot retraction is
another frequent characteristic.
Normal ristocetin-induced platelet agglutination and normal platelet size clearly rule out the Bernard-
Soulier syndromeT, a disorder of platelet adhesion. Inherited thrombocytopenias are eliminated by a
normal platelet count. Normal coagulation parameters rule out clotting disorders that can also affect
platelet function such as congenital afibrinogenemia and von Willebrand disease. Acquired
thrombasthenia must be eliminated in the absence of a family history of the disease. Platelet αIIbβ3
deficiency and abnormal platelet aggregation have been reported in patients with acute promyelocytic
leukemia [5]; the etiology of this acquired disorder is probably a chromosome 15-17 translocation.
Although the breakpoint region on chromosome 17 is heterogeneous in acute promyelocytic leukemia, in
some patients it occurs at 17q21, and this is the location of the genes for αIIb and β3 [6]. Another problem
in diagnosing GT is to eliminate patients with acquired autoantibodies that block aggregation, although
these patients would often be thrombocytopenic [7]. These antibodies can be detected immunologically by
their binding to αIIbβ3 of control platelets during incubation with the patient's serum [8].
Etiology
Cell biology
Megakaryocytes are found in the bone marrow and when mature, liberate large numbers of platelets into
the blood circulation. In GT, platelets fail to aggregate in response to all natural agonists, including ADP,
thrombin and collagen despite their undergoing a normal shape change. Thrombasthenic platelets can
also adhere to exposed subendothelial tissue and secretion from storage granules is initiated. However,
the subsequent reactions of platelet spreading on the exposed surface and thrombus build-up are
defective [9]. In the 1970s, Nurden and Caen demonstrated that platelets from patients with GT had
selective abnormalities in their membrane glycoprotein (GP) composition [10]. This led to the recognition
that the disease was provoked by specific deficiencies of GPIIb and GPIIIa. It was later established that (i)
GPIIb and GPIIIa were present in the platelet membrane as a heterodimeric molecule and (ii) as αIIbβ3,
the complex was a member of the ubiquitous integrin family of cell surface receptors [11,12]. Significantly,
GT is now generally recognized as the most frequent inherited integrin disorder.
Nurden A. Glanzmann thrombasthenia. Orphanet Encyclopedia, September 2005.
http://www.orpha.net/data/patho/GB/uk-Glanzmann.pdf 2
3. In man, expression of the αIIb gene (and therefore of the αIIbβ3 integrin) is restricted to cells of the
megakaryocytic cell lineage. Expression of the β3 gene is more widespread, with the vitronectin receptor
(αvβ3) being expressed in many cell types, including endothelial cells, osteoblasts, smooth muscle cells,
and leukocytes [12]. Despite this, patients with β3 gene defects appear not to have a more severe form of
the disease (discussed below). In the platelet, αvβ3 is a rare component, approximately 50 copies being
found at the surface, and this compares to upwards of 50,000 copies of αIIbβ3 [13]. In the seconds
following binding of stimuli to platelets, αIIbβ3 straightens from a bent conformation and demonstrates
receptor activity for fibrinogen [14]. Although fibrinogen is the predominant ligand in plasma, a role of VWF
(von Willebrand Factor) in conditions of high shear is to be emphasised, while fibronectin, vitronectin and
CD40L may also participate [15-17]. The inability to bind adhesive proteins when stimulated explains the
platelet phenotype in GT. Fibrin binding to αIIbβ3 allows some hemostatic function when residual integrin
is present [18]. Furthermore, GT platelets appear able to attach to fibrin independently of activated αIIbβ3
under flow suggesting the presence of an alternative platelet receptor for fibrin [19].
Genetic basis
A continually updated database is available on the Internet (http://sinaicentral.mssm.edu/intranet/research
/glanzmann): it currently contains a list of about 100 mutations giving rise to GT. The αIIb and β3 genes
are both affected and while posttranslational defects predominate, mRNA stability can also be affected. In
brief, integrin synthesis occurs in the megakaryocytes with αIIbβ3 complex formation in the endoplasmic
reticulum (ER). Noncomplexed or incorrectly folded gene products fail to undergo processing in the Golgi
apparatus and are rapidly degraded intracellularly [20,21]. One exception is the ability of normally
synthesised β3 to complex with αv and form αvβ3 (see above). Figures 1A and B show those mutations
where supplementary information (family studies, site-directed mutagenesis) links them to the GT
phenotype. Deletions and insertions, nonsense and missense mutations are common causes of GT.
Splice site defects and frameshifts are also widespread. Large deletions are rare.
As shown in Fig. 1A, the αIIb gene is composed of 30 exons. In an early and classic study, three
Israeli Arab kindreds were shown to possess a 13-bp deletion leading to 6 amino acids deletion in the αIIb
protein [22]. The affected region, including Cys107, was postulated to be critical for posttranslational
processing of αIIb. Missense mutations in exons encoding the extracellular β-propeller region of αIIb [23]
have shown how the extracellular calcium-binding domains of αIIb are essential for αIIbβ3 biogenesis [24-
26]. Site-directed mutagenesis involving various amino acid substitutions at position 324 of αIIb illustrated
just how the GT phenotype depended on both the nature of the substituted amino acid and its
replacement [26]. Mutations affecting the membrane-proximal calf-2 domain showed that while this region
was not essential for complex formation in the ER, it was necessary for transport into and/or through the
Golgi apparatus [21,27]. These are but a few selected examples of αIIb defects.
Figure 1A. Schematic representation of the structure of the αIIb gene together with a
representative spectrum of the types of genetic abnormalities that give rise to GT.
The defects responsible for variant forms of the disease are in blue type, those which are prevalent in ethnic groups are in green.
Asterisks indicate the number of times that the same genetic defect has been described in apparently unrelated families. For a
continually updated list of defects please consult the ISTH database (http://sinaicentral.mssm.edu/intranet/research/glanzmann).
UTR: untranslated region, del = deletion, ins = insertion, inv = inversion, term = premature termination, stop = stop codon. For
simplicity, the initial genetic defect is highlighted. Frameshifts and aberrant splicing are not always given.
Nurden A. Glanzmann thrombasthenia. Orphanet Encyclopedia, September 2005.
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4. The organisation of the β3 gene is shown in Figure 1B. It is composed of 15 exons and mutations are
again widely distributed within the gene. An 11 bp deletion leading to protein termination shortly before
the transmembrane domain of β3 was first described in six Iraqi Jews with type I disease [22]. This defect
prevented normal membrane insertion of the integrin and also αvβ3 expression both in platelets and other
cells. Although most β3 mutations affect αIIbβ3 and αvβ3 expression, rare mutations allow αvβ3
expression while preventing αIIbβ3 processing [28].
Patients with mutations allowing αIIbβ3 to be processed but in whom integrin function is abolished are
of particular interest. In most of these patients, it is the β3 gene that is affected. In brief, many of the
variants have platelets with sufficient αIIbβ3 to normally allow aggregation but in which the activation-
dependent expression of adhesive protein binding sites on the integrin does not occur [29,30]. As well as
providing information on the ligand-binding pocket on the extracellular domains, variant molecules have
highlighted the role of the αIIb and β3 intracellular tails in integrin signaling and even for integrin trafficking
[31-33]. For some variants, clot retraction can occur even if aggregation is prevented [34]. Finally, recent
studies on two patients have revealed that disruption of disulfide bridges in the β3 EGF (Epidermal
Growth Factor) extracellular domains gives rise to a constitutively active integrin, able to spontaneously
bind fibrinogen [35,36]. Here, aggregation fails to occur because of the absence of free counter receptors
allowing platelet to platelet bridging.
The recent application of mutation screening on a national basis first in Italy and then in India has re-
emphasized how a wide array of mutations can be found in GT patients within a single country.
Interestingly, while 17 out of 21 candidate mutations were in the αIIb gene of the Italian patients, β3
mutations with emphasis on exon 4 appear to characterize the Indian patients [37,38].
Nurden A. Glanzmann thrombasthenia. Orphanet Encyclopedia, September 2005.
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5. Figure 1B. Schematic representation of the structure of the β3 gene together with a representative
spectrum of the types of genetic abnormalities that give rise to GT.
Note that abnormalities are abundant in both αIIb and β3 genes and that no parts of either gene appear to be exempt. For
further information see the legend to Figure 1A.
Clinical manifestations
Early reports emphasized the clinical variability of this bleeding syndrome: some patients had only
minimal bruising while others had frequent, severe and potentially fatal hemorrhages. Hemorrhagic
symptoms occur only in patients homozygous for GT; the heterozygous condition is mostly asymptomatic,
even though these subjects have only a half-normal concentration of platelet αIIbβ3 [4]. The sites of
bleeding in GT are clearly defined: purpura, epistaxis, gingival hemorrhage, and menorrhagia are nearly
constant features; gastrointestinal bleeding and hematuria are less common but can cause serious
complications [39,40]. It is important to note that deep visceral hematomas, a characteristic of coagulation
disorders such as hemophilia, are not usually seen. In most cases, bleeding symptoms manifest rapidly
after birth even if occasionally GT is only diagnosed later in life. Epistaxis is a common cause of severe
bleeding, and is typically more severe in childhood. In general, the bleeding tendency in GT decreases
with age. The rare co-existence of GT with other inherited diseases such as mild von Willebrand disease
may accentuate the clinical severity of bleeding [27,39].
Although GT can be a severe hemorrhagic disease, the prognosis is excellent with careful supportive
care. Most adult patients are in good health and their disease has a limited effect on their daily lives.
Death from hemorrhage in diagnosed patients is rare unless associated with trauma or other disease (e.g.
cancer). In contrast, families often report deceased siblings on diagnosis of GT.
Correlation of clinical disease with the platelet molecular abnormality
Clinical observations suggest little or no correlation between the amount of residual platelet αIIbβ3 and
the severity of hemorrhagic disease [4,39]. Among the patients studied over many years in Paris [4], some
with negligible bleeding symptoms have virtually no detectable αIIbβ3, while others who have 10%-15% of
normal levels of functional platelet αIIbβ3 have experienced severe hemorrhage. It can be postulated that
Nurden A. Glanzmann thrombasthenia. Orphanet Encyclopedia, September 2005.
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6. the absence of αvβ3 function in vascular cells may contribute to the hemorrhagic tendency. However,
even among families in whom no β3 can be demonstrated, bleeding ranges from severe to moderate and
sporadic. Since therapeutic inhibition of platelet αIIbβ3 function prevents arterial thrombosis [41], patients
are empirically protected from this disease. It has been speculated that patients with GT may also be
protected from atherosclerotic disease. However, studies within ethnic groups in Israel have suggested
that this is not so [42]. Patients with GT also are not protected against venous thrombosis where plasma
coagulation factors are of primary importance [43].
Mice lacking β3 integrins develop thickened bones because of dysfunctional osteoclasts [44].
However, upregulation of α2β1 integrin compensates for lack of αvβ3 in osteoclasts from Iraqi-Jewish
patients and so this feature may not translate to humans [45]. Other studies with β3 knockout mice show
increased expression of Flk-1 on β3null endothelial cells with increased vascular endothelial growth factor
(VEGF) signaling and enhanced angiogenesis and tumour growth [46]. How this or an observed
decreased fertility translate to GT patients with β3 gene defects are topics for urgent study.
Epidemiology
A review of 177 patients with GT (of which 113 were literature reports and 64 were seen at the Hôpital
Lariboisière, Paris) showed that 102 (58%) were female [4]. This finding may reflect the added problem
with menorrhagia. The average age of the 113 patients for whom age was given was only 20. This may
reflect improvements in diagnostic procedures. The frequency of consanguinity in affected families is
noticeable, and GT has an increased incidence in populations in whom marriage among close relatives is
an accepted custom. For example, in the review of 177 patients [4], only 12 were reported from the United
States. In contrast, fifty-five patients were from Israel and Jordan and 42 were from South India. In certain
ethnic groups, such as South Indian Hindus, Iraqi Jews, French gypsies and Jordanian nomadic tribes,
thrombasthenia may actually be a common hereditary hemorrhagic disorder. This has recently been
borne out by a report of 382 patients in Iran [47]. For these reasons it would be imprudent to give an
estimation of worldwide prevalence.
Diagnostic methods
Mucocutaneous bleeding with absent platelet aggregation in response to all physiologic stimuli is
pathognomonic for GT, and abnormal clot retraction is rarely observed in other disorders [39]. When these
two signs are associated with a normal platelet count and morphology, the diagnosis of GT is clear-cut.
Use of the PFA-100 system (Dade-Behring, Miami, USA) can replace bleeding time for GT [48]. The PFA-
100 measures the closure time when blood is passed through collagen-based filters under flow; blood
from GT patients fails to plug the filter. Platelet αIIbβ3 deficiency should always be confirmed in new
patients, and this can be done with monoclonal antibodies and flow cytometry [24,35]. The detection of
trace amounts of intracellular αIIb or β3 in a patient’s platelets by western blotting [27,28], can give clues
to the identity of the affected gene, while the presence of nonprocessed precursor pro-αIIb will suggest a
block in integrin biosynthesis [25,26].
In the detailed analysis of experience gained at Hôpital Lariboisière in Paris, 50 of 64 patients (78%)
had type I disease, 9 patients (14%) had type II disease with residual αIIbβ3, and 5 patients (8%) were
classified as variant GT, [4] a subgroup diagnosed by the inability of αIIbβ3 to express activation-
dependent epitopes (recognized by the absence of binding of monoclonal antibodies such as PAC-1 or
FITC-fibrinogen in flow cytometry) [29-34].
Only in ethnic groups with high consanguinity can procedures permitting the rapid screening of given
mutations be used. This is the case for the Iraqi-Jewish and Arab groups in Israel and for a Manouche
gypsy population in France [49-51]. Here, rapid screening procedures include allele-specific restriction
enzyme analysis (ASRA) [51]. Otherwise, the patient needs to be referred to a specialist laboratory, for
direct sequencing of the relevant genes.
Carrier analysis, prenatal diagnosis and genetic counseling
Initial studies attempted to diagnose carriers for GT by measuring the number of αIIbβ3 receptors on
platelets. However, an occasional overlap between obligate heterozygotes and ostensibly normal donors
whose platelets had a low αIIbβ3 expression made interpretation of the results difficult. Prenatal diagnosis
performed by measuring αIIbβ3 on platelets isolated from cord blood has been attempted, but is
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7. accompanied by a high risk of bleeding and of spontaneous abortion [52]. So it is best to first identify the
genetic lesion within the family in question. Then, carrier diagnosis can be determined with relative ease
particularly if sites are created (or lost) for restriction enzymes. Restriction digest analysis of PCR-
amplified fragments from DNA isolated from blood or urine was first used to screen subjects for the Iraqi-
Jewish and Arab mutations [49]. The presence of these mutations could also be confirmed in prenatal
diagnosis using DNA extracted from chorionic villi (discussed by French [20]). Carriers have also been
detected within the French gypsy populations using ASRA methodology [51]. Finally, prenatal diagnosis in
GT has been achieved using the polymorphic markers BRCA1 and THRA1 on chromosome 17 [53].
Genetic counseling can be given with the following reservations: (i) when screening is followed for a
single mutation within an ethnic population, the presence of a second Glanzmann’s defect may go
undetected and (ii) that individuals with the same mutation may differ widely in the frequency and severity
of bleeding.
Management including treatment
Despite variations in the severity and frequency of bleeding episodes, most GT patients receive blood
transfusions [39,40]. Local bleeding can be treated by local measures, such as fibrin sealants. Epistaxis
and gingival bleeding are successfully controlled in most patients by nasal packing or the application of
gel foam soaked in topical thrombin. Regular dental care is essential to prevent gingival bleeding. For
teeth extractions, or for hemorrhage accompanying the loss of deciduous teeth, hemostasis can be
significantly improved by the application of individually prepared plastic splints that provide physical
support for hemostasis.
Severe menorrhagia is a frequent clinical problem and is usually associated with an excessively
proliferative endometrium caused by estrogen dominance. It can be effectively treated with high doses of
progesterone. Maintenance treatment with birth control pills should follow. Severe gastrointestinal
bleeding is a problem in isolated cases. Iron deficiency anemia, which can develop insidiously with
gingival oozing or minor menorrhagia, is a frequent problem.
Bleeding following trauma or surgical procedures can be severe and transfusions are often given by
precaution or should be available on standby. Pregnancy and in particular, delivery, represent a
particularly severe hemorrhagic risk. Platelet transfusions are required not only prior to delivery, but
sometimes should be continued for at least a week [39]. Successful delivery by Cesarean section, with
platelet transfusions, has been reported. Note that if platelet transfusions are required, the most HLA-
compatible platelet concentrates must be chosen in order to avoid platelet anti-HLA alloimmunization.
The fact that most patients receive red cell and/or platelet transfusions on more than one occasion,
makes the production of isoantibodies reactive with αIIbβ3 likely [4,39]. Such antibodies are antigen-
driven and are produced against different epitopes on the integrin [54]. They may block platelet
aggregation, as well as leading to the rapid removal of transfused platelets by immune mechanisms.
Whether a particular category of patient is more likely to form isoantibodies is as yet unknown. When
present at high titre, the antibodies cause patients to become refractory to further transfusions. Antibodies
have been successfully removed prior to surgery by immunoadsorption on Protein A Sepharose, although
this is a complex procedure whose use is restricted to specialized centers [55]. Recently, recombinant
factor VIIa (NovoSeven® ; Novo Nordisk A/S, Malov, Denmark) has been successfully used in GT and
represents an alternative approach to early stopping of bleeding, especially for patients with antibodies
and/or a history of refractoriness to transfusion [56]. It is often used in association with anti-fibrinolytic
agents. Thromboembolic events are a rare but potential hazard. Recombinant factor VIIa appears to
enhance deposition of the αIIbβ3-deficient platelets on the subendothelial matrix through their interaction
with fibrin formed as a result of an increased thrombin generation [19]. The stability of the newly-formed
clot is increased and its permeability decreased [57]. Nevertheless, the efficacity of recombinant factor
VIIa in children with GT has been questioned [58]. Rarely, in some patients, the condition has been
thought to be sufficiently serious for allogeneic bone-marrow transplantation to be performed [39,59]. In
the first report, donors were siblings and the transplantation was successful [59].
Unresolved questions
Awaiting discovery, perhaps, are abnormalities of the cytoplasmic proteins now thought to regulate the
activation state of αIIbβ3 for adhesive proteins [60]. The observation that a series of platelet receptor
Nurden A. Glanzmann thrombasthenia. Orphanet Encyclopedia, September 2005.
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8. gene haplotypes can markedly affect bleeding severity and bleeding times in patients with von Willebrand
disease type I [61], points to the bleeding tendency in congenital disorders being governed by the score of
an ensemble of risk factors. As well as gene polymorphisms affecting platelet receptors, those influencing
coagulation factors, and the functioning of vascular cells may also be involved. The application of
proteomic and gene microarray technologies to platelet disorders such as GT may help determine
whether bleeding risk in individual patients can be predicted. Although the work is at an early stage,
animal models of gene therapy show that GT may be an appropriate disease for such an approach and
research is progressing in this direction [62].
Finally, as national and international networks are set up, and sequencing centers become involved in
genotyping, especially among ethnic groups and third world countries, healthcare of GT will improve on a
worldwide basis.
Acknowledgement: The author acknowledges the support provided by GIS-Maladies Rares to the
French National Network on 'Inherited Diseases of Platelet Production and Function'.
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