This document summarizes the 2018 classification system for vascular anomalies from the International Society for the Study of Vascular Anomalies (ISSVA). It describes how the classification divides vascular lesions into vascular tumors and vascular malformations. For vascular malformations, it further divides them into simple, combined, those involving major vessels, and those associated with other anomalies. The document then discusses the molecular underpinnings of several types of vascular anomalies, noting that many are caused by mutations in genes involved in the RAS/MEK/ERK and PI3K/Akt/mTOR pathways. Specific gene mutations are linked to venous malformations (TIE2, PIK3CA, AKT), glomuvenous mal
The role of inflammatory reaction in chronic venous disease of the lower limbKETAN VAGHOLKAR
Chronic venous disease is the problem which is assuming alarming proportions in subjects whose occupation involves prolonged sitting or standing. The exact mechanism by which the venous system gets damaged continues to be a subject of endless research. The role of inflammation is a significant factor in the evolution of chronic venous disease. Awareness of this mechanism can help in both prevention and treatment of this complex vascular disorder. The paper reviews inflammatory mechanism underlying the pathogenesis of chronic venous disease in lower limbs.
Diseases of the veins can involve varicose veins, chronic venous insufficiency, deep vein thrombosis, and superior vena cava syndrome. Varicose veins and chronic venous insufficiency are caused by damaged valves that allow blood to pool in the veins under gravity, distending and damaging the veins over time. Deep vein thrombosis occurs when blood clots form in the deep veins, usually in the legs, which can lead to pulmonary embolism if pieces of the clot break off. Superior vena cava syndrome involves the occlusion of the superior vena cava by lung cancer or other causes in most cases.
Despite the advances in diagnostic methods and techniques for surgical treatment in the last two decades, aortic diseases remain a major cause of mortality and cardiovascular morbidity, challenging physicians and molecular biologists. It is believed that about 600 million years ago, during the Cambrian period, variant forms of life appeared, among them were the oxygen-producing cyano bacteria.
Association between Galectin-3 and oxidative stress parameters with coronary ...komalicarol
Galectin-3 (Gal-3), as a mediator of inflammation and fibrosis, has been reported to be a biomarker of severity in
coronary artery disease (CAD). The study aimed to assess the relationships between coronary artery disease (CAD) and risk factors,
including parameters of oxidative stress in Tunisian patients CAD.
Association Between Galectin-3 and Oxidative Stress Parameters with Coronary ...semualkaira
Galectin-3 (Gal-3), as a mediator of inflammation and fibrosis, has been reported to be a biomarker of severity in
coronary artery disease (CAD). The study aimed to assess the relationships between coronary artery disease (CAD) and risk factors,
including parameters of oxidative stress in Tunisian patients CAD
This document discusses acute myeloid leukemia (AML) and its acute complications. It defines AML as a clonal expansion of myeloid precursor cells with reduced capacity to differentiate. Common clinical presentations include fever, bleeding, and fatigue due to excessive proliferation of myeloid cells in the bone marrow leading to pancytopenia. Two major acute complications discussed are leukostasis, which can cause pulmonary and neurological symptoms, and tumor lysis syndrome, which results in electrolyte abnormalities and renal impairment.
1. The document discusses Chronic Cerebrospinal Venous Insufficiency (CCSVI), a condition linked to multiple sclerosis (MS) where veins draining the brain and spinal cord are narrowed or blocked.
2. It provides details on diagnosing and treating CCSVI using procedures like Doppler ultrasound, MRI, venography, and venous angioplasty to widen blocked veins.
3. While the relationship between CCSVI and MS is still being studied, the document reports that over 600 MS patients treated for CCSVI experienced reduced fatigue, improved quality of life, psychological state, and physical condition based on evaluation scales.
Vasculitis is inflammation of blood vessels that can affect single or multiple organ systems. It is classified based on the size of vessels involved - large, medium, or small. Common large vessel vasculitis includes giant cell arteritis and Takayasu arteritis. Pathogenesis involves immune complex formation, ANCA, and T lymphocyte responses. Clinical manifestations are variable and depend on organ systems involved. Diagnosis involves criteria based on symptoms, labs like ESR, and biopsy when possible. Treatment focuses on reducing inflammation and preventing complications.
The role of inflammatory reaction in chronic venous disease of the lower limbKETAN VAGHOLKAR
Chronic venous disease is the problem which is assuming alarming proportions in subjects whose occupation involves prolonged sitting or standing. The exact mechanism by which the venous system gets damaged continues to be a subject of endless research. The role of inflammation is a significant factor in the evolution of chronic venous disease. Awareness of this mechanism can help in both prevention and treatment of this complex vascular disorder. The paper reviews inflammatory mechanism underlying the pathogenesis of chronic venous disease in lower limbs.
Diseases of the veins can involve varicose veins, chronic venous insufficiency, deep vein thrombosis, and superior vena cava syndrome. Varicose veins and chronic venous insufficiency are caused by damaged valves that allow blood to pool in the veins under gravity, distending and damaging the veins over time. Deep vein thrombosis occurs when blood clots form in the deep veins, usually in the legs, which can lead to pulmonary embolism if pieces of the clot break off. Superior vena cava syndrome involves the occlusion of the superior vena cava by lung cancer or other causes in most cases.
Despite the advances in diagnostic methods and techniques for surgical treatment in the last two decades, aortic diseases remain a major cause of mortality and cardiovascular morbidity, challenging physicians and molecular biologists. It is believed that about 600 million years ago, during the Cambrian period, variant forms of life appeared, among them were the oxygen-producing cyano bacteria.
Association between Galectin-3 and oxidative stress parameters with coronary ...komalicarol
Galectin-3 (Gal-3), as a mediator of inflammation and fibrosis, has been reported to be a biomarker of severity in
coronary artery disease (CAD). The study aimed to assess the relationships between coronary artery disease (CAD) and risk factors,
including parameters of oxidative stress in Tunisian patients CAD.
Association Between Galectin-3 and Oxidative Stress Parameters with Coronary ...semualkaira
Galectin-3 (Gal-3), as a mediator of inflammation and fibrosis, has been reported to be a biomarker of severity in
coronary artery disease (CAD). The study aimed to assess the relationships between coronary artery disease (CAD) and risk factors,
including parameters of oxidative stress in Tunisian patients CAD
This document discusses acute myeloid leukemia (AML) and its acute complications. It defines AML as a clonal expansion of myeloid precursor cells with reduced capacity to differentiate. Common clinical presentations include fever, bleeding, and fatigue due to excessive proliferation of myeloid cells in the bone marrow leading to pancytopenia. Two major acute complications discussed are leukostasis, which can cause pulmonary and neurological symptoms, and tumor lysis syndrome, which results in electrolyte abnormalities and renal impairment.
1. The document discusses Chronic Cerebrospinal Venous Insufficiency (CCSVI), a condition linked to multiple sclerosis (MS) where veins draining the brain and spinal cord are narrowed or blocked.
2. It provides details on diagnosing and treating CCSVI using procedures like Doppler ultrasound, MRI, venography, and venous angioplasty to widen blocked veins.
3. While the relationship between CCSVI and MS is still being studied, the document reports that over 600 MS patients treated for CCSVI experienced reduced fatigue, improved quality of life, psychological state, and physical condition based on evaluation scales.
Vasculitis is inflammation of blood vessels that can affect single or multiple organ systems. It is classified based on the size of vessels involved - large, medium, or small. Common large vessel vasculitis includes giant cell arteritis and Takayasu arteritis. Pathogenesis involves immune complex formation, ANCA, and T lymphocyte responses. Clinical manifestations are variable and depend on organ systems involved. Diagnosis involves criteria based on symptoms, labs like ESR, and biopsy when possible. Treatment focuses on reducing inflammation and preventing complications.
Vasculitis is inflammation of blood vessels that can affect single or multiple organ systems. It is classified based on the size of vessels involved. Diagnosis involves clinical features, lab tests like ESR, and biopsy. Treatment depends on type but often involves steroids. Giant cell arteritis and Takayasu arteritis specifically involve medium and large vessels. Giant cell arteritis commonly affects the temporal artery and presents with headaches. Both require long term steroids to prevent complications.
Disseminated intravascular coagulation (DIC) is an acquired syndrome caused by the pathological activation of intravascular coagulation and fibrinolysis, disrupting hemostatic balance. It is initiated by the release of tissue factor from endothelial cells or white blood cells in response to trauma, infection, ischemia or other stresses. This leads to the activation of coagulation pathways and uncontrolled thrombin generation, consuming coagulation factors and platelets and producing microthrombi throughout the circulatory system. Bleeding and organ dysfunction can result from inadequate hemostasis and end-organ ischemia. Laboratory tests may show elevated prothrombin time, activated partial thromboplastin time, d-dimers and fibrin degradation products,
This document discusses the diversity of blood vessels and how that diversity influences patterns of disease in vasculitis. It makes three key points:
1) Blood vessels develop specialized structures and functions depending on the tissues they supply, so vessels of the same size in different organs are quite different. This vascular diversity influences disease vulnerability.
2) Infectious agents can target specific vessel types depending on complementary adhesion molecules on the vessel and pathogen. This selectivity may explain disease patterns.
3) Experimental models show infections can cause vasculitis limited to vessels derived from specific embryonic lineages, like neuroectoderm-derived vessels in the aortic arch. This suggests developmental origins influence disease patterns.
Acute Pericarditis Diagnosis and Management Summary.docxwrite22
Acute Pericarditis Diagnosis and Management Summary examines the diagnosis and management of acute pericarditis. It discusses how acute pericarditis is diagnosed using a combination of clinical features, electrocardiography, chest X-ray, and echocardiography. Treatment involves the use of nonsteroidal anti-inflammatory drugs to reduce pain and inflammation. Corticosteroids may also be used in some cases. The prognosis is generally good if the underlying cause is identified and treated appropriately.
This document discusses the classification of acute myeloid leukemia (AML). It provides an overview of classifications proposed over time including the French-American-British (FAB) classification from 1976 based on morphology and cytochemistry. The 2008 World Health Organization classification expanded genetic subtypes and incorporated cytogenetic and molecular information along with morphology. Accurate classification involves evaluating blast percentage, cell morphology, dysplasia, immunophenotyping, cytogenetics and molecular genetics to identify distinct biological entities of AML.
1) The document discusses vascular anomalies, specifically infantile hemangiomas.
2) Infantile hemangiomas are the most common vascular tumor of infancy, affecting around 2-3% of children, most commonly on the face and neck.
3) They typically appear as red, raised lesions within the first few months of life and then slowly involute over 5-10 years, leaving residual discoloration or texture changes to the skin.
Week 7 Hematological SystemOften in the medical field, an empha.docxcockekeshia
Week 7: Hematological System
Often in the medical field, an emphasis is placed on the importance of the heart and the lungs. While these two organs are vital to the sustainability of life, the blood is what makes the cardiovascular and respiratory systems function—it’s the connection for the heart and lungs. For this reason, disorders of the hematological system can be potentially devastating for patients. Consider the case of Connie Prochnow. Connie was diagnosed with leukemia after seeking medical care for bruising, shortness of breath, and exhaustion. Her blood disorder resulted in alterations that impacted other body systems, including her respiratory system (UW Health, 2012). Since the heart and the lungs rely so heavily on the blood, it is important that hematological disorders are quickly identified and managed.
This week, as you focus on hematological disorders commonly presented to advanced practice nurses, you examine the pathophysiology of anemia. You also explore the impact of patient factors on anemic disorders.
Reference
Prochnow, C. (n.d.). Restoring hope: A cancer patient shares her story. Retrieved September 11, 2012, from http://www.uwhealth.org/uw-carbone-cancer-center/restoring-hope-a-cancer-patient-shares-her-story/20371
Learning Objectives
Students will:
· Analyze the pathophysiology of anemia
· Compare the pathophysiology of iron deficiency anemia to the pathophysiology of other types of anemia
· Evaluate the impact of patient factors on anemic disorders
· Understand and apply key terms, concepts, and principles related to alterations of the hematological system
Photo Credit: JPC-PROD/iStock/Getty Images Plus/Getty images
Learning Resources
Required Readings
Huether, S. E., & McCance, K. L. (2012). Understanding pathophysiology (Laureate custom ed.). St. Louis, MO: Mosby.
· Chapter 19, “Structure and Function of the Hematologic System”
This chapter examines components of the hematologic system, development of blood cells, mechanisms of hemostasis, and hematologic value changes in pediatrics and geriatrics. It also focuses on common blood tests for hematologic disorders.
· Chapter 20, “Alterations of Hematologic Function”
This chapter focuses on common alterations of hematologic function, including alterations of erythrocyte function, leukocyte function, lymphoid function, splenic function, platelets, and coagulation.
· Chapter 21, “Alterations of Hematologic Function in Children”
This chapter expands on alterations of hematologic function by presenting disorders that affect children, such as disorders of erythrocytes, coagulation, and platelets.
McPhee, S. J., & Hammer, G. D. (2010). Pathophysiology of disease: An introduction to clinical medicine (Laureate Education, Inc., custom ed.). New York, NY: McGraw-Hill Medical.
· Chapter 6, “Blood Disorders”
This chapter begins by exploring the anatomy and physiology of blood and the coagulation system. It then examines two types of anemia caused by red cell disorders.
This document reviews Takayasu arteritis, a rare form of large vessel vasculitis. It discusses the history and description of the disease. The clinical features include diminished or absent pulses, vascular bruits, hypertension, and involvement of the aorta, its branches and pulmonary arteries. Diagnosis is based on criteria from the American College of Rheumatology and angiography is the gold standard. Differential diagnoses and classification systems are also covered. Management aims to suppress inflammation and preserve vascular function.
3 Disturbabce of blood circulation 2021.pdfvanastaciost
This document outlines a lecture plan on local blood circulation disorders. It discusses various types of disorders including arterial hyperemia, venous hyperemia, ischemia, stasis, thrombosis, and embolism. For each disorder, it provides definitions and discusses etiology, pathogenesis, clinical manifestations, and consequences. It also lists some suggested reading materials and includes diagrams on anatomy of local blood circulation and classifications of arterial hyperemia.
This document summarizes a study examining the matrix composition of different types of coronary culprit plaques, including stable plaques and those with erosion or rupture. The study found that plaque erosion was associated with accumulation of hyaluronan and decorin, as well as expression of CD44 and immature smooth muscle cells. Plaque erosion may be promoted by these matrix components, particularly hyaluronan binding to CD44, which could increase thrombosis and smooth muscle cell proliferation/migration. The differential accumulation of matrix proteins provides insights into the pathogenesis of plaque erosion.
203 pathologic substrate of coronary plaque erosionSHAPE Society
This document summarizes a study examining the matrix composition of different types of coronary culprit plaques, including stable plaques and those with erosion or rupture. The study found that plaque erosion was associated with accumulation of hyaluronan and decorin, as well as expression of CD44 and immature smooth muscle cells. Plaque erosion may be promoted by these matrix components, particularly hyaluronan binding to CD44, which could increase thrombosis and smooth muscle cell proliferation/migration. The differential accumulation of matrix proteins provides insights into the pathogenesis of plaque erosion.
This document summarizes a study examining the composition of coronary culprit plaques in patients who died of sudden coronary death. The study found differences in proteoglycan and hyaluronan accumulation between stable plaques and those with erosion or rupture. Plaques with erosion showed high levels of decorin and hyaluronan, which may promote thrombosis by reducing endothelial adherence and activating platelet adhesion receptor CD44. The results provide insights into the pathogenesis of plaque erosion and suggest hyaluronan accumulation creates a thrombogenic substrate.
The document discusses pathology of blood and lymphatic vessels. It describes the three main cellular components of vessel walls: endothelial cells, smooth muscle cells, and pericytes. Endothelial injury is critical for thrombus formation, atherosclerosis, and effects of hypertension. Endothelial dysfunction and activation are terms used to describe changes in endothelial cells in response to stimuli. Vascular injury ultimately results in intimal thickening. The document also discusses diseases of arteries including atherosclerosis, hypertensive vascular disease, inflammatory vasculitides, and others.
This document provides an overview of vasculitis, including classification, pathophysiology, clinical manifestations, investigations, and management approaches. It discusses several specific large vessel vasculitides - giant cell arteritis, Takayasu arteritis, and polyarteritis nodosa. Giant cell arteritis commonly involves temporal arteries and causes headaches. Takayasu arteritis primarily affects the aorta and its branches. Polyarteritis nodosa preferentially involves the skin, nerves, gastrointestinal tract and kidneys. Diagnosis relies on tissue biopsy and imaging. Treatment focuses on glucocorticoids, with additional immunosuppressants for severe or refractory disease.
This document summarizes a review article on the current state and future directions of hematopoietic stem cell engineering. The review discusses how early clinical trials using first-generation gamma-retroviral vectors showed successes in treating immune deficiencies but also safety issues like leukemia. This prompted improvements in vector design, targeted gene delivery methods, and use of pluripotent stem cells. The review evaluates these new approaches and highlights the remaining challenges to developing safer and more effective hematopoietic stem cell therapies.
ARVC is a heritable heart muscle disorder that predominantly affects the right ventricle. It is caused by genetic defects in cardiac desmosomes, which are important for cell-to-cell adhesion. This leads to progressive loss of right ventricular myocardium and replacement by fibrofatty tissue. ARVC can cause dangerous ventricular arrhythmias and is a leading cause of sudden cardiac death in young people. Diagnosis involves imaging tests and electrocardiography to detect right ventricular structural abnormalities and arrhythmias.
Systematization and diagnosis of vasculitides. Mikhail ValivachMikhail Valivach
This document provides an overview of the systematization and diagnosis of vasculitides. It discusses that vasculitides can be primary or secondary, and focuses on primary vasculitides. The key factors in diagnosing and classifying primary vasculitides are the size of affected vessels, the primary pathogenic mechanisms (such as immune complexes, ANCA, or anti-GBM antibodies), the type of secondary inflammatory reaction (granulomatous or eosinophilic), the distribution of affected organs, and the severity of vascular damage. Histology through biopsy is important for diagnosis, showing features like angiocentric inflammatory infiltration and vascular wall damage. Different classification systems are used, including the Chapel Hill definitions.
Takotsubo syndrome diagnostic criteria.
position papers :Mayo clnic ,HFA and InterTAK Diagnostic Criteria.Takotsubo Syndrome and COVID-19.Noninvasive Multimodality Imaging
in the Diagnosis and Management
of Patients with Takotsubo Syndrome
Endovascular complications: Antiplatelet management for flow diversionbijnnjournal
Up to 3−5% of the general population is affected by cerebral aneurysms that are associated with both modifiable
as well as non-modifiable risk factors ranging from familial to acquired neurovascular conditions. The initial
treatment option was aneurysm clipping and evolved to including primary or adjuvant endovascular treatment.
Aneurysm re-rupture, although rare, can have devastating consequences such as intracranial bleeding and carotidcavernous fistula. Emergent surgery in view of delayed aneurysm rupture in patients maintained on dual antiplatelet
therapy presents with the need to carefully assess the procedure-related risk factors and evaluate the patients’
platelet function. With the advent of novel technology, flow diverters came into play
Advanced practice nurses often diagnose and treat patients with vein disorders such as chronic venous insufficiency (CVI) and deep venous thrombosis (DVT). While the symptoms of CVI and DVT can be noticeable, they are sometimes mistaken for other conditions, making diagnosis difficult. This assignment explores the epidemiology, pathophysiology, and clinical presentation of CVI and DVT. It compares the pathophysiology of CVI and DVT and how venous thrombosis differs from arterial thrombosis. It also discusses how a selected patient factor such as genetics, gender, ethnicity, age, or behavior could impact the pathophysiology of CVI and DVT and how diagnosis and treatment would be tailored accordingly. Mind maps are created for CVI
This document provides an overview of vascular anomalies including hemangiomas and vascular malformations. It begins with an introduction and historical background before classifying these lesions. Common congenital vascular tumors like hemangiomas are described in detail including their pathogenesis, clinical features, complications and histology. Vascular malformations such as capillary, lymphatic and venous malformations are also discussed in terms of their development, presentation and characteristics. The diagnosis and management of these vascular anomalies are mentioned.
This document discusses acute limb ischemia, its arterial anatomy, etiology, pathology, clinical presentation, diagnosis, classification, and treatment. It provides details on endovascular methods for treatment including catheter-directed thrombolysis and mechanical thrombectomy. CDT involves traversing the occlusion with a guidewire and infusion catheter to infuse thrombolytic drugs directly into the clot. Mechanical thrombectomy uses devices to aspirate or fragment the clot. The document outlines the procedure, complications, and post-procedure management of endovascular treatments for acute limb ischemia.
Vasculitis is inflammation of blood vessels that can affect single or multiple organ systems. It is classified based on the size of vessels involved. Diagnosis involves clinical features, lab tests like ESR, and biopsy. Treatment depends on type but often involves steroids. Giant cell arteritis and Takayasu arteritis specifically involve medium and large vessels. Giant cell arteritis commonly affects the temporal artery and presents with headaches. Both require long term steroids to prevent complications.
Disseminated intravascular coagulation (DIC) is an acquired syndrome caused by the pathological activation of intravascular coagulation and fibrinolysis, disrupting hemostatic balance. It is initiated by the release of tissue factor from endothelial cells or white blood cells in response to trauma, infection, ischemia or other stresses. This leads to the activation of coagulation pathways and uncontrolled thrombin generation, consuming coagulation factors and platelets and producing microthrombi throughout the circulatory system. Bleeding and organ dysfunction can result from inadequate hemostasis and end-organ ischemia. Laboratory tests may show elevated prothrombin time, activated partial thromboplastin time, d-dimers and fibrin degradation products,
This document discusses the diversity of blood vessels and how that diversity influences patterns of disease in vasculitis. It makes three key points:
1) Blood vessels develop specialized structures and functions depending on the tissues they supply, so vessels of the same size in different organs are quite different. This vascular diversity influences disease vulnerability.
2) Infectious agents can target specific vessel types depending on complementary adhesion molecules on the vessel and pathogen. This selectivity may explain disease patterns.
3) Experimental models show infections can cause vasculitis limited to vessels derived from specific embryonic lineages, like neuroectoderm-derived vessels in the aortic arch. This suggests developmental origins influence disease patterns.
Acute Pericarditis Diagnosis and Management Summary.docxwrite22
Acute Pericarditis Diagnosis and Management Summary examines the diagnosis and management of acute pericarditis. It discusses how acute pericarditis is diagnosed using a combination of clinical features, electrocardiography, chest X-ray, and echocardiography. Treatment involves the use of nonsteroidal anti-inflammatory drugs to reduce pain and inflammation. Corticosteroids may also be used in some cases. The prognosis is generally good if the underlying cause is identified and treated appropriately.
This document discusses the classification of acute myeloid leukemia (AML). It provides an overview of classifications proposed over time including the French-American-British (FAB) classification from 1976 based on morphology and cytochemistry. The 2008 World Health Organization classification expanded genetic subtypes and incorporated cytogenetic and molecular information along with morphology. Accurate classification involves evaluating blast percentage, cell morphology, dysplasia, immunophenotyping, cytogenetics and molecular genetics to identify distinct biological entities of AML.
1) The document discusses vascular anomalies, specifically infantile hemangiomas.
2) Infantile hemangiomas are the most common vascular tumor of infancy, affecting around 2-3% of children, most commonly on the face and neck.
3) They typically appear as red, raised lesions within the first few months of life and then slowly involute over 5-10 years, leaving residual discoloration or texture changes to the skin.
Week 7 Hematological SystemOften in the medical field, an empha.docxcockekeshia
Week 7: Hematological System
Often in the medical field, an emphasis is placed on the importance of the heart and the lungs. While these two organs are vital to the sustainability of life, the blood is what makes the cardiovascular and respiratory systems function—it’s the connection for the heart and lungs. For this reason, disorders of the hematological system can be potentially devastating for patients. Consider the case of Connie Prochnow. Connie was diagnosed with leukemia after seeking medical care for bruising, shortness of breath, and exhaustion. Her blood disorder resulted in alterations that impacted other body systems, including her respiratory system (UW Health, 2012). Since the heart and the lungs rely so heavily on the blood, it is important that hematological disorders are quickly identified and managed.
This week, as you focus on hematological disorders commonly presented to advanced practice nurses, you examine the pathophysiology of anemia. You also explore the impact of patient factors on anemic disorders.
Reference
Prochnow, C. (n.d.). Restoring hope: A cancer patient shares her story. Retrieved September 11, 2012, from http://www.uwhealth.org/uw-carbone-cancer-center/restoring-hope-a-cancer-patient-shares-her-story/20371
Learning Objectives
Students will:
· Analyze the pathophysiology of anemia
· Compare the pathophysiology of iron deficiency anemia to the pathophysiology of other types of anemia
· Evaluate the impact of patient factors on anemic disorders
· Understand and apply key terms, concepts, and principles related to alterations of the hematological system
Photo Credit: JPC-PROD/iStock/Getty Images Plus/Getty images
Learning Resources
Required Readings
Huether, S. E., & McCance, K. L. (2012). Understanding pathophysiology (Laureate custom ed.). St. Louis, MO: Mosby.
· Chapter 19, “Structure and Function of the Hematologic System”
This chapter examines components of the hematologic system, development of blood cells, mechanisms of hemostasis, and hematologic value changes in pediatrics and geriatrics. It also focuses on common blood tests for hematologic disorders.
· Chapter 20, “Alterations of Hematologic Function”
This chapter focuses on common alterations of hematologic function, including alterations of erythrocyte function, leukocyte function, lymphoid function, splenic function, platelets, and coagulation.
· Chapter 21, “Alterations of Hematologic Function in Children”
This chapter expands on alterations of hematologic function by presenting disorders that affect children, such as disorders of erythrocytes, coagulation, and platelets.
McPhee, S. J., & Hammer, G. D. (2010). Pathophysiology of disease: An introduction to clinical medicine (Laureate Education, Inc., custom ed.). New York, NY: McGraw-Hill Medical.
· Chapter 6, “Blood Disorders”
This chapter begins by exploring the anatomy and physiology of blood and the coagulation system. It then examines two types of anemia caused by red cell disorders.
This document reviews Takayasu arteritis, a rare form of large vessel vasculitis. It discusses the history and description of the disease. The clinical features include diminished or absent pulses, vascular bruits, hypertension, and involvement of the aorta, its branches and pulmonary arteries. Diagnosis is based on criteria from the American College of Rheumatology and angiography is the gold standard. Differential diagnoses and classification systems are also covered. Management aims to suppress inflammation and preserve vascular function.
3 Disturbabce of blood circulation 2021.pdfvanastaciost
This document outlines a lecture plan on local blood circulation disorders. It discusses various types of disorders including arterial hyperemia, venous hyperemia, ischemia, stasis, thrombosis, and embolism. For each disorder, it provides definitions and discusses etiology, pathogenesis, clinical manifestations, and consequences. It also lists some suggested reading materials and includes diagrams on anatomy of local blood circulation and classifications of arterial hyperemia.
This document summarizes a study examining the matrix composition of different types of coronary culprit plaques, including stable plaques and those with erosion or rupture. The study found that plaque erosion was associated with accumulation of hyaluronan and decorin, as well as expression of CD44 and immature smooth muscle cells. Plaque erosion may be promoted by these matrix components, particularly hyaluronan binding to CD44, which could increase thrombosis and smooth muscle cell proliferation/migration. The differential accumulation of matrix proteins provides insights into the pathogenesis of plaque erosion.
203 pathologic substrate of coronary plaque erosionSHAPE Society
This document summarizes a study examining the matrix composition of different types of coronary culprit plaques, including stable plaques and those with erosion or rupture. The study found that plaque erosion was associated with accumulation of hyaluronan and decorin, as well as expression of CD44 and immature smooth muscle cells. Plaque erosion may be promoted by these matrix components, particularly hyaluronan binding to CD44, which could increase thrombosis and smooth muscle cell proliferation/migration. The differential accumulation of matrix proteins provides insights into the pathogenesis of plaque erosion.
This document summarizes a study examining the composition of coronary culprit plaques in patients who died of sudden coronary death. The study found differences in proteoglycan and hyaluronan accumulation between stable plaques and those with erosion or rupture. Plaques with erosion showed high levels of decorin and hyaluronan, which may promote thrombosis by reducing endothelial adherence and activating platelet adhesion receptor CD44. The results provide insights into the pathogenesis of plaque erosion and suggest hyaluronan accumulation creates a thrombogenic substrate.
The document discusses pathology of blood and lymphatic vessels. It describes the three main cellular components of vessel walls: endothelial cells, smooth muscle cells, and pericytes. Endothelial injury is critical for thrombus formation, atherosclerosis, and effects of hypertension. Endothelial dysfunction and activation are terms used to describe changes in endothelial cells in response to stimuli. Vascular injury ultimately results in intimal thickening. The document also discusses diseases of arteries including atherosclerosis, hypertensive vascular disease, inflammatory vasculitides, and others.
This document provides an overview of vasculitis, including classification, pathophysiology, clinical manifestations, investigations, and management approaches. It discusses several specific large vessel vasculitides - giant cell arteritis, Takayasu arteritis, and polyarteritis nodosa. Giant cell arteritis commonly involves temporal arteries and causes headaches. Takayasu arteritis primarily affects the aorta and its branches. Polyarteritis nodosa preferentially involves the skin, nerves, gastrointestinal tract and kidneys. Diagnosis relies on tissue biopsy and imaging. Treatment focuses on glucocorticoids, with additional immunosuppressants for severe or refractory disease.
This document summarizes a review article on the current state and future directions of hematopoietic stem cell engineering. The review discusses how early clinical trials using first-generation gamma-retroviral vectors showed successes in treating immune deficiencies but also safety issues like leukemia. This prompted improvements in vector design, targeted gene delivery methods, and use of pluripotent stem cells. The review evaluates these new approaches and highlights the remaining challenges to developing safer and more effective hematopoietic stem cell therapies.
ARVC is a heritable heart muscle disorder that predominantly affects the right ventricle. It is caused by genetic defects in cardiac desmosomes, which are important for cell-to-cell adhesion. This leads to progressive loss of right ventricular myocardium and replacement by fibrofatty tissue. ARVC can cause dangerous ventricular arrhythmias and is a leading cause of sudden cardiac death in young people. Diagnosis involves imaging tests and electrocardiography to detect right ventricular structural abnormalities and arrhythmias.
Systematization and diagnosis of vasculitides. Mikhail ValivachMikhail Valivach
This document provides an overview of the systematization and diagnosis of vasculitides. It discusses that vasculitides can be primary or secondary, and focuses on primary vasculitides. The key factors in diagnosing and classifying primary vasculitides are the size of affected vessels, the primary pathogenic mechanisms (such as immune complexes, ANCA, or anti-GBM antibodies), the type of secondary inflammatory reaction (granulomatous or eosinophilic), the distribution of affected organs, and the severity of vascular damage. Histology through biopsy is important for diagnosis, showing features like angiocentric inflammatory infiltration and vascular wall damage. Different classification systems are used, including the Chapel Hill definitions.
Takotsubo syndrome diagnostic criteria.
position papers :Mayo clnic ,HFA and InterTAK Diagnostic Criteria.Takotsubo Syndrome and COVID-19.Noninvasive Multimodality Imaging
in the Diagnosis and Management
of Patients with Takotsubo Syndrome
Endovascular complications: Antiplatelet management for flow diversionbijnnjournal
Up to 3−5% of the general population is affected by cerebral aneurysms that are associated with both modifiable
as well as non-modifiable risk factors ranging from familial to acquired neurovascular conditions. The initial
treatment option was aneurysm clipping and evolved to including primary or adjuvant endovascular treatment.
Aneurysm re-rupture, although rare, can have devastating consequences such as intracranial bleeding and carotidcavernous fistula. Emergent surgery in view of delayed aneurysm rupture in patients maintained on dual antiplatelet
therapy presents with the need to carefully assess the procedure-related risk factors and evaluate the patients’
platelet function. With the advent of novel technology, flow diverters came into play
Advanced practice nurses often diagnose and treat patients with vein disorders such as chronic venous insufficiency (CVI) and deep venous thrombosis (DVT). While the symptoms of CVI and DVT can be noticeable, they are sometimes mistaken for other conditions, making diagnosis difficult. This assignment explores the epidemiology, pathophysiology, and clinical presentation of CVI and DVT. It compares the pathophysiology of CVI and DVT and how venous thrombosis differs from arterial thrombosis. It also discusses how a selected patient factor such as genetics, gender, ethnicity, age, or behavior could impact the pathophysiology of CVI and DVT and how diagnosis and treatment would be tailored accordingly. Mind maps are created for CVI
This document provides an overview of vascular anomalies including hemangiomas and vascular malformations. It begins with an introduction and historical background before classifying these lesions. Common congenital vascular tumors like hemangiomas are described in detail including their pathogenesis, clinical features, complications and histology. Vascular malformations such as capillary, lymphatic and venous malformations are also discussed in terms of their development, presentation and characteristics. The diagnosis and management of these vascular anomalies are mentioned.
This document discusses acute limb ischemia, its arterial anatomy, etiology, pathology, clinical presentation, diagnosis, classification, and treatment. It provides details on endovascular methods for treatment including catheter-directed thrombolysis and mechanical thrombectomy. CDT involves traversing the occlusion with a guidewire and infusion catheter to infuse thrombolytic drugs directly into the clot. Mechanical thrombectomy uses devices to aspirate or fragment the clot. The document outlines the procedure, complications, and post-procedure management of endovascular treatments for acute limb ischemia.
This document discusses various embolic agents that can be used to treat gastrointestinal bleeding, including gelatin sponges, polyvinyl alcohol microspheres, coils, n-butyl cyanoacrylate (NBCA), and Onyx. It provides details on the properties, advantages, disadvantages and appropriate uses of each agent depending on the location and type of bleeding. The goal is to select an embolic material that can be delivered precisely to the bleeding site while avoiding non-target embolization.
This document discusses acute lower limb ischemia, including its clinical evaluation, etiology, pathology, classification, diagnosis, and treatment. It notes that acute lower limb ischemia involves a sudden deterioration in arterial blood supply to the leg. The main causes are embolism, thrombosis, trauma, or iatrogenic causes. Diagnosis involves clinical assessment, Doppler ultrasound, and imaging tests like CTA or angiography. Treatment depends on the severity and includes anticoagulation, endovascular procedures like catheter-directed thrombolysis, mechanical thrombectomy, or surgery. Complications can include bleeding, distal embolization, or failure to recanalize, and outcomes are correlated with how quickly revascularization can be achieved.
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This study analyzed angiographic findings from 41 genicular artery embolization (GAE) procedures to treat knee osteoarthritis pain. The authors described variations in genicular arterial anatomy and proposed a new angiographic classification system. A total of 91 genicular arteries were identified and embolized. The most common arteries embolized were the descending genicular artery, medial inferior genicular artery, and medial superior genicular artery. The study classified branching patterns into medial and lateral types and identified anatomic variations such as common origins between arteries. Understanding genicular arterial anatomy is important for performing successful GAE while avoiding complications.
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2. Int. J. Mol. Sci. 2022, 23, 2358 2 of 13
hemangioma, and tufted angioma (TA)), locally aggressive or borderline (e.g., kaposiform
hemangioendothelioma (KHE), and Kaposi’s sarcoma), and malignant (e.g., angiosarcoma
and epithelioid hemangioendothelioma).
Table 1. Overview table of ISSVA classification 2018, modified Table in Ref. [1].
Vascular Anomalies
Vascular Tumors Vascular Malformations
Benign
Simple Combined
Of Major
Named Vessels
Associated with
Other Anomalies
Capillary malformations
defined as two or
more vascular
malformations
found in one lesion
abnormalities in the
origin/course/number
of major blood vessels
that have
anatomical names
syndromes in which
vascular malformations
are complicated by
symptoms other than
vascular anomalies
Locally aggressive
or Borderline
Lymphatic malformations
Venous malformations
Malignant
Arteriovenous malformations *
Arteriovenous fistula *
* High-flow lesions.
Meanwhile, vascular malformations are subclassified into four types. The simple
type is further subclassified based on the type of blood vessels with anomalies: capillary,
lymphatic, venous, and arteriovenous malformations. In the combined type, two or
more simple vascular malformations are found in one lesion. The malformation of major
named vessels refers to abnormalities in the origin/course/number of major blood vessels
that have anatomical names. Malformations associated with other anomalies include
syndromes in which vascular malformations are complicated by symptoms other than
vascular anomalies, including soft tissue or skeletal abnormalities, such as leg-length
discrepancy and segmental hypertrophy (e.g., Klippel–Trenaunay syndrome and Sturge–
Weber syndrome). In addition, some relatively rare diseases are presented as “provisionally
unclassified vascular anomalies”.
Elsewhere, a description on the PIK3CA-related overgrowth spectrum (PROS) has
been added as an appendix. PROS is now defined to include diseases with heterogeneous
segmental overgrowth phenotypes due to the somatic activating mutations of PIK3CA
(gene coding PI3K p110α subunit). PROS is stated to often be accompanied by various
vascular malformations.
3. Gene Mutations and Molecular Biological Mechanisms in Vascular Anomalies
As described above, the identification of gene mutation(s) in each disease through
the widespread use of next-generation sequencers is a clue to the understanding of the
2018 ISSVA classification. Causative genes for vascular anomalies are often found on
molecules on the RAS/MEK/ERK pathway and PIK3CA/Akt/mTOR pathway (Figure 1).
The RAS/MEK/ERK pathway, as the so-called RASopathy, mainly causes high-flow vascu-
lar malformations, including arteriovenous malformations and vascular tumors. On the
other hand, the PIK3CA/Akt/mTOR pathway, as PIKopathy, induces slow-flow vascular
malformations, such as venous or lymphatic malformations. The clinical characteristics
and molecular biological mechanisms of each lesion are described below.
3.1. Venous Malformation
Venous malformation was previously known as “cavernous hemangioma”. It man-
ifests as a soft subcutaneous mass with a normal to blue-purple coloring surface. Many
cases are sporadic, while hereditary types are known as “familial mucocutaneous venous
malformations”.
Among vascular anomalies, venous malformations are one of the diseases in which
causative genes are primarily identified. A genetic analysis using blood samples from pa-
tients with familial mucocutaneous venous malformations initially identified the presence
of heterozygous germline missense point mutations: a C-to-T nucleotide transition leading
to an arginine-to-tryptophan substitution at position 849 in the kinase domain of Tie2 [2]. It
3. Int. J. Mol. Sci. 2022, 23, 2358 3 of 13
was unclear at that time, however, why localized lesions occurred without involving all
blood vessels, despite the presence of germline mutations in all cells of a patients’ body,
and why the penetrance of the mutation was low.
3, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/ijms
s Vascular Malformations
Simple Combined Of Major Named Vessels
Associated with Other
Anomalies
Capillary malformations
defined as two or more
vascular malformations
found in one lesion
abnormalities in the origin/
course/number of major blood
vessels that have anatomical
names
syndromes in which vascular
malformations are complicated
by symptoms other than vas-
cular anomalies
r Lymphatic malformations
Venous malformations
Arteriovenous malformations*
Arteriovenous fistula*
ions
Figure 1. Diagram illustrating signaling pathways involved in the pathogenesis of vascular anoma-
lies.
Figure 1. Diagram illustrating signaling pathways involved in the pathogenesis of vascular anomalies.
Other several somatic heterozygous mutations (e.g., p.L914F) were, thereafter, iden-
tified in a Tie2 gene allele, which was normal in blood DNA and in the lesional DNA of
patients with familial venous malformations [3]. Such ‘second-hit’ mutations in lesional
DNA explain the reasons for localized lesions with the noninvolvement of all blood vessels
and the low penetrance of the mutation. Tie2 mutations are now known to also be found in
patients with sporadic venous malformations, and it is recognized that some patients also
have mutations in PIK3CA or Akt, which are downstream molecules of Tie2. The mecha-
nism by which these gene mutations induce characteristic morphological abnormalities of
veins still requires clarification, but there are several hypotheses (Figure 2).
For example, Tie2 is a receptor molecule that is specifically expressed on ECs; there
should, therefore, be no abnormalities of vascular smooth muscle cells themselves in a ve-
nous malformation. However, Tie2 mutations induces autophosphorylation, not expression,
and a dysregulated Tie2 signaling pathway due to the mutations in ECs may affect the
expression of cytokines, such as angiopoietin-2 and PDGF [4], resulting in the misguiding
of smooth muscle cells to the surroundings of blood vessels and leading to an abnormal
venous dilation. A second hypothesis is that the gene mutations of the Tie2 signaling path-
way induce the clustering, proliferation, or chemotaxis of ECs [5]. Simultaneously, mTOR
at the downstream of this pathway induces cell senescence; this leads to morphological
abnormalities, but not tumorigenesis [6]. Thirdly, changes in the angiogenic potential, blood
vessel permeability of ECs, or arteriovenous identity loss induced by the Tie2 mutations
may be involved in the abnormal dilation [4].
3.2. Glomuvenous Malformation
In the ISSVA classification, a glomuvenous malformation is classified into the category
of venous malformations. Histologically, the lesions are due to the proliferation of immature
smooth muscle cells (glomus cells). Sporadic cases can be painful and appear below the
nails, while hereditary cases can manifest as multiple lesions.
4. Int. J. Mol. Sci. 2022, 23, 2358 4 of 13
nt. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 2
Figure 2. Our hypothetical model of the role of mutations in Tie2, PIK3CA, and Akt in the p
genesis of venous malformation.
Figure 3. Our hypothetical model of the role of glomulin mutations in the pathogenesis of gl
venous malformation.
Figure 2. Our hypothetical model of the role of mutations in Tie2, PIK3CA, and Akt in the pathogen-
esis of venous malformation.
Heterozygous germline mutations in the glomulin gene have been identified in the
gene analysis of blood DNA in patients with familial glomuvenous malformations (e.g.,
the deletion mutation of 157delAAGAA and point mutation c.C108A), but with a low
penetrance. An analysis of the lesional DNA in individual patients confirmed second-hit
mutations of the glomulin gene (980delCAGAA) [7].
This somatic mutation is not likely to affect the expression, but cause the loss-of-
function of glomulin. Wild-type glomulin proteins bind to and inhibit the FK binding
protein 12 (Figure 3). The FK binding protein also blocks TGF-β signals, but mutant
glomulin cannot inhibit the FK binding protein, which leads to an excessive reduction in
TGF-β signals [7]. Immature glomus cells may proliferate due to the impairment of the
TGF-β-mediated smooth muscle cell differentiation.
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW
Figure 2. Our hypothetical model of the role of mutations in Tie2, PIK3CA, and Akt in the
genesis of venous malformation.
Figure 3. Our hypothetical model of the role of glomulin mutations in the pathogenesis of
venous malformation.
Figure 3. Our hypothetical model of the role of glomulin mutations in the pathogenesis of glomuve-
nous malformation.
5. Int. J. Mol. Sci. 2022, 23, 2358 5 of 13
Furthermore, they may also activate PI3K signals through interactions with the hepa-
tocyte growth factor receptor, c-met [8].
3.3. Lymphatic Malformation
Lymphatic malformation is a congenital lymphatic dysplasia. It is classified into
two types: the macrocystic type, in which 1–3 large cystic lesions are present, and the
microcystic type, in which small cystic lesions are aggregated. In addition to an abnormal
expression of the molecules involved in lymphangiogenesis, such as the vascular endothe-
lial growth factor (VEGF)-C and VEGF receptor type3 (VEGFR3), PIK3CA mutations have
been detected in lymphatic ECs of the lesions [4]. Similar to epithelial cancers, the most
common PIK3CA mutations found in lymphatic malformation are activating mutations
in the helical (p.E542K) and kinase (p.H1047R and p.H1047L) domains [9]. p.E109del,
p.C420R, p.E545K, p.Q546K, and p.H1047L have also been reported [10].
In mice, forced changes in p110α activity led to embryonic lethality due to the in-
complete development of blood vessels; the PIK3CA signal may, therefore, be a pathway
essential for vascular development [4]. PIK3CA mutations in lymphatic ECs may stimulate
the expression of vegf-c or vegfr3, induce the binding of pik3ca to the cellular membrane,
or increase cell proliferation, chemotaxis, and angiogenesis through the activation of down-
stream akt/mtor [8]. similar mechanisms to venous malformation may exist in the process
of the abnormal lymphatic dilation (e.g., changes in chemotaxis, proliferation, or angiogenic
potential of ecs and misguide of vascular smooth muscle cells) [4].
The early embryonic activation of p110α was indicated in a mouse model study to, pre-
dominantly, lead to the formation of lesions that recapitulated features of human macrocys-
tic lymphatic malformation, whereas its activation during late embryonic or neonatal devel-
opment resulted in microcystic lesions. Accordingly, the cell circumstances/environments
at the timing of gene mutation occurrence may explain differences in the clinical features of
lymphatic malformations.
3.4. Arteriovenous Malformation
Arteriovenous malformation is defined as a congenital abnormal connection of arteries
and veins, which disrupts normal blood flow and oxygen circulation. According to the
Schobinger Staging system, clinical manifestation varies from cutaneous warm, pink-blue
shunting to ulceration, bleeding, and cardiac failure.
Mutations in the genes of the RAS pathway, including KRAS (e.g., p.G12D and
p.G12V), MAP2K1 (e.g., p.F53L, p.Q56P, p.K57N, p.Q58del, and p.D67Y), and BRAF (e.g.,
p.V600E), have been detected [11–13]. Although the influence of these mutations on the
expression and activation of RAS pathway molecules is not fully understood, downstream
MEK/ERK signals have been found to be activated in the lesion [14]. In addition, morpho-
logical changes in ECs, an increase in sprouting behavior, the enlargement of the vessel
lumen, and abnormal connections between arteries and veins without cell proliferation are
induced by RAS activation; gene mutations in the RAS pathway may be, therefore, strongly
involved in the pathogenesis [15].
3.5. Klippel–Trenaunay Syndrome
Klippel–Trenaunay–Weber syndrome was previously defined as a triad of heman-
gioma simplex, varicose veins, and bony/soft tissue hypertrophy involving an extremity.
It is currently classified into two distinct diseases; Parkes Weber syndrome is defined as
vascular malformations involving high-flow arterial components (arteriovenous fistulae) in
addition to affected-limb hypertrophy, whereas Klippel–Trenaunay syndrome is combina-
tion of slow-flow vascular malformations (capillary, lymphatic, and venous components)
accompanied with limb hypertrophy.
PIK3CA was identified as a causative gene of Klippel–Trenaunay syndrome, and the
disease has been regarded as one of PROS. A recent study identified any one of five muta-
tions (p.C420R, p.E542K, p.E545K, p.H1047R and p.H1047L) in 20 of 21 patients [16].
6. Int. J. Mol. Sci. 2022, 23, 2358 6 of 13
PIK3CA mutations, on the other hand, are also detected in lesions of venous or lym-
phatic malformations. Germline PIK3CA mutations, as described above, lead to embryonic
lethality. Venous or lymphatic malformations are usually localized, so mutations are
thought to occur late during development, affecting a single clone of ECs [4]. On the other
hand, mosaic mutations in the early embryonic phase may result in PROS. These PIK3CA
mutations have also been detected in adult epithelial tumors, such as breast cancers or
colon cancers, but other gene mutations are also present in many cases [4]. However,
PIK3CA mutations alone do not induce overgrowth in mice models [5], so there is also
a possibility that environmental factors, other gene mutations, or mutations in other cells,
such as fibroblasts, may be required for the formation of overgrowth lesions [4,5].
3.6. Sturge–Weber Syndrome
This syndrome was originally regarded as neurocutaneous disease, which involves
a facial hemangioma simplex reaching the first branch of the trigeminal nerve, ophthalmo-
logic abnormalities (especially congenital glaucoma), and neurologic signs (seizure, mental
retardation, hemiparesis).
Mosaic gene mutations of GNAQ (e.g., p.R183Q) or GNA11 (p.R183C, p.R183H,
p.Q209L, and p.Q209P) in ECs were recently detected [17–19]. They did not change the
protein expression, and are thought to activate downstream MEK/ERK pathways, but still
require clarification of the detailed mechanism. Furthermore, the mechanism by which
the mutated GNAQ/GNA11 genes induce capillary malformations is also still unknown,
but there are several hypotheses. First, GNAQ or GNA11 protein may be related to EC
sensing of shear stress imposed by blood flow, and their mutants may impair the ability of
EC to distinguish between laminar and disturbed flow [20]. A second hypothesis is that
GNAQ gene may activate the PIK3/Akt pathway in addition to the MEK/ERK pathway,
and PIK3CA mutations have also been found in Sturge–Weber syndrome [18]. Abnormal
capillary dilation may occur via the same mechanism as indicated for venous or lymphatic
malformations through PIK3CA/Akt/mTOR. A third hypothesis is that EC differentiation
may be impaired by the mutations, leading to progressive dilatation of immature venule-
like vasculatures [18]. Recently, the gene mutations of GNAQ and GNA11 have also been
detected even in the lesions of sporadic capillary malformation.
3.7. Infantile Hemangioma
Concerning vascular tumors, causative genes have not been sufficiently identified in
comparison to vascular malformations. For example, infantile hemangioma is a benign
vascular tumor caused by the uncontrolled proliferation of vascular ECs. Causative genes
have not been described in the ISSVA classification 2018, but cultured infantile hemangioma-
derived ECs (hemECs) have been found to have an increased proliferation and migration
activity [21]. Furthermore, they are clonal based on analyses of X-chromosome inactivation,
while non-ECs from the lesions did not exhibit clonality [22]. Infantile hemangioma has,
therefore, been thought to be caused by an “intrinsic abnormal activation” of ECs that leads
to local clonal expansion, rather than a secondary response of ECs to external factors.
The following hypothesis was first proposed as a possible molecular mechanism:
hemangiomas are clonal expansions of cells that have originated from embolized placental
cells or bone marrow cells. For example, the embolism of maternal placenta-derived cells
may occur in the fetal skin, leading to localized proliferation. This is based on the finding
that the expression pattern of cellular markers (e.g, GLUT-1, merosin, FcRII, Lewis Y
antigen, type 3 iodothyronine deiodinase, indoleamine 2,3-deoxygenase, and IGF2) and
transcriptomes in infantile hemangioma tissue differ from that of ECs in the surrounding
skin, but resemble those of ECs lining fetal microvessels in the human placenta [23].
This hypothesis is also supported by the evidence that chorionic villous sampling, which
causes trauma to the placenta and may induce cellular transfer between maternal and fetal
circulations, increases the incidence of the tumor. In addition, the high incidence of infantile
hemangioma in preterm babies may also be associated with placental complications that
7. Int. J. Mol. Sci. 2022, 23, 2358 7 of 13
lead to premature birth. There is no direct evidence for this, however, such as the detection
of mother-derived XX chromosome cells in the lesions of infantile hemangioma in boys [24].
According to another hypothesis, tumor cells of infantile hemangioma might be de-
rived from undifferentiated stem cells or progenitor cells (e.g., dormant angioblasts or cells
recruited to the lesions from a reservoir of stem/progenitor cells). Khan et al. identified
infantile hemangioma-derived endothelial progenitor cells (hemEPCs) by their mRNA
expression patterns or their response to endostatin, and indicated that hemEPCs and
hemECs share common properties with cord blood EPCs [25]. In addition, Kleinman
reported an elevation of the level of circulating EPCs in babies with infantile hemangioma,
and that they may be recruited into tumors at the proliferating stage, leading to tumor
formation [26]. Furthermore, mesenchymal stem cells derived from infantile hemangioma
(hemMSCs) at the proliferating stage exhibited higher adipogenic activity than those from
lesions at the involuting stage and from normal skin, supporting the hypothesis that MSCs
reside in the tumor and are the source of fibrofatty tissues seen in the involuted phase [27].
Infantile hemangioma-derived stem cells (hemSCs) express CD90, a mesenchymal cell
marker, which is one of the genes upregulated in proliferating lesions compared to in-
voluting lesions [28,29]. Normal human dermal microvascular ECs (HDMECs) required
mesenchymal supporting cells to form vessels in subcutaneous implants in immunodefi-
cient mice [30], whereas the implantation of hemSCs alone could form functional vessels
exhibiting an infantile hemangioma-like phenotype with a high GLUT-1 expression and
could differentiate into adipocytes [28]. Other cell types, including hemECs, hemEPCs,
cord blood EPCs, normal human fibroblasts, and bone marrow-derived mesenchymal stem
cells, did not form vessels in the same mouse model. Accordingly, hemSC may mainly
represent progenitor cells for infantile hemangioma.
On the other hand, we have also demonstrated that hemECs maintain activated
VEGF signaling pathways in vitro [31]. VEGF receptor type 2 (VEGFR2) and down-
stream signaling molecules such as ERK and Akt were constitutively activated in cul-
tured hemECs, resulting in the upregulated proliferation and migration in the absence of
exogenous VEGF [31].
In addition, as the cause of VEGFR2 activation in hemECs, we found the downreg-
ulation of VEGF receptor type 1 (VEGFR1), resulting in an increase in VEGF that binds
to VEGFR2. Interestingly, VEGFR1-null mice died at E8.5 to E9.0 due to overgrowth of
ECs and the disorganization of blood vessels, both of which are characteristic of infantile
hemangioma [32,33]. An abnormality in pathways that control the VEGFR1 expression
may, therefore, play a significant role in the pathogenesis of infantile hemangioma.
As the mechanism of VEGFR1 downregulation, we identified a putative binding site
of the nuclear factor in activated T cells (NFAT) on a region of the VEGFR1 promoter. NFAT
is known to be activated by the Ca++/calmodulin-dependent phosphatase calcineurin, and
a low NFATc2 activation and low basal levels of cytoplasmic Ca++ were found in hemECs.
In addition, the expression of active β1 integrin determined by the HUTS-21 antibody
was reduced in hemECs compared with in HDMECs. A link between integrins and Ca++
signaling has been well established, and the inactivation of the β1 integrin may cause the
suppression of the Ca++-NFAT-VEGFR1 pathway in hemECs. Consistently, the activation of
the β1 integrin by its stimulatory antibody in hemECs could reduce VEGFR2 phosphoryla-
tion, induce the binding of NFATc2 to the VEGFR1 promoter, and stimulate the expression
of VEGFR1.
We also found germline heterozygous amino acid substitutions in tumor endothelial
marker-8 (TEM8) and VEGFR2 in a portion of hemECs: a G-to-A transition replaces alanine
by threonine in the transmembrane domain of the integrin-like molecule TEM8 (p.A326T).
On the other hand, a T-to-C transition changes cysteine into arginine at position 482 in the
Ig-like domain V of the VEGFR2 extracellular region.
TEM8 is also known as Anthrax toxin receptor 1, and is an integrin-like receptor
expressed in ECs [34]. The overexpression of wild-type TEM8 in hemECs with mutated
TEM8 induced the amount of activated β1 integrin, stimulated the association between
8. Int. J. Mol. Sci. 2022, 23, 2358 8 of 13
NFATc2 and the Flt-1 promoter, and upregulated VEGFR1 expression. In turn, the overex-
pression of mutant TEM8 in HDMECs induced an infantile hemangioma-like phenotype.
The overexpression of wild-type VEGFR2 in hemECs with mutated VEGFR2 also normal-
ized the infantile hemangioma-like phenotype.
Immunoprecipitation assays showed that VEGFR2 could form complexes with β1 in-
tegrin and TEM8 in hemECs, and that mutations in VEGFR2 and TEM8 resulted in an in-
creased interaction among the three proteins. An increased complex formation among the
three molecules and the subsequent inactivation of the β1 integrin-NFATc2-VEGFR1 path-
way are features that are common to all hemECs that have been tested, even to hemECs in
which we did not yet find mutations. We speculate that hemangioma formation in cases
where we did not find gene mutations may be associated with mutations in genes encod-
ing other pathway components, perhaps other cell surface or cytoplasmic proteins that
interact with integrins/TEM8/VEGFR2, components of the Ca++-NFAT-VEGFR1 pathway,
or downstream targets of VEGFR2.
However, because hemECs exhibit clonality, the germline mutations in TEM8 and
VEGFR2 must be associated with a secondary somatic event to trigger the clonal expansion
of tumor cells within the hemangioma lesions [22]. We, therefore, conclude that the changes
to the TEM8 and VEGFR2 amino acid sequence represent risk factor mutations for infantile
hemangioma, similar to familial cases of venous malformation or glomuvenous malfor-
mations as described above. Given their emergence after birth and the age-dependent
involution of infantile hemangioma, we also hypothesized that physiological events, in-
cluding perinatal hypoxia or mechanical stress, during delivery would be a trigger of
hemangioma formation in infants with germline mutations with TEM8 and VEGFR2.
To prove the hypothesis, we tried to plot the localization of 104 infantile hemangioma
on the head and face as well as capillary malformations. As a result, the lesions of infantile
hemangioma in the jaw or chin areas were significantly less common than other areas. This
tendency was not found in 40 patients with capillary malformation. Mechanical stress
to the jaw or chin areas may be lesser than in other areas in normal cephalic delivery,
so these data may indicate the contribution of mechanical stress as a trigger of infantile
hemangioma, not capillary malformation [35].
On the other hand, based on above hypothesis, we also tried to confirm that head and
neck lesions were more frequent in the group in which infantile hemangioma appeared
after birth compared with the patients in which it was present at birth [36]. A slight such
tendency was observed, but the difference was not statistically significant. Meanwhile,
we unexpectedly found a statistically significant increase in the frequency of multiple
lesions in infantile hemangioma after birth compared with those present at birth. This
may indicate there may be different triggers between the two groups. In other words,
infantile hemangioma present at birth are likely caused by a local trigger, while lesions
appearing after birth may be induced by systemic factors in addition to local triggers,
such as cytokines related to systemic neovascularization after birth.
3.8. Tufted Angioma and Kaposiform Hemangioendothelioma
TA is a relatively rare and benign vascular tumor of infancy clinically presenting
as violaceous, indurated, or nodular plaques with pain, focal hyperhidrosis, and hyper-
trichosis. Histopathologically, the tumor shows confluent lobules or “cannonballs” of
spindled ECs with slitlike lumina embedded in a fibrotic background [37]. Some lesions
show spontaneous regression, but the underlying pathobiology of TA is poorly understood.
On the other hand, KHE, first reported by Zukerberg et al. in 1993, is characterized
by a locally aggressive/borderline malignant behavior and morphological features similar
to Kaposi sarcoma. TA is currently thought to be the dermal counterpart of KHE with
a benign clinical course due to the superficial origin.
Kasabach–Merritt syndrome (KMS), a consumptive coagulopathy characterized by
profound thrombocytopenia, hypofibrinogenemia, and microangiopathic anemia with up
9. Int. J. Mol. Sci. 2022, 23, 2358 9 of 13
to 24 percent mortality [37,38], may affect approximately 70% of all patients with KHE and
approximately 10% of patients with TA [39].
Although the etiologies of TA, KHE, and KMP are poorly understood, TA and KHE
mainly occur in early childhood, suggesting the involvement of gene mutations in their
pathogenesis. Lim et al. found GNA14 mutations c.614AT (p.Q205L) in these lesions [40].
However, these mutations are not specific to TA and KHE, and they were also detected in
other rare vascular tumors, which are potential differential diagnoses [37,38]. Ten Broek
et al. analyzed the epigenetic genomewide methylation profile, and demonstrated that
KHE and TA share a common origin without a relationship to vascular malformation [41].
4. Future Issues in Molecular Biologics of Vascular Anomalies
In vascular anomalies, although causative genes in each lesion have been identified,
most mechanisms are still unknown, as described above. In particular, there are no gene
mutations in all ECs at each lesion. For example, the frequency of alleles with mutations in
the lesional tissue is, approximately, 10% in patients with lymphatic malformations or with
Sturge–Weber syndrome. The mechanism by which such a small population of cells with
mutated genes contribute to the formation of each lesion still requires clarification [20,42].
In addition, the positions of mutated nucleotides differ even in the same causative gene of
each disease, so respective mutations may have different mechanisms.
PROS caused by PIK3CA mutations includes several diseases such as Klippel–Trenaunay
syndrome, CLOVES syndrome, and megalencephaly-capillary malformation-polymicrogyria
(MCAP). However, the reason for clinical features markedly differing among PROS is also
unclear. Whether they depend on the positions of a mutated nucleotide of PIK3CA, the tim-
ing of occurring mutations, or cell types in which mutations occur still requires clarification.
5. Future Perspective of Novel Therapies
The potential usefulness of molecular targeting drugs for vascular anomalies was
indicated, consisting of hypotheses on the pathogeneses of each disease, as described
above. In the future, treatment with biologics may eventually become available (Table 2),
as demonstrated for inflammatory skin diseases or malignant tumors.
Table 2. Candidates of molecular targeting drugs for vascular anomalies.
Diseases Target Drug
VEGF receptor Pazopanib
PROS PI3K Alpelisib
PROS Akt Miransertib
Venous malformation
Lymphatic malformation
mTOR Rapamycin
Arteriovenous malformation BRAF Vemurafenib
Arteriovenous malformation MEK Trametinib
In particular, Venot et al. showed that PI3K inhibitors were effective for PROS-
associated vascular anomalies and tissue overgrowth [43]. Currently, sirolimus (rapamycin),
an mTOR inhibitor, is one of the most promising drugs for various vascular anomalies,
such as venous or lymphatic malformations [44]. A clinical trial of oral sirolimus for lym-
phatic malformations was conducted in Japan, and based on the favorable results of the
trial, the drug was approved in 2021.
Numerous investigations have also reported the effect of sirolimus on KMP induced in
TA and KHE, and mTOR has been implicated in the development of KMP, a fatal complica-
tion. Furthermore, lesions of TA and KHE themselves also shrink by oral sirolimus [45,46],
indicating that the involvement of mTOR in the pathogenesis of TA and KHE, and that
overlapping pathways with vascular malformations are activated in these lesions.
10. Int. J. Mol. Sci. 2022, 23, 2358 10 of 13
Meanwhile, mTOR inhibitors are considered to be ineffective for capillary malforma-
tions with the GNAQ mutation. However, rapamycin can enhance the efficacy of pulsed
dye laser by suppressing neoangiogenesis after laser treatment [47]. We are currently
conducting a phase II clinical trial of sirolimus gel for several vascular anomalies (venous
malformation, lymphatic malformation, TA, and KHE) for the first time in the world. These
attempts may broaden treatment options for intractable vascular anomalies.
6. Conclusions: Molecular Aspect
As shown in the summative table (Table 3), in venous malformation, gene mutations
in Tie2/PIK3CA/Akt signaling pathway molecules in ECs may affect cytokine expression,
resulting in the misguiding of smooth muscle cells to the surrounding blood vessels and
leading to abnormal venous dilation. These mutations may also induce both proliferation
and senescence of ECs, which leads to morphological abnormalities.
Table 3. Molecular aspect of vascular anomalies.
Diseases Causative Genes Possible Function
Venous malformation TIE2, PIK3CA, Akt
Affect cytokine expression, resulting in misguiding of
smooth muscle cells to the surroundings of blood vessels
and leading to abnormal venous dilation
Induce both proliferation and senescence of endothelial
cells, which leads to morphological abnormalities
Glomuvenous malformation Glomulin
Inhibit TGF-β-mediated smooth muscle cell differentiation
and induce the proliferation of immature glomus cells
Activate PI3K signals through interactions with c-met
Lymphatic malformation PIK3CA
Stimulate cytokine expression
Induce the binding of PIK3CA to the cellular membrane,
or increase endothelial cell proliferation, chemotaxis,
and angiogenesis
Arteriovenous malformation RAS
Induce morphological changes in endothelial cells
Induce sprouting behavior, enlargement of the vessel lumen,
and abnormal connections between arteries and veins
Klippel-Trenaunay syndrome PIK3CA
Mosaic mutations in the early embryonic phase cause
segmental hypergrowth
Capillary malformation
Sturge-Weber syndrome
GNAQ, GNA11
Impair the ability of endothelial cells to distinguish between
laminar and disturbed flow
Activate the PIK3/Akt pathway
Infantile hemangioma
VEGFR2
TEM8, etc.
Increase the interaction among VEGFR2, TEM8 and integrin
Subsequent inactivation of the
integrin-NFATc2-VEGFR1 pathway cause
VEGFR2 phosphorylation and endothelial activation
Tufted angioma
Kaposiform hemangioendothelioma
GNA14 ?
In glomuvenous malformation, mutated glomulin proteins may activate PI3K signals
through interactions with c-met. Furthermore, they may inhibit TGF-β-mediated smooth
muscle cell differentiation and induce the proliferation of so-called glomus cells.
PIK3CA mutations in lymphatic malformation may stimulate the expression of VEGF-
C or VEGFR3, induce the binding of PIK3CA to the cellular membrane, or increase cell pro-
liferation, chemotaxis, and angiogenesis through the activation of downstream Akt/mTOR.
Similar mechanisms to venous malformation may exist in the process of the abnormal
lymphatic dilation.
RAS pathway mutations in arteriovenous malformation may activate MEK/ERK
signals. In addition, morphological changes in ECs, an increase in sprouting behavior,
11. Int. J. Mol. Sci. 2022, 23, 2358 11 of 13
the enlargement of the vessel lumen, and abnormal connections between arteries and veins
without cell proliferation may be induced by RAS activation.
PIK3CA was identified as a causative gene of Klippel–Trenaunay syndrome, and mosaic
mutations in the early embryonic phase may result in the development of this disease.
GNAQ or GNA11 mutations in capillary malformation may impair the ability of
ECs to distinguish between a laminar and disturbed flow. A mutated GNAQ may also
activate the PIK3/Akt pathway, and an abnormal capillary dilation may occur via the same
mechanism as indicated for venous or lymphatic malformations.
Mutations in VEGFR2 and TEM8 in infantile hemangioma resulted in an increased
interaction among VEGFR2, TEM8, and integrin. The subsequent inactivation of
the integrin/NFATc2/VEGFR1 pathway may cause VEGFR2 phosphorylation and
endothelial activation.
Author Contributions: Writing—original draft preparation, K.K.; writing—review and editing, M.J.;
validation and visualization, Y.Y. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Acknowledgments: We acknowledge the proofreading and editing by Benjamin Phillis at the Clinical
Study Support Center, Wakayama Medical University.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
ECs endothelial cells
HDMEC human dermal microvascular ECs
hemECs infantile hemangioma-derived ECs
hemEPCs infantile hemangioma-derived endothelial progenitor cells
hemMSCs infantile hemangioma-derived mesenchymal stem cells
hemSCs infantile hemangioma-derived stem cells
ISSVA International Society for the Study of Vascular Anomalies
KHE kaposiform hemangioendothelioma
KMS Kasabach-Merritt syndrome
MCAP megalencephaly-capillary malformation-polymicrogyria
NFAT nuclear factor in activated T cells
PROS PIK3CA-related overgrowth spectrum
TA tufted angioma
TEM8 tumor endothelial marker-8
VEGF vascular endothelial growth factor
VEGFR1 VEGF receptor type 1
VEGFR2 VEGF receptor type2
VEGFR3 VEGF receptor type3
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