BIOS222 Pathology and Clinical Science 2 & 3
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1 BIOS222 Pathology and Clinical Science 2 & 3 Session 6 Lymphatic and Haematological Disorders 4 Bioscience Department
2 Session Learning Outcomes At the end of the session, student should be able to: o Define and discuss the clinical features, pathophysiology, investigations and management of various myeloproliferative disorders including myelofibrosis, essential thrombocythemia and polycythaemia rubra vera. o Define and discuss the clinical features, pathophysiology, investigations and management of various bleeding disorders including haemophilia and Von Willebrand s disease. o Discuss the clinical features, investigations, and management of disseminated intravascular coagulation. o Understand the haematological disorders and other factors predisposing to venous thrombosis and management of the same. Endeavour College of Natural Health 2
3 Session Plan o Myeloproliferative Disorders: Myelofibrosis Essential thrombocythemia Polycythemia rubra vera o Bleeding Disorders: Disorders of primary haemostasis Coagulation disorders o Throbotic disorders: Disseminated intravascular coagulation Venous thrombosis Endeavour College of Natural Health 3
4 Myeloproliferative Disorders Endeavour College of Natural Health 4
5 Myeloproliferative Disorders Definition: a group of chronic conditions characterized by clonal proliferation of marrow erythroid precursors, megakaryocytes, or myeloid cells. o Includes conditions like: Myelofibrosis Essential thrombocythaemia Polycythaemia rubra vera Chronic myeloid leukaemia (covered in session 5) o Aetiology: Genetic mutation on chromosome 9 that codes for JAK-2 Endeavour College of Natural Health 5
6 Myelofibrosis o Definition: a rare disease of the bone marrow in which there is excessive collagen fibres build up forming scar tissue inside the marrow cavity. This is due to the uncontrolled growth of fibroblasts and pleuripotent stem cell. It is also known as myeloid metaplasia, leucoerythroblastosis or chronic myelosclerosis. o Pathophysiology: Hypercellular bone marrow with an excess of abnormal megakaryocytes release growth factors reactive proliferation of fibroblasts fibrosed bone marrow blood cell maturation fails leucoerythroblastic anaemia and giant platelets extra medullary hematopoiesis Endeavour College of Natural Health 6
7 Myelofibrosis o Clinical features: Fatigue, Pallor, shortness of breath, palpitations Fever, sweating, itching Unexpected bleeding Night sweat, Weight loss Bone pains in the legs Splenomegaly Pain in the left shoulder and upper left portion of the body Endeavour College of Natural Health 7
8 Myelofibrosis o Diagnosis: Full blood count Peripheral blood smear Bone marrow biopsy Serum urate and folate Genetic analysis for JAK-2 o Management: Red cell transfusions Folic acid supplements Cytotoxic therapy Splenectomy HSCT JAK-2 inhibitor Endeavour College of Natural Health 8
9 Myelofibrosis: Excessive collagen fibres build up forming scar tissue inside the marrow cavity due to the uncontrolled growth of fibroblasts and pleuripotent stem Genetic mutation on chromosome 9 that codes for JAK-2 in 50% cases Uncontrolled/Clonal proliferation of blood cells. Hypercellular bone marrow with an excess of abnormal megakaryocytes Release growth factors Reactive proliferation of fibroblasts fibrosed bone marrow Failure of blood cell maturation leucoerythroblastic anaemia and giant platelets Extra medullary haematopoiesis Bone pains in the legs Symptoms of Anaemia: Fatigue, Pallor, shortness of breath, palpitations Increased predisposition to infection: Fever, sweating Systemic signs and symptoms: Night sweat, Weight loss Splenomegaly, splenic infarction and perisplenitis, Pain in the left shoulder and upper left portion of the body Diagnosis: FBC Peripheral blood smear Bone marrow biopsy Serum urate and folate Genetic analysis for JAK-2 Management: Red cell transfusions Folic acid supplements Cytotoxic therapy Splenectomy HSCT JAK-2 inhibitor Endeavour College of Natural Health 9
10 Essential Thrombocythaemia o Definition: a disease characterised by malignant proliferation of megakaryocytes that results in a raised level of circulating platelets that are often dysfunctional leading to a tendency of bleeding and thrombotic episodes. o Clinical features: Bleeding from GIT, Respiratory tract and skin Blood in stools Easy bruising Dizziness Enlarged lymph nodes Headaches Epistaxis Ulcers on the fingers and toes Cerebral stroke Endeavour College of Natural Health 10
11 Essential Thrombocythaemia o Management: low-dose aspirin Inhibitor of megakaryocyte maturation Intravenous radioactive phosphorus (32P) o Complications: Acute leukaemia Myelofibrosis Endeavour College of Natural Health 11
12 Polycythaemia Rubra Vera o Definition: A clonal stem cell disorder in which there is an increase in haemoglobin, PCV and red cell count. o Clinical features: Mainly in patients over the age of 40 years Symptoms of hyper viscosity Symptoms of peripheral arterial disease or a cerebrovascular accident Venous thromboembolism Peptic ulceration Plethora with deep cyanosis Hepatosplenomegaly and gout Aquagenic pruritus Endeavour College of Natural Health 12
13 o Diagnosis: Polycythaemia Rubra Vera Full blood count Genetic analysis for JAK-2 Absence of causes of a secondary erythrocytosis Bone marrow examination o Management: Aspirin Venesection Bone marrow suppression Radioactive phosphorus o Complications: Cerebrovascular attacks Coronary events Acute leukaemia Myelofibrosis Endeavour College of Natural Health 13
14 Polycythaemia Rubra Vera Cause of a secondary erythrocytosis High erythropoietin due to tissue hypoxia Inappropriately increased erythropoietin Exogenous erythropoietin administration Conditions High altitude Cardiorespiratory disease High-affinity haemoglobins Renal disease (hydronephrosis, cysts, carcinoma) Other tumours (hepatoma, bronchogenic carcinoma, uterine fibroids, phaeochromocytoma, cerebellar haemangioblastoma) Performance-enhancing drug-taking in athletes Endeavour College of Natural Health 14
15 Bleeding Disorders Endeavour College of Natural Health 15
16 Disorders of Primary Haemostasis Definition: The failure of initial formation of the platelet plug o Aetiology: Vessel wall abnormalities Hereditary haemorrhagic telangiectasia Platelet function disorders Idiopathic thrombocytopenic purpura Thrombotic thrombocytopenic purpura Von Willebrand disease (will be covered under clotting disorders) Endeavour College of Natural Health 16
17 Hereditary Haemorrhagic Telangiectasia Definition: It is an autosomal dominant disease characterised by bleeding from multiple telangiectases which consist of localised collection of non-contractile capillaries. o Aetiology: Genetic mutations in the genes encoding endoglin and activin receptor-like kinase, which are endothelial cell receptors for transforming growth factor-beta (TGF-β), a potent angiogenic cytokine. Endeavour College of Natural Health 17
18 Hereditary Haemorrhagic o Clinical features: Telangiectasia o Recurrent bleeds, particularly epistaxis, o Haematemesis, haemoptysis or bleeding elsewhere o Iron deficiency due to occult gastrointestinal bleeding o Telangiectases and small aneurysms on the fingertips, face and tongue, and in the nasal passages, lung and gastrointestinal tract o Larger pulmonary arteriovenous malformations leading to arterial hypoxaemia o Predisposition to paradoxical embolism, resulting in stroke or cerebral abscess. Endeavour College of Natural Health 18
19 Hereditary Haemorrhagic Telangiectasia o Management: No universal treatment Regular iron therapy Local cautery or laser therapy New Zealand Dermatological Society Inc., 2012, hereditary haemorrhagic telangiectasis, Endeavour College of Natural Health 19
20 Idiopathic Thrombocytopenic Purpura Definition: It is a disease characterised by a severe reduction in the number of circulating platelets due to an autoimmune attack on the platelets, the antibody being IgG type. o Clinical features: Easy bruising or sometimes epistaxis Menorrhagia in females Spontaneous bleeding Purpuric spots and haemorrhages on skin Iron deficiency anaemia Endeavour College of Natural Health 20
21 Idiopathic Thrombocytopenic Purpura o Management: No treatment required if a platelet count of more than /L Prednisolone intravenous immunoglobulin with corticosteroids Platelet transfusion Foot with acute purpura and petechiae Grossman, S, Porth, CM 2013, Porth s pathophysiology, Concepts of Altered Health States, 9th edn, Lippincott Williams & Wilkins Endeavour College of Natural Health 21
22 Thrombotic Thrombocytopenic Purpura o Definition: It is a rare disorder that likely results from introduction of platelet-aggregating substances into the circulation leading to abnormal platelet aggregation and adhesion to the endothelium. o Clinical features: Purpura, petechiae, Vaginal bleeding, Neurologic symptoms: headache, seizures, altered consciousness o Management: Plasmapheresis Plasma infusion Endeavour College of Natural Health 22
23 Haemophilia A o Definition: Haemophilia A is an X-linked recessive disorder of factor VIII deficiency that is characterised by a lifelong tendency to excessive haemorrhage and a greatly prolonged coagulation time. Endeavour College of Natural Health 23
24 o Clinical features: Haemophilia A Superficial injury presents with massive bleeding Spontaneous bleeding into skin, muscle and joints Typically large joints involved, especially knees, elbows, ankles and hip Muscle haematomas, most commonly in the calf and psoas muscles Hot, swollen and very painful joint Synovial hypertrophy, destruction of the cartilage and secondary osteoarthrosis Retroperitoneal and intracranial bleeding Endeavour College of Natural Health 24
25 Haemophilia A o Diagnosis: Bleeding time (BT) Prothrombin time (PT) Activated Partial Thromboplastin Time (APTT) Von Willebrand Factor (vwf ) assays Factor VIII assays o Management: Intravenous infusion of factor VIII concentrate Vasopressin receptor agonist Endeavour College of Natural Health 25
26 Haemophilia B o Definition: Hemophilia B, or Christmas disease, is an inherited, X-linked, recessive disorder that results in deficiency of functional plasma coagulation factor IX. o Clinical features: Similar to Haemophilia A o Diagnosis: Factor IX assays o Management: Intravenous infusion of factor IX concentrate Endeavour College of Natural Health 26
27 Von Willebrand Disease o Definition: Von Willebrand disease is a relative common hereditary bleeding disorder characterized by a quantitative or qualitative deficiency of von Willebrand factor (vwf). o Clinical features: Superficial bruising, epistaxis, menorrhagia Gastrointestinal haemorrhage Bleeding episodes much less common than in severe haemophilia Excessive haemorrhage may only be observed after trauma or surgery Endeavour College of Natural Health 27
28 o Diagnosis: o Management: Von Willebrand Disease Bleeding time (BT) Prothrombin time (PT) Activated Partial Thromboplastin Time (APTT) Von Willebrand Factor (vwf ) assays Factor VIII assays Vasopressin receptor agonist Intravenous infusion of factor VIII with vwf concentrate Endeavour College of Natural Health 28
29 Thrombotic disorders Endeavour College of Natural Health 29
30 Disseminated Intravascular Coagulation o Definition: It is characterised by systemic activation of the pathways involved in coagulation and its regulation which may result in the generation of intravascular fibrin clots causing multi organ failure, with simultaneous coagulation factor and platelet consumption causing bleeding. o Aetiology: Infection/sepsis Trauma Obstetricconditions Severe liver failure Malignancy Tissue destruction Vascular abnormalities Toxic/immunological Endeavour College of Natural Health 30
31 Disseminated Intravascular o Clinical features: Coagulation Coagulation and formation of microemboli Bleeding: petechiae, purpura, oozing from puncture sites, or severe hemorrhage Tissue hypoxia and necrotic damage to vital organs Renal, circulatory, or respiratory failure Acute bleeding ulcers Convulsions and coma Hemolytic anemia Endeavour College of Natural Health 31
32 Disseminated Intravascular Coagulation o Diagnosis: International Society for Thrombosis and Haemostasis scoring system for diagnosis: Presence of an associated disorder fibrin degradation products Prothrombin time Fibrinogen level Platelet count o Management: Treatment of underlying cause Intensive care Blood component therapy Heparin Antifibrinolytic therapy is contraindicated Endeavour College of Natural Health 32
33 Venous Thrombosis o Definition: It is the most common presentation of venous thromboembolic disease. Factors predisposing to venous thrombosis Patient factors Surgical conditions Age, coexisting disorders, obesity, patient Hx or FHx of deep vein thrombosis or pulmonary embolism, OCP and HRT Abdominal or pelvic surgery, joint replacement or hip fracture surgery. Medical conditions Haematological conditions MI, IBD, pneumonia, Malignancy, Nephrotic syndrome, immobility following a stroke PCV, essential thrombocythaemia, myelofibrosis Endeavour College of Natural Health 33
34 o Management: Venous Thrombosis Elevation and analgesia Thrombolysis Anticoagulation with low molecular weight heparin Coumarin anticoagulant, such as warfarin o Complications: Post-thrombotic syndrome: Persistent leg swelling, heaviness and discoloration Ulceration around the medial malleolus. Endeavour College of Natural Health 34
35 Reading and Resources o o o o o o o Crowley LV, 2012, An Introduction to Human Diseases Pathology and Pathophysiology Correlations, 9th edn, Jones and Bartlett Learning Grossman SC & Porth CM 2014, Porth s Pathophysiology- Concepts of Altered Health States, 9th edn. Wolters Kluwer Health - Lippincott, Williams & Wilkins Hinson, J, Raven, P & Chew, S 2010, The endocrine system: basic science and clinical conditions, 2nd edn, Churchill Livingstone Elsevier, Edinburgh Jamison, JR 2006, Differential diagnosis for primary care: a handbook for health care practitioners, 2nd edn, Churchill Livingstone Elsevier, Edinburgh. Jarvis, C, 2012 Physical Examination & Health Assessment, 6th ed., Elsevier Saunders, Philadelphia. Kumar, P & Clark, M 2012, Kumar and Clark s clinical medicine, 8th edn, Saunders Elsevier, Edinburgh. Kumar, V, Abbas, AK & Aster, JC 2015, Robbins & Cotran pathologic basis of disease, 9th edn, Elsevier Saunders, Philadelphia. Endeavour College of Natural Health 35
36 o o o o o o Reading and Resources Lee, G & Bishop, P 2009, Microbiology and infection control for health professionals, 4th edn, Pearson Education, Frenchs Forest, NSW. McCance, KL, Heuther, SE, & Brashers, VL 2014, Pathophysiology: the biologic basis for disease in adults and children, 7th edn, Elsevier. Michael-Titus, A, Revest, P & Shortland, P 2010, The nervous system: basic science and clinical conditions, 2nd edn, Churchill Livingstone Elsevier, Edinburgh Mosby s dictionary of medicine, nursing and health professions 2013, 9th edn, Elsevier, St. Louis, MO. Tortora, GJ & Derrickson, B 2014, Principles of anatomy and physiology, 14th edn, John Wiley & Sons, Hoboken, NJ. VanMeter, KC & Hubert, RJ 2014, Gould's pathophysiology for the health professions, 5th edn, Elsevier, St Louis, MO. o Walker, BR, Colledge, NR, Ralston, SH, & Penman, ID (eds) 2014, Davidson s principles and practice of medicine, 22nd edn, Churchill Livingstone Elsevier, Edinburgh. Endeavour College of Natural Health 36
37 COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been reproduced and communicated to you by or on behalf of the Endeavour College of Natural Health pursuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice. Endeavour College of Natural Health 37
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