Hematological Disorders - General Pathology 3º PDF

Approach to the patient with hematological disorders: hematopoiesis, coagulation process, anemias, thalassemia, haemoglobinopathies and polycythemia GENERAL PATHOLOGY 3º Prof. Luis D’Marco, MD, MSc, PhD.  Approach to the patient with hematological disorder...

Approach to the patient with hematological disorders: hematopoiesis, coagulation process, anemias, thalassemia, haemoglobinopathies and polycythemia GENERAL PATHOLOGY 3º Prof. Luis D’Marco, MD, MSc, PhD.  Approach to the patient with hematological disorders Abnormalities detected in the blood are caused not only by primary diseases of the blood and lymphoreticular systems but also by diseases affecting other body systems. The clinical assessment of patients with this abnormalities must include a general history and examination, as well as a search for symptoms and signs of abnormalities of red cells, white cells, platelets, haemostatic systems, lymph nodes, and lymphoreticular tissues.  Functional anatomy and physiology Blood flows throughout the body in the vascular system, and consists of: Red cells, transport oxygen from the lungs to the tissues. White cells, which defend against infections. Platelets, interact with blood vessels and clotting factors to maintain vascular integrity and prevent bleeding. Plasma, which contains proteins with many functions, including antibodies and coagulation factors.  Haematopoiesis Describes the formation of blood cells, an active process that must maintain normal numbers of circulating cells and be able to respond rapidly to increased demands such as bleeding or infection. During development, haematopoiesis occurs in the yolk sac, liver, and spleen, and subsequently in red bone marrow in the medullary cavity of all bones. In childhood, red marrow is progressively replaced by fat (yellow marrow) so that, in adults, normal haematopoiesis is restricted to the vertebrae, pelvis, sternum, ribs, clavicles, skull, upper humeri, and proximal femora. However, red marrow can expand in response to increased demands for blood cells. Structural organization of normal bone marrow  Stem cells All blood cells are derived from pluripotent haematopoietic stem cells. These comprise only 0.01% of the total marrow cells, but they can self-renew (i.e. make more stem cells) or differentiate to produce a hierarchy of lineage-committed progenitor cells. The resulting primitive progenitor cells cannot be identified morphologically, so they are named according to the types of cell (or colony) they form during cell culture experiments. CFU–GM (colony-forming unit – granulocyte, monocyte) is a progenitor cell that produces granulocytic and monocytic lines, CFU–E produces erythroid cells, and CFU–Meg produces megakaryocytes and ultimately platelets.  Growth factors GF produced in bone marrow stromal cells, control the survival, proliferation, differentiation and function of stem cells and their progeny. Some, such as, IL-3, stem cell factor (SCF) and granulocyte, macrophage–colony-stimulating factor (GM–CSF), act on a wide number of cell types at various stages of differentiation. Others, such as EPO, granulocyte–colony-stimulating factor (G–CSF) and thrombopoietin (Tpo), are lineage-specific. Many of these GF are now synthesised by recombinant DNA technology and used as treatments: EPO to correct renal anaemia in CKD G–CSF to hasten neutrophil recovery after chemotherapy. Stem cells and growth factors in haematopoietic cell development (BFU–E = burst-forming unit – erythroid; CFU–E = colony-forming unit – erythroid; CFU–GM = colony-forming unit - granulocyte, monocyte; CFU–Meg = colony-forming unit – megakaryocyte; Epo = erythropoietin; G–CSF = granulocyte–colony-stimulating factor; GM–CSF = granulocyte, macrophage–colony-stimulating factor; IL = interleukin; M–CSF = macrophage–colonystimulating factor; SCF = stem cell factor; Tpo = thrombopoietin) Blood cell development Maturation pathway of red cells, granulocytes and platelets Clinical examination in blood disease  Red cells Red cell precursors formed in the bone marrow from the erythroid progenitor cells (erythroblasts). These divide and acquire haemoglobin, which turns the cytoplasm pink; the nucleus condenses and is extruded from the cell. The first non-nucleated red cell is a reticulocyte, which still contains ribosomal material in the cytoplasm, giving these large cells a faint blue tinge (‘polychromasia’). Increased numbers of circulating reticulocytes (reticulocytosis) reflect increased erythropoiesis. Proliferation and differentiation of red cell precursors is stimulated by erythropoietin (polypeptide hormone produced by renal interstitial peritubular cells in response to hypoxia).  Haemoglobin Haemoglobin is a protein specially adapted for oxygen transport. It is composed of four globin chains, each surrounding an iron-containing porphyrin pigment molecule termed haem. Haemoglobin A represents over 90% of adult haemoglobin, whereas Haemoglobin F is the predominant type in the fetus. need iron !!! Each haem molecule contains a ferrous ion (Fe2+), to which oxygen reversibly binds; the affinity for oxygen increases as successive oxygen molecules bind.  Platelets Platelets are formed in the bone marrow from megakaryocytes. Mature megakaryocytes are large cells with several nuclei and cytoplasm containing platelet granules. Large numbers of platelets then fragment off from each megakaryocyte into circulation. The formation and maturation of megakaryocytes are stimulated by thrombopoietin produced in the liver. Platelets circulate for 8–10 days before they are destroyed in the reticuloendothelial system. Some 30% of peripheral platelets are normally pooled in the spleen and do not circulate.  Haemostasis Blood must be maintained in a fluid state in order to function as a transport system but must be able to solidify to form a clot following vascular injury in order to prevent excessive bleeding, a process known as haemostasis. Successful haemostasis is localised to the area of tissue damage and is followed by removal of the clot and tissue repair. This is achieved by complex interactions between the vascular endothelium, platelets, von Willebrand factor, coagulation factors, natural anticoagulants and fibrinolytic enzymes. Dysfunction of any of these components may result in haemorrhage or thrombosis. Normal Hemostasis  Normal Hemostasis The internal and external anatomy of a platelet  cannot have higher ventilation without change in the HR Anaemia - Around 30% of the total world population is anaemic and half of these, some 600 million people, have iron deficiency. - The classification of anaemia by the size of the red cells (MCV) indicates the likely cause EXAM QUESTION MEAN CORPUSCULAR VOLUME = classification of anaemia Causes of anaemia  Clinical assessment - Iron deficiency anaemia is the most common type of anaemia worldwide. - A dietary history should assess the intake of iron and folate, which may become deficient in comparison to needs. - Past medical history may reveal a disease such as CKD (anaemia of chronic disease), or previous surgery. - Family history and ethnic background may raise suspicion of haemolytic anaemias (haemoglobinopathies and hereditary spherocytosis). - A drug history may reveal the ingestion of drugs that cause blood loss (e.g. aspirin and anti-inflammatory drugs), haemolysis (e.g. sulphonamides) or aplasia (e.g. chloramphenicol). The regulation of iron absorption, uptake and distribution in the body high hepcidin 0.52 males, > 0.48 females) for more than 2 months should be investigated. ‘True’ polycythaemia (or absolute erythrocytosis) indicates an excess of red cells, while ‘relative’, ‘apparent’ or ‘low-volume’ polycythaemia is due to a decreased plasma volume. These involve increased erythropoiesis in the bone marrow, either due to a primary increase in marrow activity, or in response to increased EPO levels in chronic hypoxaemia, or due to inappropriate secretion of EPO. Athletes who seek to benefit from increased oxygen-carrying capacity have been known to use EPO to achieve this. Apparent erythrocytosis with a raised Hct, normal red cell mass (RCM) and reduced plasma volume may be associated with hypertension, smoking, alcohol and diuretic use. Classification and causes of erythrocytosis  Polycythemia vera Definition and Epidemiology PV, literally meaning “increased numbers of red blood cells in the blood” is a syndrome resulting from a clonal multipotent hematopoietic stem cell (HSC) defect. PV is relatively uncommon with an incidence of 1 to 3 in 100,000 people and a median age at diagnosis of 65 years.  Polycythemia vera Clinical Presentation Typically, patients complain of headache, visual problems, mental clouding, and pruritus after bathing. Occlusive vascular events such as stroke, myocardial ischemia, and digital pain, paresthesias, or gangrene are common. Pulmonary, deep vein, hepatic, and portal vein thromboses may occur. Paradoxically, patients are also predisposed to hemorrhagic events such as gastrointestinal and mucosal bleeding by abnormal platelet function. Physical examination may show retinal vein occlusion, ruddy cyanosis, digital ischemia, and splenomegaly.  Diagnostic Criteria for Polycythemia Vera a PV diagnosis requires meeting either all three major criteria or the first two major criteria and one minor criterion. b Criterion number 2 (bone marrow biopsy) may not be required in cases with sustained absolute erythrocytosis: hemoglobin levels 18.5 g/dL in men (hematocrit 55.5%) or 16.5 g/dL in women (hematocrit 49.5%) if major criterion 3 and the minor criterion are present. However, initial myelofibrosis (present >20% of px) can only be detected by performing a bone marrow biopsy; this finding may predict a more rapid progression to overt myelofibrosis (post- PV MF).  Treatment Low-dose aspirin and treatment of asymptomatic thrombocytosis decrease thromboembolic events in low- and high-risk PV patients and are especially important in older patients with significant cardiovascular risk factors. Cytoreductive therapy is indicated for patients who cannot tolerate and/or fail phlebotomy, older patients with a prior history of and/or coexisting risk factors for cardiovascular events, and those with symptomatic splenomegaly. Commonly used therapies include hydroxyurea, pegylated interferon-α, and anagrelide.  Haemoglobinopathies These diseases are caused by mutations affecting the genes encoding the globin chains of the Hb molecule (2 alpha and 2 non-alpha globin chains). Alpha globin chains are produced throughout life, including in the fetus, so severe mutations may cause intrauterine death. Production of non-alpha chains varies with age; fetal haemoglobin (HbF-αα/γγ) has two gamma chains, while the predominant adult haemoglobin (HbA-αα/ββ) has two beta chains. A constant small amount of Hb A2 (HbA2-αα/δδ, usually