Podcast
Questions and Answers
What role do endothelial cells play in the haemostatic mechanism under normal conditions?
What role do endothelial cells play in the haemostatic mechanism under normal conditions?
What occurs when injury happens to a blood vessel?
What occurs when injury happens to a blood vessel?
Which of the following statements best describes the activation process of coagulation factors?
Which of the following statements best describes the activation process of coagulation factors?
How can acquired coagulation defects be distinguished from inherited problems?
How can acquired coagulation defects be distinguished from inherited problems?
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What is the primary function of activated coagulation factors in the haemostatic process?
What is the primary function of activated coagulation factors in the haemostatic process?
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What is the primary role of factors 8 and 9 in hemostasis?
What is the primary role of factors 8 and 9 in hemostasis?
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Which of the following is a characteristic lab finding for von Willebrand’s disease?
Which of the following is a characteristic lab finding for von Willebrand’s disease?
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Which of the following best describes disseminated intravascular coagulation (DIC)?
Which of the following best describes disseminated intravascular coagulation (DIC)?
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What does a positive D-dimer assay indicate?
What does a positive D-dimer assay indicate?
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What is the primary function of von Willebrand factor (vWF) in hemostasis?
What is the primary function of von Willebrand factor (vWF) in hemostasis?
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What is a common issue faced when using plasma-derived factor 8 for treatment?
What is a common issue faced when using plasma-derived factor 8 for treatment?
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Which of the following statements regarding the coagulation factors in severe cases of bleeding is correct?
Which of the following statements regarding the coagulation factors in severe cases of bleeding is correct?
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Which condition is characterized by high fibrin degradation product concentrations?
Which condition is characterized by high fibrin degradation product concentrations?
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What is necessary for the coagulation reaction to produce thrombin?
What is necessary for the coagulation reaction to produce thrombin?
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Which factor has the shortest half-life among vitamin K dependent clotting factors?
Which factor has the shortest half-life among vitamin K dependent clotting factors?
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What is the primary mechanism of action for warfarin?
What is the primary mechanism of action for warfarin?
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What can decrease sensitivity to warfarin?
What can decrease sensitivity to warfarin?
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Which of the following is a direct thrombin inhibitor?
Which of the following is a direct thrombin inhibitor?
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What is a general advantage of direct acting oral anticoagulants (DOACs) over warfarin?
What is a general advantage of direct acting oral anticoagulants (DOACs) over warfarin?
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What causes thrombocytopenia in patients?
What causes thrombocytopenia in patients?
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How does rivaroxaban differ from warfarin?
How does rivaroxaban differ from warfarin?
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What is a common side effect of excessive vitamin K intake in patients on anticoagulants?
What is a common side effect of excessive vitamin K intake in patients on anticoagulants?
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What is the role of von Willebrand factor in clot formation?
What is the role of von Willebrand factor in clot formation?
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Which of the following correctly describes the structure of platelets?
Which of the following correctly describes the structure of platelets?
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What is the primary function of tissue factor in the coagulation process?
What is the primary function of tissue factor in the coagulation process?
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What occurs during the amplification phase of coagulation?
What occurs during the amplification phase of coagulation?
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Which of the following statements best describes anticoagulation mechanisms?
Which of the following statements best describes anticoagulation mechanisms?
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In laboratory testing, what is the purpose of adding calcium after binding it with sodium citrate?
In laboratory testing, what is the purpose of adding calcium after binding it with sodium citrate?
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What might prolonged thrombin time indicate?
What might prolonged thrombin time indicate?
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How can one differentiate between a deficiency of a coagulation factor and the presence of an inhibitor?
How can one differentiate between a deficiency of a coagulation factor and the presence of an inhibitor?
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Which factor deficiency is indicated by prolonged prothrombin time with normal activated partial thromboplastin time?
Which factor deficiency is indicated by prolonged prothrombin time with normal activated partial thromboplastin time?
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What causes the clinical symptoms of haemophilia?
What causes the clinical symptoms of haemophilia?
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What is the function of fibrinogen in coagulation?
What is the function of fibrinogen in coagulation?
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What is the role of calcium in the coagulation cascade?
What is the role of calcium in the coagulation cascade?
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What is the typical value range for normal APTT?
What is the typical value range for normal APTT?
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What is the normal range for hemoglobin levels in males?
What is the normal range for hemoglobin levels in males?
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What condition is indicated by a reduced mean corpuscular volume (MCV)?
What condition is indicated by a reduced mean corpuscular volume (MCV)?
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Which component is most commonly associated with iron in red blood cells?
Which component is most commonly associated with iron in red blood cells?
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What does a high red cell distribution width (RDW) indicate?
What does a high red cell distribution width (RDW) indicate?
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What is the lifespan of a typical red blood cell?
What is the lifespan of a typical red blood cell?
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What is the average amount of hemoglobin in a red blood cell categorized as normochromia?
What is the average amount of hemoglobin in a red blood cell categorized as normochromia?
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Which of the following is a likely effect of prolonged storage of blood samples?
Which of the following is a likely effect of prolonged storage of blood samples?
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What does a reticulocyte count increase in the blood usually indicate?
What does a reticulocyte count increase in the blood usually indicate?
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What is the primary factor that leads to the bleeding disorder associated with a lack of von Willebrand factor (vWF)?
What is the primary factor that leads to the bleeding disorder associated with a lack of von Willebrand factor (vWF)?
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Which treatment is typically used for women experiencing heavy menstrual periods due to von Willebrand disease?
Which treatment is typically used for women experiencing heavy menstrual periods due to von Willebrand disease?
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How does DDAVP function in the management of von Willebrand disease?
How does DDAVP function in the management of von Willebrand disease?
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Which of the following laboratory findings would typically be expected in a patient with von Willebrand disease?
Which of the following laboratory findings would typically be expected in a patient with von Willebrand disease?
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What is a common consequence of liver disease related to hemostasis?
What is a common consequence of liver disease related to hemostasis?
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Which of the following factors is NOT a common predisposing factor for venous thromboembolism?
Which of the following factors is NOT a common predisposing factor for venous thromboembolism?
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What initial treatment is often administered postoperatively to reduce the risk of venous thromboembolism?
What initial treatment is often administered postoperatively to reduce the risk of venous thromboembolism?
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In suspected pulmonary embolism, which diagnostic imaging is typically first utilized?
In suspected pulmonary embolism, which diagnostic imaging is typically first utilized?
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What role does vitamin K play in the mechanism of warfarin?
What role does vitamin K play in the mechanism of warfarin?
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Which of the following describes a common sign of deep vein thrombosis?
Which of the following describes a common sign of deep vein thrombosis?
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How might patients with liver disease display symptoms related to their condition?
How might patients with liver disease display symptoms related to their condition?
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What does a normal D-dimer level indicate in the context of venous thromboembolism?
What does a normal D-dimer level indicate in the context of venous thromboembolism?
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What is the prognosis for a patient who experiences massive pulmonary embolism?
What is the prognosis for a patient who experiences massive pulmonary embolism?
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What is the most likely cause of Mr. PB's elevated D-dimer levels?
What is the most likely cause of Mr. PB's elevated D-dimer levels?
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Which laboratory finding is indicative of macrocytic anemia in Mr. PB?
Which laboratory finding is indicative of macrocytic anemia in Mr. PB?
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What is a significant consequence of liver disease on coagulation status?
What is a significant consequence of liver disease on coagulation status?
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Which of the following treatments is appropriate for Mr. PB's subdural hematoma?
Which of the following treatments is appropriate for Mr. PB's subdural hematoma?
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Which symptom suggests a possible pulmonary embolism in Ms. Al?
Which symptom suggests a possible pulmonary embolism in Ms. Al?
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What is the primary purpose of thrombo prophylaxis in patients like Ms. Al?
What is the primary purpose of thrombo prophylaxis in patients like Ms. Al?
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What would indicate the need for a CT pulmonary angiography in a patient suspected of having a pulmonary embolism?
What would indicate the need for a CT pulmonary angiography in a patient suspected of having a pulmonary embolism?
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Which cell type is primarily associated with the findings in Mr. PB's blood smear indicating liver disease?
Which cell type is primarily associated with the findings in Mr. PB's blood smear indicating liver disease?
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What is a common risk factor for developing DVT in patients post-surgery?
What is a common risk factor for developing DVT in patients post-surgery?
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What is the role of low molecular weight heparin in the treatment of pulmonary embolism?
What is the role of low molecular weight heparin in the treatment of pulmonary embolism?
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Which type of blood cell count is essential for evaluating a patient's coagulation status?
Which type of blood cell count is essential for evaluating a patient's coagulation status?
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During a full blood examination, which component is measured to assess the concentration of red blood cells?
During a full blood examination, which component is measured to assess the concentration of red blood cells?
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What immediate action should be taken when pulmonary embolism is suspected in a patient?
What immediate action should be taken when pulmonary embolism is suspected in a patient?
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What is the most common cause of abnormal platelet aggregation?
What is the most common cause of abnormal platelet aggregation?
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Which of the following agonists is NOT commonly used to test platelet aggregation?
Which of the following agonists is NOT commonly used to test platelet aggregation?
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How does aspirin affect platelet aggregation?
How does aspirin affect platelet aggregation?
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What characterizes the secondary wave of platelet aggregation in response to certain agonists?
What characterizes the secondary wave of platelet aggregation in response to certain agonists?
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What laboratory finding indicates a deficiency rather than a blockage in coagulation?
What laboratory finding indicates a deficiency rather than a blockage in coagulation?
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Which condition is commonly NOT associated with the development of DIC?
Which condition is commonly NOT associated with the development of DIC?
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What is the primary mechanism by which aspirin inhibits platelet aggregation?
What is the primary mechanism by which aspirin inhibits platelet aggregation?
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What genetic disorder is characterized by excessive bleeding and may present as easy bruising and heavy menstrual bleeding?
What genetic disorder is characterized by excessive bleeding and may present as easy bruising and heavy menstrual bleeding?
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In the presented cases, which factor most likely contributed to the patient's heavy menstrual bleeding?
In the presented cases, which factor most likely contributed to the patient's heavy menstrual bleeding?
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Which finding is indicative of acute hemolysis in DIC?
Which finding is indicative of acute hemolysis in DIC?
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What is the effect of iron deficiency on von Willebrand factor levels?
What is the effect of iron deficiency on von Willebrand factor levels?
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What is the primary role of thromboxane A2 in hemostasis?
What is the primary role of thromboxane A2 in hemostasis?
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Which therapeutic agent is used to manage bleeding in severe von Willebrand disease?
Which therapeutic agent is used to manage bleeding in severe von Willebrand disease?
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What indicates a mixed coagulation disorder rather than a singular deficiency?
What indicates a mixed coagulation disorder rather than a singular deficiency?
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Which statement is true regarding the pathophysiology of DIC?
Which statement is true regarding the pathophysiology of DIC?
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What is the purpose of flow cytometry in immunological investigations?
What is the purpose of flow cytometry in immunological investigations?
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Which of the following treatments might be inappropriate for patients with SCID?
Which of the following treatments might be inappropriate for patients with SCID?
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Which investigation is mandatory for assessing lymphocyte levels in a patient?
Which investigation is mandatory for assessing lymphocyte levels in a patient?
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What serves as a treatment approach for boosting immune function in patients with phagocytic disorders?
What serves as a treatment approach for boosting immune function in patients with phagocytic disorders?
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Which factor is crucial when considering targeted investigations for inherited immune disorders?
Which factor is crucial when considering targeted investigations for inherited immune disorders?
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What is the primary characteristic of the chronic phase of chronic myeloid leukaemia (CML)?
What is the primary characteristic of the chronic phase of chronic myeloid leukaemia (CML)?
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Which feature is most indicative of the accelerated phase of CML?
Which feature is most indicative of the accelerated phase of CML?
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What is the significance of the Philadelphia chromosome in diagnosing CML?
What is the significance of the Philadelphia chromosome in diagnosing CML?
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What symptom is least likely to occur in a patient with acute progression of CML?
What symptom is least likely to occur in a patient with acute progression of CML?
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What type of investigation is primarily used to diagnose myelodysplastic syndromes (MDS)?
What type of investigation is primarily used to diagnose myelodysplastic syndromes (MDS)?
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Which of the following treatments is most commonly used for CML to delay accelerated or blast phases?
Which of the following treatments is most commonly used for CML to delay accelerated or blast phases?
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Which clinical finding is common in the later stages of myelodysplastic syndromes (MDS)?
Which clinical finding is common in the later stages of myelodysplastic syndromes (MDS)?
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What is the typical clinical presentation of a patient in the blast phase of CML?
What is the typical clinical presentation of a patient in the blast phase of CML?
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In which myeloproliferative neoplasm does an increase in red blood cells, white blood cells, and platelets occur?
In which myeloproliferative neoplasm does an increase in red blood cells, white blood cells, and platelets occur?
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What is a common characteristic of benign myeloid disorders compared to malignant disorders?
What is a common characteristic of benign myeloid disorders compared to malignant disorders?
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Which characteristic is indicative of myelodysplastic syndromes in older populations?
Which characteristic is indicative of myelodysplastic syndromes in older populations?
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What is the primary function of tyrosine kinase inhibitors in the treatment of CML?
What is the primary function of tyrosine kinase inhibitors in the treatment of CML?
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What underlying condition can lead to the development of myelodysplastic syndromes?
What underlying condition can lead to the development of myelodysplastic syndromes?
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What is a primary function of dendritic cells in the immune system?
What is a primary function of dendritic cells in the immune system?
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Which statement best describes neutrophils?
Which statement best describes neutrophils?
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What characteristic distinguishes lymphoid progenitor cells?
What characteristic distinguishes lymphoid progenitor cells?
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Which of the following is NOT a characteristic of the innate immune system?
Which of the following is NOT a characteristic of the innate immune system?
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What is the primary mechanism of phagocytosis?
What is the primary mechanism of phagocytosis?
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What main role do basophils play in the immune response?
What main role do basophils play in the immune response?
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How does gastric acid contribute to the immune system?
How does gastric acid contribute to the immune system?
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What do cytokines stimulate in relation to neutrophils?
What do cytokines stimulate in relation to neutrophils?
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Which component is part of the inflammatory response?
Which component is part of the inflammatory response?
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What type of cells do monocytes differentiate into when they enter tissues?
What type of cells do monocytes differentiate into when they enter tissues?
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Which of the following describes the function of natural killer (NK) cells?
Which of the following describes the function of natural killer (NK) cells?
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What is the result of neutrophilia?
What is the result of neutrophilia?
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What is the primary clinical sign of anaemia?
What is the primary clinical sign of anaemia?
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Which condition is characterized by hypochromic microcytic anemia and pencil cells on a peripheral blood film?
Which condition is characterized by hypochromic microcytic anemia and pencil cells on a peripheral blood film?
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Which component is NOT considered a mechanical barrier in the immune system?
Which component is NOT considered a mechanical barrier in the immune system?
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What identifies a severe allergic response related to eosinophils?
What identifies a severe allergic response related to eosinophils?
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What is the role of commensal flora in relation to pathogens?
What is the role of commensal flora in relation to pathogens?
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Which type of white blood cells primarily fights against bacterial infections?
Which type of white blood cells primarily fights against bacterial infections?
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What is the term for the formation of RBCs in a stacked coin-like formation found in certain diseases?
What is the term for the formation of RBCs in a stacked coin-like formation found in certain diseases?
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In which condition is the presence of immature granulocytes in the blood particularly concerning?
In which condition is the presence of immature granulocytes in the blood particularly concerning?
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Which of the following is a classic feature of chronic myeloid leukaemia?
Which of the following is a classic feature of chronic myeloid leukaemia?
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What is the expected reticulocyte count in hemolysis with significant reticulocytosis?
What is the expected reticulocyte count in hemolysis with significant reticulocytosis?
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What condition may indicate a need for a peripheral blood film investigation?
What condition may indicate a need for a peripheral blood film investigation?
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Which type of anemia is characterized by the presence of lots of target cells?
Which type of anemia is characterized by the presence of lots of target cells?
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How does an increase in platelets manifest in thrombocytosis?
How does an increase in platelets manifest in thrombocytosis?
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What blood cell change is most commonly associated with chronic infections?
What blood cell change is most commonly associated with chronic infections?
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What condition commonly leads to thrombocytopenia?
What condition commonly leads to thrombocytopenia?
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What type of antigens do T lymphocytes primarily recognize?
What type of antigens do T lymphocytes primarily recognize?
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What is the role of plasma cells in the immune response?
What is the role of plasma cells in the immune response?
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Which cells are primarily responsible for phagocytosing pathogens?
Which cells are primarily responsible for phagocytosing pathogens?
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Which types of immunoglobulins are primarily affected in X-linked agammaglobulinemia?
Which types of immunoglobulins are primarily affected in X-linked agammaglobulinemia?
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What is the primary function of memory B cells?
What is the primary function of memory B cells?
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Which of the following describes the main role of T helper cells?
Which of the following describes the main role of T helper cells?
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What defines the primary defect in Severe Combined Immunodeficiency (SCID)?
What defines the primary defect in Severe Combined Immunodeficiency (SCID)?
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Which type of immune response is primarily targeted by T cytotoxic cells?
Which type of immune response is primarily targeted by T cytotoxic cells?
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What is a common consequence of CD4+ T cell depletion, such as in AIDS?
What is a common consequence of CD4+ T cell depletion, such as in AIDS?
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What characterizes Wiskott-Aldrich syndrome?
What characterizes Wiskott-Aldrich syndrome?
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Which type of antibody production is most affected by Common Variable Immune Deficiency (CVID)?
Which type of antibody production is most affected by Common Variable Immune Deficiency (CVID)?
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What is the typical clinical feature of DiGeorge syndrome?
What is the typical clinical feature of DiGeorge syndrome?
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What type of cell is primarily involved in recognizing and responding to mycobacterial infections in the cellular immune response?
What type of cell is primarily involved in recognizing and responding to mycobacterial infections in the cellular immune response?
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What is a typical finding in a patient with X-linked agammaglobulinemia during clinical examination?
What is a typical finding in a patient with X-linked agammaglobulinemia during clinical examination?
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What is the most common form of chronic granulomatous disease caused by?
What is the most common form of chronic granulomatous disease caused by?
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What condition is characterized by recurrent bacterial infections and giant lysosomal granules in cells?
What condition is characterized by recurrent bacterial infections and giant lysosomal granules in cells?
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Which statement best describes the function of B lymphocytes in humoral immunity?
Which statement best describes the function of B lymphocytes in humoral immunity?
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What is a primary cause of infections in patients with Chediak-Higashi syndrome?
What is a primary cause of infections in patients with Chediak-Higashi syndrome?
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How do T lymphocytes contribute to cell-mediated immunity?
How do T lymphocytes contribute to cell-mediated immunity?
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What condition is characterized by an absolute decrease in circulating neutrophils?
What condition is characterized by an absolute decrease in circulating neutrophils?
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Which inherited condition involves defects in neutrophil function and is very rare?
Which inherited condition involves defects in neutrophil function and is very rare?
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What is the primary role of neutrophils in the immune response to intracellular infections?
What is the primary role of neutrophils in the immune response to intracellular infections?
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How is neutrophil count generally affected by treatment with granulocyte colony-stimulating factor (GCSF)?
How is neutrophil count generally affected by treatment with granulocyte colony-stimulating factor (GCSF)?
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What is one consequence of chronic granulomatous disease?
What is one consequence of chronic granulomatous disease?
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Which of the following is a complication associated with Chediak-Higashi syndrome?
Which of the following is a complication associated with Chediak-Higashi syndrome?
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In which scenario would you typically see neutrophilia?
In which scenario would you typically see neutrophilia?
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What mechanism do antibodies use to prevent infection at mucosal surfaces?
What mechanism do antibodies use to prevent infection at mucosal surfaces?
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What is a common acquired cause of neutropenia?
What is a common acquired cause of neutropenia?
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Study Notes
Haemostasis
- The haemostatic system is the body's natural process of stopping bleeding. Healthy blood vessels are lined with endothelial cells that suppress this system.
- When an injury occurs, the endothelial cells are damaged and blood vessels expose their subendothelial matrix, which contains collagen and tissue factors. This triggers the haemostatic response.
- The haemostatic response involves platelet aggregation, activation of the coagulation pathway, and vasoconstriction, all mediated by cytokines and mediators.
Platelet Aggregation
- Platelets are tiny anucleate cells produced in the bone marrow from megakaryocytes.
- A single megakaryocyte can produce thousands of platelets.
- Platelets circulate in the blood for a few days before being destroyed in the reticuloendothelial system.
- Normal blood contains 150-400 million platelets per litre.
- Platelets do not normally adhere to healthy endothelial cells.
- Upon injury, the subendothelial matrix is exposed and attracts von Willebrand Factor (vWF).
- vWF binds to collagen in the matrix and then to platelets, especially in conditions of high blood flow.
Secondary Platelet Activation
- Secondary activation of platelets leads to irreversible binding at the site of injury. This is triggered by agonists like thromboxane A2 and adenosine diphosphate (ADP).
- Cyclo-oxygenase inhibitors, like aspirin, block thromboxane A2 production.
- Drugs blocking ADP receptors, like clopidogrel and ticlopidine, inhibit platelet aggregation.
Von Willebrand Factor (vWF)
- vWF is a large multimeric protein synthesized by endothelial cells.
- Some vWF is secreted into the blood or subendothelial matrix, while the remaining vWF is stored in cytoplasmic granules and released during stress.
- vWF has multiple binding sites for collagen. When bound to collagen, vWF activates and binds to platelet surface receptors, facilitating plug formation.
- vWF also carries clotting factor VIII in the blood.
- Without vWF, factor VIII has a very short survival time in the bloodstream.
The Coagulation Reaction
- The coagulation reaction involves many proteins in blood, including inactive enzymes known as zymogens.
- These zymogens are activated by cleavage at specific sites, allowing them to participate in the clotting cascade.
- Other components are co-factors, which are not catalytically active but accelerate the catalytic activity of other factors.
- Most clotting factors are produced in the liver.
- The coagulation reaction can only occur properly when the clotting factors are present on a charged lipid membrane like the surface of an activated platelet, and in the presence of calcium.
Initiation
- The main goal of the initiation phase is to produce small amounts of thrombin.
- Tissue factor, which is expressed by many extravascular cells, is exposed upon endothelial breach.
- Tissue factor activates factor VII, which is present in trace amounts in the blood.
- This complex activates downstream factors and converts prothrombin to thrombin.
Amplification
- Tiny quantities of thrombin activate other clotting factors and cofactors in a positive feedback loop, generating more thrombin.
Clot Formation
- When sufficient thrombin is produced, fibrinogen is cleaved to fibrin.
- These fibrin monomers polymerise to form a clot.
Regulation
- Thrombin generation also activates negative feedback mechanisms that degrade the procoagulant factors 5a and 8a.
- The positive and negative feedback mechanisms operate simultaneously, regulating the coagulation cascade.
- Negative regulators include activated protein C, which along with protein S, degrades 5a and 8a.
- Antithrombin III directly inhibits thrombin, factor 10a, and other coagulation serine proteases.
- Heparin, present on endothelial cells and used therapeutically, stimulates antithrombin activity.
Coagulation Laboratory
- Laboratory tests do not consider patients' medical history or physical examinations.
- Some individuals may have abnormal clotting studies but do not experience bleeding problems.
- Blood is collected from patients and mixed with sodium citrate to bind calcium and prevent coagulation.
- Calcium is added later to allow coagulation reactions to proceed.
- Citrated blood is centrifuged to separate red blood cells, leukocytes, and platelets from plasma.
- Plasma, which contains clotting factors, and platelets are used for clotting tests.
Prothrombin Time (PT)
- Citrated plasma is prewarmed and a mixture of thromboplastin (tissue factor) and calcium is added.
- A clot forms after 12-18 seconds.
- Thromboplastin activates factor VII, which further activates factor X. This leads to the formation of the prothrombinase complex and thrombin generation.
- A normal PT depends on factor VII, the tenase complex (factors X, V, and II), and fibrinogen.
- Thromboplastin is obtained from rabbit brain or bovine lung.
- Multiple commercial preparations of thromboplastin exist, leading to varying coagulation times.
- The International Normalized Ratio (INR) standardizes these times. Laboratories use the INR to express a patient's prothrombin time as a ratio to a control value.
Activated Partial Thromboplastin Time (APTT)
- Assesses the complete coagulation pathway, excluding factor VII.
- Citrated plasma is prewarmed and incubated with phospholipid and an activator of contact factors.
- The activator is usually a negatively charged surface, activating the contact factors XI and XII.
- After sufficient time (incubation period) to form factor XIa, calcium is added, and the clotting time is monitored.
- Factor XIa activates factor IX. Factor IXa combines with factor VIII and phospholipid to form the tenase complex, which cleaves factor X, generating factor Xa.
- Factor Xa assembles the prothrombinase complex and produces thrombin.
- An extended APTT indicates a deficiency in any of these factors, or the presence of an inhibitor.
- Normally, the APTT is around 22-24 seconds.
Thrombin Time (TT)
- Thrombin is added to citrated plasma to assess how efficiently thrombin can clot plasma fibrinogen.
- Prolonged TT indicates the presence of thrombin inhibitors (e.g. heparin), fibrin polymerisation inhibitors, or fibrinogen deficiency.
Differentiating Factor Deficiency from Inhibitor Presence
- A prolonged clotting time can be due to either a specific factor deficiency or the presence of an inhibitor.
- A mixing test is performed to differentiate between the two.
- Equal volumes of patient plasma and normal plasma are mixed, and coagulation tests are performed on the mixed sample.
- If the clotting time is normal, the patient has a factor deficiency.
- If the clotting time is prolonged, the patient has an inhibitor present.
Interpreting Specific Abnormalities in Coagulation Tests
- Prolonged APTT with normal PT and TT: Deficiency in factors XII, XI, IX, or VIII.
- Prolonged PT, normal APTT and TT: Deficiency in factor VII.
- Prolonged PT and APTT, normal thrombin time: Common pathway deficiency (factors X, V, or II). This is common in patients receiving warfarin or with liver disease.
- Prolonged APTT, PT, and TT: Heparin therapy or a complex deficiency state (multiple protein deficiencies). This can also occur in disseminated intravascular coagulation (DIC), fibrinogen abnormalities, or fibrinogen deficiency.
- Prolonged bleeding, high APTT, and normal INR: Factors VIII, IX, or XI deficiency.
- Asymptomatic patients, prolonged APTT, and normal INR: Factor XII deficiency (based on inheritance).
Haemophilia
- Haemophilia is a genetic bleeding disorder caused by a deficiency in one of the clotting factors, usually factor VIII (haemophilia A) or factor IX (haemophilia B).
- The genes for factors VIII and IX are located on the X chromosome. Males have only one copy of the X chromosome.
- Female carriers are usually asymptomatic.
- Genetic tests can identify abnormalities.
- Many of these deficiencies result from new mutations.
- Clinical symptoms include bleeding into joints (haemarthrosis), muscles (haematoma), or delayed bleeding from cuts and scratches.
- This delay is due to the initial haemostatic response, mediated by platelets and vasoconstriction. However, consolidation of the clotting response requires thrombin generation, involving factors VIII and IX.
- Only small amounts of factors VIII and IX are needed for normal haemostasis. Severe cases require 5% of normal levels.
- Treatment includes managing acute bleeding episodes and preventing further bleeding.
- Replacement therapy involves administering factor VIII either purified from human plasma or through recombinant protein.
- Plasma-derived factor VIII is extracted from a pool of thousands of donors and purified extensively.
- This method faces challenges, including limited supply, the possibility of disease transmission despite donor screening, and the potential for undetected diseases.
Disseminated Intravascular Coagulation (DIC)
- DIC is a consumptive coagulopathy, characterized by normal or sometimes reduced platelet counts and prolonged coagulation times.
- The severity of DIC influences the APTT, INR, and TT.
- Mild DIC may have normal coagulation parameters, but elevated fibrin degradation products (D-dimers) may be present.
- In moderate or severe cases, all levels are elevated, and confirmation of DIC requires elevated D-dimers, alongside potential platelet count or coagulation time abnormalities.
D-Dimer Assays
- When thrombin acts on fibrinogen, fibrinopeptide A is cleaved, generating fibrin monomers, which form dimers.
- Polymerised fibrin is degraded by plasmin, generating fragments, including D-dimers.
- D-dimers are cross-linked D fragments, indicative of fibrin formation in vivo and subsequent degradation by plasmin.
- D-dimer assays utilize monoclonal antibodies that specifically recognize D-dimers but not other fibrinogen or fibrin fragments.
- A positive D-dimer test suggests DIC.
Von Willebrand Disease
- VWF, along with platelets, is crucial for primary haemostasis.
- vWF is a large multimeric protein synthesized by endothelial cells.
- It has multiple binding sites for various proteins, including collagen.
- When bound to collagen, vWF can engage platelet surface receptors, leading to adhesion and activation.
- Key platelet receptors for vWF binding are glycoprotein 1b-V-X (missing in patients with Bernard-Soulier syndrome) and glycoprotein 2b-3a (missing in patients with Glanzmann thrombasthenia).
- In the absence of vWF, factor VIII has a short survival time in the bloodstream.
- A deficiency in vWF leads to a bleeding disorder due to impaired platelet adhesion at injury sites and reduced factor VIII levels.
- Von Willebrand disease is a common genetic disorder affecting approximately 1% of the population.
- It is autosomal dominant and can have variable expression, often skipping generations.
- Most patients have mild to moderate bleeding disorders, leading to nosebleeds, excessive bruising, and post-traumatic or surgical bleeding.
- Severe bleeding after tooth extraction is common in patients with vWD.
- Most patients with vWD require minimal treatment.
- Women with heavy periods can benefit from tranexamic acid (an inhibitor of the fibrinolytic system).
- Patients undergoing planned surgery might be managed with the vasopressin analogue DDAVP.
- DDAVP stimulates the release of stored vWF from endothelial cell granules into circulation, normalizing haemostasis for several hours.
- Patients with severe vWD require vWF administration, typically purified from human plasma.
- Patients often have prolonged APTT due to low factor VIII levels but normal INR and platelet counts.
- vWF levels can be measured via immunoassays or functional assays evaluating collagen binding activity.
Investigating a Von Willebrand Disease Patient
- Prolonged skin bleeding time (not frequently performed due to poor reproducibility and invasiveness).
- Abnormal platelet adhesion.
- Reduced collagen binding.
- Reduced platelet aggregation response to the antibiotic ristocetin and reduced ristocetin cofactor activity.
- Reduced vWF antigen levels.
Liver Disease and Haemostasis
- The liver synthesizes most of the procoagulant proteins required for haemostasis, including fibrinogen, factor X, factor V, factor VII, factor IX, factor VIII, and factor XI.
- The liver synthesizes natural anticoagulant proteins such as antithrombin, protein C, and protein S.
- The liver clears activated clotting factors and protease/inhibitor complexes.
- The liver also synthesizes many proteins involved in activating and inhibiting fibrinolysis.
- Liver disease disrupts the normal synthesis of these factors, making patients more susceptible to bleeding.
- Other contributing factors include:
- Enlarged spleen (caused by portal hypertension) leading to platelet pooling and reduced platelet count in circulation.
- Enlarged veins in the lower oesophagus and stomach (oesophageal varices caused by portal hypertension) that are prone to bleeding.
- Biliary obstruction, which can interfere with vitamin K absorption, leading to low levels of vitamin K-dependent factors.
Assessing Patients with Liver Disease and Haemostasis
- Clinical Evaluation: Assess history for aetiological factors like alcohol consumption and drug usage. Look for signs like jaundice, enlarged liver and spleen, and ascites.
- Laboratory Tests: Complete blood count (CBC), liver function tests (LFTs), INR, APTT, fibrinogen. Abnormal INR and APTT results should correct when mixed with normal plasma.
- Treatment: Potential treatment options include draining a haematoma (e.g. subsural haematoma), reversing the haemostatic abnormality with infused plasma-derived clotting factors, and administering vitamin K in cases of vitamin K deficiency.
Thrombosis - Venous Thrombosis and Pulmonary Embolism
-
Predisposing Factors:
- Major surgery requiring anesthesia for more than 45 minutes.
- Prolonged immobilisation.
- Age greater than 40.
- Cancer, particularly excluding skin cancers. Adenocarcinomas, such as gastric or pancreatic cancers, carry the highest risk.
- Certain medications, including oral contraceptives or hormone replacement therapy.
-
Postoperative Intervention: Patients undergoing major surgery receive injections of unfractionated or low molecular weight heparin postoperatively to reduce the risk of venous thromboembolism (VTE).
Pulmonary Embolism (PE)
-
Clinical Presentation:
- Breathlessness.
- Pleuritic chest pain, sometimes absent or mimicking angina.
- Pain and swelling in the leg can indicate deep vein thrombosis (DVT).
-
Diagnosis:
- Urgent imaging, such as a V/Q scan (radioactive isotopes to visualize circulation and ventilation) or CT pulmonary angiography, confirms the diagnosis when PE is suspected.
- Ultrasound of the legs for DVT supports the diagnosis of PE.
- While a normal D-dimer level is rare in VTE patients, it is non-specific and cannot diagnose the condition definitively.
-
Management:
- Evidence of cardiorespiratory compromise suggests a large embolus significantly obstructing pulmonary circulation.
- Oxygen therapy and full anticoagulation with heparin or low molecular weight heparin are initiated to prevent new thrombi formation.
- Existing emboli are broken down by the fibrinolytic system.
- In patients with massive pulmonary embolism, tissue plasminogen activator (tPA) may be used to restore pulmonary circulation.
Long-Term VTE Management (Warfarin)
- Warfarin is the most common anticoagulant used in the community due to its oral availability.
- Heparin and low molecular weight heparin are only available parenterally.
- New anticoagulants, known as Direct Oral Anticoagulants (DOACs), are increasingly used for patients with atrial fibrillation and venous thromboembolism.
- Warfarin acts as a vitamin K antagonist, inhibiting the recycling (gamma carboxylation) of vitamin K activity.
- Vitamin K is a dietary component found in leafy green vegetables and is produced by gut bacteria.
How is Warfarin Produced?
-
Information about the production of warfarin is not included in the provided text.### Coagulation Reactions
-
Coagulation requires close interaction between clotting factors 2, 7, 9, and 10.
-
These factors bind to negatively charged lipid membranes (platelet surfaces) in the presence of calcium ions.
-
Efficient binding requires a post-translational modification: gamma carboxylation of glutamic acid residues near the N-terminus of the protein.
-
Gamma carboxylation depends on carboxylase and vitamin K, which acts as a co-factor.
-
Warfarin's anticoagulant effect stems from inhibiting the production of active vitamin K-dependent clotting factors.
Warfarin Absorption and Sensitivity
- Warfarin is completely absorbed after ingestion.
- It binds to albumin in the blood, is metabolized and excreted by the liver, and has a half-life of 20-40 hours..
- Sensitivity to warfarin can be increased by antibiotics, poor diet/fasting, drugs competing for protein binding, and liver disease/congestion.
- Sensitivity can be decreased by vitamin K administration, excessive green vegetables in the diet, and drugs that increase hepatic drug metabolism.
- Factor 7, with the shortest half-life among the vitamin K-dependent clotting factors, is used to measure warfarin's effects.
- INR (International Normalized Ratio) is used to monitor warfarin therapy. The therapeutic range for INR is between 2 and 3.5.
- INR values above 5 significantly increase the risk of spontaneous bleeding.
Direct Acting Oral Anticoagulants (DOACs)
- DOACs are long-term anticoagulants that directly inhibit thrombin or factor Xa.
- Direct thrombin inhibitors, like dabigatran (Pradaxa), specifically inhibit thrombin.
- Dabigatran is primarily used for stroke prevention in atrial fibrillation, can also be used for venous thromboembolism, but requires initial anticoagulation with low molecular weight heparin.
- It is mainly excreted renally and requires twice-daily administration.
- Direct factor Xa inhibitors, like rivaroxaban (Xarelto) and apixaban (Eliquis), directly inhibit factor Xa.
- Rivaroxaban is administered once a day, apixaban twice a day.
- Renal excretion accounts for only 30% of drug elimination for this class.
Advantages of DOACs over Warfarin
- Fixed doses, adjusted only for age and renal function, eliminating INR-based dose adjustments.
- No need for INR monitoring due to fixed doses.
- Very few significant drug interactions.
- Similar or better efficacy and bleeding risks compared to warfarin.
- No strict dietary modifications needed (unlike warfarin patients who must avoid vitamin K).
Investigation of Platelet Disorders
- Platelet count is part of a full blood count.
- Thrombocytopenia (low platelet count) is confirmed by examining a blood film.
- Causes of low platelet count are further investigated by history and measurement of other parameters.
Platelet Count Reduction Causes
- Excessive destruction: immune-mediated, disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura.
- Decreased production: leukaemia, aplastic anaemia.
- Platelet pooling: splenomegaly.
- Ineffective production (thrombopoiesis): B12/folate deficiency, myelodysplasia.
Platelet Count Increase Causes
- Thrombocytosis/thrombocythaemia: primary or secondary.
- Secondary/reactive thrombocytosis follows acute or chronic inflammation, infections, splenectomy, malignancy, or bleeding.
- Primary thrombocytosis can be difficult to distinguish from secondary causes. Splenomegaly may indicate a primary event.
- Primary patients might also have defective in vitro platelet function.
Platelet Aggregation
- Platelet aggregation is measured in an aggregometer.
- It tests platelets' ability to respond to various agonists (ADP, adrenaline, thrombin, collagen, arachidonic acid, and ristocetin).
- Abnormal aggregation most commonly results from anti-inflammatory or aspirin use.
- Aspirin is an irreversible inhibitor; as little as 100mg can inhibit aggregation for up to a week (platelet lifespan).
- Patients must discontinue aspirin and all anti-inflammatories before platelet function studies.
Factors Affecting Platelet Aggregation
- Intact platelet membrane structure.
- Fibrinogen.
- Intact prostaglandin pathway.
Prostaglandin Pathway
- Arachidonic acid is released from the platelet membrane.
- Cyclo-oxygenase oxidizes this essential fatty acid to produce prostaglandin endoperoxides.
- Thromboxane synthetase converts these to thromboxane A2, a potent vasoconstrictor and mediator of platelet aggregation.
- Thromboxane A2 is a labile product and quickly breaks down to thromboxane B2.
- Aspirin and other anti-inflammatories inhibit cyclo-oxygenase.
- Aspirin irreversibly acetylates cyclo-oxygenase, affecting platelet function for the remainder of the platelet's life, while other anti-inflammatories have a more reversible effect.
- Aspirin inhibits arachidonic acid-mediated platelet aggregation, preventing a secondary wave of aggregation in response to agonists like adrenalin, ADP, and collagen at low concentrations.
Haemostasis and Thrombosis Cases
Case 1: Mr. AW
- 55-year-old male presenting to the ED with unprovoked pain in the back and groin worsening over 4-6 hours.
- No trauma, hematuria, or gastrointestinal bleeding reported.
- Not on antiplatelets or anticoagulants.
- Massive iliopsoas muscle engorgement indicating hematoma.
- High APTT (48 seconds, normal range: 26-38 seconds).
- Low hemoglobin.
- Factor 8, 9, 11, and 12 deficiencies or blockage are suspected, indicating an intrinsic pathway issue.
- Mixing test: APTT remains high (43 seconds) indicating no correction upon mixing with normal plasma.
- Factor 8 is low (6%, normal range: 50-100%), and a factor 8 inhibitor is detected (7 Bethesda units/mL, 45%).
- The patient experienced genitourinary, intramuscular, and other site bleeding, with intracranial hemorrhage being rare in contrast to congenital hemophilia A.
Case 2
- Reptilase time high (reptilase is similar to thrombin time, but uses snake venom and is unaffected by heparin)
- INR, PT, APTT all high
- Fibrinogen low
- D-dimer high
- High thrombin clotting time
- All corrected upon mixing studies - deficiency
Case 2: Causes of DIC
- Shock.
- Sepsis.
- Hemolysis.
- Malignancy.
- Trauma.
- Pancreatitis.
- Hepatic failure.
- Burns.
- Major surgery.
- Pulmonary embolism (PE).
- Extracorporeal membrane oxygenation (ECMO).
- Transplant rejection.
- Transfusions.
- Obstetric complications: pre-eclampsia, amniotic fluid embolism, intrauterine death, absorption.
- Vascular disorders: Kasabach-Merritt syndrome, large aneurysms.
Case 2: Pathophysiology of DIC
- Mononuclear cells express tissue factor, triggering thrombin generation and fibrinogen conversion to fibrin.
- Increased platelet vessel wall interaction and activation of platelets contribute to microvascular clot formation.
- Activated platelets release P-selectin, upregulating tissue factor expression.
- Fibrin binding to TLR 4 and thrombin to specific protease-activated receptors (PARs) on inflammatory cells modulates inflammation by releasing proinflammatory cytokines.
- Cytokines suppress endogenous fibrinolysis and physiological anticoagulant pathways like the activated protein C (APC) pathway .
Case 3: 25-year-old Woman
- Patient presents with heavy periods, pelvic ultrasound reveals no abnormalities.
- Low hemoglobin, low mean corpuscular volume (MCV), and high APTT - indicating microcytic anemia, specifically iron deficiency anemia.
- Mixing study is normal.
- Iron deficiency is confirmed:
- Factor 8: 31% (normal range: 50-150%, carried by von Willebrand factor).
- Von Willebrand factor antigen: 35% (normal range: 50-150%).
- Von Willebrand factor collagen binding assay: 34% (normal range: 50-150%).
- Blood group: O Rh+ (vWF lasts longer in A or B blood groups due to glycosylation, hence levels are naturally lower in O patients as it is broken down faster).
Case 3: History Taking
- Menstrual history: length, regularity, duration.
- Bleeding disorder history: easy bleeding/bruising after injury, type and sites of bleeding/bruising, drug history.
- Age of onset, family history, easy bruising after medical procedures.
Case 3: Diagnosis & Management
- Diagnosis: von Willebrand Disease (vWD).
- vWD affects 1% of the population and is usually autosomal dominant,
- Presents as a mild to moderate bleeding disorder manifesting as nose bleeds, easy bruising, heavy menstrual bleeding, and post-traumatic/post-surgical bleeding.
- Excessive bleeding after tooth extraction is suggestive of vWD.
- Surgical procedures are managed with vasopressin analogue – DDAVP. DDAVP infusion releases vWF stored in endothelial cell granules, normalizing hemostasis for several hours.
- Severe vWD requires infusions of concentrated vWF purified from human plasma.
Case 4: Mr PB
- Alcoholic liver disease, presenting with fluctuating conscious state.
- Unwell since a head injury 5 days ago.
- Multiple bruises, yellow skin discoloration, and signs of chronic liver disease.
- Subdural hematoma, prompting urgent full blood count and coagulation profile.
Case 4: Lab Results
- Low hemoglobin.
- Low platelets.
- High MCV (macrocytic).
- High INR.
- High APTT - both corrected on mixing test.
- High D-dimers - liver disease patients have "mini-DIC" with a medium platelet activation rate.
Case 4: Smear Analysis
- Smear shows target cells and spur cells.
- Abnormal liver function tests indicate target cells as a result of liver disease.
- Spur red cells have elongated projections.
- Burr cells have blunted borders, typical of uremia; spur cells are associated with liver disease.
- Macrocytic anemia is due to the liver's role in vitamin B12 metabolism and transport.
- Liver disease also affects cholesterol metabolism, contributing to spur cell formation.
Case 4: Diagnosis & Management
- Liver disease is the cause of abnormal coagulation due to the liver's role in producing fibrinogen, prothrombin, and factors 5, 7, 8, 9, 10, and 11.
- Management includes draining the subdural hematoma, infusing plasma clotting factors to reverse hemostasis deficiencies, and administering vitamin K to address vitamin K deficiency.
Case 5: Ms AL
- 63-year-old woman, carcinoma of the sigmoid colon removed.
- Two small nodules of metastatic carcinoma found in the liver.
- Recovered well, but slow to mobilize due to wound infection pain.
- Post-discharge, experiencing increasing shortness of breath, dizziness, and right-sided chest pain worse when breathing in (pleuritic pain).
- Low blood pressure, pulse rate of 110, respiratory rate of 24.
- Auscultation of the lungs reveals a coarse rubbing sound over the right lung.
- Swelling and tenderness of the left leg, with dilated subcutaneous veins.
Case 5: Investigation & Assessment
- ECG shows sinus tachycardia.
- Arterial blood gases indicate low oxygen, low CO2, low O2 saturation, and high D-dimers.
- Oxygen and heparin are administered to manage pulmonary embolism (PE), particularly low molecular weight heparin.
Case 5: DVT Management Factors
- Location of the clot: proximal vs. distal (implications for clot rupture, with proximal clots being more susceptible).
- Presence of a patent foramen ovale (heart shunt from right to left, increasing stroke risk).
- Post-thrombotic syndrome, where the body dissolves a large clot and may also dissolve venous valves, increasing the likelihood of future DVTs.
- Provoked vs. unprovoked DVT: in unprovoked cases, investigate for thrombophilia (inherited or acquired disorders that increase blood clotting and clotting risk).
Case 5: Imaging
- CT pulmonary angiography provides better anatomical visualization of the clot compared to other scans. Areas of no contrast are called eminences.
Case 5: DVT risk factors
- Major surgery.
- Immobility: hospitalization and poor post-operative mobility.
- Age over 40 years.
- Cancer.
- Acute or chronic medical illness: heart failure, myocardial infarction, inflammatory bone disease, active rheumatic disease, nephrotic syndrome, chronic lung disease.
- Malignancy: active malignancy, myeloproliferative neoplasm, cancer treatments.
- Hormones: contraceptive pill, near pregnancy, hormone replacement therapy (HRT).
- Known thrombophilia.
- Obesity, venous stasis, previous DVT, prolonged immobility.
Case 5: Treatment
- Oxygen support.
- Low molecular weight heparin administration.
- For massive pulmonary emboli with cardiovascular compromise, thrombolytic therapy using tissue plasminogen activator (tPA) is used to restore pulmonary circulation.
Full Blood Examination
Learning Outcomes
- Demonstrate knowledge of FBC and bone marrow test indications.
- Demonstrate knowledge of FBC components.
- Understand the mechanisms and causes of high/low hemoglobin, white cell counts, and platelet counts.
Introduction
- Basic hematological tests used for screening, diagnosing, and monitoring hematological diseases like anemias, leukemia, and overall health.
- Blood comprises red blood cells (RBCs), white blood cells (WBCs), platelets, and plasma.
Hematological Tests
- Complete blood count (CBC) / full blood count (FBC).
- Peripheral blood film.
- Bone marrow aspiration/trephine biopsy.
- Flow cytometry.
- Cytogenetics and molecular testing.
Complete Blood Count / FBC
- Results are generated by automatic hematological analyzers.
- Results include:
- RBC count.
- WBC count (including differential count): the machine reports percentages and absolute counts of different WBC types.
- Platelet count.
- Hemoglobin.
- Hematocrit (blood concentration).
- Red cell indices: mean cell volume (MCV), mean cell hemoglobin (MCH), red cell distribution width (RDW), reticulocyte count (developing RBCs).
Specimen Tube
- Lavender-top tube for FBC.
- Contains ethylenediaminetetraacetic acid (EDTA), a potassium salt anticoagulant (1.5 mg/mL).
- Sodium and potassium salts chelate calcium molecules, preventing coagulation.
- Minimal changes to RBC parameters and morphology.
- Excess EDTA can cause WBC/RBC shrinkage, degernative changes, platelet swelling, and disintegration.
- Fill the tube up to the indicated line to avoid issues.
Normal Ranges (Male)
- Normal hemoglobin: 13-18 g/dL.
- HCT: 0.4-0.54.
- MCV (average RBC size): 76-96 fL..
- MCH (average hemoglobin in RBCs): 27-32 pg.
- RDW (variation in RBC size): 12-15%.
- WBC count: 4-11 (abnormal values indicate blood problems).
- Platelets: 150-400.
Normal Ranges (Female)
- Hemoglobin, RBC level, and hematocrit are slightly lower than in men.
- MCV, MCH, RDW, WBC, and platelet ranges are the same as in men.
- Children have separate normal ranges.
Normal Red Blood Cell
- Biconcave disc shape.
- 7-8 micrometer diameter.
- Highly flexible, allowing navigation through small vessels.
- Central pallor, half the diameter of the RBC.
- 120-day lifespan.
- Contains hemoglobin: most common type in adults is hemoglobin A, with 2 beta and 2 alpha chains and a haem group with iron.
- RBCs are one of the body's largest iron stores.
- The RBC membrane is a lipid bilayer.
- Contains various proteins essential for cell shape and fragility.
Mean Corpuscular Volume (MCV)
- Average RBC size.
- Normal range: 76-96 fL.
- Used to classify anemias partially.
- MCV increases with prolonged storage, so samples should reach the lab within 4 hours to avoid bloating.
- Reduced MCV: microcytosis.
- Increased MCV: macrocytosis.
- Normal MCV: normocytosis.
Mean Cell Hemoglobin (MCH)
- Average amount of hemoglobin in an RBC.
- Partly used for anemia classification.
- Calculated from hemoglobin measurement and red cell count.
- Normal values: 27-32 picograms.
- More stable than MCV.
- Low MCH: hypochromia.
- High MCH: hyperchromia.
- Normal MCH: normochromia.
Red Cell Distribution Width (RDW)
- Variation in RBC sizes.
- High RDW indicates significant size variation (anisocytosis), often seen in iron deficiency anemia.
Reticulocytes
- Immature RBCs, a small percentage circulating in blood (0.5-2.5%).
- Bluer and larger than normal RBCs (polychromasia).
- Increased reticulocytes in peripheral blood film mean increased polychromasia, indicating:
- Hemolysis (cell breakage).
- Hemorrhage (bleeding).
- Hematinic patients (taking iron supplements to increase RBC count).
Hematocrit
- Proportion of whole blood composed of erythrocytes.
- Higher levels reflect greater oxygen-carrying capacity but also higher viscosity.
- Hematocrit is more influenced by plasma volume changes (dehydration) than hemoglobin.
- Hb x 3.3 = Hct (a rough guide).
Blood Components
- Blood is composed of plasma and red blood cells (RBCs).
- Anemia results in a low RBC count, leading to increased plasma and a decreased hematocrit (ratio of RBCs to total blood volume).
- Polycythemia (high RBC count) results in decreased plasma and an elevated hematocrit.
Anemia Classification
-
Hypochromic microcytic anemia (MCV <80 fl) is characterized by smaller RBCs with reduced hemoglobin content.
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Causes:
- Megaloblastic: B12/folate deficiency
- Non-megaloblastic: Myelodysplastic syndrome, hemolysis with reticulocytosis (large reticulocytes can skew MCV), physiological (pregnancy, neonates), alcoholism, hypothyroidism.
- Investigations: B12/folate levels, reticulocyte count, peripheral blood film (PBF), liver function tests (LFTs).
-
Causes:
White Blood Cell Count and Differential
- Most modern hematology analyzers perform an automated 5-part differential count (including: neutrophils, lymphocytes, monocytes, eosinophils, and basophils).
- White cells are categorized into granulocytes and lymphocytes.
- IG (immature granulocytes) are also assessed.
- Abnormalities in cell counts can indicate different underlying conditions.
Neutrophils
- 2-5 lobes to the nucleus.
- Pale blue to pink cytoplasm with granules (enzymes for killing pathogens).
Lymphocytes
- Smaller than neutrophils.
- Single round oval nucleus.
- Minimal sky-blue cytoplasm, may have small purple granules.
Monocytes
- Variably shaped nucleus.
- Important phagocytic cells (engulf pathogens).
- Blue-grey cytoplasm with fine granules and vacuoles.
Eosinophils
- Pink cytoplasm with abundant red to orange granules.
- 2-3 lobes to the nucleus, less than neutrophils.
Basophils
- Typically have 2 lobes (difficult to see).
- Deep purple to black granules, uneven distribution and may obscure the nucleus.
White Cell Abnormalities
Monocytosis
- Increased monocytes.
- Causes: Chronic bacterial infections, connective tissue diseases (lupus, rheumatoid arthritis), hematological malignancies (chronic myelomonocytic leukemia).
Eosinophilia
- Increased eosinophils.
- Causes: Allergy, parasitic diseases, skin diseases (psoriasis, urticaria, atopic dermatitis), drug sensitivity, chronic myeloid leukemia, chronic eosinophilic leukemia.
Lymphocytosis
- Increased lymphocytes.
- Causes: Infections (infectious mononucleosis, HIV, rubella), chronic lymphocytic leukemia, non-Hodgkin lymphoma (bone marrow involvement).
Platelet Abnormalities
Thrombocytosis (increased platelets)
- Causes: Iron deficiency, splenectomy, infection/inflammation (connective tissue diseases, inflammatory bowel disease), myeloproliferative neoplasms (essential thrombocythaemia, chronic myeloid leukaemia).
Thrombocytopenia (decreased platelets)
- Causes:
- Failure of platelet production: May-Hegglin anomaly and other congenital disorders, drugs, viral infections.
- Bone marrow failure: Aplastic anemia, cytotoxic drugs, radiotherapy, leukemia, myelodysplastic syndrome, myelofibrosis, megaloblastic anemia, HIV infection.
- Increased platelet consumption: Immune thrombocytopaenia purpura, infections, drug induced (heparin and some vaccines), disseminated intravascular coagulation (DIVC), thrombotic thrombocytopenic purpura.
- Abnormal distribution (splenomegaly): Bone marrow produces the correct number of megakaryocytes but they are sequestered and destroyed by the enlarged spleen.
Peripheral Blood Film (PBF)
- Examination of a stained blood smear under a microscope.
- Used to diagnose various blood disorders, including anemia, hematological malignancies, and thrombocytopenia.
PBF Analysis
Red Cells
- Size changes (microcytosis, macrocytosis).
- Morphology (shape and structure).
- Hemoglobinization (color).
- Shape (spherocytes, target cells, etc.).
- Red cell inclusions (parasites).
- Rouleaux (RBCs in a coin-stack formation) - seen in plasma cell myeloma and severe infections.
- Agglutination (random clumping of RBCs) - associated with cold autoimmune hemolytic anemia.
White Cells
- Amount (leucocytosis, leukopenia).
- Presence of immature cells (blasts/granulocyte precursors) - indicates potential leukemia.
- Dysplasia (morphological abnormalities).
- White cell inclusions.
Platelets
- Clumping can interfere with automated platelet count accuracy.
- Size variations.
Myeloid Disorders
- Affect the myeloid cell line (producing RBCs, platelets, granulocytes, and monocytes).
- Can be due to increased or decreased cell numbers or malignant dysfunction.
Benign Myeloid Disorders
- Neutrophilia: Bacterial infections, inflammation, metabolic disorders, drug reactions.
- Neutropenia: Drug therapy, viral infections, immune disorders.
- Eosinophilia: Allergic reactions, parasitic and fungal infections, autoimmune diseases, drug sensitivity.
- Basophilia: Viral infections, severe allergic responses.
- Monocytosis: Chronic bacterial infections, connective tissue diseases, protozoal infections.
Malignant Myeloid Disorders
- Clonal stem cell disorders (abnormal proliferation of a single type of stem cell).
- Examples:
- Leukemia: Acute myeloid leukemia (AML), chronic myeloid leukemia (CML).
- Myeloproliferative Neoplasms (MPN): CML, polycythemia vera (PV), essential thrombocythaemia (ET), myelofibrosis (MF).
- Myelodysplastic Syndromes (MDS).
Acute Myeloid Leukemia (AML)
- Malignant disease of the bone marrow due to genetic alterations in normal haematopoietic cells.
- Arrested maturation of haematopoietic precursors.
- High blast cell count in the blood.
AML Risk Factors
- Most cases have no identifiable risk factor.
- Potential factors: Pre-existing hematological disorders, congenital disorders (Fanconi anemia, Down syndrome), environmental exposures (benzene, radiation), therapeutics (chemotherapy, radiation therapy).
AML Clinical Signs and Symptoms
- Anemia (fatigue, dyspnea, dizziness).
- Neutropenia (fever, frequent infections).
- Thrombocytopenia (easy bruising, bleeding).
- Abdominal fullness/swelling (enlarged spleen or liver).
- Enlarged lymph nodes.
- Weight loss.
- Bone pain.
AML Treatment
- Tailored to patient age and disease status.
- Treatment options: Chemotherapy, stem cell transplantation, platelet and clotting factor transfusions.
Myeloproliferative Neoplasms (MPN)
- Increased production of one or more haematopoietic cell lines.
- Increased WBCs, RBCs, and platelets in peripheral blood.
MPN Types
- Chronic myeloid leukemia (CML).
- Polycythemia vera (PV).
- Essential thrombocythemia (ET).
- Myelofibrosis (MF).
Common MPN Mutations
- Philadelphia chromosome (Ph).
- Janus Kinase 2 (JAK2) gene.
- Calreticulin (CALR) gene.
- Thrombopoietin receptor (MPL) gene.
Chronic Myeloid Leukemia (CML)
- Myeloproliferative disorder.
- Increased production of granulocytic cell line.
- Cells are abnormal but capable of maturation.
- Increased granulocytes and their immature precursors in the peripheral blood.
- Associated with genetic abnormality t(9, 22) (Philadelphia chromosome).
CML Disease Phases
- Chronic phase: Good control, few symptoms.
- Accelerated phase: Unstable phase, difficult to control.
- Blast phase: Poor control, aggressive disease course, similar to acute leukemia, requires aggressive treatment.
CML Clinical Presentation
- Fatigue, weight loss, decreased exercise tolerance.
- Low-grade fever, excessive sweating.
- Infections due to poorly developed neutrophils.
- Elevated WBC count.
- Splenomegaly (left upper quadrant abdominal pain, early satiation).
- Hepatomegaly.
- Bleeding, petechiae, ecchymoses.
- Bone pain and fever.
- Increasing splenomegaly.
- Increasing anemia, thrombocytopenia, basophilia.
CML Diagnosis
- FBE (including differential WCC and peripheral blood film).
- Bone marrow analysis.
- Diagnosis based on morphology of white cells in peripheral blood (leukocytosis with a left shift), chromosomal translocation t(9:22).
CML Treatment
- Goal: Delay onset of accelerated or blastic phase.
- Options: Antineoplastic agents (tyrosine kinase inhibitors), interferons, chemotherapy (in preparation for bone marrow transplantation), supportive therapy (RBC or platelet transfusions).
Other Myeloproliferative Neoplasms
Polycythaemia Vera
- Increased RBCs, WBCs, and platelets.
- Symptoms: Shortness of breath, abdominal fullness, itching, headache, blurred vision.
Essential Thrombocytosis
- Increased platelets.
- Symptoms: Itching, blood clots, bleeding, night sweats, headaches, dizziness.
Myelofibrosis
- Increased fibrous tissue in bone marrow due to an anomaly in megakaryocytes (platelet precursors).
- Symptoms: Fatigue, anemia, bleeding, itching, night sweats, gout, enlarged spleen.
Myelodysplastic Syndromes (MDS)
- Immature cells in bone marrow fail to develop into mature blood cells.
- Potential causes: Genetic predisposition, haematopoietic stem cell injury (chemotherapy, radiation, genotoxic chemicals).
- Cytopenia (decreased RBCs, WBCs, and platelets).
MDS Presentation
- More common in older adults.
- Early stages: Often asymptomatic.
- Later stages: Fatigue, abnormal bleeding, shortness of breath, anemia, frequent infections.
MDS Clinical Findings
- Cytopenia in the peripheral blood.
- Dysplastic cell features (abnormal morphology):
- Neutrophils: Abnormal nuclear shapes, hypogranulation of cytoplasm.
- Erythrocytes: Nucleated RBCs (immature cells).
Diagnosis and Management of Myeloid Disorders
- History and physical examination.
- Blood tests: FBE, biochemistry, microbiology.
- Bone marrow biopsy: Cytogenetics, molecular genetics, immunophenotyping, histochemistry, imaging tests.
Management Approaches
- Dependent on the specific disorder, severity, and patient factors.
- Options: Monitoring, chemotherapy/radiotherapy/immunotherapy, transfusions, stem cell transplantation, surgery, supportive care.
Susceptibility to Infection
- The immune system is our body's defense against pathogens.
- Two major systems: Innate and adaptive immune system.
- Innate immune system is the first line of defense.
- White blood cells (WBCs) play a crucial role in fighting infections.
- Immune deficiency can lead to increased susceptibility to infections.
Host Defense System
-
Innate Immune System: Immediate, non-specific defense.
- Physical barriers: Skin, mucous membranes.
- Chemical barriers: Lysozymes, antimicrobial peptides.
- Cellular components: Phagocytes (neutrophils, macrophages), natural killer (NK) cells.
- Inflammatory response: Increases blood flow to the infected area, recruits immune cells.
- Complement system: A group of proteins that can kill pathogens directly or enhance other immune responses.
White Blood Cells
- Neutrophils: First responders to infection, engulf and kill bacteria.
- Macrophages: Engulf pathogens, present antigens to T cells, release inflammatory signals.
- Lymphocytes: Specific recognition of pathogens, generate an adaptive immune response. - T Lymphocytes: Destroy infected cells directly or help other immune cells. - B Lymphocytes: Produce antibodies.
Immune Deficiency
- Can lead to increased susceptibility to infections.
-
Causes of immune deficiency:
- Genetic disorders - Acquired conditions (HIV, cancer, medications)
-
Spectrum of infections: Varies depending on the specific immune deficiency.
- Primary immune deficiency: Usually diagnosed in early childhood.
- Secondary immune deficiency: Acquired later in life due to various causes.
Approaches To Patients With Increased Susceptibility to Infections
- Detailed medical history: Including past infections, family history of immune disorders.
- Physical examination: Check for signs of infection, lymphoid tissues, or other abnormalities.
- Laboratory tests: Complete blood count (CBC), blood cultures, immunoglobulin levels, complement tests, specific antibody tests.
- Imaging studies: Chest x-ray, CT scan, MRI, etc.
Key Points
- Myeloid disorders affect the production and function of myeloid cells.
- They can be benign or malignant.
- Understanding the mechanisms of myeloid disorders is essential for diagnosis and treatment.
- The immune system is crucial for fighting infection.
- Immune deficiencies can lead to increased susceptibility to infections.
- Effective management of patients with immune deficiency requires a comprehensive approach.
Immune System
- The Immune System is crucial for protecting the body from foreign invaders.
- It works as a complex network of cells and organs that identify, attack, and eliminate harmful substances.
Innate Immunity
- The innate immune system is the first line of defense against pathogens.
- It's a non-specific response, meaning it acts against a broad range of threats.
- Components:
- Anatomic Barriers: Skin, mucous membranes, cilia in the respiratory tract.
- Physiological Barriers: Gastric acid, tears, saliva, urine.
- Phagocytic Cells: Neutrophils, macrophages, monocytes.
- Inflammatory Response: Heat, redness, swelling, pain.
Adaptive Immunity (Acquired Immunity)
- The adaptive immune system is a more specific and targeted response that develops over time.
- It remembers past encounters with pathogens, leading to faster and stronger responses in subsequent infections.
- Key characteristics:
- Specificity: Recognizes unique antigens on pathogens.
- Diversity: Can recognize billions of different antigens.
- Memory: Retains a "memory" of past pathogens for faster responses later on.
- Self/Non-Self Recognition: Distinguishes between body's own cells and foreign invaders.
Hematopoiesis (Blood Cell Formation)
- Multipotent stem cells give rise to two major lineages:
-
Myeloid Progenitors: Develop into various blood cells, including:
- Megakaryocytes (Platelet Precursors)
- RBC Precursors
- Mast Cells
- Myeloblasts (which differentiate further into neutrophils, eosinophils, basophils, and monocytes).
-
Lymphoid Progenitors: Give rise to:
- NK cells (Natural Killer cells)
- Lymphocytes (T and B cells), important for adaptive immunity (mature B cells become plasma cells that produce antibodies).
-
Myeloid Progenitors: Develop into various blood cells, including:
Effector Cells and Phagocytes
- Effector Cells: Cells that carry out immune functions.
- Phagocytes: Cells that engulf and digest foreign invaders.
Neutrophils
- The most abundant white blood cell in the body.
- Crucial role in innate immunity and phagocytosis.
- Contain granules with enzymes that help break down pathogens.
- Their production is stimulated by colony-stimulating factors (CSFs).
Neutrophil Disorders
- Neutrophilia: Elevated neutrophil counts – can be caused by bacterial infections, inflammation, certain medications, or certain cancers.
- Neutropenia: Low neutrophil levels – can be caused by various factors like medications, infections, autoimmune disorders, and bone marrow problems.
Inherited Neutrophil Defects
- Chediak-Higashi Syndrome: Rare genetic disorder with defective lysosomes, resulting in compromised phagocytosis and recurrent infections.
- Chronic Granulomatous Disease (CGD): Genetic disorder with a defective phagocyte oxidase enzyme, impairing production of reactive oxygen species (ROS) - essential for killing microbes.
Dendritic Cells
- Important antigen-presenting cells.
- Found in the skin, mucous membranes, and other tissues.
- Present antigens to T cells to initiate adaptive immune responses.
Natural Killer Cells
- Part of innate immunity, but can also participate in adaptive responses.
- Kill abnormal cells such as tumor cells and virus-infected cells.
Inflammation
- One of the body's initial responses to infection.
- Characterized by redness, swelling, heat, and pain due to increased blood flow and chemical mediators.
- Mediators include:
- Prostaglandins: Induce fever and blood vessel dilation.
- Leukotrienes: Attract white blood cells to the site of injury.
- Interferons: Antiviral effects.
Adaptive Immune Response
- Two Arms:
- Humoral Immunity: Mediated by antibodies (produced by B cells) circulating in blood and lymph. Antibodies neutralize and eliminate pathogens.
- Cell-Mediated Immunity: Mediated by T cells. Some T cells activate phagocytes to destroy ingested pathogens, while others kill infected cells directly.
Note on Granules
- Basophils and Mast cells: Have large, granules containing histamine and heparin.
- Eosinophils: Contain red-orange granules.
Phagocytosis
- A process by which cells engulf and destroy pathogens.
- Involves adherence, ingestion, formation of a phagosome, fusion with a lysosome to form a phagolysosome, and digestion of the pathogen.
Adaptive Immunity
- Adaptive immunity is characterized by specific recognition of antigens by lymphocytes.
- B lymphocytes produce antibodies that bind to antigens.
- T lymphocytes (cytotoxic and helper) regulate immune responses.
- Antigen-presenting cells (APCs) like macrophages, dendritic cells, and B lymphocytes present antigens to B and T lymphocytes.
B Lymphocytes
- B lymphocytes originate and mature in the bone marrow.
- Naïve B cells differentiate into plasma cells and memory cells upon antigen encounter.
- Plasma cells produce antibodies, while memory cells provide long-lasting immunity.
- Antibodies neutralize toxins and pathogens by binding and preventing them from interacting with their targets.
T Lymphocytes
- T lymphocytes originate in the bone marrow and mature in the thymus.
- They recognize antigens presented by MHC molecules on the surface of other cells.
- MHC I is found on all nucleated cells, while MHC II is only found on APCs.
- T helper cells (CD4+) recognize MHC II, while cytotoxic T cells (CD8+) recognize MHC I.
- CD4+ T cells release cytokines that activate other immune cells, including cytotoxic T cells, B cells, and phagocytes.
- CD8+ T cells directly kill infected or cancerous cells via toxins.
Regulatory T Cells
- Regulatory T cells help to suppress the immune response when it is no longer needed.
- They prevent autoimmunity and maintain immune homeostasis.
Spectrum of Infections Associated with Immune Deficiencies
- B cell deficiencies lead to pyogenic bacterial infections, enteric bacterial and viral infections.
- T cell deficiencies result in viral and other intracellular microbial infections.
- Innate immune deficiencies cause a variety of infectious complications.
- Hyposplenism/asplenia increases susceptibility to encapsulated organisms like Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.
Acquired Immune Deficiencies
- Hematological malignancies disrupt immune function through clonal expansion of abnormal cells.
- Immunosuppressive therapy weakens the immune system.
- Bone marrow infiltration by cancer cells impairs immune cell production.
- Acquired Immunodeficiency Syndrome (AIDS) specifically targets CD4+ T cells, causing severe immunodeficiency.
Primary Immunodeficiency Syndromes
- Congenital immunodeficiencies are caused by genetic defects affecting various components of the immune system.
- Examples include:
- X-linked agammaglobulinemia (XLA): A B cell disorder caused by a failure of B cell maturation, leading to an absence of antibodies.
- Common Variable Immune Deficiency (CVID): The most common primary immunodeficiency characterized by low levels of immunoglobulins and antibodies.
- DiGeorge syndrome: T cell deficiency caused by a deletion on chromosome 22, leading to thymic aplasia or hypoplasia.
- Ataxia telangiectasia: A combined B and T cell disorder with a characteristic clinical presentation of ataxia and telangiectasia.
- Wiskott Aldrich syndrome: A combined B and T cell deficiency characterized by eczema, thrombocytopenia, and immunodeficiency.
- Severe Combined Immunodeficiency (SCID): A potentially fatal disorder caused by genetic defects affecting T cell development and function.
Clinical Approach to Patients with Increased Infection Susceptibility
- Careful clinical history is crucial in diagnosing immune deficiencies.
- Investigations include complete blood count (CBC), liver function tests (LFTs), renal profile, serology (HIV), blood culture and sensitivity, and targeted investigations.
- Targeted investigations may include flow cytometry, lymphocyte proliferation assays, immunoglobulin level measurement, neutrophil function assays, cytokine stimulation assays, and DNA testing.
Treatment of Immune Deficiencies
- Treatment focuses on addressing the underlying cause and preventing further infections.
- This may include antibiotic treatments, prophylactic antibiotics, vaccinations, and immunomodulatory therapies.
- Bone marrow or hematopoietic stem cell transplantation may be considered in suitable cases.
- Gene therapy offers a potential future treatment option for certain genetic defects.
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This quiz explores the vital role of endothelial cells in the haemostatic mechanism under normal conditions and the subsequent responses to blood vessel injury. You'll also examine the activation process of coagulation factors and differentiate between acquired and inherited coagulation defects. Test your knowledge on the primary functions of activated coagulation factors in haemostasis.