Polycythemia & Granulocytopoiesis: Hematology | Medical Science Optional Notes for UPSC PDF Download

Polycythemia

Types of Polycythemia

1. Absolute Polycythemia:

   • Primary (Polycythemia Vera):
     • A rare, chronic myeloproliferative disorder characterized by the overproduction of red blood cells in the bone marrow.
     • It is often associated with an increase in white blood cells and platelets.
     • Polycythemia vera is considered a clonal disorder of the bone marrow.
   • Secondary (Secondary Polycythemia):
     • Occurs as a response to factors outside the bone marrow that stimulate increased red blood cell production.
     • Common causes include chronic hypoxia (as seen in chronic lung diseases), high-altitude living, and certain tumors that produce erythropoietin.

2. Relative Polycythemia:

   • Also known as hemoconcentration or stress polycythemia.
   • Results from a decrease in the volume of plasma rather than an absolute increase in red blood cell production.
   • Common causes include dehydration, severe burns, and conditions that lead to increased loss of fluids, causing a relative increase in the concentration of red blood cells.

Clinical Features

• Increased hematocrit, hemoglobin, and red blood cell count.
• Symptoms may include fatigue, weakness, headache, and, in severe cases, complications related to increased blood viscosity, such as thrombosis.

Diagnosis:

• Complete blood count (CBC) is used to measure hematocrit, hemoglobin, and red blood cell count.
• Additional tests may be conducted to determine the cause of polycythemia, such as genetic testing for polycythemia vera or investigations into underlying conditions causing secondary polycythemia.

Treatment:

• Treatment depends on the underlying cause.
• For polycythemia vera, therapeutic phlebotomy (removal of blood) is often used to reduce red blood cell levels.
• Secondary polycythemia may require addressing the primary condition, such as improving oxygenation in chronic lung diseases.

Complications:

• If left untreated, polycythemia can lead to complications such as blood clots, strokes, and heart attacks due to increased blood viscosity.

Polycythemia is a complex condition with various causes, and accurate diagnosis and management depend on identifying the underlying type and etiology of the disorder.

Granulocytopoiesis: Stages of Granulocyte Development

• Not distinguishable histologically.
• Serves as the precursor cell with the potential to differentiate into specific cell types.

Myeloblast:

• Large cell with blue-staining cytoplasm.
• Large nucleus.
• Clear area near the nucleus, indicative of the Golgi apparatus.

Promyelocyte:

• Rather large cell with azurophilic (not specifically stained) granules.
• Azurophilic granules contain enzymes involved in cellular defense.

Myelocyte:

• Overall cell is still rather large.
• Round nucleus without indentation.
• Granules stain appropriately for the series:
  • Pink for eosinophilic granules.
  • Blue for basophilic granules.
  • Neutral for neutrophilic granules.

Metamyelocyte:

• Cell size is about that of a mature granulocyte.
• Nucleus exhibits slight indentation.
• Granules present, staining appropriately for the granulocytic series.

Band Cell:

• Cell is about the size of a mature granulocyte.
• Nucleus with definite indentation, resembling a horseshoe.
• Prominent granules that stain appropriately for the granulocytic series.

Mature (Segmented) Granulocyte:

• Cell is mature and resembles normal, mature granulocytes in the blood.
• Characterized by a lobed nucleus.
• Prominent granules that stain appropriately for the granulocytic series.

Notes:

• The progression from myeloblast to mature granulocyte represents the stages of granulocytopoiesis, the development of granulocytes.
• The different staining patterns of granules correspond to the specific characteristics of eosinophils, basophils, and neutrophils.
• The segmented nucleus is a distinctive feature of mature granulocytes.

Since mature lymphocytes and monocytes look essentially like their precursor cells and pluripotent stem cells, intermediate forms cannot be identified histologically.

Megakaryocytopoiesis 

• IL-1 
• IL-3
• IL-6
• IL-11
• Erythropoietin

Also,

• Granulocyte-macrophage colony stimulating factor (GM-CSF) 
• Fibroblast growth factor (FGF)
• Stem cell factor (SCF)
• Leukemia inhibitory factor (LIF)
• Thrombopoietin
• Stromal cell-derived factor 1 (SDF-1)

Morphological Characteristics of Platelets

1. Origin and Formation:

   • Platelets are anucleated cells that arise from the cytoplasmic fragmentation of megakaryocytes in the bone marrow.
   • Megakaryocytes are large, multinucleated cells that release fragments (platelets) into the bloodstream.

2. Size:

   • Platelets have a typical diameter of approximately 2-3 micrometers.

3. Shape:

   • Circulate in a discoid (disc-shaped) form under normal conditions.

4. Lifespan:

   • The average lifespan of platelets in humans is approximately 10 days.

5. Activation-Induced Changes:

   • Following activation, platelets undergo dramatic changes in shape and ultrastructure.
   • Membranes become ruffled with cytoplasmic projections.

6. Granule Centralization and Discharge:

   • Granules within platelets are centralized and discharged upon activation.
   • Granules contain various substances, including enzymes, clotting factors, and signaling molecules.

7. Ultrastructural Changes:

   • Activation leads to alterations in platelet ultrastructure.
   • Membrane ruffling, cytoplasmic changes, and granule centralization are part of the dynamic response to activation.

Functional Role:

• Platelets play a crucial role in hemostasis, the prevention and cessation of bleeding.
• Upon vascular injury, platelets adhere to the exposed collagen, become activated, change shape, and release substances that contribute to clot formation.

Platelet Activation:

• Triggered by various stimuli, such as injury or exposure to specific molecules.
• Activated platelets are essential for forming a hemostatic plug at the site of vascular injury.

Dynamic Response to Injury:

• The ability of platelets to change their shape and release granule contents allows them to dynamically respond to vascular injury and participate in the formation of blood clots.

Understanding the morphological characteristics and functional dynamics of platelets is essential for appreciating their role in maintaining vascular integrity and preventing excessive bleeding in the body.

Platelet Granules

1. Alpha Granules:

• Size: Largest (~200-400 nm).
• Number: About 50-60 alpha granules per platelet.
• Content:
  • Contain a variety of platelet factors.
  • Major storage site for platelet proteins.
  • Rich in adhesive glycoproteins.
  • Contains small GTP-binding proteins.
  • Relevant adhesion polypeptides include thrombospondin, P-selectin, platelet factor 4, beta-thromboglobulins, GPIb, GPIIb/IIIa, and P-selectin.
• Functional Role:
  • Involved in hemostasis and thrombosis.
  • Release of contents contributes to clot formation and wound healing.

2. Dense Granules:

• Size: Intermediate (~200-250 nm).
• Number: About 3-8 dense granules per platelet.
• Content:
  • High concentrations of adenine nucleotides (ATP and ADP).
  • High calcium and phosphate content.
  • Contains small GTP-binding proteins.
  • Contains relevant adhesion polypeptides.
  • Contains factors involved in coagulation (Factors V, XI, XIII, fibrinogen, von Willebrand factor, and high molecular weight kininogens).
• Functional Role:
  • Involved in platelet aggregation, clot retraction, and coagulation.

3. Lysosomes:

• Size: Smallest (~150 nm).
• Number: Number not specified.
• Content:
  • Intraluminal acidic pH.
  • Hydrolytic enzymes active towards various substrates.
• Functional Role:
  • Less well understood compared to alpha and dense granules.
  • Likely involved in intracellular degradation processes.

Overall:

• These granules collectively contribute to the dynamic and complex functions of platelets in hemostasis and thrombosis.
• The release of contents from alpha and dense granules plays a crucial role in clot formation, wound healing, and the inflammatory response.

Understanding the diversity and contents of platelet granules is essential for comprehending the intricate mechanisms involved in platelet function and their significant roles in maintaining vascular integrity and responding to vascular injury.

Platelet Disorders

1. Von Willebrand Disease:

   • Characteristics:
     • Most common inherited bleeding disorder.
     • Autosomal dominant inheritance.
   • Defect:
     • Defective adhesion of platelets to subendothelial components.
     • Low levels of factor VIII.
   • Platelet Function:
     • Platelets aggregate to all agents except ristocetin.

2. Bernard-Soulier Syndrome:

   • Characteristics:
     • Autosomal recessive inheritance.
   • Defect:
     • Deficiency of platelet glycoprotein Ib-IX-V.
   • Platelet Function:
     • Defect with platelet adhesion.
     • Platelets aggregate to all agents except ristocetin.

3. Glanzmann Thrombasthenia:

   • Characteristics:
     • Autosomal recessive inheritance.
   • Defect:
     • Deficiency of platelet glycoprotein IIb-IIIa.
   • Platelet Function:
     • Defect with platelet aggregation.
     • Platelets do not aggregate to any agents except ristocetin.

Summary:

• Von Willebrand Disease: Defective platelet adhesion, low factor VIII, and normal aggregation to most agents except ristocetin.
• Bernard-Soulier Syndrome: Deficient platelet glycoprotein Ib-IX-V, leading to impaired adhesion, with normal aggregation to most agents except ristocetin.
• Glanzmann Thrombasthenia: Deficient platelet glycoprotein IIb-IIIa, causing defective aggregation, and no aggregation to any agents except ristocetin.

Note:

• Ristocetin is a substance used in laboratory testing to induce platelet aggregation, and abnormalities in aggregation responses help diagnose these platelet disorders.
• These disorders highlight the importance of specific platelet glycoproteins in adhesion and aggregation processes, contributing to the overall understanding of platelet function and hemostasis.

Platelet aggregation tests use a panel of platelet agonists (adenosine diphosphate [ADP], epinephrine, collagen, and ristocetin) to measure platelet activation and aggregation in vitro. Ristocetin (similar to vWF) binds to platelet membrane by means of Gp Ib-IXa receptor.
Hence, in Bernard-Soulier syndrome, no response (or no aggregation) is seen with ristocetin.
It is also abnormal in von Willebrand disease. However, it normalizes after the addition of normal plasma (wnich contains vWF) since there is no defect in binding receptors.

Metabolism of IRON