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Hematology

Destruction

While hematopoiesis focuses on the generation of blood cells, the physiological mechanisms of cell destruction are equally critical for maintaining homeostasis. The body must balance the production of new cells with the removal of senescent (aged) or damaged cells. If destruction exceeds production, cytopenias (anemia, leukopenia, thrombocytopenia) occur; if destruction is insufficient, potentially harmful or malignant cells may accumulate

The primary system responsible for this “waste management” is the Mononuclear Phagocyte System (MPS) - formerly known as the Reticuloendothelial System (RES). This network of macrophages, stationed primarily in the spleen, liver, and bone marrow, acts as a filter to monitor the blood, remove cellular debris, and recycle essential components like iron and amino acids

Lineage-Specific Destruction Mechanisms

Erythrocyte Destruction (Hemolysis)

Red blood cells have a finite lifespan of approximately 120 days. As they age, their metabolic machinery (glycolysis) slows, and their membranes become rigid. They are removed via two distinct pathways:

  • Extravascular Hemolysis (Normal Pathway)
    • This accounts for roughly 90% of RBC destruction
    • Mechanism: Senescent RBCs lose flexibility and cannot navigate the narrow cords of the splenic red pulp (culling). Macrophages identify “eat me” signals (such as antibody coating or membrane changes) and phagocytize the cell
    • Recycling: The macrophage breaks down hemoglobin. Globin is recycled into amino acids. Iron is salvaged and stored as ferritin or transported by transferrin. Heme is converted to bilirubin, carried to the liver by albumin, conjugated, and excreted
    • Clinical Sign: Elevated unconjugated bilirubin without hemoglobinuria
  • Intravascular Hemolysis (Pathological/Minor Pathway)
    • This accounts for <10% of destruction but is clinically significant in acute reactions
    • Mechanism: RBCs rupture directly within the blood vessels due to trauma, complement activation, or toxins
    • Salvage: Free hemoglobin is toxic to the kidneys. The plasma protein Haptoglobin binds free hemoglobin to carry it to the liver for processing
    • Clinical Sign: When haptoglobin is depleted, free hemoglobin appears in the urine (hemoglobinuria) and eventually leads to iron deposition in renal cells (hemosiderinuria)

Leukocyte Destruction (Apoptosis & Clearance)

White blood cells differ from RBCs in that they contain potent enzymes and inflammatory mediators. Therefore, their destruction must be carefully controlled to prevent damage to surrounding tissues

  • Apoptosis (Programmed Cell Death)
    • This is the primary method of removal. It is a “clean” death where the cell shrinks, chromatin condenses, and the membrane blebs without rupturing
    • Signals: Triggered by intrinsic pathways (mitochondrial stress/loss of survival signals) or extrinsic pathways (Death Receptor activation)
    • Clearance: Apoptotic cells flip phosphatidylserine to their outer membrane surface. Macrophages recognize this signal and engulf the cell before it releases its toxic contents
  • Necrosis (Uncontrolled Death)
    • This occurs during severe infection or trauma. The cell swells and bursts, releasing intracellular contents. This triggers an inflammatory response, recruiting more WBCs to the area

Platelet Destruction (Senescence & Feedback)

Platelets circulate for approximately 8–10 days. Their removal is unique because it is directly linked to the regulation of new production

  • Desialylation (The Molecular Clock)
    • As platelets circulate, they gradually lose sialic acid from their surface glycoproteins. This exposes galactose residues
    • Ashwell-Morell Pathway: The liver contains receptors that bind these exposed galactose residues, leading to the internalization and destruction of the old platelet
    • The TPO Link: Crucially, when the liver destroys these platelets, it is stimulated to produce Thrombopoietin (TPO). This signals the bone marrow to produce more platelets, creating a perfect feedback loop
  • Splenic Sequestration
    • At any given time, approximately one-third of the total platelet mass is sequestered in the spleen. The spleen acts as a reserve pool and a site for filtration of antibody-coated platelets

Clinical Laboratory Implications

The laboratory plays a vital role in distinguishing between Production Failure (Bone Marrow issue) and Increased Destruction (Peripheral issue)

  • Hemolysis Indicators
    • Increased: Reticulocyte count (marrow compensation), Lactate Dehydrogenase (LDH - released from ruptured cells), Indirect Bilirubin
    • Decreased: Haptoglobin (consumed by scavenging free hemoglobin)
    • Morphology: Presence of Spherocytes (extravascular damage) or Schistocytes (intravascular/mechanical damage)
  • Platelet Destruction Indicators
    • MPV (Mean Platelet Volume): Increases during destruction because the marrow releases young, large platelets (“stress platelets”) to compensate
    • IPF (Immature Platelet Fraction): An elevated percentage of reticulated (RNA-containing) platelets indicates the marrow is functioning and trying to keep up with peripheral destruction (e.g., in Immune Thrombocytopenia - ITP)
  • Leukocyte Anomalies
    • Necrosis markers: The presence of “smudge cells” (fragile lymphocytes) or vacuolated neutrophils may indicate issues with cell integrity or severe stress, though smudge cells are often an artifact of slide preparation in CLL, they represent cellular fragility
    • Pyknosis: Dark, condensed, shrinking nuclei in neutrophils seen on a smear indicate a cell undergoing apoptosis (dying)