AG

Blood Chapter 18 Part 3 – Key Terms (WBCs, Platelets, Hemostasis)

White Blood Cells (WBCs): Origin, Regulation, and Roles

  • All blood cells originate from hemocytoblasts (hematopoietic stem cells) that differentiate into two major lineages:

    • Myeloid stem cells → produce all WBCs except lymphocytes; mature in the red bone marrow.
    • Lymphoid stem cells → produce lymphocytes (lymphopoiesis).

  • Lymphocytes are produced in the red bone marrow, but T cells mature in lymphoid tissue (thymus).

  • Overall WBC production is regulated by colony-stimulating factors (CSFs): hormones that stimulate production of specific blood cells:

    • M-CSF → stimulates monocyte production.
    • G-CSF → stimulates production of granulocytes (neutrophils, eosinophils, basophils); example: Neupogen is a G-CSF.
    • GM-CSF → stimulates granulocyte and monocyte production.
    • Multi-CSF → accelerates production of granulocytes, monocytes, platelets, and RBCs (via myeloid stem cells) – i.e., everything except lymphocytes.

  • Typical white blood cell counts (from Table 19-3):

    • Total WBCs: 7{,}000 per μL (range 5{,}000-10{,}000).
    • Granulocytes
    • Neutrophils: 4{,}150 per μL (range 1{,}800-7{,}300); differential 50-70 ext{ } ext{%}
    • Eosinophils: 165 per μL (range 0-700); differential 2-4 ext{%}
    • Basophils: 44 per μL (range 0-150); differential <1 ext{%}
    • Agranulocytes
    • Monocytes: 456 per μL (range 200-950); differential 2-8 ext{%}
    • Lymphocytes: 2{,}185 per μL (range 1{,}500-4{,}000); differential 20-30 ext{%}

  • WBC morphological and functional notes (from Table 19-3):

    • Neutrophils: round cell with a lobed nucleus; cytoplasm with pale inclusions. Function: phagocytic; engulf pathogens/debris in tissues; release cytotoxic enzymes and chemicals. Move into tissues after several hours; survive minutes to days depending on tissue activity; produced in red bone marrow.
    • Eosinophils: round cell; nucleus typically two lobes; large red-staining granules. Function: phagocytic of antibody-labeled materials; release cytotoxic enzymes; reduce inflammation; increase in allergic and parasitic situations. Move into tissues after several hours; survive minutes to days; produced in red bone marrow.
    • Basophils: round cell; dense blue-stained granules; nucleus not easily seen. Function: enter damaged tissues and release histamine and other chemicals that promote inflammation. Survival time unknown; assist mast cells in producing inflammation; produced in red bone marrow.
    • Monocytes: very large cell; kidney-shaped nucleus; abundant pale cytoplasm. Function: enter tissues to become macrophages; engulf pathogens or debris. Move into tissues after 1–2 days; survive for months or longer; produced primarily in red bone marrow.
    • Lymphocytes: generally small with round nucleus and very little cytoplasm. Function: cells of the lymphatic system, providing defense against specific pathogens or toxins. Survive for months to decades; circulate between blood and tissues; produced in red bone marrow and lymphatic tissues.

  • Platelets (thrombocytes): brief overview

    • Platelets are cell fragments produced from large cells called megakaryocytes.
    • They have vesicles containing clotting factors and lack a nucleus.
    • Circulate for about 9-12 days; removed by phagocytes in the spleen.
    • Approximately two-thirds stay in circulation, one-third are reserved for emergencies in the spleen.

  • Platelet production (thrombopoiesis)

    • Occurs in bone marrow.
    • Pathway: Hemocytoblasts → Myeloid Stem Cells → Megakaryocytes; megakaryocytes shed cytoplasmic packets that become platelets.
    • Hormonal regulation:
    • Thrombopoietin (TPO) increases platelet formation and megakaryocyte production.
    • Multi-CSF promotes formation and growth of megakaryocytes.

  • Platelet counts and function (from Table 19-3):

    • Platelets: 350{,}000 per μL (range 150{,}000-500{,}000).
    • Function: Hemostasis – clump together and stick to vessel walls (platelet phase); activate intrinsic pathway of coagulation phase.
    • Platelets remain in the bloodstream or in vascular organs; intact for 7-12 days.
    • Platelets are produced by megakaryocytes in red bone marrow.

Hemostasis: Stoppage of Bleeding

  • Hemostasis is the process that stops bleeding and involves three overlapping phases:

    • Vascular (vasoconstriction/spasm) phase
    • Platelet phase (platelet plug formation)
    • Coagulation (blood clotting) phase

  • Why hemostasis matters: prevents excessive blood loss from injuries while allowing vessel repair; involves biochemical signaling, cellular adhesion, and a cascade of clotting factors.

The Vascular Phase of Hemostasis

  • When a vessel is cut, a vascular spasm occurs to reduce blood flow.

  • Endothelial cells contract and expose the basement membrane to the bloodstream.

  • Endothelial cells release chemical factors:

    • ADP (adenosine diphosphate)
    • Tissue factor (TF, Factor III)
    • Prostacyclin

  • They also release local hormones called endothelins, which stimulate smooth muscle contraction and cell division.

  • Endothelial plasma membranes become sticky, promoting adhesion of platelets to the damaged area and to each other, helping seal the broken end.

  • Conceptual model (from text): vascular injury leads to a contracting response and a transition to platelet adhesion and subsequent steps.

The Platelet Phase of Hemostasis

  • Platelet adhesion means platelets attach to sticky endothelium, basement membranes, and exposed collagen fibers.

  • Platelet aggregation means platelets stick together, forming a platelet plug that closes small vessel breaks.

  • When activated, platelets release a suite of chemicals that promote further aggregation, vascular spasm, clotting, and vessel repair (positive feedback).

  • Key released substances include: ADP, PDGF, Ca^{2+}, and platelet factors (
    PF-3
    ); these amplify the response.

  • Visual summary (textual):

    • Endothelium and basement membrane become sites for platelet adhesion.
    • Platelets become activated and recruit additional platelets via chemical signals.
    • A platelet plug forms to temporarily seal the break while coagulation proceeds.

The Coagulation Phase (Blood Clotting)

  • Coagulation converts blood from a liquid to a gel through a cascade of chemical reactions involving calcium, enzymes, and proenzymes.

  • Outcomes of the coagulation cascade:

    • Activation of thrombin (the central enzyme)
    • Conversion of fibrinogen to insoluble fibrin, forming a fibrin mesh that stabilizes the platelet plug and traps RBCs and platelets.

  • Three coagulation pathways feed into a common pathway:

    • Extrinsic pathway
    • Intrinsic pathway
    • Common pathway

  • Goals of the pathways: convert circulating fibrinogen into insoluble fibrin;

    • The fibrin mesh stabilizes the clot, preventing further bleeding.

  • Extrinsic pathway (starts outside the bloodstream)

    • Damaged cells in the vessel wall release Tissue Factor (TF, Factor III), which leaks into the blood.
    • TF (III) + Ca^{2+} + Factor VII forms an enzyme complex that activates Factor X.
    • Diagrammatic note: Extrinsic Pathway → TF III + Ca^{2+} + VII → Activation of Factor X.

  • Intrinsic pathway (occurs within the blood)

    • Triggered by exposure to collagen fibers; slower activation.
    • Exposed collagen activates Factor XII (XIIa) with help from Platelet Factor 3 (PF-3).
    • The cascade then activates Factors VIII and IX, which in turn activate Factor X.
    • Diagrammatic note: Intrinsic Pathway → XII → (VIII, IX) → X.

  • Common pathway (where intrinsic and extrinsic converge)

    • Activated Factor X forms the enzyme complex prothrombinase.
    • Prothrombinase converts Prothrombin to Thrombin.
    • Thrombin converts Fibrinogen to Fibrin.
    • Fibrin forms a mesh that traps RBCs and platelets, completing the clot.
    • Diagrammatic note: X → Prothrombinase → Prothrombin → Thrombin; Thrombin converts Fibrinogen to Fibrin.

  • Key components in the coagulation cascade (as described in text): TF (Factor III), Factor X, Factor VII, Factor VIII, Factor IX, PF-3, Ca^{2+}, Prothrombin, Thrombin, Fibrinogen, Fibrin.

  • Ca^{2+} and various clotting factors are essential cofactors/elements in these reactions.

  • Haemophilia (disorder affecting coagulation)

    • Haemophilia involves deficiencies in Factor VIII or Factor IX.
    • It is an X-linked recessive trait and more common in men.
    • Treatment involves synthetic clotting factors.

Regulation and Implications of Clotting

  • Positive feedback in coagulation

    • Thrombin stimulates clotting by feedback loops that increase tissue factor (TF) activity and platelet factor 3 (PF-3).
    • This creates a self-amplifying loop: Thrombin → TFIII (extrinsic) and PF3 (intrinsic) → more thrombin.

  • Restriction of clotting (anticoagulant mechanisms)

    • Plasma contains anticoagulants that limit clot formation.
    • Antithrombin-III inhibits several clotting factors, including thrombin.
    • Heparin (released by basophils and mast cells) enhances Antithrombin-III activity.
    • Endothelial cells release thrombomodulin, which activates Protein C.
    • Protein C (inactivates some clotting factors) and stimulates plasmin formation, contributing to clot dissolution.
    • Prostacyclin (released by endothelium) inhibits platelet aggregation.

  • Fibrinolysis (clot dissolution)

    • A slower process that dissolves clots when healing has progressed.
    • Thrombin and tissue plasminogen activator (t-PA) activate plasminogen → plasmin.
    • Plasmin digests fibrin strands, dissolving the clot.
    • Key reactions: ext{Plasminogen}
      ightarrow ext{Plasmin}; ext{Plasmin}
      ightarrow ext{Fibrin degradation}.

  • Calcium ions (Ca^{2+}) and Vitamin K in clotting

    • Both Ca^{2+} and Vitamin K are essential for the clotting process.
    • Deficiency leads to impaired clotting.
    • Vitamin K is needed to produce four clotting factors and is produced in the large intestine; it is also obtained from the diet.
    • Warfarin is an anticoagulant that works by antagonizing Vitamin K, thereby impairing synthesis of vitamin K-dependent clotting factors.

  • Vitamin K-dependent factors and clinical relevance

    • The activity of several clotting factors depends on Vitamin K; disruptions can lead to bleeding disorders.
    • Warfarin therapy requires monitoring and is used to reduce thrombotic risk by limiting the body’s ability to form clots.

  • Other clinical notes

    • Basophils and mast cells release heparin, which participates in anticoagulation.
    • The balance between clot formation and dissolution is critical to prevent both hemorrhage and thrombosis.

Quick Reference: Key Terms and Pathways

  • Hemocytoblasts: stem cells that give rise to blood cells.
  • Myeloid stem cells: give rise to most WBCs, platelets, RBCs; mature in red bone marrow.
  • Lymphoid stem cells: give rise to lymphocytes; lymphocytes produced in bone marrow; T cells mature in thymus.
  • Colony-stimulating factors (CSFs): regulate production of blood cells (M-CSF, G-CSF, GM-CSF, Multi-CSF).
  • Neutrophil, Eosinophil, Basophil: granulocytes with specific functions in immune defense and inflammation.
  • Monocytes, Lymphocytes: agranulocytes with macrophage differentiation and targeted immune responses.
  • Platelets: cytoplasmic fragments from megakaryocytes; essential for hemostasis.
  • Hemostasis: the stoppage of bleeding via vascular, platelet, and coagulation phases.
  • TF (Factor III): tissue factor, initiates extrinsic pathway.
  • PF-3 (Platelet Factor 3): phospholipid surface on platelets aiding coagulation (intrinsic pathway).
  • Ca^{2+}: calcium ion cofactor required in multiple clotting steps.
  • Prothrombinase: enzyme that converts Prothrombin to Thrombin.
  • Thrombin: central enzyme that converts Fibrinogen to Fibrin and amplifies clotting.
  • Fibrin: insoluble protein forming the mesh that stabilizes the clot.
  • Haemophilia: deficiency of Factor VIII or IX; X-linked.
  • Warfarin: anticoagulant that antagonizes Vitamin K, reducing clotting factor activity.

Summary of Pathways (concise equation-style view)

  • Extrinsic pathway initiation:
    • TF (Factor III) + Ca^{2+} + Factor VII → activation of Factor X
  • Intrinsic pathway propagation:
    • Collagen exposure → Factor XII → PF-3 → activation of Factors VIII and IX → activation of Factor X
  • Common pathway convergence:
    • Factor X (with Factor V) forms Prothrombinase → Prothrombin → Thrombin → Fibrinogen → Fibrin
  • Fibrin clot stabilization:
    • Thrombin converts Fibrinogen to Fibrin → Fibrin mesh traps cells and platelets
  • Clot dissolution (fibrinolysis):
    • Thrombin + t-PA → Plasminogen → Plasmin → Fibrin degradation