HEMATOPOIETIC GROWTH FACTORS AND COAGULATION FACTORS

• Hematopoiesis


  The production of blood cells
• Hematopoiesis


  • It is a tightly regulated system, exquisitely responsive to functional demands including infection, allergic reaction, immune challenge, hemorrhage, inflammation, and hypoxia
• Hematology


  The study of blood cells (e.g., erythrocytes, leukocytes, and platelets) and proteins in the circulatory system
• Common blood disorders such as anemia, leukocytosis, and bleeding are indirect consequences of infection, inflammation, malnutrition, and malignancy
• Hematologic malignancies could produce more severe bleeding, but their prevalence is less common than blood disorders
• Advances in recombinant DNA technology have permitted cloning and production of growth factors and blood coagulation factors for the management of hematologic disorders
• Hematopoietic stem cells


  Common precursor from which all hematopoietic cells are believed to derive
• Stem cells constitute only about 0.05% of bone marrow, but this population is maintained through a self-renewal system
• Lineage commitment by bone marrow

  Pluripotent stem cells undergo irreversible differentiation into daughter cells that are committed to lineages of unique hematopoietic cell types
• Hematopoietic growth factors

  Drive the late stage of the differentiation and maturation process of hematopoietic cell types
• Many hematopoietic growth factors are now cloned and recombinant proteins are available for biologic and therapeutic studies
• Some hematopoietic growth factors exhibit overlapping specificities for cells of different lineages, particularly in the early stages of differentiation
• Erythropoietin (EPO), thrombopoietin (TPO), granulocyte colony-stimulating factor (CSF), and macrophage colony-stimulating factor (MCSF)

  Lineage-specific growth factors that tend to act on maturation and deployment of a given type of blood cell
• Colony-stimulating factor


  Named for their ability to stimulate target cells to divide and grow into colonies of cells in culture
• Interleukins


  Proteins produced by leukocytes that act on neighboring leukocytes
• While most interleukins support leukocyte growth or lymphocytopoiesis, many also exhibit broad or pleotropic effects on cells of many lineages
• Neutropenia

  Decreased blood neutrophil numbers below 1800 cells/mm3
• Recurrent infections which typically are inconsequential in healthy subjects, could produce significant consequences in neutropenia, and can be devastating for immunocompromised patients
• There are many acquired causes of neutropenia, with infections, drugs, and immune disorders being the most common
• Granulocyte colony-stimulating factor (GCSF, filgrastim)


  Can correct neutropenia and reduce infectious morbidity in infected patients with a variety of causes of severe neutropenia
• Granulocyte macrophage colony-stimulating factor (GM-CSF, sargramostim)

  Has also been used successfully in neutropenic patients
• Hemostasis

  The process of blood clot formation at the site of vessel injury
• Hemostasis


  Begins with the formation of the platelet plug, followed by activation of the clotting cascade, and propagation of the clot
• Factor IXa, factor VIIIa, calcium, phospholipids, factor X

  Major multicomponent complexes in the coagulation cascade
• Factor VIII

  Synthesized as a single chain polypeptide of 2351 amino acids, circulates in plasma in a noncovalent complex with von Willebrand factor, and its cleavage by thrombin or factor Xa is necessary to activate it
• Hemophilia A

  Factor VIII deficiency
• Hemophilia B


  Factor IX deficiency
• Plasma-derived concentrate therapy in the 1970s and 1980s was associated with serious viral complications, including hepatitis C virus (HCV) and HIV infection
• The current use of donor-screening, virucidal techniques, and the advent of recombinant products have led to a generation of products with extremely low risk of viral transmission
• Colony-stimulating factors (CSFs)


  Secreted glycoproteins that bind to receptor proteins on the surfaces of hemopoietic stem cells, thereby activating intracellular signaling pathways that can cause the cells to proliferate and differentiate into a specific kind of blood cell
• Granulocyte colony-stimulating factor (G-CSF)


  A growth and differentiation factor for neutrophils and their precursor cells, also activates mature neutrophils, and acts in synergy with other hematopoietic growth factors
• Macrophage colony-stimulating factor (M-CSF)


  Serves as a growth, differentiation and activation factor for macrophages and their precursor cells
• Granulocyte macrophage colony-stimulating factor (GM-CSF)


  A proliferation/differentiation factor of hematopoietic progenitor cells, particularly those yielding neutrophils and macrophages, and also activates mature hematopoietic cells
• 1. CSF and GM-CSF have proven useful in the treatment of neutropenia, and all three CSF types are (or are likely to be) useful in the treatment of infectious diseases, some forms of cancer and the management of bone marrow transplants
• Hemostasis


  The rapid arrest of blood loss upon vascular damage, in order to maintain a relatively constant blood volume
• Hemostatic process


  1. Congregation and clumping of blood platelets at the site of vascular injury

  2. Localized constriction of the blood vessel

  3. Induction of the blood coagulation cascade
• Blood coagulation cascade

  Dependent upon a large number of blood clotting factors, which act in a sequential manner
• The initial steps of the blood clotting cascade can occur via two distinct pathways: extrinsic and intrinsic, with clotting occurring much more rapidly when initiated via the extrinsic pathway
• Genetic defects can lead to clotting disorders
• Blood coagulation

  1. Conversion of soluble serum protein, fibrinogen, into insoluble fibrin

  2. Fibrin monomers aggregate at site of damage to form a clot (thrombus)

  3. Effective for small vessel injuries, ineffective for large veins/arteries