Seminar 2

• Thrombopoiesis


  The direct production of platelets from megakaryocyte cytoplasm via ENDOMITOSIS (multiple nuclear/mitotic division without cytoplasmic division, generating giant multinucleated or polypoid cells)

  
• Platelets


  • Fragments of megakaryocytes
  • Size: 1 - 4 um in diameter (average of 2.5)
• Parts of a Platelet

  • CHROMOMERE - granular and centrally located
  • HYALOMERE - surrounds the chromomere, non-granular and clear to light blue
• Composition of Platelets


  • 60% CHON
  • 8% CHO
  • Various minerals, water and nucleotide
• Peripheral Zone


  • Site responsible for platelet adhesion and aggregation
  • Glycocalyx - amorphous exterior/surface coat
  • Gp Ib - receptor for vWF
  • Gp IIb/IIIa - receptor for fibrinogen
  • Gp Va - receptor for thrombin
  • Plasma membrane - contain glycoproteins, phospholipids and platelet VIII:vWF; serves as a physical and chemical barrier between the intracellular and extracellular constituents of the platelets
  • Submembranous area
• Sol Gel Zone

  • For contraction and support
  • Microfilaments - actin and myosin (actomyosin/thrombosthenin) are responsible for CLOT RETRACTION/ contractile process
  • Microtubules - tubulin (responsible for maintaining the shape of the platelet)
• Contents of Alpha Granules

  • vWF
  • B-thrombospondin (TSP)
  • Fibronectin - Platelet albumin
  • B-thromboglobulin (BTG) and platelet factor 4 (PF4) - inhibit heparin
  • Platelet-derived growth factor (PDGF) - stimulates smooth muscle cell proliferation
  • Platelet Fibrinogen (FGN) - stimulates coagulation, adhesion and aggregation
  • Factor V or Va
• Contents of Dense Granules


  • Calcium
  • ADP (stimulates platelet aggregation)
  • Serotonin/ 5-hydroxytryptamine (5-HT) (vasoconstriction)
  • ATP
  • Catecholamines (EP/NEP)
• Lysosomes


  • Neutral protease, Acid hydrolase, Bacteriocidal enzymes - May digest materials that the platelets endocytoses
• Dense Tubular System (DTS)


  • Site of arachidonic metabolism
  • "control center" for platelet activation
  • Site of prostaglandin (eicosanoid/prostaglandin) synthesis and Ca++ sequestration
  • Derived from smooth ER of megakaryocyte

  
• Open Canalicular System (OCS)/ Surface-connected Canalicular System (SCSS)


  • Provides direct communication between internal and external platelet environment
  • Serves as delivery routes for endocytosis and for secretion of granular contents upon platelet activation
• Hemostasis


  A complex process by which the body spontaneously stops bleeding and maintains blood on fluid state w/in the vessel compartment
• Abnormalities of Hemostasis


  • Hemorrhage
  • Thrombosis
• Stages of Hemostasis


  • Primary Hemostasis
  • Secondary Hemostasis
• Primary Hemostasis


  • Involves BLOOD VESSELS (collagen) and PLATELETS
  • Initial formation of a platelet plug in response to a vascular injury
• Primary Hemostasis


  1. Vasoconstriction

  2. Adhesion

  3. Activation

  4. Secretion

  5. Aggregation
• Vasoconstriction


  First response to TISSUE (BLOOD VESSEL) INJURY, initiated by SEROTONIN and THROMBOXANE A2
• Adhesion


  Attachment of platelet to exposed sub endothelial surface of an injured blood vessel
• Activation


  Morphologic (discoid to spherical) and functional changes in platelets, calcium dependent process, initiated by agonists
• Secretion


  Release of platelet granules
• Aggregation


  Platelet attachment to each other, requires the presence of FIBRINOGEN and CALCIUM, induced by stimuli such as ADP, thrombin, TxA2, collagen
• Secondary Hemostasis


  Involves the interaction of COAGULATION FACTORS, formation of IRREVERSIBLE/PERMANENT FIBRIN CLOT
• Coagulation Factors


  • Serine proteases: II, VII, IX, X, XI, XII, Prekallikrein, HMWK
  • Cofactors: V, VIII
  • Transglutaminase: XIII
  • Fibrinogen: most concentrated coagulation factor
• Classification of Coagulation Factors

  • Substrate - substance on which the enzymes act
  • Zymogen - enzyme precursor
  • Cofactor - component that aids in the stabilization and enhancement of zymogen activation to the active enzyme form
  • Calcium
• Coagulation Factors


  • I - Fibrinogen
  • II - Prothombin
  • III - Tissue Factor
  • IV - Calcium
  • V - Proaccelerin
  • VI - Obsolete
  • VII - Proconvertin
  • VIII - Anti-Hemophilic Factor
  • IX - Plasma Thromboplastin Component (PTC)
  • X - Stuart-Prower Factor
  • XI - Plasma Thromboplastin Antecedent (PTA)
  • XII - Hageman Factor
  • XIII - Fibrin Stabilizing Factor
  • Prekallikrein
  • High Molecular Weight Kininogen (HMWK)
• Coagulation Factor Groups


  • Fibrinogen Group (I, V, VIII, XIII)
  • Prothrombin Group (II, VII, IX, X)
  • Contact Group (XI, XII, PK, HMWK)
• Disorders of Hemostasis and Hemostasis Testing

  • Disorders of Primary Hemostasis
  • Bleeding (Vascular) Disorders
• Bleeding (Vascular) Disorders


  • Hereditary Connective Tissue Defects
  • Acquired Connective Tissue Defects
  • Hereditary Alterations of Blood Vessel Walls
• Ehlers-Danlos syndrome


  Hypermobility syndrome, defect in PEPTIDASE ENZYME (which converts procollagen to collagen), INCREASED VASCULAR PERMEABILITY
• Pseudoxanthoma elasticum

  Elastic fibers in small arteries are CALCIFIES and STRUCTURALLY ABRNORMAL
• Scurvy/ Vitamin C deficiency


  Deficiency in ascorbic acid (collagen formation)
• Senile purpura/ Age-related purpura/ Solar purpura

  Degradation of collagen, elastin and subcutaneous fat
• Hereditary hemorrhagic telangiectasia/ Osler-Weber-Rendu disease


  Blood vessel walls are thin, dilated, and has decreased ability to contract, telangiectasias (dilated superficial blood vessels that create small, focal red lesions), epistaxis: universal findings, PERMANENT
• Congenital Hemangiomata/ Hemangiomata-Thrombocytopenia Syndrome/ Kasabach Merritt syndrome


  Vascular tumors that s
• Platelets


  • Calcified and structurally abnormal
  • Disorder of primary hemostasis
• Bleeding (vascular) disorders


  • Acquired connective tissue defects
  • Hereditary alterations of blood vessel walls
  • Acquired alteration of blood vessel wall
  • Endothelial damage
• Hereditary hemorrhagic telangiectasia/ Osler-Weber-Rendu disease


  • Most common vascular wall defect
  • Blood vessel walls are thin, dilated, and has decreased ability to contract
  • Telangiectasias (dilated superficial blood vessels that create small, focal red lesions)
  • Occur throughout the body but are most obvious on the face, lips, tongue, conjunctiva, nasal mucosa, fingers, toes, and trunk and under the tongue
  • Epistaxis: universal findings
  • Permanent
• Congenital Hemangiomata/ Hemangiomata-Thrombocytopenia Syndrome/ Kasabach Merritt syndrome


  • Vascular tumors that swell and bleed at the surface
• Diabetes mellitus


  • Thickening of capillary basement membranes and formation of atherosclerosis in the larger vessels which block normal blood flow
• Amyloidosis


  • Deposition of fibrillary protein (amyloid) causing vessel obstruction