Blood Physiology Hemostasis Dr. Sherwan R Sulaiman MD / MSc / PhD www.doctorsherwan.com

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Blood PhysiologyHemostasisDr. Sherwan R
SulaimanMD / MSc / PhDwww.doctorsherwan.com
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Events in Hemostasis

• Hemostasis-prevention of blood loss
• Mechanisms
• vascular spasm
• formation of a platelet plug
• blood coagulation
• fibrous tissue growth to seal

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Hemostasis

• Vascular Constriction-associated w/ trauma
• neural reflexes
• SNS induced constriction from pain
• local myogenic spasm
• responsible for most of the constriction
• local humoral factors
• thromboxane A2 from platelets
• Spasm ? trauma

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Platelet Plug

• Platelets function as whole cells
• but cannot divide
• Platelets contain
• actin myosin
• enzymes calcium
• ADP ATP
• Thromboxane A2
• serotonin
• growth factor

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Platelet Cell Membrane

• Contains
• Glycoproteins that avoid the normal
  endothelium but adhere to damaged area
• Phospholipids containing platelet factor 3
• a.k.a. thromboplastin-initiates clotting

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Mechanism of Platelet Activation

• When platelets contact damaged area they 1)
  swell
• 2) irregular form w/ irradiating processes
  protruding from surface
• 3) contractile proteins contract causing
  granule release
• 4) secrete ADP, Thromboxane A2 serotonin

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Thromboxane A2

• 1) Vasoconstrictor
• 2) Potentiates the release of granule
• contents
• (not essential for release to occur)

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Platelets

• Important in minute ruptures
• lack of platelets associated with small
  hemorrhagic areas under skin and throughout
  internal tissues
• half-life of 8-12 days
• eliminated primarily by macrophage action
• (greater than 1/2 of all macrophages in spleen)
• 150,000-300,000 per ?l

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Role of Endothelium

• Prevents platelet aggregation
• produces PGI2 (prostacyclin)-
• vasodilator
• stimulates platelet adenyl cyclase which
  suppresses release of granules
• limits platelet extension
• produces factor VIII (clotting)

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Prostaglandin synthesis

• Phospholipid ?Arachidonic acid requires Lipase
• Arachidonic acid?PGG2-PGH2 requires fatty acid
  cyclooxygenase
• PGG2-PGH2?Thromb. A2 requires Thromb. synthetase
• PGG2-PGH2?PGI2 requires Prostacyclin synthetase
• Aspirin and Ibuprofen block Fatty acid
  cyclooxygenase

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Anticoagulants vs Lysis of clots

• Anticoagulants
• prevents clots from forming
• chelators-tye up calcium (citrate, oxylate)
• heparin- complexes with Antithrobin III
• dicumarol-inhibition of Vit. K dependent factors
• factors II, VII, IX, X (synthesized by
  hepatocytes
• Aka cumadin, warfarin
• Lysis of Clots
• Plasmin (from plasminogen)

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Activators of Plasminogen

• Endogenous Activators
• tissues
• plasma
• urine
• Exogenous Activators
• streptokinase
• tPA (tissue plasminogen activator)

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Aspirin Ibuprofen

• Block both thromboxane A2 prostacyclin
  production by blocking fatty acid cyclooxygenase
  which converts arachidonic acid to PGG2 PGH2
  (intermediates)
• Why take aspirin to prevent heart attacks?

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Reperfusion injury

• Most of the frank tissue damage associated with
  infarction occurs upon reperfusion
• associated with the formation of highly reactive
  oxygen species with unpaired electrons. free
  radicals
• When pressure on tissues relieved again
  perfused with blood, free radicals are generated

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Collateralization

• The ability to open up alternate routes of blood
  flow to compensate for a blocked vessel
• Angiogenesis
• Vasodilatation
• Role of the SNS ??
• May impede
• May augment

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Blood Coagulation- Thrombosis

• Extrinsic mechanism-initiated by chemical factors
  released by damaged tissues
• Intrinsic mechanism-requires only components in
  blood trauma to blood or exposure to collagen
  (or foreign surface)

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Clotting factors

• I- fibrinogen
• II- Prothrombin
• III- Thromboplastin
• IV- Calcium
• V- Proaccelerin
• VII- Serum prothombin conversion acclerator
• VIII- antihemophilic factor (A)

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Clotting factors (cont.)

• IX- antihemophilic factor B christmas factor
• X- Stuart factor
• XI- antihemophilic factor C
• XII- Hageman factor
• XIII- Fibrin-stabilizing factor
• Prekallikrein- Fletcher factor
• High molecular weight kininogen
• Platelets

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Hepatocytes role in clotting

• Liver synthesizes 5 clotting factors
• I (fibrinogen)
• II (prothrombin)
• VII (SPCA)
• IX (AHF B)
• X (Stuart factor)
• Coumarin (warfarin or cumadin) depresses liver
  formation of II, VII, IX, X by blocking action of
  vitamin K

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Hemophilia

• Sex linked on X chromosome
• occurs almost exclusively in males
• 85 of cases- defect in factor VIII
• 15 of cases- defect in factor IX
• varying degree of severity from mild ? severe

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Blood Coagulation

• The key step is the conversion of fibrinogen to
  fibrin which requires thrombin
• thrombin
• fibrinogen---------------gtfibrin

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Intrinsic pathway

• Factor XII activated when blood contacts a
  negatively charged surface (collagen, glass)
• Activated XII Kalikrein Kinnogen will activate
  Factor XI
• Activated XI Ca will activate both Factors IX
  VIII
• Activated IX VIII Phospholipid Ca will
  activate Factors X V
• Activated X V Phospholipid Ca will
  convert Prothrombin to Thrombin

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Extrinsic Pathway

• Tissue thromboplastin Factor VII Ca will
  activate Factors X V
• Activated X V Phospholipid Ca will
  convert Prothrombin to Thrombin

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Final Common Steps

• Once Fibrinogen has been converted to Fibrin by
  Thrombin it is changed from the soluble monomer
  to the insoluble polymer by the activated Factor
  XIII
• Factor XIII is activated by Thrombin and Ca

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Lysis of Clots

• Clots may be liquefied by (fibrinolysis) by a
  proteolytic enzyme plasmin
• It circulates in the blood in an inactive form
  known as plasminogen
• Activators are found in tissues, plasma, and
  urine
• It can also be activated by exogenous activators
  such as tPA, or streptokinase

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Risk factors in Heart Disease

• Increasing age
• Male gender
• Heredity (including race)
• Tobacco Smoke
• High blood cholesterol
• High blood pressure
• Physical inactivity
• Obesity/overweight
• Diabetes Mellitus
• High blood homocysteine

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Homocysteine

• Amino acid in the blood that may irritate blood
  vessels promoting atherosclerosis
• Can also cause cholesterol to change into
  oxidized LDL
• Can make blood more likely to clot
• High levels in blood (gt 12 ?mol/L) can be reduced
  by increasing intake of folic acid, B6 and B12