The Fascinating World of Haemostasis and Thrombosis

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The Fascinating World of Haemostasis and
Thrombosis

• Susan Louw

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Haemostasis and Thrombosis
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Unfortunately Clotting Pathways are IMPORTANT
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The Role Players

• Endothelium
• Platelets
• Coagulation Factors

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Steps in Haemostasis

• Vasoconstriction
• Platelet
• activation
• adhesion
• aggregation
• Coagulation
• Fibrinolysis

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The Endothelial Cell sitting on the fence

• Dual role
• Anticoagulant
• Pro-coagulant

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Vascular Disorders

• Inherited
• Hereditary Haemorrhagic Telangiectasia
• Connective Tissue disorders
• Acquired
• Simple benign bruising
• Senile purpura
• Scurvy
• Steroid purpura

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Blood Dust ? No They are Platelets!!

• Each day produce 1 x 1011 platelets
• Production can increased 10- to 20-X
• Circulatory half-life 10 days
• Arise from megakaryocyte each giving rise to 1
  000 to 3 000 platelets

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Platelet Granule Content

• Dense bodies 
•  ADP
• 653 mM
•  ATP
• 436 mM
•  Calcium
• 2181 mM
•  Serotonin
• 65 mM
•  Pyrophosphate
• 326 mM
•  GDP
•  Magnesium
• -Granule 
•  Platelet-specific proteins
•    Platelet factor 4 (PF4)
•     -Thromboglobulin ( -TG) family (platelet
  basic protein, low-affinity platelet factor 4,
  -thromboglobulin, -thromboglobulin-F)
•   Multimerin
•   Adhesive glycoproteins

•  Angiogenic factors
•    Vascular endothelial growth factor
•    PF4 (inhibitor)
•  Fibrinolytic inhibitors
•     2-Plasmin inhibitor ( 2-PI)
   Plasminogen-activator inhibitor-1 (PAI-1)
•  Albumin
•  Immunoglobulins
•  Granule membrane-specific proteins
•    P-selectin (CD62P)
•    CD63 (LAMP-3)
•    GMP 33 (thrombospondin fragment)
• Other secreted or released proteins6 
•  Protease nexin
•  Angiogenic factors
•    Vascular endothelial growth factor
•    PF4 (inhibitor)
•  Fibrinolytic inhibitors
•     2-Plasmin inhibitor ( 2-PI)
   Plasminogen-activator inhibitor-1 (PAI-1)
•  Albumin

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Size does NOT matter (we are only 1.5 ?m in
diameter after all)

• anucleate cell fragments
• adhere to damaged blood vessels
• aggregate one with another
• and facilitate generation of thrombin

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Platelet Disorders Q Q

• Quantity
• Failure of production (Bone Marrow failure)
• Increased destruction
• ITP
• Drug related
• Infections
• TTP
• DIC
• Splenomegaly

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Platelet Disorders Q Q

• Quality
• Hereditary
• Glanzmanns Thrombasthenia
• Bernard-Soulier syndrome
• Storage pool disease
• Acquired
• Anti-platelet drugs
• Uraemia
• Myeloproliferative and dysplasic disorders

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Platelet Disorders

• Mucocutaneous bleeding

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Coagulation factors Proteins
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Grouping of Coag Factors

• Vit K dependent zymogens
• Soluble cofactors
• (V VIII)
• Factor XI
• Cell-associated factors
• Fibrinogen
• Factor XIII
• Plasma coagulation protease inhibitors

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Vit K dependent zymogens

• Protrombin (Factor II)
• Factor VII
• Factor IX
• Factor X
• Protein C

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Vit K dependent zymogens

• Why is Vitamin K called Vitamin K?
• What happened to Vitamin F, G, H, I?
• Hendrik Dam (1929) - Denmark
• Newborn chicks on cholesterol free diet bleed
• Corrected by addition of a substance called
  Koagulations-Vitamin to diet

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Vit K dependent zymogens
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• Coagulation factors achieve result by inducing
  conformational change in next factor

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Vit K dependent zymogens

• FVIIa its co-factor TF extrinsic tenase
• FIXa its co-factor FVIIa intrinsic tenase
• FXa its co-factor Fva prothrombinase
• Thrombin (FIIa) no co-factor for procoagulant
  activity but associates with thrombomodulin for
  its anticoagulant activity cleaving and
  activating Protein C

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Inhibitors

• Essential Evil
• Life-saving

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Inhibitors of Coagulation

• Tissue Factor Pathway Inhibitor
• Antithrombin
• Protein Z / Protein Z Dependent Protease Inhibitor

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Finally - there is fibrinolysis

• all blood clots are reorganised and resorbed
• main enzyme responsible for this process
  plasmin
• regulated by various activators and inhibitors

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Physiologist Johannes Müller (1801-1858)
described fibrin, the substance of a thrombus

• Multitude of drugs developed
• To prevent inappropriate thrombus formation
• To stop excessive bleeding
• To actively lyse clots

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How important is thrombosis and haemostasis

• ...Arterial, cardiac and venous thromboembolism
  are
• major causes of death and disability in
  developed countries. DVT may also be followed by
  the post-thrombotic leg syndrome which includes
  chronic venous ulceration another major consumer
  of health service costs...
• ...Deep venous thrombosis (DVT) and its sequela,
• pulmonary embolism, are the leading causes of
  preventable in-hospital mortality...