Transcript The Facinating World of Haemostasis and Thrombosis

The Fascinating World of
Haemostasis and Thrombosis
Susan Louw
Haemostasis and Thrombosis
Unfortunately Clotting Pathways
are IMPORTANT
The Role Players
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Endothelium
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Platelets
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Coagulation Factors
Steps in Haemostasis
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Vasoconstriction
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Platelet
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activation
adhesion
aggregation
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Coagulation
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Fibrinolysis
The Endothelial Cell:
sitting on the fence
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Dual role
 Anticoagulant
 Pro-coagulant
Vascular Disorders
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Inherited
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Hereditary Haemorrhagic Telangiectasia
Connective Tissue disorders
Acquired
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Simple benign bruising
Senile purpura
Scurvy
Steroid purpura
Blood Dust ?
No – They are Platelets!!
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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
Platelet Granule Content
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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
Fibrinogen
von Willebrand factor (vWF)
von Willebrand factor propeptide
Fibronectin
Thrombospondin-1
Vitronectin
Coagulation factors
Factor V
Protein S
Factor XI
Mitogenic factors
Platelet-derived growth factor (PDGF)
Transforming growth factor- (TGF- )
Endothelial cell growth factor
Epidermal growth factor (EGF)
Insulin-like growth factor 1
Angiogenic factors
Vascular endothelial growth factor
PF4 (inhibitor)
Fibrinolytic inhibitors 2-Plasmin inhibitor ( 2-PI) Plasminogen-activator inhibitor-1 (PAI-1)
Albumin Immunoglobulins
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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
Immunoglobulins
Granule membrane-specific proteins
P-selectin (CD62P)
CD63 (LAMP-3)
GMP 33 (thrombospondin fragment)
Other secreted or released proteins6
Protease nexin I
Gas6
Amyloid -protein precursor (protease nexin II)
Tissue factor pathway inhibitor (TFPI)
Factor XIII
1-Protease inhibitor
Cl-inhibitor
High molecular weight kininogen 2-Macroglobulin
Vascular permeability factor
Interleukin-1
Histidine-rich glycoprotein
Chemokines
MIP-1 (CCL3)
RANTES (CCL5)
Size does NOT matter
(we are only 1.5 m in diameter after all)
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anucleate cell fragments
adhere to damaged blood vessels
aggregate one with another
and facilitate generation of thrombin
Platelet Disorders – Q & Q:
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Quantity
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Failure of production (Bone Marrow failure)
Increased destruction
ITP
 Drug related
 Infections
 TTP
 DIC
 Splenomegaly
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Platelet Disorders – Q & Q:
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Quality
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Hereditary
Glanzmann’s Thrombasthenia
 Bernard-Soulier syndrome
 Storage pool disease
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Acquired
Anti-platelet drugs
 Uraemia
 Myeloproliferative and –dysplasic disorders
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Platelet Disorders
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Mucocutaneous bleeding
Coagulation factors = Proteins
Grouping of Coag Factors
Vit K dependent zymogens
Soluble cofactors
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(V & VIII)
Factor XI
Cell-associated factors
Fibrinogen
Factor XIII
Plasma coagulation protease inhibitors
Vit K dependent zymogens
Protrombin
(Factor II)
 Factor VII
 Factor IX
 Factor X
 Protein C
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Vit K dependent zymogens
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Why is Vitamin K called Vitamin K?
What happened to Vitamin F, G, H, I?
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Hendrik Dam (1929) - Denmark
Newborn chicks on cholesterol free diet bleed
Corrected by addition of a substance called
“Koagulations-Vitamin” to diet
Vit K dependent zymogens
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Coagulation factors achieve result by
inducing conformational change in
next factor
Vit K dependent zymogens
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FVIIa & its co-factor: TF = “extrinsic tenase”
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FIXa & its co-factor FVIIa: = “intrinsic tenase”
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FXa & its co-factor Fva: = “prothrombinase”
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Thrombin (FIIa) no co-factor for procoagulant activity
but associates with thrombomodulin for its anticoagulant
activity = cleaving and activating Protein C
Inhibitors
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Essential Evil
Life-saving
Inhibitors of Coagulation
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Tissue Factor Pathway Inhibitor
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Antithrombin
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Protein Z / Protein Z Dependent Protease
Inhibitor
Finally - there is fibrinolysis
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all blood clots are
reorganised and resorbed
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main enzyme responsible
for this process = plasmin
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regulated by various
activators and inhibitors
Physiologist Johannes Müller (1801-1858)
described fibrin, the substance of a thrombus
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Multitude of drugs developed
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To prevent inappropriate thrombus formation
To stop excessive bleeding
To actively lyse clots
How important is thrombosis and
haemostasis
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...”Arterial, cardiac and venous thromboembolism are
major causes of death and disability in developed
countries. DVT may also be followed by the postthrombotic 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”...