The Fascinating World of Haemostasis and Thrombosis Susan
The Fascinating World of Haemostasis and Thrombosis Susan Louw
Haemostasis and Thrombosis
Unfortunately Clotting Pathways are IMPORTANT
The Role Players n Endothelium n Platelets n Coagulation Factors
Steps in Haemostasis n Vasoconstriction n Platelet n n n activation adhesion aggregation n Coagulation n Fibrinolysis
The Endothelial Cell: sitting on the fence n Dual role n Anticoagulant n Pro-coagulant
Vascular Disorders n Inherited n n n Hereditary Haemorrhagic Telangiectasia Connective Tissue disorders Acquired n n Simple benign bruising Senile purpura Scurvy Steroid purpura
Blood Dust ? No – They are Platelets!! n n 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 n n n n n n n n n n Dense bodies ADP 653 m. M ATP 436 m. M Calcium 2181 m. M Serotonin 65 m. M Pyrophosphate 326 m. M GDP Magnesium -Granule Platelet-specific proteins: Platelet factor 4 (PF 4) -Thromboglobulin ( -TG) family (platelet basic protein, low-affinity platelet factor 4, thromboglobulin, -thromboglobulin-F) Multimerin Adhesive glycoproteins Fibrinogen von Willebrand factor (v. WF) 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 PF 4 (inhibitor) Fibrinolytic inhibitors 2 -Plasmin inhibitor ( 2 -PI) Plasminogen-activator inhibitor-1 (PAI-1) Albumin Immunoglobulins n n n n n n n n n n Angiogenic factors Vascular endothelial growth factor PF 4 (inhibitor) Fibrinolytic inhibitors 2 -Plasmin inhibitor ( 2 -PI) Plasminogen-activator inhibitor-1 (PAI-1) Albumin Immunoglobulins Granule membrane-specific proteins P-selectin (CD 62 P) CD 63 (LAMP-3) GMP 33 (thrombospondin fragment) Other secreted or released proteins 6 Protease nexin I Gas 6 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 (CCL 3) RANTES (CCL 5)
Size does NOT matter (we are only 1. 5 m in diameter after all) n n anucleate cell fragments adhere to damaged blood vessels aggregate one with another and facilitate generation of thrombin
Platelet Disorders – Q & Q: n Quantity n n Failure of production (Bone Marrow failure) Increased destruction ITP n Drug related n Infections n TTP n DIC n Splenomegaly n
Platelet Disorders – Q & Q: n Quality n Hereditary Glanzmann’s Thrombasthenia n Bernard-Soulier syndrome n Storage pool disease n n Acquired Anti-platelet drugs n Uraemia n Myeloproliferative and –dysplasic disorders n
Platelet Disorders n Mucocutaneous bleeding
Coagulation factors = Proteins
Grouping of Coag Factors 1. 2. Vit K dependent zymogens Soluble cofactors 1. 3. 4. 5. 6. 7. (V & VIII) Factor XI Cell-associated factors Fibrinogen Factor XIII Plasma coagulation protease inhibitors
Vit K dependent zymogens Protrombin (Factor II) n Factor VII n Factor IX n Factor X n Protein C n
Vit K dependent zymogens n n Why is Vitamin K called Vitamin K? What happened to Vitamin F, G, H, I? n n n 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
n Coagulation factors achieve result by inducing conformational change in next factor
Vit K dependent zymogens n FVIIa & its co-factor: TF = “extrinsic tenase” n FIXa & its co-factor FVIIa: = “intrinsic tenase” n FXa & its co-factor Fva: = “prothrombinase” n Thrombin (FIIa) no co-factor for procoagulant activity but associates with thrombomodulin for its anticoagulant activity = cleaving and activating Protein C
Inhibitors n n Essential Evil Life-saving
Inhibitors of Coagulation n Tissue Factor Pathway Inhibitor n Antithrombin n Protein Z / Protein Z Dependent Protease Inhibitor
Finally - there is fibrinolysis n all blood clots are reorganised and resorbed n main enzyme responsible for this process = plasmin n regulated by various activators and inhibitors
Physiologist Johannes Müller (1801 -1858) described fibrin, the substance of a thrombus n Multitude of drugs developed n n n To prevent inappropriate thrombus formation To stop excessive bleeding To actively lyse clots
How important is thrombosis and haemostasis n n . . . ”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”. . .
- Slides: 28