Blood: Haemostasis L3 Flashcards
what is Haemostasis
the arrest of bleeding from a broken blood vessel
- capillaries, arterioles, venules
what are platelets
cellular elements of the blood
- they are fragments of large cells from bone marrow called megakaryocytes
- have no nucleus
what hormone regulated megakaryocytes and platelet production and where is it made
thrombopoietin
produced in liver and kidneys
describe thrombopoiesis
-platelet synthesis
- starts with hematopoietic stem cell
- differentiate into megakaryoblasts - megakaryoblasts follow myeloid line
- develop into megakaryocytes by undergoing repeated mitotic cycles without ever actually dividing.
- Megakaryocytes are massive cells with multiple copies of DNA - thrombopoietin stimulates megakaryocyte to extend arm through bone marrow sinusoids into blood vessels
- Break off as platelets
Produce about 1011 a day
1000-3000 platelets/megakaryocyte in its life span
describe the structure of platelets
Exterior coat – rich in glycoproteins (adhesion, aggregation and activation)
Tubular System - site of thromboxane A2 synthesis and release
Microtubules and microfilaments – maintain shape
Granules – alpha: contain clotting mediators including von Willebrand factor, factors V, VIII and fibrinogen;
delta (dense bodies): contain ADP, Ca++ and serotonin, required for platelet activation and clotting
mitochondria
where are platelets stored and when are they released
in the spleen (short life span- undergo apoptosis and phagocyted in liver and spleen)
released by contraction of the spleen activated by sympathetic nervous system
what are the 3 main steps in Haemostasis
- vascular spasm (contraction of vessel)
- formation of platelet plug
- blood coagulation
describe vascular spasm
- damage to vessel causing damaged cells and platelets to release potent vasoconstrictors such as serotonin and ADP at cut site
- causes smooth muscle layer in vessel wall to constrict slowing flow of blood and limiting blood loss - ends of endothelial layer pushed together by the spasm becoming sticky
- adhere to each other
- aided by platelets that stick to exposed collagen
describe formation of platelet plug
- platelet adhesion
- platelets stick to each other using von Willebrand’s factors (plasma protein secreted by endothelial cells and platelets - platelet activation
- activation causes platelets to have irregular shape with many protruding pseudopodia
- they are more sticky this way
- Secrete things that cause them to stick together and attract more platelets - plug is formed
- seals the break in the lining
what is the function of the platelet plug
- seal break
- compaction/ strengthening
- further vasoconstriction
- stimulate clotting cascade
what is the role of Prostacyclin (PGI2) which is released by normal vessel lining
inhibits platelet aggregation
limits platelet plug to the damaged region of the vessel preventing it’s spread to normal, undamaged tissue.
describe Blood coagulation
aka blood clotting
-process changing liquid blood to a solid gel (clot or thrombus)
- Clot strengthens and supports the platelet plug
what is the final step in blood coagulation
fibrinogen (large soluble plasma protein) converted to fibrin (insoluble thread like molecule) which RBC get trapped in
what factors are involved in the final steps of blood clotting
- thrombin (IIa- active 2)
- turn fibrinogen (factor 1) into fibrin monomers - XIII (active 13) and calcium
- turns fibrin monomer to fibrin polymer which forms the clot
what are the three pathways of blood clotting
- intrinsic
- Initial stimulus is exposed collagen (through damage to the endothelium wall). - extrinsic
- Initial stimulus is blood contact with damaged tissue outside of the blood vessel that exposes tissue factor (also known as factor III; or tissue thromboplastin). - common pathway
- I and E join in the later stages of coagulation
describe intrinsic pathway
- blood vessel damaged
- active XII (12) activates XII (11) which activates IX (9) which activates X (10) (active X is start of common pathway)
describe extrinsic pathway
- damage to tissue outside blood vessel
- exposes tissue factor III (3)
- tissue factor III and active VII (thromboplastin) activates IX (9) which activates X
give 2 examples of positive feedback in the pathways
- high levels of thrombin leads to more XI being activated
- high levels of active X causes more tissue factor III and VII (thromboplastin)
what does Anti-thrombin do in the anti clotting system
inhibits clotting factors including thrombin
what does Thrombomodulin do in the anti clotting system
binds to thrombin stopping its clotting effects and inactivates factors Va and VIIIa
what does tissue factor pathway inhibitors do in the anti clotting system
bind to factor III/VIIa complex preventing it from activiating IX and X
binds directly to Xa
what does Thrombin do in the anti clotting system
binds to its receptor stimulating production of prostaglandins (PGl), nitric oxide and ADP to inhibit further platelet aggregation
what is Fibrinolysis
clot break down
describe fibrinolysis
Aggregated platelets secrete platelet derived growth factor β (PDGF β) that recruits fibroblasts from the surrounding tissue.
Fibroblasts form scar tissue at the site of the damage.
Simultaneous with healing - clot is dissolved by a fibrinolytic enzyme called plasmin.
what is plasmin activated by
tissue plasminogen activator (t-PA), secreted by endothelial cells.
t-PA needs to bind fibrin to become active, hence only works on clot.
give summary of clotting factors
Clotting factors other than III, V, VIII and XIII are proteases that activate downstream factors
III, V and VIII are glycoproteins
XIII is a transglutaminase
give 4 types of haemostasis disorders
- excessive or inadequate clotting
- acquired (something happens that changes physiology) or inherited
- defects of platelets
- quantitative (thrombocytopaenia)
- qualitative (thrombopathy) - Deficiency or dysfunction of coagulation factors (coagulopathy)
acquired disorders are more common than inherited
- give examples
- renal disease – lack of thrombopoeitin
- hepatic disease - lack of fibrinogen
- vitamin K deficiency – needed for synthesis of clotting factors II, VII, IX and X (VK needed)
- drug-induced disorders
include effects on platelet activity
e.g. aspirin and other non-steroidal anti-inflammatory drugs inhibit thromboxane A2 synthesis and secretion
give examples of inherited disorders
- Structural defects to vascular system.
- Thrombotic disorder: an alteration to haemostasis that impairs capacity to combat clot formation
- Quantitative (thrombocytopaenia) or qualitative (thrombopathy) defects of platelets
- Deficiency or dysfunction of coagulation factors (coagulopathy)
what is Haemorrhage
“Black and blue” marks caused by internal bleeding.
Due to degradation of haemoglobin to biliverdin, bilirubin and heamosiderin
- Come from break down of heam
Eventually removed by plasmin and phagocytosis
Thrombosis - Excessive/unwanted clotting
what are consequences of thrombosis
- Thrombus – Blood clot within a vessel or the heart
- Embolus – detached mass able to travel in a vessel
Solid, liquid or gas - Embolism - the lodging of an embolus
- Thrombo-embolism – blockage by a thrombus
- Stenosis – abnormal narrowing of a passage in the body
Virchow’s Triad describes three risk factors for thrombosis:
what are they
- Blood stasis e.g. deep vein thrombosis (DVT)
- Blood not moving around body in normal way blood more likely to clot - Changes in the vessel wall
– injury, inflammation - Thrombogenic changes in the blood – hypercoagulability (causes/risk factors include obesity, smoking, pregnancy, cancer, age; can be inherited)
how does thrombosis effect blood flow
- Thromboembolism
Need to get to high percentage of blocking before it really affects blood flow
what treatments are there for thrombosis
anticoagulant drugs
Warfarin: Most widely prescribed oral anticoagulant; inhibits vitamin K.
Heparin: endothelial cell–derived polysaccharide.
Given by injection (not absorbed through gut).
Activates antithrombin III (AT)
Used where the likelihood of forming clots is increased:
- atrial fibrillation (an irregular heart beat where blood can pool and clot in the heart) sits in heart- more likely to clot
- aortic valve replacement
- recent surgery
- autoimmune disease attacking fat and protein components of blood vessel walls
what is Thrombocytopenia
quantitative platelet disorder that sees low platelet count
caused by
autoimmune disease
drug induced – inhibition of platelet synthesis (eg interferon, alcohol), immunologic destruction of platelets (eg ibuprofen, tamoxifen)
results in Easy bruising, petechial rash, mucous membrane bleeding or excessive bleeding after minor trauma
- Petechiae
what is Thrombotic thrombocytopenic purpura
platelet disorder caused by formation of small clots in the circulation; results in low platelet numbers.
Spontaneous aggregation of platelets and initiation of the clotting cascade
Rare but serious disorder; can be congenital, an autoimmune disease or caused by toxins
give 3 examples of inherited coagulopathies
1.von Willebrand’s Disease:
- Lack of von Willebrand factor ->. poor platelet aggregation. Common symptom: excessive gum bleeding. Autosomal dominant. Mild.
2. Haemophilia A:
- Deficiency in factor VIII. X-linked recessive disorder. Excessive bleeding
3. Haemophilia B:
- Deficiency in factor IX. Also known as ‘Christmas disease’. Less server
- both associated with excessive bleeding
- Severity depends on how much factor VIII or IX is present in blood.
Treatment: replacement of ‘missing’ clotting factor
