Haemostasis Flashcards
Haemostasis definition
mechanism that ensures blood remains fluid, whilst damaged vessels are equickly fixed to stop excess loss
Problems with haemostasis can lead to (2):
either haemorrhage or excessive blood clot formation
Primary Haemostasis
interactions between platelets and vascular endothelial cells
Secondary Haemostasis
clotting factors - coagulation cascade
Erythropoiesis - Thrombopoiesis
key thing to know is haematopoetic progenitor starts both pathways, splits off into a megakaryocyte progenitor and a erythopoeitic progenitor
Megakaryoctyes:
- location
- form and key features
- reside in the bone marrow
- form platelets via endomitosis:
- DNA replication
- new organelle formation
- but no cell division
Endomitosis process
- the megakaryocyte skeleton
rearranges and pro-platelet
extensions are formed in the
periphery of the megakaryocyte - microtubules facillitate the
movement of organelles in the pro-
platelet extensions, which consist
of part of the megakaryocyte
cytoplasm
Platelet Membrane:
- membrane glycoprotein: 1a,1b,2a,2b,3a,6
Glycoprotein 1b on platelet membrane
- initial platelet attachment to Von
Willebrand Factor and the vascular
endothelium
Glycoprotein 1a,2a,6 on platelet membrane
platelet adhesion to collagen
Glycoprotein 2b,3a on platelet membrane
adhesion to fibrinogen and additional adhesion to Von Willebrand Factor, platelet to platelet adhesion
Platelet Granules Contents: Electron Dense Granules:
- nucleotides (ADP)
- serotonin
- Ca2+: essential for the coagulation
cascade
Platelet Granules Content: Alpha Granules:
- Fibrinogen: fibrin precursor
- Von Willebrands Factor
- Factor V: coag cascade
- Heparin antagonist
- Platelet Derived Growth Factor
(PDGF): vascular repair
Normal Blood Vessel
Blood Vessel after Injury
Platelet function:
- adhesion
- aggregation
- release of alpha granule content
Von Willebrand Factor:
- is
- synthesised by
- large multimeric glycoprotein
- synthesised by endothelial cells
and megakaryocytes
Megakaryocyte are dependent on
protein called Thrombopoeitin (TPO) dependent
binds to receptor on megakaryocytes called MPL,
hence thrombopoetin is essential for formation of megakaryocytes and platelets
Endomitosis is an incomplete form of mitosis.
True or False?
True
Megakaryocytes nuclei contain how many chromosomes
contain up to 368 chromosomes
Megakaryocytes are multi-nucleated.
True or False?
True due to incomplete mitosis (endomitosis)
Platelets are formed as a response to the activity of
thrombopoeitin or TPO from megakaryocytes, and platelets are cytoplasmic fragments of megakaryocytes
Platelets contain many organelles.
True or False?
False
limited number of organelles, especially mitochondria
Coagulation Cascade:
Extrinsic pathway is triggered, feeds into the common pathway. Tissue factor interacts with Factor VIIa (7a), leads to the activation of factor X, which interacts with factor 5 in order to convert a small amount of prothrombin into thrombin.
Interaction between extrinsic and common pathway produces a small amount of thrombin, which is not sufficient to convert substantial amounts of fibrinogen to fibrin, needed for the sealing of vascular wounds by forming a blood clot.
Therefore the thrombin produced from the interaction between the extrinsic and common pathway, is used to initiate the intrinsic pathway, leading to the conversion of more factor 10 into activated form, conversion of more prothrombin to thrombin, a mroe substantial amount
Tissue factor and factor 7 interact to activate factors specific to the intrinsic pathway (9 and 11), which activate factor ten and hence mroe thrombin activated
What are the names of the three paths of the coagulation cascade?
- intrinsic
- extrinsic
- common
Enzymes that take part in the coagulation cascade: how are they circulated in body and name
- circulate in plasma in an inactive
form as pro-enzymes and will
participate in pathway once
activated - XIIa (12a), XIa (11a), IXa (9a), Xa
(10a), VIIa (7a), Prothrombin II
Names of the cofactors that participate in the coagulation cascade and general purpose
- VIIIa (8a), Va (5a)
- proteins that interact with an
enzyme for a step to be completed
Coagulation Cascade: Extrinsic Pathway:
- initiation of the coag cascade is
EXTRINSIC: - begins with the interaction
between tissue Factor and Factor
VII (7) - the tissue Factor-Factor VII complex
will activate Factor X as well as
Factor IX and Factor XI (in the
intrinsic) - a small amount of thrombin is formed
- not sufficient for the conversion of
fibrinogen to fibrin
Coagulation Cascade: Intrinsic Pathway:
- AMPLIFICATION of coag cascade:
- Thrombin (produced during the
extrinsic pathway) activates Factor
VIII (8) and Factor V (5) - AN EXAMPLE OF A POSITIVE
FEEDBACK LOOP - the intrinsic pathway relies on the
presence of Ca2+, platelet dense
granules contain Ca2+ - more Factor X activated
- INCREASED generation of thrombin
produced - increased conversion of fibrinogen
to fibrin
Coagulation Cascade: Common Pathway:
- stops bleeding and clot formation:
- Thrombin hydrolyses fibrinogen
and releases fibrin monomers - fibrin monomers form fibrin
polymer, which is important for
platelet aggregation and the
formation of a haemostatic plug - the pathway depends on Factor X
and Factor V (intrinsic pathway),
both of which circulate in the
plasma.
Platelets are involved in the extrinsic pathway.
True or False?
False
Platelets are involved in the intrinsic pathway
Coagulation Factors have a short half life in plasma.
True or False?
True
few hours
will degrade when not needed
What is the coagulation factor with the longest plasma half life?
- Factor I
- Fibrinogen
- 90 hours
What is the coagulation factor with the second longest plasma half life?
- factor II
- prothrombin
- 65 hours
Vitamin K and the coagulation cascade
- fat soluble vitamin, present in veg
and synthesised by gut bacteria - essential for the synthesis of the
active forms of Factors: II
(prothrombin), VII (7), IX (9) and X
Vitamin K deficiency in newborns is due to
dietary restrictions
Vitamin K deficiency in adults can be duet to:
- dietary restrictions
- liver disease decreases the
absorption of vitamin K
Warfarin can increase the risk of bleeding out. Why?
- warfarin is a vitamin K inhibitor
- stops the activity of vitamin K
reductase, which recycles vitamin K - lack of vitamin K means less
synthesis of active forms of
coagulation factors II
(prothrombin), VII, IX,X - less likely to form coagulation plug
Haemostasis: TFPI:
- stands for
- type of molecule and size
- synthesis
- location
- function
- tissue factor pathway inhibitor
- small protein
- produced by endothelial cells
- present in platelets and circulates
in plasma - TFPI inhibits Xa, VIIa and tissue
factor*** - ensures that coagulation cascade is
only activated in sites of vascular
injury
Excessive activity of the coagulation cascade
- excessive blood clot formation
- obstruction of blood flow in the
circulatory network
Coagulation Inhibition: label and describe:
- endothelial cells contain a receptor
called thrombomodulin, which
binds to thrombin, when thrombin
is not needed - interaction between thrombin and
thrombomodulin activates Protein
C, which is normally present on
endothelial cells bound to the
endothelial protein C receptor - activation of protein C will lead to
the destruction of coagulation
factors 8 and 5 and hence the
inhibition of the intrinsic pathway - protein C needs cofactor to
function, which is protein S - protein S promotes the destruction
Protein C cofactor:
- Protein S assists protein C in
binding on the surface of platelets - - protein S is vitamin K dependent
Protein C activation leads to the destruction of which coagulation factors?
5 and 8
Where is protein C synthesised?
liver
Protein S and Protein C are both
serine proteases
Antithrombin as a coagulation inhibitor:
- antithrombin is a small
glycoprotein, synthesised by
endothelial cells and enters
circulation - ANTITHROMBIN INHIBITS SERINE
PROTEASES: factor IX,X,XI (9,10,11)
Heparin is an anti-coagulant, enhances the activity of which anti-coagulation inhibitor
antithrombin
Antithrombin
Fibrinolysis:
- anti-coagulation mechanism to
prevent excessive clot formation - acts in balance with blood
coagulation - PLASMINOGEN, an inactivated
proenzyme IS CONVERTED TO
PLASMIN BY THROMBIN - plasmin is a serine protease
- plasmin limits the growth of
thrombus by degrading fibrin
polymers
fibrinolysis
Thrombocytopenia is
Thrombocytopenia: low platelet number.
Clotting disorders can affect (3):
- platelet function
- the coagulation cascade
- coagulation inhibition.
Thrombocytopenia (low platelet number) is a possible sign of
bone marrow failure
Thrombocytopenia can be caused by
- bone marrow failure?
- autoimmune disease of platelets
- rare herediatry disorders that
affect platelet function can be
caused by gene mutations
Haemophillia A:
- deficiency in Factor VIII
- hereditary disease that passes on
from mother to son (X linked) - prevalence is 30-100/10^6
- 1/3 cases have no family history
Haemophilia B:
- deficiency in Factor IX
- very similar and can be mistaken
- has a lower prevalence (1/5
haemophilia A cases)
Von Willebrand disease:
- various mutations can reduce the
function of VWF or limit its
synthesis - autosomal dominant inheritance
- more prevalent in females
- degree of bleeding varies between
patients
Ashkenazi Jews coagulation disorder
Factor XI deficiency (rare)
Thrombosis:
- platelets and fibrin form thrombi
(blood clotting cascade) at sites of
injury - in thrombosis blood clots can form
due to inflammation causing blood
flow obstruction - eg arterial and venous thrombosis
- thrombosis can cause MI,
cerebrovascular disease
Hereditary risk factors for thrombosis:
- Factor V Leiden gene mutation:
changes arg to glut on Factor V
hence protein C does not efficiently
bind to Factor V, hence not
inactivated - hereditary antithrombin deficiency
- protein c or s deficiency
- hereditary elevated levels of
thrombin - elevated levels of VWF
