Clotting disorders Flashcards
Haematology : Primary Haemostasis
1 . __Endothelial injury__
* Endothelin released causing vasospasm of smooth muscle
2 . Post injury - Endothelial collagen exposure
3 . Von Willibrand factor
* Released by damaged endothelial cell
* Bind to exposed endothelial collagen
4 . Adhesion
* Platelets bind to VWF on collagen via GP1B surface protein } Activates platelets
5 . Activation of platelets - causing release of;
I) VWF - attract more platelets
I) Adenosine diphosphate (ADP) and Thromboxane A2
* Act on free platelets : cause expression of GPIIB/IIA surface protein
6 . Fibrinogen - circulating blood protein
* Binds to GPIIB/IIA surface protein on platelets } ties them together
7 . Platelet plug formed
* NO + Prostaglandin release by undamaged endothelial cell - platelet inhibitor to manage size of plug
Haematology : Secondary Haemostasis - Extrinsic athway
Process of forming a fibrin mesh to reinforce the platelet plug
1. Damaged blood vessel - exposes smooth muscle
* Smooth muscle : Tissue Factor 3 on surface
2 . Factor VII (7) binds to a Factor III (3) and a calcium ion
* VIIa-TF complex on the surface of the smooth muscle cells
3 .IIa-TF complex cleaves clotting factor X
* Factor X —activated—> Factor Xa (10a)
4 . Factor Xa (10a) activates Factor V (5)
* Factor Va (5a)
5 . Factor Va (5a) binds to Ca2+ ion
* *Prothrombinase complex*
6 . Prothrombinase complex activates Factor II (2) (Prothrombin)
* Thrombin (Factor IIa (2a))
Haematology : Secondary Haemostasis - Post Factor 2 activation
__Factor II (2) activates to following clotting factors;__
1. Factor V (5) } common pathway
2. Factor VIII (8)
Fibrin mesh formation
3 . Fibrinogen (Factor 1) —> Fibrin (Factor Ia)
* Fibrin tether platelets to one another and hold the platelet plug together
4 . Factor XIII (13) —> Factor XIIIa (13a)
i) Factor XIIIa (13a) + Calcium ion
* Reinforces fibrin mesh - by forming crosslinks between Fibrin chain
Haematology : Instrinsic Pathway
1. Factor XII (12) + Phosphate ion —-activation—> Factor XIIa (12a)
* PO4- ion on surface of activated platelets/endothelial collagen from injury
2. Factor XII (12) activates Factor XI (11)
* Factor XIa (11a)
3. Factor XIa (11a) activates Factor IX (9)
* Factor IXa (9a)
5. Factor IX (9) —Factor XIa (11)——-activation —-> Factor IXa (9a)
6. Factor IXa (9) + Ca2+ion + Factor VIIIa (8a) complex } activates Factor X
* Factor Xa (10a)
Haematology : Common Pathway
- Factor X (10) is cleaved -> Factor Xa (10a)
- Factor Xa (10a) + Factor V (5) -> Factor Va (5a)
- Factor Xa (10a) + factor Va (5a) + calcium -> Prothrombinase complex
- Prothrombin (FactorII) —> thrombin (factor IIa)
Thrombin activates platelets, cofactors ( V, VII, IX);
- Cleaves fibrinogen
- Stabilising factor -> factor XIIIa + calcium -> cross-links in mesh
Vitamin K : Physiology
Fat soluble vitamin K (phylloquinone)
1. Stomach absorption : via emulsification by bile salts
2. Small intestine : integrated into chylomicrons
Transported via portal circulation
3. Liver : Vitamin K used to synthesis
* Clotting factors : II, VII, IX, X
* Anticoagulant : Protein C and Protein S -
Vitamin K deficiency : Causes
1 . Issues with fat absorption :
* Diseases of small intestine/gall bladder
* Prolonged use of abx - elimination of gut flora/diarrhoea
2 . Liver disease: unable to synthesise coagulation factor/anticoagulant
Vitamin K deficiency : Diagnosis
Prothrombin time + APTT + INR } Prolonged
Vitamin K deficiency : Management
1 . SC injection of Phytonadione
2 . Increase consumption of dietary vitamin K - ie. Green, leafy vegetables
Vitamin K : Production of clotting factors
Which clotting factors?
Vitamin K is important in the production of coagulation factors;
(extrinsic pathway)
__1. Factor 2 (Prothrombin)__
__2. Factor 7__
__3. Factor 9__
__4. Factor 10__
Warfarin MOA
- Inhibits production of Vitamin K
- Prevents co-factors 1972
- Protein C
Partial Thromboplastin time : MOA
- Partial thromboplastin time
* Activity of Intrinsic pathway factors
* Factor 8, 9, 11, 12
INR : Definition
- Standardised version of Prothrombin time
Haemophilia A : Definition
- Most **common inherited haemophilia **
- X linked recessive disorder of factor IX (9)
Haemophilia A : Pathophysiology
- Deficiency in Factor 8
- Leads to : Impaired inactivation of intrinsic pathway —> Defect in common coagulation pathway
- Increased bleeding
Haemophilia A : Clinical features
1. Haemoarthrosis within joints
2. Spontaneous bleeding - easy bruising, haematoma
Haemophilia A : Diagnosis
- __Partial thromboplastin time__ : ___Prolonged___ - Intrinsic pathway affected
- __Prothrombin time__ : ___Normal___ - Extrinsic pathway not affected
- Platelet count : Normal
Haemophilia A : Management
- Desmopressin : stimulates von Willebrand factor release, promotes stabilisation of residual factor VIII release.
- Factor VIII infusions
Haemophilia B - Definition
X linked deficiency of factor 9 affecting the clotting in the intrinsic pathway
Haemophilia B - Pathophysiology
1.. Deficiency in Factor 9 protein
2.. Intrinsic pathway affected : Factor 9 combines with Factor 8 to activate factor 10
3. Impaired Haemostasis
Haemophilia B - Diagnosis
- Partial thromboplastin time : ___Prolonged___ - Intrinsic pathway affected
- Prothrombin time : Normal - Extrinsic pathway intact
- Factor IX clotting levels : Low
Haemophilia B - Management
1. Factor IX infusion
(Desmopressin is not effective - stimulates vWF which only stabilises factor VIII)
Von Willebrand disease : Definition
- Inherited autosomal dominant mutation of allele
* Leading to : Insufficient production of vWF factor
* Most common inherited bleeding ddisorder
Von Willebrand disease : Pathophysiology
1. Von Willebrand factor
* synthesised and stored in the endothelial (blood vessel) cells and platelets.
2. Injury to blood vessel
* releases histamine and thrombin which stimulates endothelial/platelet cells to produce vWF factor
3. WF factors works to :
* Attach to platelet receptors and binds platelets to site of injury
* Binds to Factor VIII to prevent degradation by protein C + protein S
4. Deficiency of function/amount of vWF leads to __impairs platelet aggregation__
- causes dysfunction of factor VIII.
Von Willebrand disease : Clinical features
Excessive bleeding from minimal trauma ;
* Epitaxis
* Mucosal bleeding
* Menorrhagia
Typically no haemotoma/haemoarthrosis
Von Willebrand disease : Diagnosis
VwF deficiency leads to low Factor 13 levels
1. APTT time : Prolonged
1. Low Factor 8 levels : higher rate of breakdown from Protein C/S
Von Willebrand disease : Management
1. Tranexamic acid : mild bleeding
2 . Desmopressin :
* Raises levels of vWF
* induces release of vWF from Weibel-Palade bodies which are storage granules of vWF in endothelial cells
Direct factor Xa inhibitors : Example
- Rivoroxaban
* Excreted by Liver - Apixaban
- Endoxaban
Direct factor Xa inhibitors :Reversal
Andexanet alfa* except for Endoxaban
*Andexanet alfa is a recombinant form of human factor Xa protein
Direct thrombin inhibitor : Example
Dabigatran
Direct thrombin inhibitor : Reversal
Idarucizumab
would typically feature constitutional symptoms, as well as bleeding and recurrent infections.
Neutropenia and thrombocytopenia
Acute rapid production of immature cells
Chronic - mature cells, elevated lymphocytes, CML granulocytosis
