Clotting cascade - Haemostasis - BB Flashcards
First line of defence against bleeding
Vasoconstriction
In response to endothelial damage - release of endothelins
Endothelins - potent vasoconstrictors/ proteins
What is the most common mechanism of action for coagulation factors
when activated - become serine proteases
Factor X activation
Xa converts
– prothrombin (II) –> Thrombin (IIa)
Trombin (IIa) converts
– Fibrinogen (I) –> Fibrin (Ia)
Tissue factor also known as
thromboplastin
Where is tissue factor expressed?
In sub-endothelial cells (not expressed in endothelial cells)
- therefore no sig exposure to circulating blood
Exposed by endothelial damage
Tissue factor activates which pathway of clotting cascade?
Extrinsic pathway
Interacts with VII to make VIIa
TF:VIIa cofactor - activates factor X
Thrombin causes activation and positive feedback via which clotting factors?
Va (5)
VIIIa (8)
XIa (11)
IXa:VIIIa (9:8 cofactor)
All feedback and activate factor X->Xa
Haemophelia is caused by low levels of which clotting factors?
IXa (9) or VIIIa (8)
Which clotting factor is produced in endothelial cells?
Factor VIII (8)
Multicomponent complexes are what 3 components bound together
and what do they need?
- Active clotting factor functioning as an enzyme
- Co-factor
- Substrate
Requires:
- phospholipid (either from TF bearing cells or platelets)
- calcium (Co-factor)
Substrate is always factor X (–>Xa)
Extrinsic Xase
TF:VIIa
Phospholipid of TF-bearing cells
Enzyme: Factor VIIa
Co-factor: tissue factor (TF)
Substrate: factor X (converting into Xa)
Intrinsic Xase
IXa:VIIIa
Phospholipid: from platelets
Enzyme: factor IXa (9)
Cofactor: Factor VIIIa
Substrate: Factor X
Calcium’s role in clotting cascade:
Required for clot formation
Used to be called factor IV
Stored by platelets - released on activation
NOTE: EDTA in blood-sample-tubes binds to calcium and prevents clotting
Factor XIII (13)
And how is it activated
Crosslinks fibrin - stabilising the fibrin plug
Requires calcium as a co-factor
Activated by thrombin (IIa) formation
Factor XII (12) role:
Can activate factor XI->XIa (11) — Thrombin also does this conversion
Activated contact with negatively charged substance such as silica
Basis for Partial Thromboplastin Time (PTT)
First in the intrinsic pathway
Full coagulation cascade:
Link between inflammation and clotting
Intrinsic pathway requires KININS for normal function
Kinins are generated by factor XII (12a)
Bradykinin significance (and clinical scenarios)
Features:
- Vasodilator
- Increases vascular permeability
- Pain
Clininical scenarios:
- ACE inhibitors can raise bradykinin levels
- DANGEROUS side effect of angioedema - (swelling of face and tongue - C1 inhibitor deficiency
- C1 inhibitor also breaks down bradykinin - and so deficiency leads to hereditary angioedema
Pathway through which bradykinin is generated: (complement)
Factor XII –> XIIa
(XIIa converts)
Prekallikrein (PK) –> Kallikrein
(Kallikrein converts)
High molecular weight Kininogen (HMWK) –> Bradykinin
Prekallikrein deficiency
Rare condition
Results in increased PTT - as intrinsic pathway cannot be activated
NO BLEEDING PROBLEMS - as extrinsic pathway is not affected
3 Important deactivators of coagulation (coagulation inhibitors)
- Anti-thrombin III
- Proteins C and S
- Tissue factor pathway inhibitor
Antithrombin III
Is a serpin protein (inhibitor of serine proteases)
Inhibits serine proteases which are:
=== Factors II,IX,X,XI,XII
Activated by endothelium (heparan sulphate)
- — Prevents clot formation on healthy endothelium
- —- Basis for role of heparin (activates antithrombin)
Deficiency – leads to hypercoagulable state
Which factors do antithrombin activate
II (2) IX (9) X (10) XI (11) XII (12)
Protein C
Produced in liver as zymogen
Activated form - activated protein C (APC)
— Activated by thrombomodulin (cell membrane protein)
APC -> primarily activates factors Va and VIIIa
Protein S
Circulates in active form
Needed by protein C to inactivate factors Va and VIIIa
Thrombomodulin
Cell membrane protein of endothelial cells
Binds to thrombin – to form complex which activates Protein C–> APC
Tissue factor pathway inhibitor (TFPI)
Inactivates Xa via 2 mechanisms:
- directly binds to Xa - deactivating it
- Binds to TF:VIIIa complex preventing X activation
Plasma levels are increased with heparin administration (which may contribute to antithombotic effect)
NOT VERY CLINICALLY RELEVANT
Plasminogen synthesis and activation:
Synthesised in liver as zymogen
Converted to active enzyme - plasmin
- Activated by:
- Tissue plasminogen activator (tPA)
- Urokinase
- Streptokinase
Role of plasmin:
breakdown of fibrin
- broad substrate specificity - also breaks down clotting factors
tPA and Urokinase
Convert plasminogen to plasmin
synthesised by endothelial and other cells
Used as drug therapy for acute MI and Stroke
Streptokinase
Streptococcal protein that activates plasminogen
Can also be used in acute MI and Stroke
2 products fibrin clot breakdown
Fibrin Degradation Products (FDPs)
D-Dimer
Why is D-Dimer more sensitive than FDPs
Because presence of D-Dimers indicates the breakdown of crosslinked clots specifically
FDPs are raised in breakdown of clot and also in the absence:
– In fibrinogen breakdown
Primary fibrinolysis (hyperfibrinolysis)
Rare phenomenon - plasmin is overactive
Causes:
- raised FDPs + normal D-Dimer
Breakdown of fibrinogen (not fibrin) hence no D-Dimer
Plasmin can deplete clotting factors
Presentation and causes of hyperfibrinolysis:
Increased PT/PTT with bleeding (because clotting factors depleted)
—- LIKE DIC
Causes:
- Prostate cancer - release of urokinase
- Cirrhosis - loss of alpha-2 antiplasmin from liver
- – this is an inhibitor of plasmin
D-Dimer test:
Used to diagnose thrombotic disorders
Sensitive but not specific - elevated in many other disorders
Vitamin K
Required for synthesis of many clotting factors (Vitamin K dependent clotting factors)
Vitamin K deficiency – causes bleeding
Warfarin – is a vitamin K antagonist
Vitamin K dependednt clotting factors:
II (2) VII (7) IX (9) X (10) Protein C Protein S
ESR
Erythrocyte Sedimentation Rate
- Rate of RBC sedimentation in a test-tube
— Normal is
M: 0-22mm/hr F: 0-29mm/hr
ESR raised in inflammatory conditions
What causes a raised ESR
Inflammatory conditions - because of increased acute phase proteins in the blood (driven by increased cytokines)
KEY ACUTE PHASE REACTANTS:
- Fibrinogen
- Ferritin
- CRP
