Lecture 5.1: Haemostasis & Thrombosis Flashcards
What is Haemostasis?
The complex process that stops bleeding
What is Pro-Thrombotic?
• Stop skin cuts bleeding
• To heal bone fractures
What is Anti-Thrombotic?
• Prevent arteries & capillaries being constantly blocked
• Prevent strokes, heart attacks, and pulmonary thrombo-emboli
Stages of Haemostasis following Vessel Injury (3)
1) Primary Haemostasis - formation of unstable
platelet plug
2) Secondary Haemostasis - stabilisation of plug
with fibrin (blood coagulation system)
3) Dissolution of clot and vessel repair (fibrinolysis
& recanalisation)
Formation of Primary Haemostat Plug
1) Adhere to subendothelial structures via von
Willebrand factor (VWF)
2) Adhere to each other (aggregation)
3) Form a platelet plug held to together by
insoluble fibrin
What are the 4 Core Components of Haemostasis?
1) Vessel Wall - vascular endothelial cells
2) Platelets
3) Coagulation System
4) Fibrinolytic System
Clotting Factors: How to get from Prothrombin to Fibrin?
Prothrombin to Thrombin to Fibrinogen to Fibrin
Blood Clotting Cascade: Extrinsic Pathway
• Trauma releases Tissue Factor (Factor III)
• Endpoint of Factor X Activation
• Thrombin Activation
• Fibrin Clot Formation
Blood Clotting Cascade: Intrinsic Pathway
• Damaged endothelial lining of blood cells
promotes binding of Factor XII
• Endpoint of Factor X Activation
• Thrombin Activation
• Fibrin Clot Formation
Where are most proteins of blood coagulation made?
In the Liver
Why is tight regulation of the Coagulation System required?
Because 1 ml of blood can generate enough thrombin to convert all the fibrinogen in the body to fibrin
Thus a balance of procoagulant and anticoagulant forces is needed
Turning off the Coagulation System: Antithrombin III
• Serine protease inhibitor
• Inhibits thrombin and 10a
Turning off the Coagulation System: Protein C
• Vit K dependent zymogen
• Activated into serine protease by thrombin binding to endothelial receptor
thrombomodulin
• Cleaves co factors Va and VIIIa
• Deficiency tends to encourage thrombus formation
What are the most common thrombosis disorders?
• Deep Vein Thrombosis (DVT)
• Pulmonary Embolism (PE)
• These are collectively known as Venous
Thromboembolism (VTE)
What are Thrombophilias?
Diseases where the blood has an increased tendency to form clots
How do Inherited Disorders of Coagulation and Haemostasis generally occur?
• Single gene mutations
• Present as bleeding / thrombosis in an otherwise well patient
• E.g. Factor V Leiden (1 in 20 people), Protein C deficiency
How do Acquired Disorders of Coagulation and Haemostasis generally occur?
• Can affect any / all parts of the clotting pathways
• Arise in patients who are already systemically ill,
often with multi-organ failure
• E.g. Liver Damage, Sepsis
What is Fibrinolysis?
The breakdown of clots
What is used for Iatrogenic Enhancement of Fibrinolysis?
Streptokinase
Process of Fibrinolysis
Plasminogen to Plasmin
Plasmin converts Fibrin to Fibrin Fragments
Fibrinolytic Drugs
• Streptokinase
• Tissue Plasminogen Activator (t-PA)
• Urokinase
Fibrinolysis Inhibiting Drugs
Alpha 2 macroglobulin antiplasmin
What is Haemophilia?
• A rare condition that affects the blood’s ability to
clot
• X-Linked Recessive
• Spontaneous Internal Bleeding
• Painful Haemarthrosis
Laboratory Blood Tests of Haemostasis (3)
• Full Blood Count (Platelets)
• Prothrombin Time (PT) aka the INR Test-
measures the Extrinsic Pathway
• Activated Partial Thromboplastin Time (APTT) -
measures Intrinsic Pathway
Why is Vitamin K crucial to the Clotting Cascade/ Haemostasis?
• Vitamin K is processed in the liver
• Required to make factors II, VII, IX, Xi ie
extrinsic & intrinsic pathway factors
• Also required to make Proteins C & S
Anticogulant
What is the normal count for platelets?
150-450 x 10^9/L
What is Warfarin?
• It is a blood thinner
• Vitamin K antagonist
• Inhibits hepatic synthesis of clotting factors II,
VII, IX and X
Problems with Warfarin (4)
1) Difficulties in determining dose
2) Narrow Therapeutic Window
3) Drug/diet interactions
4) Delay in efficacy as pre-existing factors is still
available for use
How to calculate dose of Warfarin?
This has to be done empirically in each patient with frequent monitoring the INR (measure of prothrombin time)
How to overcome bleeding whilst on Warfarin? (2)
1) Vitamin K to overcome the vitamin K
antagonism and allow synthesis of vitamin K
dependent clotting factors
2) Prothrombin complex concentrate (PCC – a
mix of factors II, VII, IX and X) if immediate
reversal needed
What is DIC?
• Disseminated intravascular coagulation
• Condition in which small blood clots develop
throughout the bloodstream
• This blocks small blood vessels
What is the Pathophysiology of DIC?
• Mechanism of Thrombosis is via the tissue factor (TF)/factor VIIa pathway
• Consumes clotting factors faster than they can be replaced
• Results in subnormal clotting factors
• Then spontaneous bleeding commences in many organs – and can be fatal
What is TTP?
• Thrombotic Thrombocytopaenia Purpura
• Blood clots form in small blood vessels throughout your body
• Platelet masses (thrombi) in small vessels
• Can limit or block the flow of blood to your organs (brain, kidneys & heart)
What is the Pathophysiology of TTP?
• Patients have unusually large multimers of von Willebrand factor (vWF) in their
plasma
• They lack a plasma protease responsible for the breakdown of these large
vWF multimers
What is Thrombosis?
Thrombosis is the formation of a solid mass of blood clot within the circulatory system
Virchow’s Triad
• Venous Stasis
• Vascular Injury
• Hypercoagulability
Risk Factors for Venous Thromboembolism? (11)
• Age
• Previous VTE
• Malignancy
• Immobility/bed rest
• Post-operative
• Trauma
• Pregnancy and Puerperium
• Oral Contraceptives / HRT
• Inherited Thrombophilia
• Obesity
• Smoking
What is a Thromboembolism?
When a blood clot (thrombus) that forms in a blood vessel breaks loose, is carried by the bloodstream, and blocks another blood vessel
What is an Embolism?
Embolism is the blockage of a blood vessel (artery) by a solid, liquid or gas at a site distant from its origin
Risk Factors for Arterial Thrombosis (8)
• Age
• Smoking
• Obesity
• Atherosclerosis
• Hypertension
• Hypercholesterolaemia
• Diabetes
• Ethnicity (South Asian Ancestry)
What do Arterial Thrombi look like on a Histology slide?
• Pale/Red
• Granular
• Lines of Zahn – alternating lines of red cells and
thrombus strands
Effects of Arterial Thrombosis
• Ischaemia
• Infarction
• Depends on site and Collateral Circulation
Effects of Venous Thrombosis
• Congestion
• Oedema
• Haemorrhage
What does a white/very pale limb mean?
• The limb is bloodless
• Thrombosis of Proximal Artery
Outcomes of Thrombosis: Propagation
• Progressive spread of thrombosis
• Distally in arteries
• Proximally in veins
Outcomes of Thrombosis: Lysis
• Complete dissolution of thrombus
• Fibrinolytic system active, clot busted and blood flow re-established
• Therapeutic: DVT signs & symptoms treated with warfarin
Outcomes of Thrombosis: Embolism
• Part of thrombus breaks off travels through
bloodstream lodging at distant site
Outcomes of Thrombosis: Organisation
• Reparative process
• Growth of fibroblasts and capillary proliferation (similar to granulation tissue)
• These result in the attachment of the thrombus to the vessel wall
Outcomes of Thrombosis: Recanalisation
• One or more channels formed through organising thrombus
• Bloodflow re-established but usually incompletely
Effects of Major Pulmonary Embolism
• Medium sized vessels blocked
• Patients short of breath
• Pleuritic chest pain +/- cough and blood
• Stained sputum (Haemoptysis)
Effects of Massive Pulmonary Embolism
• >60% Reduction in Bloodflow
• Rapidly Fatal
• Haemodynamic Compromise
Effects of Minor Pulmonary Embolism
• Small peripheral pulmonary arteries blocked
• Asymptomatic or minor shortness of breath
Effects of Recurrent Minor Pulmonary Embolisms
• Leads to pulmonary hypertension
VTE Prevention (7)
• Wearing anti-embolism stockings
• Inflatable sleeves to wear around the legs and
feet
• Blood thinners to reduce the chance of a blood
clot
• Moving and walking where possible when in
hospital
• Drinking plenty of fluid to keep hydrated
• At risk patients must be offered Prophylaxis
• Risk assessment for VTE and bleeding
What is Prophylaxis?
Treatment given or action taken to prevent disease
What is DVT?
• Deep Vein Thrombosis
• A blood clot that develops within a deep vein in
the body, usually in the leg
Risk Factors for DVT (5)
• Being a Frequent Flyer
• Age
• Pregnancy
• Smoking
• Obesity
Preventions of DVTs (5)
• Anti-Embolism Stockings (AES)
• Intermittent Pneumatic Compression
• Foot Impulse Devices
• Subcutaneous Low Molecular Weight Heparin
(LMWH)
• Direct Oral Anticoagulants
Anticoagulants as Treatments for VTE (3)
• IV heparin
• Warfarin
• Direct oral anticoagulants (direct Xa inhibitors &
direct thrombin (IIa) inhibitors)
Mechanism of Action of Heparin
• Naturally occurring anticoagulant
• Potentiates effect of antithrombin III
• Mixture of glycosaminoglycan chains extracted
from porcine mucosa
How do you reverse the effects of Heparin?
Administer Protamine Sulphate
Direct Oral Anticoagulants: Direct Xa Inhibitors
• Rivaroxaban
• Apixaban
• Edoxaban
Direct Oral Anticoagulants: Direct Thrombin (IIa) Inhibitors
• Dabigatran
Advantages of Direct Oral Anticoagulants
Oral no IV needed
No monitoring
Predictable pharmacokinetics
Rapid onset of action
Minimal drug / food interactions
What is the Wells Score?
A number that reflects your risk of developing deep vein thrombosis (DVT)
How is the Wells Score calculated?
What is the D-dimer Test?
• Used to find out if you have a blood clotting disorder
• D-dimer is a fibrin degradation product
• A small protein fragment present in blood after fibrinolysis of blood clot
‘Classic’ Haemophilia
• FVIII (‘antihaemophilic factor’) not a protease, but stimulates the activity of
FIXa , a serine protease
• Activity of FVIII increased by proteolysis by thrombin and FXa
• Positive feedback amplifies clotting signal, accelerates clot formation
• Reduced FVIII results in reduced/absent clotting and prolonged bleeding
• Treatment with recombinant FVIII
How much blood is there in the body?
~5 litres of blood in our body circulation
Why is blood essential to the body?
For delivering O2, nutrients…etc to tissues
