Lesson 5 Flashcards
How many litres of blood to we have circulating in our body?
~5L
What is ‘pro-thrombotic’?
- Stop skin cuts bleeding
- To heal bone fractures
- To prevent fatal haemorrhage when placenta detaches from the uterus after childbirth
What is ‘anti-thrombotic’?
- Prevent arteries & capillaries being constantly blocked
* Prevent strokes, heart attacks, and pulmonary thrombo-emboli
Explain the homeostatic balance regarding blood?
Procoagulant factors = anticoagulant factors
Coagulant, coagulation = clotting, thrombosis
What are three stages of haemostasis following vessel injury?
- Primary haemostasis - formation of unstable platelet plug
- Secondary haemostasis - stabilisation of plug with fibrin (blood coagulation system)
- Dissolution of clot and vessel repair (fibrinolysis & recanalisation)
What are the four components of haemostasis?
- vessel wall - vascular endothelial cells
- platelets
- coagulation system
- fibrinolytic system
Defects in any of these leads to too much clotting (or little)
Explain the events that follow arterial injury?
- Vascular spasm - smooth muscle contracts -> vasoconstriction
- Platelet plug formation - injury to vessel lining exposes collagen fibres -> platelets adhere, platelets release chemicals (make sticky)
- Coagulation - fibrin forms mesh -> traps RBCs/platelets -> clot
What do endothelial cells secrete to initiate platelet plug formation?
von Willebrand factor
What normally happens within blood vessels?
Endothelial cells of intact vessels produce coagulation inhibitors (heparin-like molecule and thrombomodulin) which prevent clotting, and NO and prostacyclin which prevent platelet aggregation
Provide a description on platelets?
- 2-4 μ diameter
- anucleate cells
- lifespan 7-10 days
- megakaryocytes in marrow
- intracellular granules
- normal count = 150-450 x 10^9/l
- function: maintenance of vascular integrity
- activated by blood vessel injury
Describe the formation of primary haemostat plug by platelets
- adhere to subendothelial structures via von Willebrand factor (VWF)
- adhere to each other (aggregation)
- form a platelet plug held to together by insoluble fibrin
Describe the coagulation system to form clots
Series of inactive components (‘factors’) converted to active components
Prothrombin -> THROMBIN -> fibrinogen -> fibrin
Fibrinogen and other clotting factors circulate in the blood
What are the steps in the blood clotting cascade?
INTRINSIC PATHWAY - Damaged endothelial lining of blood cells promotes binding of factor XII
EXTRINSIC PATHWAY - Trauma releases tissue factor (factor III)
- > factor x activation - common endpoint for both pathways
- > thrombin activation
- > formation of fibrin clot
Cascade allows formation of a clot from activation of very small amounts of the initial factor
How many factors are apart of proteins of blood coagulation?
1-13
Give general facts regarding the coagulation system
1 ml of blood can generate enough thrombin to convert all the fibrinogen in the body to fibrin
Tight regulation therefore required
Balance of procoagulant and anticoagulant forces
What are two proteins that aid in turning off the coagulation system?
Antithrombin III
Protein C and S
alpha 2 macroglobulin
How does antithrombin III help in turning off the coagulation system?
- serine protease inhibitor
- Inhibits thrombin and 10a
How does protein C help in turning off the coagulation system?
- 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 i.e. thrombophilia
What are some of the most common thrombosis disorders?
Deep vein thrombosis (DVT) Pulmonary embolism (PE)
Collectively known as venous thromboembolism (VTE)
Briefly explain inherited thrombophilias
- Genetically determined disorders of haemostasis
- Increased risk of VTE
Many single gene defects
Factor V Leiden (1 in 20 people)
Protein C deficiency
What are the general rules regarding disorders of coagulation and haemostasis?
- Inherited disorders are single gene mutations
present as bleeding thrombosis in an otherwise well patient - Acquired bleeding disorders can affect any/all parts of the clotting pathways
arise in patients who are already systemically ill
multi-organ failure (liver damage, sepsis etc)
What is fibrinolysis?
When clots form, automatically the body starts breaking them down
An example of ‘balance’ - homeostasis
- Natural local secretion of enzymes
- Iatrogenic enhancement – ‘clot busting’ – via drugs eg streptokinase
State the steps of fibrinolysis
Plasminogen -> Plasmin 3 classes of fibrinolytic drugs: t-PA - tissue plasminogen activator streptokinase urokinase
Plasmin proteases fibrin -> clot dissolves (fibrin fragments)
Summarise the 4 phases of haemostasis?
- Vascular spasm
- Platelet plug formation
- Blood clotting (coagulation system)
- Clot breakdown (fibrinolytic system)
Clot formation is tightly controlled; clots are formed by ______ ________ of _______ to form _____.
Proteolytic cleavage
Fibrinogen
Fibrin
Process reversed by the enzyme ______ causing ________ _______ of fibrin - _________
Plasmin
Proteolytic cleavage
Fibrinolysis
________ process can be disrupted in certain genetic diseases. eg __________
Clotting
Haemophilia
What are laboratory blood tests of haemostasis?
Full blood count (FBC) - platelets
Clotting screening tests:
- Prothrombin time (PT) - measures the EXTRINSIC PATHWAY (factors VII, X, V, II and fibrinogen) – also called the INR test
- Activated partial thromboplastin time (APTT) - measures the INTRINSIC PATHWAY plus the final common pathways (factors XII, XI, X, IX, VIII, V, II and fibrinogen).
What are two signs of platelet disease?
- Abnormal numbers
- Abnormal function
Or combination of 1 + 2
What is the number of platelets during surgical bleeding?
surgical bleeding < 50 x 10^9/l
What is the number of platelets during spontaneous bleeding?
spontaneous bleeding < 20 x 10^9/l
What is the number of platelets if there are spontaneous small vessel platelet clots?
> 500 x 10^9
What is warfarin?
“to thin the blood” and prevent thromboses
Vitamin K antagonist
Inhibits hepatic synthesis of clotting factors II, VII, IX and X.
What are problems with warfarin?
- difficulties in determining dose – this has to be done empirically in each patient with frequent monitoring the INR (measure of prothrombin time).
- narrow therapeutic window
- drug/diet interactions
- delay in efficacy as pre-existing factors is still available for use. Therefore, an immediate acting anticoagulant, such as low molecular weight heparin, is needed while warfarin begins to work.
What can we do the manage bleeding whilst on warfarin?
- Vitamin K - overcome the vitamin K antagonism + allow synthesis of vitamin K dependent clotting factors
- Prothrombin complex concentrate (PCC – a mix of factors II, VII, IX and X) if immediate reversal needed
NOTE: warfarin is cheap but always easy to use.
More recent oral anticoagulants do NOT require therapeutic monitoring (but are more expensive).
What does DIC stand for?
Disseminated intravascular coagulation
What does TTP stand for?
Thrombotic thrombocytopaenia purpura
Give a brief description of both DIC and TTP?
Small vessel thromboses
Paradox – how can intravascular coagulation/thrombosis states lead to excess bleeding [purpura]?
What is DIC?
Consumption coagulopathy.
Within circulation, clotting is accelerated.
Consumes clotting factors faster than replaced – subnormal clotting factors
Spontaneous bleeding commences in many organs – can be fatal.
Causes: sepsis etc
What is TTP?
Platelet masses (thrombi) in small vessels
Low blood platelets & normal clotting factors
Abnormal von Willebrand factor
Purpuric bleeding in kidney, skin, brain, gut, and heart
What is the definition thrombosis?
Thrombosis is the formation of a solid mass of blood clot within the circulatory system
Describe Virchow’s triad?
Venous • Stasis of flow • Blood constituent Arterial • Blood constituent • Vessel wall intima damage
What are the risk factors of venous thromboembolism (VTE)?
- age
- previous VTE
- malignancy
- immobility/bed rest
- post-operative
- trauma
- pregnancy and puerperium
- oral contraceptives / HRT
- inherited thrombophilia
- obesity
- smoking
What are risk factors of arterial thrombosis?
- age
- smoking
- obesity
- atherosclerosis
- hypertension
- hypercholesterolaemia
- diabetes
- ethnicity - being of south Asian ancestry
Describe what arterial thrombi look like on a histology slide?
- Pale/red
- granular
- lines of Zahn – alternating lines of red cells and thrombus strands
What are the effects of arterial thrombosis?
- ischaemia and infarction
- depends on site and collateral circulation
E.g heart muscle necrosis (death of tissue), myocardial infarction
What are the effects of venous thrombosis?
congestion, oedema, haemorrhage
If the limb provides a very white appearance what form of thrombosis is this representative of?
Thrombosis of proximal artery
White = bloodless – limb
What is propagation? (Outcome of thrombosis)
- progressive spread of thrombosis
- distally in arteries
- proximally in veins
What is lysis? (Outcomes of thrombosis)
- complete dissolution of thrombus
- fibrinolytic system active, clot busted and blood flow re-established
- therapeutic: DVT signs & symptoms treated with warfarin
What is embolism? (Outcomes of thrombosis)
part of thrombus breaks off travels through bloodstream lodging at distant site
What are the effects of pulmonary embolism?
massive PE >60% reduction in blood flow rapidly fatal (haemodynamic compromise)
major PE - medium sized vessels blocked. Patients short of breath, pleuritic chest pain +/- cough and blood stained sputum (haemoptysis)
minor PE - small peripheral pulmonary arteries blocked. Asymptomatic or minor shortness of breath
recurrent minor PEs lead to pulmonary hypertension
Define embolism
Embolism is the blockage of a blood vessel by solid, liquid or gas at a site distant from its origin.
>90% of emboli are thrombo-emboli
What does thromboemboli depend on?
- Venous or arterial
2. Site of origin
What is venous thromboemboli?
systemic veins -> lungs = PE, pulmonary embolism
What is arterial thromboemboli?
- From heart via the aorta -> renal, mesenteric
- atheromatous carotid arteries -> brain (CVA)
- atheromatous abdominal aorta -> legs
If heart valve thrombi gets into the spleen what can it cause?
Splenic infarction
If atheromatous aorta gets into leg arteries what can it cause?
Foot necrosis (gangrene)
Explain what organisation is in relation to outcomes of thrombosis?
- reparative process
- growth of fibroblasts + capillary proliferation (similar to granulation tissue), which result in attachment of thrombus to vessel wall
Explain what recanalisation is in terms of outcomes of thrombosis?
- 1+ channels formed through organising thrombus
* blood flow re-established - usually incompletely
What are some causes of embolism?
Air
Nitrogen
Fat
Amniotic fluid
What are mechanical methods for prevention of VTE?
Anti-embolism stockings (AES)
Intermittent pneumatic compression
Foot impulse devices
What are pharmacological methods for prevention of VTE?
• Prophylaxis will depend on: ○ medical condition ○ suitability for the patient ○ local policy • Subcutaneous low molecular weight heparin (LMWH) • Direct oral anticoagulants
What are examples of anticoagulants used in VTE treatment?
- IV heparin
- Warfarin
- Direct oral anticoagulants (direct Xa inhibitors and direct thrombin (IIa) inhibitors)
What are some indications for the need of anticoagulants?
- VTE (DVT or PE)
- Atrial fibrillation
- Mechanical heart valves
Provide information on heparin?
- naturally occurring anticoagulant
- potentiates effect of antithrombin III
- mixture of glycosaminoglycan chains extracted from porcine mucosa
- unfractionated heparin (UH)= IV = monitoring by APPT, dose adjusted
- LMWH = SC = mixture of smaller chains = more predicable anticoagulant effect. dose calculated by body weight
- Fondaparinux = synthetic
• antidote = protamine sulphate: UH > LMWH > Fondaparinux
What are examples of direct oral anticoagulants?
Direct Xa inhibitors e.g. rivaroxaban, apixaban, edoxaban Direct thrombin (IIa) inhibitors e.g. dabigatran
Relatively new drugs
Licensed for treatment and prevention of VTE
What are advantages of direct oral anticoagulants?
Oral, no monitoring, predictable pharmacokinetics, rapid onset of action, minimal drug / food interactions
What is platelet function in primary homeostatic plug?
Adhesion - surface glycoproteins, vWF
Activation - ADP, thrombin and thromboxane
Release reactions - granule contents
Aggregation - ADP, thromboxane A2
What does venous thrombi look like?
- soft
- gelatinous
- deep red - deoxygenated
- higher cell content
What is classic haemophilia (defect in factor VII)?
- FVIII (‘antihaemophilic factor’) not a protease, stimulates activity of FIXa (serine protease)
- Activity of FVIII increased by proteolysis by thrombin and FXa. Positive feedback amplifies clotting signal, accelerates clot formation.
- Reduced/absent FVIII results in reduced/absent clotting and prolonged bleeding.
- Treatment with recombinant FVIII.
