Laura young Flashcards
Where do platelets come from and how do they get into the blood?
They bud of megakaryocytes. They are located next to the bone marrow sinusoidal endothelial cells and extend filopodia into the capillaries. 4000 platelets/ megakaryocyte
What is in platelets?
Alpha granules that contain fibrinogen, factor V, vWF, fibronectin
Dense granulse: ADP, Ca2+, Mg2+, serotonin, nucleotides
What is primary and secondary haemostasis?
Primary - platelet plug at the site of vessel injury
Secondary - formation of fibrin
What is the process of primary haemostasis?
Constriction of the vessel wall.
Platelets become activated and aggregate the site of injury, forming a temporary loose plug.
What happens to a platelet when it becomes activated?
It changes from round to pointy with filopodia. It releases granules. Forms surface for coagulation pathway.
The released granules recruit more platelets.
How do platelets form a plug?
Endothelial cells produce vasodilators (NO). Damage stops this production.
Injury exposes collagen, which circulating vWBF binds. The platelet binds to vWBF with GP-1B-V-IX.
The platelet get pulled into the wound in a rolling motion and the platelet activates.
The activated platelets change shape and release their granules to attract more platelets (ADP, TxA2) and cause vasoconstriction (serotonin, ADP and TxA2).
The shape change also exposes integrin alpha-2bB3, which binds to other platelets via fibrinogen.
Clotting pathway then starts on the platelet surface. Platelets released some factors in the coagulation pathway.
What is the function of thromboxane A2?
It is produced by platelets and it decreases cAMP levels, which increases platelet Ca2+ and results in granule release and platelet activation. This is reduced by prostacyclin produced by intact endothelial cells.
Aspirin blocks COX, which is involved in production of TxA2.
What changes the number of platelets in the blood?
Decrease production - virus infection, drugs, bone marrow failure
Increase destruction - immune thrombocytopenia, DIC
Increase production - myeloproliferative disease - polycythaemia vera, essential thrombocythemia, primary myelofibrosis
What is thrombocytopenia?
Decreased platelets.
Recurrent epistaxis and easy bruising. Petechiae
Caused by anthing that reduces the number of megakaryocytes:
Decrease production- viruses or drugs, BM failure.
Increased destruction - immune thrombocytopenia (antibodies bind -> opsonisation), disseminated intravascular coagulation, glandular fever (caused by EBV)
Other: hypersplenism (pool of platelets in spleen)
What is immune thrombocytopenia?
Antibodies bind platelets -> opsonisation. With reduced platelet production.
Treat with prednisone. Remove spleen.
Thrombopoietin receptor agonist treatment.
What is haemostasis and thrombosis?
Normal situation where a blood clot is formed to heal vascular damage.
Thrombosis is the unnecessary formation of a clot.
What is the start of the extrinsic pathway?
Tissue factor and Factor VIIa
Where is tissue factor expressed?
On the subenothelial tissues. Exposed with tissue damage.
What are calcium and phospholipids required for?
Required on the platelet membrane to stabilize the proteins on the platelet membrane.
Where does fibrinogen come from?
It is in the plasma. Links together to form fibrin.
What inhibits the first complex?
Tissue factor pathway inhibitor (TFPI) - inhibits factor VII, TF
What do protein C and S inhibit?
Factor VIII and factor V
What does anti-thrombin do?
Inhibits Xa, IXa and thrombin
What does Factor XIII do and what activates it?
Cross-links the fibrin molecules and is activated by thrombin (factor IIa). Creates the D-dimers by cross-linking.
What are the functions of thrombin?
Converts fibrinogen into fibrin.
Activates factors V, VIII, XI, XIII and protein C.
Platelet activation
What are the two classes of functional enzymes?
Proteases and co-factors.
What are the vitamin K dependent factors?
Factor II, VII, IX, X, protein C and protein S
What does vitamin K do?
Enables the factors to bind to the platelet membranes.
Controls folding of the factors GLA domains to allow them to bind to the platelet membrane.
It carboxylates the glutamate residues in the GLA domain. Also need Ca2+
How is vitamin K absorbed?
Vit K is a fat soluble vitamin that you need bile to absorb. Liver disease = no vit K absorption.
Give vitamin K to prevent haemorrhagic disease of the newborn.
Do natural inhibitors change the laboratory tests?
No - only function in the blood, don’t change the tests.
What can you do to determine if clots are breaking down?
Look for the D-dimers in the blood.
How are clots broken down?
Plasminogen is cleaved to plasmin by tissue plasminogen activator.
Plasmin then breaks down clots. Gives of D-dimers.
What factors are you looking at in an APTT?
All factors are involved except TF. But the ones you are assessing relative to a PR is factor XII, XI, IX and VIII
How is an APTT performed?
You take a venous blood sample. Calcium is removed by citrate in the tube. Collect the plasma. Add phospholipids and an activator. Add calcium and measure time to clot formation
What is the starting point of the PR ratio and what factors is it assessing?
It starts with the addition of heaps of TF, which favtor VII binds to activate factor X, which activates thrombin. No amplification step required because of the excess thrombin. Complex 1 is sufficient.
What factors deficiency would prolong the PR?
VII, X, V, prothrmbin or fibrinogen
What test would identify a co-factor deficiency?
Factor V - PR
Factor VIII - APTT
What are the inhibitors of thrombin?
Heparin
Dabigitran
How does a thrombin clotting time work?
Add activated thrombin and see how quickly it converts fibrinogen into fibrin.
This is a check for inhibitors of thrombin
What prolongs the APTT 1+1?
Lupus anticoagulant
Heparin
Dabigatran
Autoimmune antibodies against factors- usually factor VIII
How do lupus anticoagulants work?
There are antibodies in the plasma that bind to phospholipids. In the lab this is an inhibitor but in the body there is too much phospholipid to have any effect.
How does heparin prolong the APTT 1+1?
It upregulates antithrombin
Hoe do you determine if a prolonged APTT 1+1 is caused by heparin?
Use protamine, which inhibits heparin
How does dabigatram work?
Direct inhibitor of thrombin.
How do you differentiate between a lupus anticoagulant and a dabigatran inhibition?
Use the TCT
Which is more sensitive PT or APTT?
PT, so you may have a slow PT and normal APTT with mild II, X, V
What is the cause of a prolonged APTT and PR?
Multiple factor deficiency or a deficiency of either X, II, or V
What does a prolonged TCT indicate?
A thrombin inhibitor or a deficiency of fibringogen
What are the most common causes of multiple factor deficiencies?
Bleeding - loss of coagulation factors and dilation of fluids.
Warfarin or vitamkin K deficiency (II, VII, IX, X)
DIC - depletion of clotting factors
Liver disease
Most common causes of prolonged APTT and PT?
Warfarin
Vitamin K deficiency
Liver disease
How does warfarin work?
It inhibits the recycling of vitamin K.
What may be the issue with a prolonged APTT bt normal PT?
Factor VIII or IX deficiency - haemophillia - sequence factors
Administer recombinant
What is von willebrand’s disease?
vWBF binds to factor 8 in the circulation and stabilises it. So a deficiency in vWF can cause both platelet and factor VIII deficiency
What can cause DIC?
Meningicoccal septicaemia
What are the three components of virchow’s triad and some examples of those?
Blood stasis
Hypercoagulability
Vascular injury
Vascular injury - artherlosclerotic plug -MI
Trauma
Thrombosis
Stasis Post operative Economy class syndrome Pressure from a catheter or tumour Increased viscosity from polycythaemia, dehydration, or EPO.
Hypercoagulability: increased procoagulants, decreased inhibitors
What are the two manifestations of a deep vein thrombosis?
Clot in lower legs
Pulmonary embolism
How do you diagnose DVT?
Clinical symptoms:
DVT: Leg swelling, pain, oedema.
Look for D-dimers if low risk and then ultrasound if present. Go direct to ultrasound if high risk.
D-dimer is good for ruling out but not for identifying.
What is the risk with a proximal DVT?
Pulmonary embolism - 50% will progress without treatment.
How do you diagnose chest pain?
Symptoms of:
SOB
Pleuritic pain
Haemoptysis
Signs:
Tachycardia
Tachypnoea
Hypoxia
Positive D-dimer
CT-scan CT pulmonary angigraphy
What happens in massive PE?
Sudden death (15%)
Mortality (>50%)
Hypotension
severe right heat strain due to back pressure from pulmonary arteries
How do you treat massive DVT and PE?
Initially: Low molecular weight inhibits Xa through antithrombin. Suncutaneous. Fast response to treatment.
Warfarin at the same time but has a slow response.
TPA to break down clot
What is thrombophilioa?
Tendency to develop clots
Manifests as venous thromboembolism (DVT or PE)
Inherited or acquired
What are some causes of thrombophilia?
Abnormal inhibitor function:
Resistance to activated protein C (factor V leiden)
Deficiency of inhibitors:
Antithrombin, protein C and protein S deficiency
Increased factor levels:
Elevated factor II
Elevated VIII
What is factor V leiden?
Point mutation in factor V.
Protein C can’t bind and inhibit the mutated factor V -> higher factor V levels.
What do you need to be careful with regarding warfarin?
Drug interactions: antibiotics, anticonvulsants.
INR
What are two direct acting anticoagulants?
Dadbigatran - thrombin
Revaroxaban - Xa
Less chance of intracranial haemorrhage compared to warfarin.
What tests will ivaroxaban prolong?
PT
APTT to a less extent
What tests will dabigatran prolong?
TCT, APTT and PT
