Coagulation - normal and abnormal Flashcards
What are the 5 constituents of blood coagulation?
- Vessel wall lined with endothelium
- Platelets
- Coagulation factors in unactivated state
- Inhibitors of coagulation
- Fibrinolytic system and inhibitors
What are platelets derived from?
Megakaryocytes in the marrow
How are endothelial cells involved in blood coagulation/
- Line blood vessels and form a barrier
- Produce thrombomodulin and heparin sulphate to inhibit thrombin production
- Enzymes to degrade platelet granule-derived molecules
- Prostacyclins and nitric oxide
What effect do prostacyclins and nitric oxide have on blood coagulation?
Reduces platelet adhesion
What are megakaryocytes?
Cells that have undergone nuclear division but not cellular division
• Have extending pseudopods from which the platelets are budded off
• Stimulated by thrombopoietin
What stimulates platelet production?
Thrombopoietin
Where are platelets budded off into?
Marrow sinusoids
How long can platelets circulate for?
5-10 days
Where are platelets stored?
around 30% are stored in the spleen
When do platelets form a plug?
When they are attracted by lowered prostacyclin (produced by the endothelium) and collagen exposure
What released by platelets causes vasoconstriction?
- Thromboxane A2
* Serotonin
How do platelets adhere to the vessel wall?
- Von Willibrand’s factor
* Glycoprotein Ib
How do platelets adhere to each other?
- Glycoprotein IIb
- Glycoprotein IIIa
- Fibrinogen
Which 2 pathways activate the coagulation cascade?
- Intrinsic
* Extrinsic
What triggers the intrinsic pathway?
Trauma causing damaged tissue
What triggers the extrinsic pathway?
Damaged surface, leaving the endothelium damaged, collagen exposed and the aggregation of platelets
Describe how fibrinogen becomes a fibrin clot
Prothrombin (II) is converted to the active form, Thrombin (IIa) which converts Fibrinogen to Fibrin which is cross linked to a fibrin clot
What inhibits coagulation?
- Protein C
- Cofactor Factor S
- Antithrombin
- Heparin cofactor II
- Heparin
How does Protein C inhibit coagulation?
- It is activated by thombomodulin
* Binds to the thrombin complex
How does Factor S inhibit coagulation?
- Works with protein C
* Degrades factors Va and VIIIa
How does Antithrombin inhibit coagulation?
Inhibits Factors Xa and IIa
How does Heparin cofactor II inhibit coagulation?
Inhibits factor IIa
How does Heparin inhibit coagulation?
Stimulates antithrombin and heparin cofactor II
How is plasminogen activated and what is it activated to?
- By tissue plasminogen activator (tPA) from endothelial cells
- Activated to plasmin
What is Fibrin broken down into?
- Fibrin depredation products
* Including D dimers which are a good measurement of fibrinolysis
What is a therapeutic use for Streptokinase of tPA?
Treatment for clot bursting: Acute myocardial infarction, thrombotic stroke
How long does thrombolysis take and why is its timing important?
<3-4 hours
Some risk of bleeding after 4 hours
How can coagulation be measured?
• Full blood count - platelent size - platelet count - platelet granules • Bleeding time • Prothrombin time
Explain the ranges of platelet counts in a blood count and what they mean
Reference range: 150-400x109/l
• <30-50: easy bruising and purpura
• <10: major risk of bleeding
Why is the bleeding time test unreliable?
• Lots of poorly controlled variables:
- thickness of skin
- Warmth of skin
- May have punctured a vessel
What is Prothrombin time?
- Coagulation test carried out on citrated plasma
- At 37 C, thromboplastin and Ca++ is added
- The time until a clot forms is measured
Which route of clotting does PT test?
Extrinsic
What would prolong the time in a PT test and what would this be an indicator of?
• Low levels of factor II
• Low levels of factor VII
• Low levels of factor X
- indicates liver disease, warfarin
Which factors does warfarin reduce?
- II
- VII
- IX
- X
What is the Activated partial thromboplastin test?
- Ca++, kaolin and phospholipids are added to citrated plasma
- It is a measure of the intrinsic and common pathway
- Prolonged by haemophilia and heparin
What is the function of adding phospholipids in Activated partial thromboplastin test?
imitates the activation of the intrinsic system (when the endothelial lining has been damaged and phospholipids are exposed)
If a test was prolonged, what else could you do to further test?
- 50:50 mix with normal plasma to see if it is corrected
* Factor assay to look if there is a particular deficiency
What is Haemophilia A a result of?
• VIII deficiency on the X chromosome
What is Haemophilia B a result of?
• IX deficiency
What is mild haemophilia?
Chance finding, may be an issue for surgery
What is severe haemophilia?
Frequent bleeds into joints and soft tissues
What are the treatments for haemophilia?
- Gene therapy
- Transfusions
- Recombinant factor replacement
What mutation is responsible for haemophilia?
F9 mutation on the X chromosome resulting in a frameshift
What is Von Willebrand disease
- Autosomal dominant (usually)
- defect in platelet adhesion and binding of VIII
- Mild= bruising and heavy periods
- Severe = Joint/ soft tissue bleeding
What is acquired coagulation disease?
- Caused by liver disease: alcohol/autoimmune disease/hepatitis
- Affects all coagulation factors in the liver
- Abnormal PT and fibrinogen, later produces abnormal APPT
- Bleeding due to abnormal clotting, low platelets (due to lack of thrombopoietin)
- Portal hypertension causing oesophageal varies and upper GI bleeding
What is Disseminated intra-vascular coagulation (DIC)?
• Activation of clotting cascade due to: - Trauma - Malignancy e.g. prostate cancer - Sepsis - Amniotic fluid embolism • Causes depletion of clotting factors and damage due to the clot
How is DIC treated?
Treating the underlying cause and replace the clotting factors
What could a low platelet be due to?
- Under-production
- Increased use
- Abnormal distribution (e.g. in the spleen)
What are the potential causes of Thrombocytopenia due to under production?
- Abnormal marrow function: acute leukaemia, metastatic tumour, aplastic anaemia
- Expected side effect of cytotoxic chemotherapy
- Idiosyncratic and unexpected drug adverse side effects e.g. co-trimoxaxole, anti-inflammatories
What are the potential causes of Thrombocytopenia due to increased use?
Immune thrombocytopenia
• Autoimmune
• May be triggered by infection or drugs
• Auto-immunity to platelets
How could Thrombocytopenia due to increased rate be treated?
- Watch and wait
- Steroids
- Immunoglobins
- Splenectomy
- Drugs to mimic thrombopoietin
Describe abnormal distribution, causing thrombocytopenia
- Splenomegally e.g. portal hypertension, leukaemia
* Large haemangloma
What is Virchow’s triad?
Abnormal vessel wall: • Atheroma and plaque • Varicose veins • Aneurysm Abnormal flow: • Atrial fibrillation • Immobilised e.g. long distance flight, plaster cast • Varicose veins Abnormal blood component • increased haemoglobin/red cell count- polycythaemia • Increased WBC count- stasis and increased clotting\ • Increased viscosity of plasma • Reduced coagulation inhibitors
