Coagulation Flashcards
What does the endothelium produce to inhibit thrombin production
thrombomodulin and heparin
sulphate
what does the endothelium produce to reduce platelet adhesion
Prostacyclin and nitric oxide (NO)
What are the roles of the endothelial cells
- Line blood vessels and form a barrier
* Enzymes to degrade platelet granule- derived molecules
what stimulates the production of platelet
thrombopoetin (TPO)- liver derived
how long do platelets stay in the circulation and where are they stored
Circulate for 5-10 days with ?30% “stored” in spleen
What is the main role of platelets
Form a plug when attracted by lowered prostacyclin and by collagen exposure
they release granules and cause the formation of fibrin
what causes vasoconstriction
Thromboxane A2 and serotonin from platelets cause vasoconstriction
how to platelets adhere to the vessel wall
via Von Willibrand’s factor and Glycoprotein Ib
how do platelets adhere to each other
Glycoprotein IIb-IIIa and fibrinogen
what is protein C activated by
thrombomodulin-thrombin complex
examples of inhibitors to the protein cascade
- With co-factor- Factor S- Va and VIIIa are degraded
- Antithrombin (previously antithrombin III) inhibit Xa and IIa
- Heparin cofactor II inhibits Ila
- Heparin stimulates antithrombin and heparin cofactor II
how is plasminogen activated
to plasmin by tissue plasminogen activator (tPA)- from endothelial cells
what is fibrin broken down into
fibrin degradation products” including D Dimers- a measurement of fibrinolysis
• Inhibitors of fibrinolytic system
what is the time scale of thromolysis
needs to be done in <3-4 hours, some risk of bleeding afterwards
what test would you use to measure coagulation
FBC
ncludes platelet count/size/ granules but is a poor assessment of platelet function- specialised tests of aggregation can be done
what is the reference range for the FBC
Ref range 150-400 x 10 9/l
• Easy bruising and purpura when <30-50
(thrombocytopenia)
• Risk of major bleeding if <10
Prothrombin time (PT)
- All coagulation tests are done on citrated plasma- removes Ca++
- At 37C thromboplastin (brain extract!) and Ca++ added
- Measure time till clot forms- extrinsic and common pathway
- Prolonged by low levels of II X VII
what is the role of Warfarin
reduces active II VII IX X so a useful measure of dose- expressed as INR- international normalised index
Activated partial thromboplastin test (APTT)
- Ca++ kaolin and phospholipids added to citrated plasma • Measure of intrinsic and common pathway
- Prolonged in haemophilia and by heparin
Fibrinogen
• Final substrate for making fibrin
• Can be measured by clot density or by-
Thrombin time- thrombin and Ca++ added to citrated plasma
GOOD INDICATOR OF LIVER FUNTION
Correction tests and factor assays
- A prolonged PT or APTT can be tested further-
- 50:50 mix with normal plasma to see if the prolongation corrects
- Factor assays to look for specific deficiencies
Inherited blood disorders
- Haemophilia A and B- X linked defect in VIII or IX gene
- Commonly a new mutation so no family history
- Approx 1:5000 of males
- Female heterozygotes (carriers) not affected
- Can be very mild- chance finding or issue for surgery
- Severe (<1% VIII level)- frequent bleeds into joints and soft tissues
Haemophilia- treatment
no treatment other than fresh frozen plasma
Porcine and then recombinant factor replacement
• ?Prophylaxis or treatment
• Issues of Hepatitis B or C and HIV, ??nv CJD
• Gene therapy?
Von Willebrand disease
- Usually autosomal dominant
- Defect in platelet adhesion and binding of VIII
- Up to 1% of population
- Mild disease- easy bruising, heavy periods
- Severe disease- similar to haemophilia
Acquired coagulation disease- liver
• Liver disease- alcohol/autoimmune/hepatitis
- All coag factors produced in liver
- PT and fibrinogen abnormal, later APPT abnormal -bleeding due to abnormal clotting, low platelets
- portal hypertension causing oesophageal varices and upper GI bleeding
disseminated intra-vascular coagulation (DIC)
• Activation of clotting cascade due to- -trauma
-malignancy eg prostate cancer
-sepsis
-amniotic fluid embolism
Causes depletion of clotting factors and damage due to clot Treat the cause and replace clotting factors
Low platelets (thrombocytopenia)
• Could be due to –
- under-production
- increased use
- abnormal distribution
Thrombocytopenia- under production
• Abnormal marrow function
- acute leukaemia, metastatic tumour, aplastic anaemia
• Expected side effect of cytotoxic chemotherapy
• Idiosyncratic and unexpected drug adverse effect eg co-trimoxazole, anti-inflammatories
Thrombocytopenia- increase use
• Immune thrombocytopenia (ITP)
- autoimmune disease of children or adults
- may be triggered by infection or drug
- auto antibodies to platelets
- treated by watch and wait/ steroids/ immunoglobulins/ splenectomy/ drugs to mimic thromobopoetin
Thrombocytopenia- abnormal distribution
- Splenomegally eg portal hypertension, leukaemia
* Large haemangioma
ncreased risk of clotting- thrombophilia
• Inherited defects in coag inhibitors eg Protein C, S, antithrombin • Inherited defect in factor V- V Leiden
• Acquired problems- Virchow’s triad abnormal- vessel wall - flow
- blood component
Abnormal vessel wall
- Atheroma and plaque
- Varicose veins
- Aneurysm
Abnormal flow
- Atrial fibrillation
- Immobile eg long distance flight, plaster cast, surgery
- Varicose veins
Abnormal blood component
- Increased haemoglobin/red cell count- polycythaemia
- Increased WBC or platelet count- stasis and increased clotting
- Increased viscosity of plasma
- Reduced coag factor inhibitors
