Haem: Coagulation Flashcards
List some pro-coagulant factors in the body.
- Platelets
- Endothelium
- vWF
- Coagulation cascade
List some anti-coagulant factors in the body.
- Fibrinolysis
- Anti-thrombins
- Protein C/S
- Tissue factor pathway inhibitor
Which three responses are stimulated by vessel injury?
- Vasoconstriction
- Platelet activation (forms primary haemostatic plug)
- Activation of the coagulation cascade
What are the components of blood clot formation?
- Vascular endothelium
- Platelets
- Coagulation factors
- White blood cells
What are the two main functions of the endothelium?
- Synthesis of prostacyclin, vWF, plasminogen activators and thrombomodulin
- Maintain barrier between blood and pro-coagulant subendothelial structures
How many platelets are produced by each megakaryocyte?
4000
What is the life span of platelets?
10 days
NOTE: this is important because it means that the effect of antiplatelet drugs lasts for 10 days after stopping the drug
What are glycoproteins?
Cell surface proteins through which platelets can interact with the endothelium, vWF and other platelets
What do dense granules contain?
Energy stores (ATP and ADP)
Which features of platelets enable them to massively expan their surface area?
Open cannalicular system and microtubules and actomyosin
What are the two ways in which platelets can adhere to sub-endothelial structures?
DIRECTLY - via GlpIa
INDIRECTLY - via binding of GlpIb to vWF (this is MORE IMPORTANT)
which factors, released by platelets after adhesion, promote platelet aggregation?
ADP
Thromboxane A2
How do platelets bind to each other?
GlpIIb/IIIa
It also binds to fibrinogen via this receptor
Describe the effects of aspirin and other NSAIDs on the arachidonic acid pathway.
Aspirin is an irreversible COX inhibitor
Other NSAIDs reversibly inhibit COX
What is the rate-limiting step for fibrin formation?
Factor 10a
What are the effects of thrombin formation?
- Activates fibrinogen (converts it to fibrin)
- Activates platelets
- Activates profactors (factor 5 and 8)
- Activates zymogens (factor 7, 11 and 13)
Name the complex that is responsible for activating prothrombin to thrombin.
Prothrombinase complex
Outline the initiation phase of the clotting cascade.
- Damage to the endothelium results in exposure of tissue factor which binds to factor 7 and activates it to factor 7a
- The tissue factor-factor 7a complex then activates factors 9 and 10
- Factor 10a binds to factor 5a resulting in the first step of the coagulation cascade
Outline the amplification phase of the clotting cascade.
- Activated factors 5 and 10 will result in the production of a small amount of thrombin
- This thrombin will activate platelets
- Thrombin will also activate factor 11 which activates factor 9
- Thrombin also activates factor 8 and recruits more factor 5a
- Factors 5a, 8a and 9a will bind to the activated platelet
Outline the propagation phase of the clotting cascade.
- Activated factors 5, 8 and 9 will recruit factor 10a
- This results in the generation of a large amount of thrombin (thrombin burst)
- This enables the formation of a stable fibrin clot
Describe the extrinsic pathway
- Tissue activation: Damaged endothelium exposes TF
- SEVEN: VII + TF > TF-VIIa complex > activates X
- FIVE: Va + Xa > prothrombinase complex
How is the extrinsic pathway monitored?
Prothrombin time (PT)
The time in seconds that it takes plasma to clot after the addition of phospholipid, tissue factor (factor III), and calcium to the specimen
- Monitor warfarin therapy (INR)
Describe the intrinsic pathway
- Surface activation: Exposed collagen
- TWELVE: XII > XIIa
- ELEVEN: XI > XIa
- NINE: IX > IXa
- EIGHT: VIIIa complexes with IXa (tenase complex)
- TEN: X > Xa
How is the intrinsic pathway monitored?
Activated partial thromboplastin time (APTT)
The time in seconds that it takes plasma to clot after the addition of a contact agent that fully activates factors XII along with calcium and phospholipids
- Monitor heparin therapy
Describe the common final pathway
- FIVE: Va + Xa > prothrombinase complex
- Converts prothrombin to thrombin
- Thrombin cleaves fibrinogen to fibrin
- Forms stable fibrin clot
How is the common final pathway monitored?
Thrombin time (TT)
Assesses the activity of fibrinogen
Why is the prothrombinase complex important?
It allows activation of prothombin at a much faster rate
What is required for adequate production/absorption of vitamin K?
- Bacteria in the gut produce Vitamin K
- It is fat-soluble so bile is needed for viatmin K to be absorbed
What is the most common cause of vitamin K deficiency?
Warfarin
Name two factors that convert plasminogen to plasmin.
- Tissue plasminogen activator
- Urokinase
Name a factor that inhibits the tissue plasminogen activator and urokinase.
Plasmingoen activtor inhibitor 1 and 2
Name two factors that directly inhibit plasmin.
- Alpha-2 antiplasmin
- Alpha-2 macroglobulin
What is the role of thrombin-activatable fibrinolysis inhibitor (TAFI)?
Inhibitor of fibrin breakdown
Describe the action of antithrombins.
Bind to thrombin in a 1:1 ratio and this complex is excreted in the urine
How many types of antithrombin are there?
Five (antithrombin-III is the most active)
What is the most thrombogenic hereditary condition?
Antithrombin deficiency
Outline the role of protein C and protein S.
- Trace amounts of thrombin generated at the start of the clotting cascade activate thrombomodulin
- This allows protein C to bind to thrombomodulin through the endothelial protein C receptor
- Protein C is then fully activated in the presence of protein S
- Fully activated protein C will inactivate factors 5a and 8a
Why does Factor V Leiden cause a prothrombotic state?
The factor 5a will be resistant to breakdown by protein C.
State two causes of activated protein C resistance.
- Mutated factor 5 (e.g. factor V Leiden)
- High levels of factor 8
What is the role of tissue factor pathway inhibitor?
- TFPI neutralises the tissue factor-factor 7a complex once it has initiated the clotting cascade
List some categories of genetic defects that cause excessive bleeding.
- Platelet abnormalities
- Vessel wall abnormalities
- Clotting factor deficiencies
- Excess clot breakdown
List some acquired defects that cause excessive bleeding.
- Liver disease
- Vitamin K deficiency
- Autoimmune diseases (platelet destruction)
- Trauma
- Anti-coagulants/anti-platelets
List some genetic defects that cause excessive thrombosis.
- Clotting factor inhibitor deficiencies
- Decreased fibrinolysis
List the types of disorders of haemostasis.
- Vascular disorders (e.g. scurvy)
- Platelet disorders
- Coagulation disorders
- Mixed disorders (e.g. DIC)
What is the difference between immediate and delayed bleeding with regards to the underlying pathological process?
- Immediate - issue with the primary haemostatic plug (platelets, endothelium, vWF)
- Delayed - issue with the coagulation cascade
Describe the key clinical differences between platelet disorders and coagulation factor disorders.
Platelet disorders:
- Bleeding from skin and mucous membranes
- Petechiae
- Small, superficial ecchymoses
- Bleeding after cuts and scratches
- Bleeding immediately after surgery/trauma
- Usually mild
Coagulation factor disorders:
- Bleeding into soft tissues, joints and muscles
- No Petechiae
- Large, deep ecchymoses
- Haemarthroses
- No bleeding from cuts and scratches
- Delayed bleeding from surgery or taruma
- Often SEVERE
When is treatment for platelet disorders required?
Platelet count <30x109/L (this is associated with spontaneous haemorrhage)
Why is it important to look at platelets under the microscope in thrombocytopaenia?
- To check whether it is pseudothrombocytopaenia (platelets clump together giving an erroneously low result)
- Also allows identification of other abnormalities (e.g. Grey platelet syndrome - large platelets)
What can cause a decrease in platelet number?
- Decreased producton
- Decreased survival (TTP)
- Increased consumption (DIC)
- Dilution
What can cause defective platelet function?
- Acquired (e.g. aspirin)
- Congenital (e.g. thrombasthenia)
- Cardiopulmonary bypass
What can cause immune-mediated thrombocytopaenia?
- Idiopathic
- Drug-induced (e.g. quinine, rifampicin)
- Connective tissue disorder (e.g. SLE)
- Lymphoproliferative disease
- Sarcoidosis
List two non-immune mediated conditions that cause thrombocytopaenia.
DIC
MAHA
Describe the pathophysiology of ITP.
- Autoantibodies are generated against platelets
- Platelets are tagged by autoantibodies and then destroyed by the reticuloendothelial system (liver, spleen, bone marrow)
What are the main differences between acute and chronic ITP?
Acute:
- Mainly children
- Usually there is a preceding infection
- Abrupt onset of symptoms
- Lasts 2-6 weeks
- Spontaneously resolves
Chronic:
- Mainly occurs in adults
- More common in females
- Can be abrupt or indolent
- Does not resolve spontaneously
How is ITP treated?
Mainly with steroids and IVIG based on the platelet count
Give some examples of causes of thrombocytopaenia that can be diagnosed by blood film.
- Vitamin B12 deficiency
- Acute leukamia
What clotting study abnormality would be seen in Haemophilia?
Prolonged APTT
Outline the clinical features of haemophilia.
- Haemarthroses (MOST COMMON)
- Soft tissue haematomas (e.g. shortened tendons, muscle atrophy)
- Prolonged bleeding after surgery/dental extractions
NOTE: haemophilia A and B are clinically indistinguishable
What is a typical lesion seen in coagulation factor disorders?
Ecchymoses
What is the most common coagulation disorder? What is its inheritance pattern?
- Von Willebrand disease
- Autosomal dominant - type 1 and 2
- Autosomal recessive - type 3
What is the main clinical feature in von Willebrand disease?
Mucocutaneous bleeding
Outline the classification of von Willebrand disease.
- Type 1 - partial quantitative deficiency
- Type 2 - qualitative deficiency
- Type 3 - complete quantitative deficiency
Describe the relationship between vWF and factor 8.
- Binding of factor 8 to vWF protects factor 8 from being destroyed
NOTE: type 3 vWD has a very similar phenotype to haemophilia A (because absent vWF leads to low factor 8)
Describe the expected laboratory test results for the three types of von Willebrand disease.
- Type 1 - low antigen, low activity, normal multimer (decreased size)
- Type 2 - normal antigen, low activity, normal multimer (structurally abnormal)
- Type 3 - very low antigen, very low activity, absent multimer
Name a source of vitamin K.
- Green vegetables
- Vitamin K is synthesised by intestinal flora
What is vitamin K required for?
- Synthesis of factors 2, 7, 9 and 10
- Synthesis of protein C, S and Z
List some causes of vitamin K deficiency.
- Malnutrition
- Biliary obstruction
- Malabsorption
- Antibiotic therapy
Outline the pathophysiology of DIC.
- Release of thromboplastic material into the circulation causes widespread activation of coagulation and fibrinolysis
- This results in increased vascular deposition of fibrin, which leads to thrombosis of small and mid-size vessels with organ failure
- Depletion of platelets and coagulation factors leads to bleeding
List some causes of DIC.
- Sepsis (MOST COMMON)
- Trauma (e.g. fat embolism)
- Obstetric complications (e.g. amniotic fluid embolism)
- Malignancy
- Vascular disorders
- Reaction to toxin
- Immunological (e.g. transplant rejection)
Describe the typical clotting study results in DIC.
- Prolonged APTT, PT, TT
- Decreased fibrinogen
- Increased FDP
- Decreased platelets
- Schistocytes (due to shearing of red blood cells as it passes through a fibrin mesh)
Outline the treatment of DIC.
- Treat underlying disorder
- Anticoagulation with heparin
- Platelet transfusion
- FFP
- Coagulation inhibitor concentrate
Describe how liver disease leads to bleeding disorders.
- Decreased synthesis of clotting factors 2, 7, 9, 10, 11 and fibrinogen
- Dietary vitamin K deficiency
- Dysfibrogenaemia
- Enhanced haemolysis (decreased alpha-2 antiplasmin)
- DIC
- Thrombocytopaenia due to hypersplenism
Outline the treatment of:
- Prolonged PT/APTT
- Low fibrinogen
- DIC
-
Prolonged PT/APTT
- Oral vitamin K
- FFP infusion
-
Low fibrinogen
- Cryoprecipitate
-
DIC
- Replacement therapy
What is the management of vitamin K deficiency due to warfarin overdose based on?
INR
NOTE: warfarin is reversed by giving vitamin K (oral or IV). If severe, FFP or PCC could be given.
What is PCC?
Prothrombin complex concentrate (contains vitamin K-dependent clotting factors)
