Haemostasis (part 2: secondary haemostasis)

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Blood Science Mind Map on Haemostasis (part 2: secondary haemostasis), created by maisie_oj on 04/30/2013.
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Haemostasis (part 2: secondary haemostasis)
1 Describe primary and secondary homeostasis
1.1 Primary homeostasis
1.1.1 Characterised by injured blood vessel constriction/spasm (different response (vasodilation) in uninjured vessels) - followed by thrombocytic plug
1.1.2 Depends on the platelet and blood vessel wall
1.1.2.1 Platelets aggregate at the site of injury to reduce and arrest the bleeding
1.2 Secondary homeostasis
1.2.1 When the clotting cascade is activated (by tissue factor from the surface of endothelial cells and platelet secretions)
1.2.1.1 Coagulation and coagulation factors
1.2.1.1.1 Platelets, vascular and clotting factors
1.2.1.1.2 Extrinsic pathway
1.2.1.1.3 Intrinsic pathway
1.2.1.1.4 Reversed by fibrinolysis
2 Clotting cascade
2.1 Intrinsic pathway (stimulated by exposed collagen)
2.1.1 XII (Hageman factor)
2.1.1.1 XIIa
2.1.1.1.1 +
2.1.1.1.1.1 Kallikrien
2.1.1.1.1.1.1 Prekallikrien
2.1.1.1.2 +
2.1.1.1.2.1 High molecular weight kininogen (HMWK)
2.1.1.1.3 +
2.1.1.1.3.1 XI
2.1.1.1.3.2 XIa
2.1.1.1.3.2.1 +
2.1.1.1.3.2.1.1 IX
2.1.1.1.3.2.1.2 IXa
2.1.1.1.3.2.1.2.1 IXa + VIIIa (+ (Ca(2+) + phospholipids) = tenase complex
2.1.1.1.3.2.1.2.1.1 +
2.1.1.1.3.2.1.2.1.1.1 Xa
2.1.1.1.3.2.1.2.1.1.1.1 Xa + Va (+ Ca(2+) + phospholipids) = prothrombinase complex
2.1.1.1.3.2.1.2.1.1.1.1.1 Va
2.1.1.1.3.2.1.2.1.1.1.1.1.1 +
2.1.1.1.3.2.1.2.1.1.1.1.1.1.1 Thrombin (IIa)
2.1.1.1.3.2.1.2.1.1.1.1.1.1.2 V
2.1.1.1.3.2.1.2.1.1.1.1.2 +
2.1.1.1.3.2.1.2.1.1.1.1.2.1 Prothrombin (II)
2.1.1.1.3.2.1.2.1.1.1.1.2.2 Thrombin (IIa)
2.1.1.1.3.2.1.2.1.1.1.1.2.2.1 +
2.1.1.1.3.2.1.2.1.1.1.1.2.2.1.1 Fibrinogen (I)
2.1.1.1.3.2.1.2.1.1.1.1.2.2.1.2 Fibrin monomer (Ia)
2.1.1.1.3.2.1.2.1.1.1.1.2.2.1.2.1 +
2.1.1.1.3.2.1.2.1.1.1.1.2.2.1.2.1.1 Fibrin clot
2.1.1.1.3.2.1.2.1.1.1.1.2.2.1.2.1.1.1 +
2.1.1.1.3.2.1.2.1.1.1.1.2.2.1.2.1.1.1.1 Digested fibrin products
2.1.1.1.3.2.1.2.1.1.1.1.2.2.1.2.1.1.1.2 Fibrinolysis
2.1.1.1.3.2.1.2.1.1.1.1.2.2.1.2.1.1.1.3 Plasmin
2.1.1.1.3.2.1.2.1.1.1.1.2.2.1.2.1.1.1.3.1 +
2.1.1.1.3.2.1.2.1.1.1.1.2.2.1.2.1.1.1.3.1.1 Plasminogen
2.1.1.1.3.2.1.2.1.1.1.1.2.2.1.2.1.1.1.3.1.2 Urokinase
2.1.1.1.3.2.1.2.1.1.1.1.2.2.1.2.1.1.1.3.1.3 tPA
2.1.1.1.3.2.1.2.1.1.1.1.2.2.2 +
2.1.1.1.3.2.1.2.1.1.1.1.2.2.2.1 XIII
2.1.1.1.3.2.1.2.1.1.1.1.2.2.2.2 XIIIa
2.1.1.1.3.2.1.2.1.1.1.1.2.2.2.2.1
2.1.1.1.3.2.1.2.1.1.1.1.3 COMMON PATHWAY
2.1.1.1.3.2.1.2.1.1.2 X
2.1.1.1.3.2.1.2.1.1.3 VIIa (+ tissue factor)
2.1.1.1.3.2.1.2.1.1.3.1 +
2.1.1.1.3.2.1.2.1.1.3.1.1 VII
2.1.1.1.3.2.1.2.1.1.3.1.2 Tissue factor
2.1.1.1.3.2.1.2.1.1.3.1.2.1 Tissue injury
2.1.1.1.3.2.1.2.1.1.3.1.2.1.1 Extrinsic Pathway (stimulated by endothelial damage -> tissue factor release)
2.1.1.1.3.2.1.2.1.2 VIIIa
2.1.1.1.3.2.1.2.1.2.1 +
2.1.1.1.3.2.1.2.1.2.1.1 VIII
2.1.1.1.3.2.1.2.1.2.1.2 Thrombin (IIa)
2.1.1.1.3.2.1.2.1.2.1.3 vWF
2.1.1.1.3.3 Thrombin (IIa)
2.1.2 +
2.1.3 +
2.1.4 Recruits a complex of; prekallikrien, XII and HMWK
3 Coagulation factors
3.1 Generated in the liver (except VIII - at least the vWF-interacting portion)
3.1.1 VII produced in multiple organs
3.2 Three types
3.2.1 The fibrinogen family
3.2.1.1 Fibrinogen
3.2.1.2 V
3.2.1.3 VIII
3.2.1.4 XIII
3.2.2 The prothrombin family
3.2.2.1 II
3.2.2.2 VII
3.2.2.3 IX
3.2.2.4 X
3.2.2.5 Protein C
3.2.2.5.1 Binds with thrombomodulin on endothelial cells
3.2.2.5.1.1 This complex becomes activated by portein S
3.2.2.5.1.1.1 Activated complex inhibits Va and VIIa
3.2.2.6 Protein S
3.2.3 The contact family
3.2.3.1 VII (Hageman factor)
4 Monitoring haemostasis
4.1 Bleeding time (Duke's method)
4.1.1 Patient skin is cleaned with alcohol wipe
4.1.1.1 Prick made with a lancet
4.1.1.1.1 Filter paper applied to the area every 30 seconds
4.1.1.1.1.1 BT = no. of blood spots (until blleding stopped) divided by 2
4.1.1.1.1.1.1 This gives the BT in mins (normal is 3-6 mins)
4.1.1.1.1.1.1.1 Measures time for primary haemostasis
4.1.1.1.1.1.1.1.1 Not very reliable
4.1.1.1.1.1.1.1.1.1 Varies greatly between patients
4.1.1.1.1.1.1.1.1.2 In cold it is shortened (due to capillary constriction)
4.1.1.1.1.1.1.1.1.2.1 In warmth = opposite
4.1.1.1.1.1.1.1.2 Prolonged by
4.1.1.1.1.1.1.1.2.1 Lack of platelets (thrombocytopaenia)
4.1.1.1.1.1.1.1.2.2 Platelet disorders (heparin, aspirin)
4.1.1.1.1.1.1.1.2.3 Severe anaemia
4.1.1.1.1.1.1.1.2.4 vWD
4.1.1.1.1.1.1.1.2.5 Collagen vascular disease
4.2 Clotting time - capillary tube method
4.2.1 Prep and prick the patient
4.2.1.1 Fill a capillary tube up with blood
4.2.1.1.1 Every 30 secs blot the capillary tube on filter paper and drag back slightly
4.2.1.1.1.1 Fibrin formation is identified when a fibrinous clot is dragged from the capillary tube
4.2.1.1.1.1.1 Seen as a fibrin thread
4.2.1.1.1.1.1.1 Normal clotting time = 5-8 mins
4.2.1.1.1.1.1.1.1 It is increased in haemophilia
4.2.1.1.1.1.1.1.2 Not relying on primary haemostasis alone (outside of the body)
4.3 Coagulation tests
4.3.1 Measuring the intrinsic system
4.3.1.1 Activated partial thromboplastin time (aPTT)
4.3.1.1.1 Performed at 37degressC
4.3.1.1.1.1 Plasma collected (9:1 ratio of trisodium citrate anticoagulate and blood)
4.3.1.1.1.1.1 Add kaolin/elgaic acid (source of phospholipids) and Ca(2+) - activate the intrinsic pathway
4.3.1.1.1.1.1.1 Measure the time for a clot to form
4.3.1.1.1.1.1.1.1 Normal = 22-35secs
4.3.1.1.1.1.1.1.1.1 Prolonged aPTT
4.3.1.1.1.1.1.1.1.1.1 Heparin/direct thrombin inhibitors
4.3.1.1.1.1.1.1.1.1.1.1 Factor deficiencies (intrinsic factors; XII, XI, IX, VIII)
4.3.1.1.1.1.1.1.1.1.1.1.1 Common pathway factor deficiencies (X, V, II, I)
4.3.1.1.1.1.1.1.1.1.1.1.1.1 Luopus anticoagulant
4.3.1.1.1.1.1.1.1.1.1.1.1.1.1 Specific inhibitors (VIII or IX)
4.3.1.1.1.1.1.1.1.1.1.1.1.1.1.1 Possible warfarin, liver dysfunction DIC?
4.3.2 Measuring the extrinsic system
4.3.2.1 Prothrombin time (PT)
4.3.2.1.1 Performed by adding thromboplastin and Ca(2+) to plasma
4.3.2.1.1.1 Thromboplastin mimicks tissue factor (activates VII - i.e. the extrinsic system)
4.3.2.1.1.1.1 Can be human or rabbit
4.3.2.1.1.2 Measure the time for clot formation
4.3.2.1.1.2.1 Can be performed automatically or manually
4.3.2.1.1.2.1.1 Normal PT time = 11-15 secs
4.3.2.1.1.2.1.1.1 Prolonged PT time
4.3.2.1.1.2.1.1.1.1 Factor deficiency
4.3.2.1.1.2.1.1.1.1.1 VII (extrinsic pathway)
4.3.2.1.1.2.1.1.1.1.2 or, II, V and X (common pathway)
4.3.2.1.1.2.1.1.1.2 Warfarin
4.3.2.1.1.2.1.1.1.3 High dose heparin
4.3.2.1.1.2.1.1.1.4 Liver dysfunction
4.3.2.1.1.2.1.1.1.5 Vitamin K deficiency
4.3.2.1.1.2.1.1.1.5.1 VII requires vitamin K for activity
4.3.2.1.1.2.1.1.1.5.2 (So does XI - but not part of the extrinsic pathway)
4.3.2.1.1.2.1.1.1.6 Disseminated intravascular coagulation (DIC)
4.3.2.1.1.2.1.1.1.7 Lupus anticoagulant
4.3.2.1.1.2.1.2 Considerations
4.3.2.1.1.2.1.2.1 Underfilling with blood can alter the anticoagulant:blood ratio of 9:1
4.3.2.1.1.2.1.2.2 Polycythaemia alters the anticoagulant:blood ratio of 9:1
4.3.2.1.1.2.1.2.3 Errors in the optical end point analysis by...
4.3.2.1.1.2.1.2.3.1 Lipaemia
4.3.2.1.1.2.1.2.3.2 Haemolysis
4.3.2.1.1.2.1.2.3.3 Hyperbilirubinaemia
4.3.2.1.1.2.1.2.3.4 Hyperproteinaemia
4.3.2.1.1.2.1.3 Internationational normalised ratio (INR) - accounts for differences between different nationalalities
4.3.2.1.1.2.1.3.1 Can be tested using a portable electronic system
4.3.2.1.1.2.1.3.1.1 Calculation of the INR = (patients PT in secs / mean normal PT i secs)^international sensitivity index
4.3.2.1.1.2.1.3.1.1.1 Thromboplastin reagents vary in sensitivity between labs - the INR allows for standardisation by introducing an international sensitivity index (IS)
4.3.2.1.1.2.1.3.2 For the purpose of standardising the monitoring of warfarin therapy
4.3.3 Measuring the common pathway alone
4.3.3.1 Thrombin time (TT)
4.3.3.1.1 Performed by adding thrombin (IIa) to patients plasma
4.3.3.1.1.1 Measures the conversion of fibrinogen to fibrin
4.3.3.1.1.1.1 Normal = <20 secs
4.3.3.1.1.1.1.1 Shortened TT in dysfibrinogenemia
4.3.3.1.1.1.1.2 Prolonged TT in
4.3.3.1.1.1.1.2.1 DIC, liver disease, hypofibrinogenemia, heparin, lupus
4.4 Measuring fibrinogen levels
4.4.1 Detects deficiencies of fibrinogen or the ability to convert to fibrin
4.4.2 Normal = 200-400mg/dL
4.4.2.1 May do titers to assist in evaluation
4.4.2.2 Levels decreased in
4.4.2.2.1 DIC (consumption of clotting factors)
4.4.2.2.2 Liver disease (decreased synthesis)
4.4.2.2.3 Massive transfusion (dilutional coagulopathy)
4.4.2.2.4 Hypo-, dys- and afibrinogenemia
4.4.2.3 Increased in
4.4.2.3.1 Age
4.4.2.3.2 Females; pregnancy, oral contraceptive and menopause
4.4.2.3.3 Acute phase reaction
4.4.2.3.4 Disseminated malignancy
4.5 Activated clotting time (ACT)
4.5.1 Measures clot formation in intrinsic and common pathways
4.5.1.1 Freshly obtained blood added to a tube containing negatively charged particles
4.5.1.1.1 Negative charge initiates intrinsic pathway
4.5.1.1.2 Type of charged particle affects the normal length of ACT
4.5.1.1.2.1 e.g. Kaolin (90-150secs); glass (110-190secs)
4.5.1.1.2.2 Prolonged in
4.5.1.1.2.2.1 Heparin, hypothermia, platelet dysfunction, haemodilution, cardioplegic solutions, hypofibrinogenemia, factor 9intrinsic and common) deficiencies
4.5.1.1.3 Used in cardiopulmonary bypass; haemodialysis; vascular and general surgery
5 Bleeding disorders
5.1 Haemophilia A
5.1.1 X-linked (affects mostly males)
5.1.2 Severity associated with the level that factor VIII is affected
5.1.3 Bleeding - joints, gut, trauma, intracerebral haemorrhage at birth
5.1.4 Treated with recombinant factor VIII
5.1.5 Lab results
5.1.5.1 Long aPTT
5.1.5.2 Reduced fVIII activity
5.2 Anticoaglants
5.2.1 Why?
5.2.1.1 Prevent thrombus formation -> embolus
5.2.1.1.1 e.g. DVT and pulmonary embolism
5.2.2 Over-anticoagulation
5.2.2.1 Reversal urgent!
5.2.2.1.1 Heparin overdose
5.2.2.1.1.1 Give: protamine sulphate
5.2.2.1.1.2 Inhibits thrombin formation
5.2.2.1.2 Warfarin overdose
5.2.2.1.2.1 Give: vitamin K
5.2.2.1.2.2 Inhibits vitamin K activating enzymes (vitamin K-epoxide reductase)
5.2.2.1.2.2.1 Certain clotting factors arent activated (II, VII, IX, X)
5.2.2.2 Unstoppable bleeds (prolonged clotting times etc.)
5.2.3 Duration of anticoagulant therapy is important
5.2.3.1 First DVT/PE (previous risk factors) = 3 month therapy
5.2.3.2 First DVT/PE (idiopathic = spontaneous) = 6-12 months
5.2.3.3 >2 episodes = indefinite therapy
5.2.4 Targetting Xa
5.2.4.1 Why?
5.2.4.1.1 Pivotal upstream location - at the start of the common pathway
5.2.4.1.2 Primary site of cascade amplification
5.2.4.1.3 Rate-limiting component in the production of thrombin
5.2.4.2 Inhibtion of Xa
5.2.4.2.1 One molecule of Xa inhibited prevents ~138 molecules of fibrin being generated
5.2.4.3 Function of Xa - only to promote coagulation (compared to thrombin)
5.2.4.4 Indirect Xa inhibitors
5.2.4.4.1 Mediated through the binding to and activation of antithrombin(III) - e.g. heparin-like molecules
5.2.4.5 Direct Xa inhibitors
5.2.4.5.1 Bind directly to Xa (without the need for antithrombin(III)
5.2.4.5.2 Currently undergoing clinical trials
5.2.4.5.3 Inhibit Xa bound to activated platelets
5.2.4.5.3.1 i.e. trapped within a forming thrombus at the prothrombinase (Xa+Va+Ca(2+) + phospholipids)
5.2.4.5.3.2 Possible advantage over heparin and indirect Xa inhibitors
5.2.4.5.3.3 Appears to inhibit thrombus formation, but allow sufficient thrombin formation - mainting the ability to form a haemostatic plug elsewhere
5.2.4.5.3.3.1 Lower bleeding risk
5.2.5 Inhibitors of thrombin
5.2.5.1 Heparin (indirectly through antithrombin(III)
5.2.5.2 Direct = Bivalirudin
5.2.5.2.1 Binds directly to exosite 1 or active site
5.2.5.2.2 Does not bind platelet factor 4
5.2.5.2.3 Few other interactions
5.2.5.2.4 Wide therapeutic window
5.2.5.2.5 Expensive
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