Haemostasis 2 Flashcards
What is meant by abnormal bleeding
Bleeding that is: ‘Spontaneous’ Out of proportion to the trauma/injury Unduly prolonged Restarts after appearing to stop Recurrent nose bleeds and bruising in absence of injury are examples
Give examples of an abnormal bleeding history
Epistaxis not stopped by 10 mins compression or requiring medical attention/transfusion.
Cutaneous haemorrhage or bruising without apparent trauma (esp. multiple/large).
Prolonged (>15 mins) bleeding from trivial wounds, or in oral cavity or recurring spontaneously in 7 days after wound. Spontaneous GI bleeding leading to anaemia.
Menorrhagia requiring treatment or leading to anaemia, not due to structural lesions of the uterus.
Heavy, prolonged or recurrent bleeding after surgery or dental extractions.
What proportion of the population have easy bruising
12%
Summarise the normal haemostatic response
Vessel constriction
Vascular smooth muscle cells contract locally
Limits blood flow to injured vessel
Formation of an unstable platelet plug platelet adhesion platelet aggregation Limits blood loss + provides surface for coagulation (primary haemostasis)
Stabilisation of the plug with fibrin
blood coagulation
Stops blood loss
Vessel repair and dissolution of clot
Cell migration/proliferation & fibrinolysis
Restores vessel integrity
Describe the defects of primary haemostasis
Defect:
* Collagen – Vessel Wall:
o E.G. Steroid Therapy (makes walls weak), age and scurvy.
* Von Williebrand Factor (VWF):
o Von Williebrand Disease – a genetic deficiency of VWF.
* Platelets:
o Aspirin and other drugs affect platelet activity.
o Thrombocytopenia is a disease that affects the number of platelets in the bloodstream (presents with petechiae).
What is a consequence of no VWF
Platelets cannot stick Can't bind to collagen (secondary binding) No plug for coagulation Platelets need VWF to slow them down leads to continuous bleeding.
What is petechiae
Small breaks in blood vessels.
Compare the normal and abnormal (no VWF) haemostatic response
- The normal primary haemostatic response:
o Endothelial wall damage à exposed collagen binds to VWF à VWF binding sites exposed and platelets aggregate onto VWF à primary haemostatic plug formation. - VMF Deficiency (VWD) response:
o Endothelial wall damage à platelets can only bind to exposed collagen (in some situations) as no VWF à less aggregation and NO primary platelet plug formation.
List the bleeding patterns that may arise due to defects in primary haemostasis
Immediate Easy bruising Nosebleeds (prolonged: >20 mins) Gum bleeding (prolonged) Menorrhagia (anaemia) Bleeding after trauma/surgery Petechiae (specific for thrombocytopenia)
Describe the defects in secondary haemostasis
Generation of thrombin. Defect in the fibrin mesh formation:
* Thrombin converts fibrinogen to fibrin which forms the insoluble mesh around the platelets to stabilise them.
problem with blood coagulation, preventing stabilisation of plug with fibrin - deficiency of/defective coagulation factors
Describe thrombin generation and haemophilia
This thrombogram visualises the process of coagulation.
- The lag time after the TF (tissue factor) trigger due to the time taken to generate the cofactors and anticoagulant enzymes before the burst of thrombin.
- In haemophilia, F8 is missing which causes a failure in thrombin burst à slower and lower increase in thrombin à clot does not stabilise.
Where is stabilisation by coagulation particularly important
Larger blood vessels
Give some examples of secondary haemostasis
Genetic
Haemophilia: FVIII or FIX deficiency
Acquired Liver disease (most coagulation factors are made in the liver)
Drugs (warfarin – inhibits synthesis, other block function)
Dilution (results from volume replacement)
Consumption (Disseminated Intravascular Coagulation*) (acquired)
Describe haemophilia
prevents thrombin burst because no FVIII, so inadequate fibrin mesh forms to stabilise the platelet plug - plug not stabilised so will fall apart, stopping then starting bleeding again
What are the features of DIC
Generalised activation of coagulation – Tissue factor inside vasculature
Associated with sepsis, major tissue damage, inflammation
Consumes and depletes coagulation factors & platelets
Activation of fibrinolysis depletes fibrinogen
Major inflammatory reaction in sepsis causes inflammatory mediator e.g. IL6 production
IL-6/mediators stimulate cells (monocytes/endothelial cells) to make tissue factor and express on surface (inside blood vessels - so coagulation occurs inside intact blood vessels)
What are the consequences of DIC
Widespread bleeding, from iv lines, bruising, internal
Deposition of fibrin in vessels causes organ failure
Describe the bleeding patterns in secondary haemostasis
do form a platelet plug but not stabilised so:
Delayed and prolonged
Deeper inside joints and muscles
Not from small cuts (primary haemostasis ok)
Nosebleeds are rare
Bleeding after trauma/surgery
Bleeding after IM injections
Fibrin falls apart- attempts to reform- falls apart again.
What is ecchymosis
Easy bruising
Hallmark of all bleeding disorders.
What is hemarthrosis
Spontaneous bleeding in the joints and muscles- hallmark of haemophilia
How can we prevent dilutions
Replace with plasma (coagulation factors) instead of replacing RBC only.
When will bleeding occur
Reduced coagulation factors and platelets Increased Fibrinolytic factors, Anticoagulant proteins
Describe the haemostatic response in patients with haemophilia
- The normal fibrin clot formation mechanism:
o Thrombin is formed from generates fibrin from fibrinogen à fibrin crosslinks via F13a (mediated by thrombin) à stable clot forms. - Haemophilia response mechanism:
o Deficiency in F8 or F9 causes a lack of thrombin to be produced à less fibrinogen to fibrin so less fibrin à less crosslinking as less F13a produced via thrombin.
Outline problems with fibrinolysis
rarer, but excess fibrinolytic activity will remove fibrin mesh too rapidly
Describe the causes of the problems associated with fibrinolysis
Excess fibrinolytic: drug administration (e.g. Strokes) or some tumours
Deficient antifibrinolytic: antiplasmin deficiency (genetic)
Describe unbalanced haemostasis
anticoagulant excess
Usually due to therapeutic administration:
Eg heparin or thrombin and Xa inhibitors
What is meant by thrombosis
‘Intravascular coagulation’ ‘Inappropriate coagulation’ Coagulation inside a blood vessel ‘Coagulation not preceded by bleeding’ Thrombi may be Venous or Arterial
What are the consequences of a thrombosis
Obstructed flow of blood
Artery – myocardial infarction, stroke, limb ischaemia
Vein – pain and swelling
Embolism – migration of the thrombus
Venous emboli, to lungs (pulmonary embolus)
Arterial emboli, usually from heart, may cause stroke or limb ischaemia. can lodge in peripheries- cardioembolic stroke.
Why are the effects of pulmonary clots more dramatic
Lower pressure- clots have dramatic effects-
What is thrombophilia
Thrombophilia is the increased risk of thrombosis; affected by multiple thromboses, young age thrombo
Describe DVT
Deep vein thrombosis.
Venous return of blood is obstructed.
(painful, swollen leg)
Risk of P.E
Describe P.E
Pulmonary embolism (SoB, chest pain, sudden death)
What is the prevalence of venous thromboembolism
Overall 1 in 1000 - 10 000 per annum
Incidence doubles with each decade
PE is cause of 10% of hospital deaths
Estimated 25k preventable deaths per annum
Describe venous thrombosis and age
Risk of P.E increases more than DVT.
What are the consequences of thrombo-embolism
Death – VT mortality 5%.
- Recurrence – 20% in first 2 years and 4% pa thereafter.
- Thrombophlebitic Syndrome (swelling and ulcers in the leg due to damage to valves leading to stasis).
- Pulmonary Hypertension – 4% get it at 2 years.
What are the risk factors for thrombo-embolism
Genetic constitution
Effect of age and previous events, illnesses, medication
Acute stimulus
Ultimately, describe thrombosis risk
multi-causal due to interacting genetic and acquired risk factors; risk increases with age, and will only get thrombus when threshold reached
How do genetic and acquired factors cause an increased risk of thrombosis?
Virchow’s triad: There are three contributory factors to thrombosis:
blood dominant in venous thrombosis
vessel wall dominant in arterial thrombosis
flow complex, contributes to both
These may be inherited or acquired
Describe the defects in the blood in thrombosis risk (hypercoagulability)
- Deficiency of anticoagulant proteins.
o E.G. Antithrombin, Protein C and S. - Increased Coagulant Proteins/Activity.
o E.G. F8, F2, F5 Leiden (activated protein C resistance), Thrombocytosis (increased platelets).
Describe FV Leiden
Hereditary defects in white Caucasians
Resistance to protein C
Balance tips in favour of thrombosis.
Describe the role of endothelial injury in increased thrombosis
Inflammation expression: malignancy, infection, immune disorders may lead to overexpression of thrombomodulin and tissue factors
We know relatively little about the role of
the vessel wall in thrombosis.
Many proteins active in coagulation are expressed on the surface of endothelial cells eg:
Thrombomodulin
Tissue factor
Tissue factor pathway inhibitor
Describe the role of flow in increased risk of thrombosis
Reduced flow increases risk of venous thrombosis- coagulation factors more likely to accumulate.
- Increased flow may wash away coagulation factors and give less chance for a thrombus to form.
- Caused by: surgery, fracture, long rest etc
Describe thrombophilia
Clinical: Thrombosis at young age ‘idiopathic thrombosis’ Multiple thromboses Thrombosis whilst anticoagulated Laboratory Identifiable cause of increased risk AT deficiency, Factor V Leiden, global measures of coagulation activity.
What are the combined risks for thrombosis
Numerous conditions will alter blood coagulation, vessel wall and/or flow to precipitate thrombosis or make it more likely. Eg: Pregnancy Malignancy Surgery Inflammatory response
Describe the lysis of clots to treat venous thrombosis
use of tPA (plasminogen activator) to lyse fibrin, but high risk of bleeding- ONLY USE IN SEVERE CLOTS
Describe treatment to limit recurrence/extension/emboli
Increase anticoagulant activity
e.g: heparin (immediate acting, parenteral)
Lower procoagulant factors
e.g.: warfarin (oral, slow acting for long term therapy)
Inhibit procoagulant factors– direct inhibitors
Rivaroxaban (Xa), Apixaban (Xa), Dabigatran (IIa)
What are the NICE guidelines for the prevention of VT
Assess individual risk and circumstantial risk
All patients admitted should have VTE risk assessment
(hospital target >90%)
Give prophylactic antithrombotic therapy
(eg heparin for in-patients)
+/ TED stockings
Describe the importance of identifying those at risk form VTE
Identify while in high risk environment of hospital- before surgery
Ensure scale is not tipped too far (e.g in haemophiliacs)
In patents with Factor V Leiden, what do they have to be
Heterozygous- homozygous= complete deficiency- not compatible with life.
