1b Haemostasis Flashcards
What is haemostasis?
the cellular and biological processes that enable both the specific and regulated cessation of bleeding in response to vascular insult
What is haemostasis for?
Prevention of blood loss from intact vessels
Arrest bleeding from injured vessels
Enable tissue repair
What is the response to injury to endothelial cell lining?
Vessel constriction - vascular smooth muscle cells contract locally which limits blood flow to the injured vessel
What does primary haemostasis involve?
Formation of an unstable platelet plug - platelet adhesion and platelet aggregation
What is the purpose of primary haemostasis?
Limits blood loss and provides a surface for coagulation
How do platelets bind directly to the exposed collagen?
The platelets bind to the GpIa receptor = binds directly to the exposed collage
How do platelets bind to Von Willebrand Factor?
Using the GpIb receptor
What happens to the platelets after they bind and adhere to the endothelial lining?
Release of their granular contents = ADP and thromboxane A2 from arachidonic acid
How do platelets aggregate with each other in primary haemostasis?
Using the GpIIb / IIIa receptor following activation
What happens in secondary haemostasis?
Stabilisation of the plug with fibrin
blood coagulation
What is the purpose of secondary haemostasis?
Stops blood loss
What happens during fibrinolysis?
Vessel repair and dissolution of clot
Cell migration/proliferation & fibrinolysis
What is the purpose of fibrinolysis?
Restores vessel integrity
What term is used to describe low platelet numbers?
Thrombocytopenia
What are some causes of thrombocytopenia?
Bone marrow failure eg: leukaemia, B12 deficiency
Accelerated clearance eg: immune (ITP), Disseminated Intravascular Coagulation (DIC)
Pooling and destruction in an enlarged spleen
What is ITP?
Immune Thrombocytopenic Purpura
Describe how ITP occurs?
- Antiplatelet autoantibodies bind to the sensitized platelet
- The sensitized platelets are then cleared by macrophages in the spleen
What is a very common cause of thrombocytopenia?
ITP
Describe how the function of platelets might be impaired?
Hereditary absence of glycoproteins or storage granules
What causes of Glanzmann’s syndrome?
Absence of GPIIb / IIIa
What causes Bernard Soulier Syndrome
Absence of GPIb
What causes storage pool disease?
reduction in the dense granules of platelets
Which drugs might cause an acquired impairment to the function of platelets?
Aspirin, NSAID’s, Clopidogrel
What are the two common antiplatelet drugs?
Aspirin and Clopidogrel
How does aspirin work?
irreversibly blocks cyclo-oxygenase meaning Thromboxane A2 cannot be produced
Why does aspirin not affect prostacyclin synthetase?
Because it can be further generated by the endothelial cells
How does clopidogrel work?
Ireversibly blocks the ADP receptor on platelets - P2Y12 on cell membrane
What are the two functions of Von Willebrand Factor in primary haemostasis?
Binding to collagen and capturing platelets
Stabilising factor VIII (8)
What is the usual inheritance pattern of VWD?
Hereditary = autosomal inheritance pattern
- Deficiency of VWF
- VWF with abnormal function
What are the inherited conditions of primary haemostasis related to the vessel wall?
Connective tissue disorders
What are the acquire disorders of primary haemostasis related to the vessel wall?
Steroid therapy causes atrophy of the collage fibres which support the blood vessels
Ageing = senile purpura
Vasculitis
Scurvy
What is VWD?
Failure of primary haemostasis
Hereditary decrease of quantity +/ function (common)
Acquired due to antibody (rare)
What is a key sign of thrombocytopenia?
Petechiae - small red dots on the skin which are less than 3mm in size
What causes petechiae and purpura?
Bleeding underneath the skin
What is the difference between petechiae and purpura
Petechiae = < 3mm and Blanch when pressure is applied
Purpura = 3-10mm and do not blanch when pressure is applied
What conditions result in purpura on the skin?
Platelet (thrombocytopenic purpura) or vascular disorders
What are the typical bleeding features of primary haemostasis?
Immediate bleeding
Prolonged bleeding from cuts
Nose / gum / Heavy menstrual bleeding
Prolonged bleeding after trauma / surgery
Bruising
What is the medical term for nose bleeds?
Epistaxis
What is the medical term for heavy menstrual bleeding?
Menorrhagia
What type of bleeding is seen in Severe VWD?
Haemophillia like bleeding - around joints due to low FVIII
What are the visible clinical features of primary haemostasis?
Petechiae
Purpura
Ecchymosis
Senile Purpura
Increased Skin Elasticity
What would a coagulation screen (APPT and PT) show in a disorder of primary haemostasis?
Would be normal
What tests are done for disorders of primary haemostasis?
Platelet count
Bleeding time
VWF assays
Clinical Observations
What range of platelet count would result in no spontaneous bleeding but bleeding with trauma?
40-100 x 10^9 / L
What range of platelet count would result in spontaneous bleeding?
10-40 x 10^9 / L
What range of platelet count would result in severe spontaneous bleeding?
<10 x 10^9 / L
What is the treatment principle for abnormal haemostasis due to immune destruction?
Immunosuppression
Splenectomy for ITP
What is the treatment principle for abnormal haemostasis due to failure of production / function?
Replace the missing platelets / factors through prophylactic or therapeutic
Stop drugs like Aspirin
What is the treatment principle for abnormal haemostasis due to Increased Consumption?
Treat the cause
Replace as necessary
What is desmopressin and how can it help in disorders of primary haemostasis?
2-5 fold increase in VWF and Factor 8 - releases endogenous stores so only useful in mild disorders
What are other treatments of abnormal haemostasis?
Tranexamic Acid
Fibrin glue/spray
Hormonal
What is secondary haemostasis?
Coagulation
What is the role of coagulation?
To generate THROMBIN (IIA) = converts fibrinogen into fibrin
What are the three stages of secondary haemostasis?
Initiation
Amplification
Propagation
What factor is deficient in patients with Haemophillia A?
Factor 8 deficiency
What factor is deficient in patients with Haemophillia B?
Factor 9
What are some caused of acquired deficiency of coagulation factor production?
Liver disease
Anti-coagulant drugs - Warfarin and direct oral anti-coagulants
What is dilution and how does it cause a coagulation disorder?
Inadequate plasma replacement following blood transfusion, as only RBC’s are given, not plasma therefore more dilute
What is the inheritance pattern of Haemophillia?
Sex (X) Linked
What is haemophillia?
Lack of clotting factors results in a failure to generate fibrin to stabilise a platelet plug, therefore it becomes unstable, falls apart and bleeds
What is the hallmark of haemophillia?
Haemarthrosis - spontaneous joint bleeding
What specific method of treatment should be avoided in patients with haemophillia?
Intramuscular injections
Which clotting factor deficiencies are compatible with life?
Haemophillia
Which clotting factor deficiencies are not compatible with life?
prothrombin deficiency
What does a factor 12 deficiency result in?
NO bleeding at all
What does a factor 11 deficiency result in?
Bleeding after trauma but not spontaenouslt
Why might liver failure case an acquired coagulation disorder?
Most of the clotting factors are synthesised in the liver - except VWF which is made in the endothelial cells of blood vessels
What is disseminated intravascular coagulation?
Generalised activation of coagulation due to tissue factor which therefore consumes and depletes coagulation factors, resulting in thrombocytopenia
What dimer is raised in DIC?
D dimer - breakdown product of fibrin due to increased fibrinolysis
Why do superficial cuts not bleed in coagulation disorders?
The unstable platelet plug is sufficient to stop small vessel bleeds
What are the clinical features of coagulation disorders?
Bruising is common, nose bleeds are rare
Spontaneous bleeding into the muscles and joints
Delayed spontaneous bleeding after trauma, and bleeding frequently restarts after stopping
What are the two main clinical distinctions between bleeding due to platelet and coagulation defects?
Platelet = Bleeding is subcutaenous, mucosal membranes, and immediate after injury
Coagulation = bleeding is deeper (in muscle and joints) and is delayed after injury, but prolonged
What does APTT measure?
The intrinsic pathway (12 11 9 8)
What does PT measure?
The extrinsic pathway (3+7 - 10 5 2)
What four conditions could cause a normal PT time but elevated APTT time?
Haemophillia A / B
factor 8 / 9 deficiency
What condition could cause a normal APTT time but abnormal (elevated) PT time?
Factor 7 defiency
What conditions could cause both APTT and PT to be raised?
Liver disease
Anticoagulant drugs
DIC
Dilution following RBC transfer
What is used to replace all the coagulation factors?
Fresh Frozen Plasma
What does cyroprecipitate contain?
Fibrinogen, Factor 8, VWF and factor 13
What are recombinant forms of Factor 8 and 10 used for?
Used on demand to treat bleeds
What are factor concentrates?
Concentrates available for all factors except factor V.
Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X
What are some of the novel treatments for haemophillia?
Gene therapy
Bispecific antibodies
RNA silencing
Which drugs are increase fibrinolytic factors?
tPA and Heparin
What are the signs of pulmonary embolism?
Tachycardia - palpitations
hypoxia
Shortness of breath
Chest Pain
haemoptysis
sudden death
What are the signs of Deep vein Thrombosis/
Painful leg
Swelling
Redness
Warmth
May embolise to the lungs
What do most people with disorders of thrombosis die of?
haemostatic end point
What is a thrombosis?
It is an intravascular coagulation, can be venous or arterial (more commonly venous) which obstructs flow
What are the three contributory factors to Virchow’s triad?
Blood
Vessel Wall
Blood Flow
Which factor in Virchow’s triad is dominant in venous thrombosis?
Blood
Which factor in Virchow’s triad is dominant in arterial thrombosis?
Vessel wall
Which factor in Virchow’s triad contributes to both arterial and venous thrombosis?
Blood flow
What is thrombophillia?
Increased risk of venous thrombosis
What are anti-coagulant proteins?
Anti-thrombin
Protein C and Protein S
What change to anti-coagulant proteins might lead to venous thrombosis?
Decreased anticoagulant proteins
What might increase in order for a thrombosis to occur?
Coagulant factors
Platelets - in myeloproliferative disorders
How does the risk of venous thrombosis change with age?
Increases with age
How does inflammation relate to arterial thrombosis?
Many proteins active in coagulation are expressed on the surface of the endothelial cels and their expression is altered in inflammation
What is stasis and what can cause it?
reduced blood flow
Surgery, long haul flights, surgery, pregnancy
What is the cause of venous thrombosis?
Multi-causal = arises from interacting genetic and acquired risk factors, results in a cumulative risk which is over the thrombotic threshold
What is the treatment of venous thrombosis?
Assess and prevent risks
Prophylactic anti-coagulation therapy
Reduce risk of recurrance - lower procoagulant factors,(warfarin/DOACs) or increase anti-coagulant activity (Heparin)
What are some indications for anticoagulation?
Venous thrombosis
Atrial fibrillation to reduce risk of embolic stroke
Preventative following surgery or hospital admssion
What is heparin, how is it produced and what are the two ways it can be administered?
Naturally occurring glycosaminoglycan
Produced by mast cells of most speciesLong chains - Unfractionated (UFH) – intravenous administration, short half life
- Low molecular weight (LMWH) – subcutaneous administration
What are the actions of unfractionated heparin?
Enhancement of Antithrombin
Inactivation of thrombin (Hep binds AT + Thrombin)
Inactivation of FXa (Hep binds AT only)
(Inactivation of FIXa, FXIa, FXIIa)
What are the actions of LMWH?
Contain pentasaccharide sequence for binding anti thrombin
No need to monitor as it is predictable
How does warfarin work?
Blocks recycling of Vitamin K
Reduces production of coagulation factors
Induces antocoagulated state slowly
Reversible slowly by Vitamin K administration or rapidly by infusion of coag factors (ffp or pcc)
What are some side effects of warfarin?
Bleeding
Skin necrosis
Purple toe syndrome - (Disrupted atheromatous plaques bleed
Cholesterol emboli lodge in extremities)
Embryopathy Chondrodysplasia punctata - (Early fusion of epiphyses
Warfarin teratogenic in 1st trimester)
Equation for INR and what does it mean and what is the normal/target?
What might cause resistance to warfarin?
Lack of compliance
Diet - increased vit k intake
Increased metabolism Cyt P450 (CYP2C9)
Reduced binding (VKORC1)
What are DOACs?
Direct Oral Anticoagulants
What are some DOACs and where do they work?
Rivaroxaban, apixaban, edoxabanaffects fator Xa in propagation
Dabigatran affect Factor IIa in fibrin formation
What are the differences between Warfarin and DOACs
For which condition are DOACs ineffective?
Mechanical prothetic heart valve (Warfarin) and not safe for preganacy (LMWH)
In which conditions can you use DOACs or LMWH?
Surgery and initial treatment for clot or embolism (then can switch to DOAC or warfarin)
In which conditions can you use DOAC or warfarin?
Long term conditions and to reduce risk of embolic stroke
