Haemostasis Flashcards
What is haemostasis?
specific and regulated cessation of bleeding in response to vascular injury
Stopping blood flow after trauma
Reasons for homeostasis
Prevent blood loss
Enable tissue repair
Mechanism of haemostasis
Endothelial injury
Vessel constriction - limit blood flow to injured vessels
1º Homeostasis - form platelet plug to limit blood loss
2º Homeostasis - clot stabilisation w/ fibrin
Fibrinolysis - vessel repair/clot destruction
Balance model of haemostasis
Bleeding - Fibrinolytics, anticoagulants
Thrombosis - Platelets, coagulants
What can tip the balance towards bleeding
Lack of clotting factor - ^consumption/failed production
Clotting actor dysfunction - Genetic/Acq (drugs)
Summarise the mechanism of 1º Haemostasis
- Adhesion (platelets bind collagen via GP1a/damaged endothelium via VWF/GP1b)
- Activation (granule release: ADP/thromboxane A2 -> further activation and aggregation)
- Aggregation (GP2b/3a bind fibrinogen to signal formation of platelet plug)
What are the three structures that can be affected in primary haemostasis disorders?
Platelets,
VWF,
Vessel Wall
What are the two causes of platelet disorders?
Thrombocytopenia (low number),
Impaired Function
What are the two causes of thrombocytopenia, with examples?
Bone marrow failure (leukaemia/B12 deficiency)
Accelerated Clearance (ITP, DIC, Splenomegaly)
What is ITP and how does it work?
Immune Thrombocytopenic Purpura - autoantibodies bind to platelet and bring to macrophage for removal
What are the two ways of having impaired platelet function?
Hereditary (absence of glycoproteins on platelets) - rare
Acquired (NSAIDs, Aspirin, Clopidogrel)
How does aspirin work?
Inhibits synthesis of thromboxane A2 from arachidonic acid pathway - cannot form platelet plug
Irreversibly blocks COX
How long do the effects of aspirin last and why?
7 days - platelets will be regenerated
How does clopidogrel work?
Binds to ADP receptor on platelets preventing activation
Receptor P2Y12
Disorder affecting VWF
Von Willebrand disease
Hereditary red./LOF of VWF
can also be acq due to antibodies
2 Functions of VWF in haemostasis
Adhesion of platelets via GP1b
Stabilise clotting factor 8
What are the types of Von Willebrand disease?
Deficiency (Type 1 & 3), Abnormal function (Type 2)
What are some examples of vessel wall disorders?
Inherited - Ehlers Danlos Syndrome / connective tissue disorders
Acquired - Steroid Therapy, Ageing, Scurvy
What are the clinical features of disorders from primary haemostasis?
Immediate prolonged bleeding after impact, usually into the skin: nose bleeds (epistaxis), gum bleeds, menstrual heavy bleeds
What are the dermatological features of primary haemostasis disorders and how can you tell them apart?
Petechiae, Purpura, Ecchymoses: (bleeding under the skin) purpura is non-blanching with pressure(<3mm, 3-10mm, >10mm)
(pUrpura - Unblanching)
What sign is characteristic of thrombocytopenia
Petechiae - small spots caused by subdermal bleeding
<3mm
What are the main tests for primary haemostasis disorders?
Bleeding time,
Platelet count,
Clinical obs
Coag screen - PT and APTT will be normal
How to treat failure of prod/function of factors
Replace missing factors/platelets (can be prophylactic)
Stop causative drugs e.g. NSAIDs
How to treat immune destruction in abnormal haemostasis
Immunosuppression - prednisolone
Splenectomy in ITP
What are some additional general abnormal haemostasis treatment?
Desmopressin (^ VWF/factor 8),
Tranexamic Acid - antifibrinolytic
Fibrin Glue
What is the role of coagulation (2º Haemostasis)
Thrombin (IIa) formation for the conversion of fibrinogen to fibrin
Mechanism of 2º Haemostasis
- Initiation - TF on endothelium exp which activates 2,7,9,10 (rq vit.K). Small amount of thrombin formed from prothrombin
- Amplification - IIa activates 5,8 which lead to greater prothrombin activation
- Propagation - Huge burst of thrombin made to stabilise the clot
3 causes of Coag disorders
Deficiency of Coagulation Factor (Hereditary/acq)
Dilution (blood transfusion)
Increased Consumption (DIC/autoimmunity)
What are the two types of deficiency of coagulation factor with examples?
Hereditary (haemophilia A/B, factor 8/9 deficiency), Acquired (liver disease, anticoagulants)
What is Haemophilia
Failure to generate fibrin for stabilisation of platelet plug
What are the two hallmark features of haemophilia?
Haemarthrosis - bleeding into joint
Chronic leads to muscle wasting
What injections should you avoid in haemophilia?
Intramuscular - due to risk of muscle bleeding which is hard to control
Different Coag factor deficiencies
Haemophilia A/B (8/9) - severe but compatible w/ life
Prothrombin (2) Lethal
Factor 11 - Non-spontaneous bleeding post trauma
Factor 12 - No bleeding
Why does Liver failure cause disordered coagulation
Decreased production - most synthesised in the liver
(XCpt VWF/5)
What is an example of increased consumption in coagulation disorders?
Disseminated Intravascular Coagulation (DIC)
What is DIC and how does it work?
Disseminated Intravascular Coagulation - overactive Tissue Factor -> rapid coagulation -> depletion of platelets/coagulation factors -> deposition of fibrin in vessels causes organ failure
What conditions is DIC associated with?
Sepsis, Major Tissue Damage, Inflammation
What is consumed in DIC?
Coagulation Factors, Platelets, Fibrinogen
What molecule can you detect in DIC blood tests?
D-dimer (breakdown product of fibrin)
What are the clinical features of coagulation disorders?
Superficial cuts do not bleed, more deep bleeding.
Delayed but prolonged bleeding after trauma (stop start pattern)
What is the clinical distinction between bleeding of primary and secondary haemostasis defects?
Primary - superficial bleeding to skin/mucosal membranes immediately after injury
Secondary - deep bleeding into tissue, delayed but prolonged bleeding after trauma
Tests for coagulation disorders
Coagulation screen - PT, APTT, FBC
Measure Factor 8
What is the difference between PT and APTT?
Prothrombin Time measures extrinsic pathway (factor 7)
Activated Partial Thromboplastin time measures intrinsic pathway
What is measured by the PT/APTT
Time taken for clot formation (fibrin activation)
What Factors are in the Intrinsic pathway
9,10,11,12
cofactors 5,8
What Factors are in the Extrinsic pathway
1,2,3,7,10
cofactor 5
What can a prolonged APTT but normal PT be a result of?
Haemophilia A/B, Factor XI or XII deficiency (intrinsic pathway before factor 10)
What can a prolonged PT but normal APTT be a result of?
Factor VII deficiency
What can a prolonged PT and APTT be a result of?
DIC, Dilution, Liver Failure, Anticoagulant Drugs
What can a normal PT and APTT be a result of?
Healthy Patient, Primary Haemostasis Disorder
How can you replace coagulation factors?
Fresh Frozen Plasma FFP(has everything),
Cryoprecipitate (fibrinogen, VWF, 8),
Concentrates (anything apart from 5),
Prothrombin Complex concentrates PCC (2,7,9,10)
Recombinant Forms (8/9)
What are some novel treatments for haemophilia?
Gene therapy, Bispecific antibodies (mimics function of factor 8), RNA Silencing
What are two disorders of venous thrombosis?
Pulmonary Embolism,
Deep Vein Thrombosis
What are the presentations of PE?
Chest pain, (pleuritic)
dyspnoea,
tachycardia,
hypoxia,
What are the presentations of DVT?
Painful leg,
swelling,
red,
post-thrombotic syndrome (permanent damage to legs)
What type of thrombosis is seen in each component of Virchow’s triad
Abnormal blood - venous
Abnormal blood flow - venous/arterial
Abnormal vessel wall - arterial
What is it called if there is a higher hereditary risk to thrombosis?
Thrombophilia (e.g episode of thrombosis early in life)
What is the mechanism of protein C and cofactor S
Inactivate 5a/8a
What can tip the balance towards thrombosis
Red. anticoags (Antithrombin, protein C/S)
Increased coags/platelets (2/5/8/myeloproliferative disorders)
What is the role of antithrombin
Inactivates 2a/10a
What are examples of blood flow alterations leading to thrombosis?
Reduced flow - long haul flights, pregnancy (compression by baby), surgery
How can you prevent thrombosis?
Prophylactic Anticoagulant Therapy
How can you reduce the risk of recurring thrombosis?
Warfarin,
Direct Oral Anticoagulants,
Heparin (improve anticoagulation)
Indications to use anticoagulant therapy for a px?
Venous thrombosis (initial and long-term treatment)
Atrial Fibrillation
Mechanical Heart Valves
Thromboprophylaxis e.g. post surgery (low conc)
1. DOAC/LMWH
2. DOAC/Warf
3. Warf
4. doac/lmwh
Where is heparin found?
Produced by mast cells, naturally occuring glycosaminoglycan chain (GAG Chain)
What is the mechanism of action of unfractionated heparin?
Enhances antithrombin
Change active site to improve binding to Factor 10a/thrombin
Long enough to tightly bind thrombin
What are the two types of heparin?
Unfractionated (long chains),
LMWH (low molecular weight heparin)
How are these heparins administered?
Unfractionated - IV,
LMWH - subcutaneous
What is the action of LMWH?
Inhibit factor 10
too short to properly inhibit thrombin
How can you monitor the effectiveness of unfractionated heparin?
APTT - will increase over time
How can you monitor the effectiveness of LMWH and why?
Measure Anti-Xa
APTT not useful
How does Warfarin work
Vit. K antagonist - blocks its recycling
.: no 2,7,9,10, C+S
Problems with warfarin
Narrow therapeutic Index - differs btw pxs/lots of interactions
Requires constant monitoring
Takes a while to work
Pros of warfarin
Reversible
- Vit.K - slow
- FFP/PCC - fast
What are the side effects of warfarin?
Bleeding,
Skin Necrosis,
Purple toe syndrome (plaques bleed in extremities), Chondrodysplasia Punctata (bones in fetus fuse early)
How can you monitor warfarin?
International Normalised Ratio - using prothrombin time
target is usually 2-3
How can a patient build resistance to warfarin?
Lack of compliance,
increased vit K intake via diet
increased metabolism
red. binding
What do DOACs target?
10a - Rivaroxaban
2a - Dabigatran
Compare DOACs and Warfarin on onset of effect
Rapid DOAC, Slow Warfarin
Why are DOACs better than warfarin
faster
fixed dose
fewer drug interactions
No monitoring required
lower risk of bleeding
What drugs do you use for mechanical heart valves?
Warfarin (avoid DOACs as ineffective)
What drugs do you use during pregnancy?
LMWH (DOACs unsafe in pregnancy)
