🫀🫁Cardio & Resp🫀🫁 - Haemostasis Flashcards
What is haemostasis?
The cellular and biochemical processes that enables 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 are the stages of haemostasis?
Immediate response to injury
Primary haemostasis
Secondary haemostasis
Fibrinolysis
What happens immediately after injury to the endothelia cell lining?
Vessel constriction
Vascular smooth muscle cells contract locally
Limits blood flow to injured vessel
What occurs during primary haemostasis?
Formation of an unstable platelet plug
platelet adhesion
platelet aggregation
Limits blood loss + provides surface for coagulation
What occurs during secondary haemostasis?
Stabilisation of the plug with fibrin
Blood coagulation
Stops blood loss
What is the process of fibrinolysis?
Vessel repair and dissolution of clot
Cell migration/proliferation & fibrinolysis
Restores vessel integrity
Why do we need to understand haemostatic mechanisms?
Diagnose and treat bleeding disorders
Control bleeding in individuals who do not have an underlying bleeding disorder
Identify risk factors for thrombosis
Treat thrombotic disorders
Monitor the drugs that are used to treat bleeding and thrombotic disorders
Describe the balance that exists in haemostasis
How can the haemostatic balance be tipped towards bleeding?
Increase in fibrinolytic factors/anticoagulant proteins
Decrease in coagulant factors/platelets
How can the levels of a coagulant factor(s) decrease?
Lack of a specific factor
-Failure of production: congenital and acquired
-Increased consumption/clearance
Defective function of a specific factor
-Genetic
-Acquired: drugs, synthetic defect, inhibition
How do platelets undergo adhesion?
EITHER
VWF binds to collagen, platelet binds to VWF via Glp1b
OR
Platelet adheres to underlying collagen directly via Glp1a
What occurs after platelet adhesion?
Release of ADP and thromboxane A2 by activated platelets
ADP activates nearby platelets, increasing expression of GPIIb/IIIa
Thromboxane A2 promotes vasoconstriction, activating platelets and encouraging adherence to each other
What is the mechanism of platelet aggregation?
Platelets bound to collagen via VWF
Fibrinogen with a Ca2+ binds to GPIIb/IIIa of the platelet, and that of another platelet
Forms a chain of bound platelets
Forms a clot
What is the term for a low number of platelets?
Thrombocytopenia
What are the causes of thrombocytopenia?
Bone marrow failure
e.g. leukaemia, B12 deficiency
Accelerated clearance
e.g. immune (ITP), disseminated intravascular coagulation (DIC)
Impaired function
-Hereditary absence of glycoproteins or storage granules (rare)
-Acquired due to drugs: aspirin, NSAIDs, clopidogrel (common)
What is (auto-)ITP?
Auto-immune thrombocytopenic purpura
What is ITP?
Autoimmune destruction of platelets
Antiplatelet autoantibodies bind to a sensitised platelet - then phagocytosed by a macrophage
What are the main hereditary platelet defects?
What is the use of antiplatelet therapy?
Widely used in the prevention and treatment of cardiovascular and cerebrovascular disease
What is the mechanism of action of antiplatelet therapy?
Aspirin and clopidogrel used
Thromboxane A2 is produced in a series of reactions from Arachidonic acid
Aspirin irreversibly blocks cyclo-oxygenase, responsible for converting arachidonic acid to cycle endoperoxides
Clopidogrel irreversibly blocks the ADP receptor on platelets
What is the other most common category of disorders that effects primary haemostasis, other than platelet disorders or vessel wall disorders?
Von Willebrand factor disorders
Von Willebrand disease - hereditary decrease of quantity +/- function, acquired due to antibody (rare)
Briefly outline Von Willebrand disease
VWF has two functions in haemostasis
-Binding to collagen and capturing platelets
-Stabilising Factor VIII
(Factor VIII may be low if VWF is very low)
VWD is usually hereditary (autosomal inheritance pattern)
-Deficiency of VWF (Type 1 or 3)
-VWF with abnormal function (Type 2)
Briefly outline the disorders of primary haemostasis
Platelets
-Thrombocytopenia
-Drugs
Von Willebrand Factor
-Von Willebrand disease
The vessel wall
-Hereditary vascular disorders
-Steroids, age, vasculitis, scurvy
What disorders effect the vessel wall in primary haemostasis?
Inherited (rare):
-Hereditary haemorrhagic telangiectasia
-Ehlers-Danlos syndrome and other connective tissue disorders
Acquired (common):
-Steroid therapy
-Ageing (‘senile’ purpura)
-Vasculitis
-Scurvy (Vitamin C deficiency)
What are the classic signs of primary haemostasis bleeding?
Immediate
Prolonged bleeding from cuts
Nose bleeds (epistaxis):prolonged > 20 mins
Gum bleeding: prolonged
Heavy menstrual bleeding (menorrhagia)
Bruising (ecchymosis), may be spontaneous/easy
Prolonged bleeding after trauma or surgery
What is the characteristic feature of thrombocytopenia?
Petechiae
What are purpura a sign of?
Platelet (thrombocytopenic purpura) or vascular disorders
What is seen in sever VWD?
Haemophilia-like bleeding (due to low FVIII)
What is there difference between petechiae and purpura?
What are the investigations for disorders of primary haemostasis?
Platelet count, platelet morphology
Bleeding time (PFA100 in lab)
Assays of von Willebrand Factor
Clinical observation
Note –coagulation screen (PT, APTT) is normal (except more severe VWD cases where FVIII is low)
What are the principles for treating primary haemostasis due to failure of production/function?
Replace missing factor/platelets e.g. VWF containing concentrates
i) Prophylactic
ii) Therapeutic
Stop drugs e.g. aspirin/NSAIDs
What are the principles for treating primary haemostasis due to immune destruction?
Immunosuppression (e.g. prednisolone)
Splenectomy for ITP
What are the principles for treating primary haemostasis due to increased consumption?
Treat cause
Replace as necessary
List some additional haemostatic treatments
Desmopressin (DDAVP)
-Vasopressin analogue
-2-5 fold increase in VWF (and FVIII)
-releases endogenous stores (so only useful in mild disorders)
Tranexamic acid - antifibrinolytic
Fibrin glue/spray
Other approaches e.g hormonal (oral contraceptive pill for menorrhagia)
What is the primary objective of the coagulation cascade?
To generate thrombin (IIa), which converts fibrinogen to fibrin
Deficiency of any coagulation factor results in a failure of thrombin generation and hence fibrin formation
What are the different forms of coagulation disorders?
Deficiency of coagulation factor production
Dilution
Increased consumption
What are the different coagulation disorders relating to deficiency of coagulation factor production?
Hereditary
-Factor VIII/IX: haemophilia A/B
Acquired
-Liver disease
-Anticoagulant drugs - warfarin, DOACs
What are the different coagulation disorders relating to dilution?
Acquired
-Blood transfusion
What are the different coagulation disorders relating to increased consumption?
Acquired
-Disseminated intravascular coagulation (DIC) – common
-(Immune – autoantibodies – rare)
What are the main hereditary coagulation disorders?
Haemophilia A (factor VIII)
Haemophilia B (factor IX)
Others are very rare (autosomal recessive)
What is the overall clinically significant result of haemophilia?
Failure to generate fibrin to stabilise platelet plug
What is the “hallmark” of haemophilia?
Haemarthrosis - bleeding into joint space
Chronic haemarthrosis leads to muscle wasting
Which method of drug/substance delivery should be avoided in patients with haemophilia?
Intramuscular injections
How do the various coagulation factor deficiencies have different consequences?
How can acquired coagulation disorders arise?
Liver failure – decreased production
-Most coagulation factors are synthesised in the liver
Anticoagulant drugs
Dilution
-Red cell transfusions no longer contain plasma
-Major haemorrhage requires transfusion of plasma as well as red cells and platelets
Increased consumption (to be cont.)
How can increased consumption related coagulation disorders arise?
Disseminated intravascular coagulation
-Generalised activation of coagulation- tissue factor
-Associated with sepsis, major tissue damage, inflammation
-Consumes and depletes coagulation factors
-Platelets consumed
- thrombocytopenia
-Activation of fibrinolysis depletes fibrinogen – raised D-dimer
(a breakdown product of fibrin)
-Deposition of fibrin in vessels causes organ failure
How can platelet and coagulation defects be clinically distinguished?
What are the available tests for coagulation disorders?
Screening tests (‘clotting screen’)
-Prothrombin time (PT)
-Activated partial thromboplastin time (APTT)
-Full blood count (platelets)
Coagulation factor assays (for Factor VIII etc)
Tests for inhibitors
What parts of the coagulation cascade do PT and APTT test?
Prothrombin time (PT) tests the Extrinsic pathway
Activated partial thromboplastin time (APTT) tests the Intrinsic pathway
What causes an elevated PT only?
Factor VII deficiency
What things cause both APTT and PT elevation?
Liver disease
Anticoagulant drugs e.g. warfarin
DIC (platelets and D dimer)
Dilution following red cell transfusion
What causes elevated APTT only?
Haemophilia A/B
Factor XI deficiency
How can missing coagulation factors be replaced?
Plasma (fresh frozen plasma FFP)
Cryoprecipitate
Factor concentrates
Recombinant forms of FVIII and FIX are available
What coagulation factors are contained in FFP?
Contains all coagulation factors
What is cryoprecipitate rich in?
Fibrinogen
VWF
VIII
XIII
What coagulation factors can be given in the form of factor concentrates?
Concentrates available for all factors except factor V
Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X
What are the novel treatments available for haemophilia?
How does a pulmonary embolism present?
Tachycardia
Hypoxia
Shortness of breath
Chest pain
Haemopysis
Sudden death
How does a deep vein thrombosis present?
Painful leg
Swelling
Red
Warm
May embolise to lungs
Post thrombotic syndrome
What is post thrombotic syndrome?
Chronic complication of deep vein thrombosis (DVT) caused by damage to vein valves
Leads to venous hypertension
Symptoms include leg pain, swelling, heaviness, skin discoloration, and sometimes ulcers
Management involves compression stockings, leg elevation, exercise, and in severe cases, surgical options
What is thrombosis?
Intravascular, inappropriate coagulation
Usually venous (can be arterial)
Obstructs flow
May embolise to lungs
What are the three contributory factors for thrombosis?
Virchow’s triad:
Blood - dominant in venous thrombosis
Vessel wall - dominant in arterial thrombosis
Blood flow - contributes equally to both arterial and venous thrombosis
How does blood contribute to thrombosis?
Blood composition - most notable coagulation factors and tendency to coagulate
More of a factor in venous thrombosis
How does the vessel wall contribute to thrombosis?
Vessel wall damage (such as from atherosclerosis) plays a critical role in triggering clot formation
Damage to the vessel wall exposes collagen and tissue factors that activate platelets and coagulation cascades (also atherosclerotic plaque rupture)
More of a factor in arterial thrombosis
How does blood flow contribute to thrombosis?
Blood flow abnormalities contribute to thrombosis in both veins and arteries
Slow blood flow in veins promotes thrombosis
Turbulent blood flow in arteries promotes thrombosis
When might slowed blood flow be encountered?
Surgery, long haul flight, pregnancy
Just some examples
Increased risk of venous thrombosis: ‘thrombophilia’ –how may this present?
Thrombosis at young age
‘Spontaneous thrombosis’
Multiple thromboses
Thrombosis whilst anticoagulated
What components of coagulation contribute to increased coagulation/thrombosis?
Factor VIII
Factor II
Factor V Leiden
(increase activity due to activated protein C resistance)
Myeloproliferative disorders (platelets increase)
What are the anticoagulant proteins and which factors do they effect?
Protein C
Protein S
VIIIa and Va
What are the treatments for venous thrombosis?
Prevention
-Assess and prevent risks
-Prophylactic anticoagulant therapy
Reduce risk of recurrence/extension
-Lower procoagulant factors
e.g. warfarin, DOACs
-Increase anticoagulant activity
e.g. heparin
What are some indications for anticoagulation?
Therapeutic
Venous thrombosis
-Initial treatment to minimise clot extension/embolisation (< 3 months)
-Long term treatment to reduce risk of recurrence
Atrial fibrillation
-Reduce risk of embolic stroke
Preventative (Thromboprophylaxis)
e.g. following surgery, during hospital admission, during pregnancy
What is heparin?
Naturally occurring glycosaminoglycan
Produced by mast cells of most species
Porcine products used in UK
Varying numbers of saccharides in chains – differing lengths
Long chains (Unfractionated (UFH)) – intravenous administration, short half life
- Low molecular weight (LMWH) – subcutaneous administration
What are the actions of Unfractionated heparin (UFH)
Enhancement of Antithrombin
Inactivation of thrombin (Hep binds Antithrombin + Thrombin)
Inactivation of FXa (Hep binds AT only)
(Inactivation of FIXa, FXIa, FXIIa)
What are the actions of LMWH?
Helps antithrombin bind to Xa
Contain pentasaccharide sequence for binding AT
Predictable dose response in most cases so does not require monitoring (cf UFH)
What is the effect of UFH on APTT?
What is the effect of LMWH on APTT?
What is warfarin?
Vitamin K antagonist
How do vitamin K antagonists work?
Inhibit the enzyme vitamin K epoxide reductase and quinone reductase
Necessary for recycling vitamin K to its active form
Inhibition of the enzyme leads to reduction in production of II (prothrombin), VII, IX, and X
Outline warfarin in a clinical setting:
administration, function, reversibility
Competes with Vitamin K – complicated metabolism
Many dietary, physiological and drug interactions
Narrow therapeutic index and requires monitoring
Reduces production of functional coagulation factors
Induces an anticoagulated state slowly
Reversible
-Reversed slowly by Vit K administration - takes several hours to work
-Reversed rapidly by infusion of coagulation factors (e.g. PCC, FFP)
What forms of resistance to Warfarin can patients show?
Lack of patient compliance
-Measure warfarin levels
-Proteins Induced by Vitamin K Absence (PIVKA)
Diet, Increased Vit K intake
Increased metabolism Cyt P450 (CYP2C9)
Reduced binding (VKORC1)
What are DOACs and how do they work?
Direct Oral Anticoagulants
Directly inhibit coagulation pathway at certain steps
Rivaroxaban, Apixaban, Edoxaban act on Xa
Dabigatran acts on IIa (Thrombin)
What are the differences between onset/offset of warfarin and DOACs?
Warfarin has slow onset/offset
DOACs are rapid
How are warfarin and DOACs dosed?
Warfarin has variable dosing
DOACs have fixed dosing
What are the differences in the interactions that warfarin and DOACs have?
Warfarin has many interactions
DOACs has few
Warfarin has food effects, DOACs don’t
How does renal dependence and reversibility compare between warfarin and DOACs?
Warfarin has no renal dependence, DOACs have some
Warfarin reversed by Vit K/PCCs
Specific antidotes are available for Dabigatran, in development for FXa inhibitors
What is the anticoagulant of choice for venous thrombosis?
Initial treatment to minimise clot extension/embolisation (< 3 months)
-DOAC or LMWH for first few days followed by DOAC or warfarin
Long term treatment to reduce risk of recurrence
-DOACs or warfarin
What is the anticoagulant of choice for atrial fibrillation?
Reduce risk of embolic stroke
-DOAC or warfarin
What is the anticoagulant of choice for a patient with a mechanical prosthetic heart valve?
Warfarin
DOACs not effective and should be avoided
What anticoagulants should be used for thromboprophylaxis?
Note lower doses are used compared to therapeutic uses
Following surgery - LMWH or DOAC
During hospital admissions - LMWH (DOACs not recommended)
During pregnancy - LMWH (DOACs not safe in pregnancy)
