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 the purpose of haemostasis?
Prevention of blood loss from intact vessels
Arrest bleeding from injured vessels
enable tissue repair
what are the 4 major steps of haemostasis?
vasoconstriction, primary haemostasis, secondary haemostasis, fibrinolysis
what occurs during the vasoconstriction step of haemostasis?
Endothelinis released from endothelial lining of blood vessels, these bind to specific receptors on the smooth muscle of the blood vessels causing vasoconstriction and the release of NOX and prostaglandins
What does the balance of haemostasis depend on?
The balance between coagulation factors which cause a clot and fibrinolytic factors which break down the clot
What is the role of platelets following injury to a blood vessel wall?
Stick to damaged endothelium and become activated, causing a change in their structure to form spicules to encourage platelet-platelet adhesion aswell as stimulating the platelet release reaction
In what two ways do platelets bind to damaged endothelium following injury to a blood vessel?
Directly to collagen via the platelet GPIa receptor or indirectly via von Willebrand factor (VWF) which binds to platelet GPIb
What occurs during the platelet release reaction?
The platelet membrane is invaginated to form a surface-connected canalicular system in which the contents of their granules can be released
What are the important components of platelet granules?
ADP, fibrinogen, VWF
What is VWF a specific carrier for?
Factor 8
How is VWF synthesized?
Synthesized by endothelial cells and megakaryocytes
What does ADP do in the platelet release reaction?
Binds to P2Y12 receptor resulting in further platelet recruitment activation and aggregation
What are the roles of nitric oxide and prostacyclin under normal conditions?
Ensure blood remains thin
What occurs during primary haemostasis?
VWF in the blood binds to exposed collagen on endothelial cells. Platelets bind to VWF using GP1B. This activates the platelets allow them to bind more platelets and release VWF and serotonin.
GP2a/3b receptor exposed allowing platelets to bind fibrinogen - links platelets to form a plug
What happens to platelets when activated?
Change shape and the membrane forms spicules
What does the release of calcium from platelets in primary haemostasis allow for?
Secondary haemostasis
What is prostacyclin?
Vasodilator that circulates to ensure inappropriate coagulation does not occur
What is the action of aspirin?
Binds irreversibly to COX enzyme which inhibits thromboxane A2 receptors meaning less platelet aggregation
what is the action of clopidogrel?
Antiplatelet drug - binds to and blocks ADP P2Y12 receptors. Effects last 7 days
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
What things can cause a decrease in coagulant factors and platelets, but an increase in fibrinolytic factors and anticoagulant proteins?
Lack of a specific factor - failure of production: congenital and acquired. Increased consumption/clearance
Defective function of a specific factor - genetic or acquired
What is the purpose of primary haemostasis?
To limit blood loss and provide a surface for coagulation
What does thrombocytopoenia describe?
Low platelet numbers
What are the two mechanisms behind thrombocytopenia?
Bone marrow failure: leukaemia, B12 deficiency
Accelerated clearance: immune (ITP), disseminated intravascular coagulation
What is ITP?
Immune cytopoenic purpura: sufficient numbers are made but are destroyed in peripheral circulation and cleared by reticuloendothelial cells
What is disseminated intravascular coagulation?
Pooling and destruction of platelets in an enlarged spleen
What are the three main types of disorder of primary haemostasis?
Platelets
VWF
Vessel wall
What are some hereditary causes of impaired platelet function?
Hereditary absence of glycoproteins or storage granules:
Glanzmanns thromboasthenia
Bernard soulier syndrome
Storage pool disease
What is Glanzmanns thrombasthenia?
Absence of Gp2b/3a on surface of platelets
What is Bernard soulier syndrome?
Absence of GP1B receptors on platelets
What is storage pool disease?
Reduction in granular contents of platelets
What drugs can cause impaired platelet function?
Aspirin, NSAIDS, clopidogrel -> common
What is Von willebrands disease?
A deficiency or defective VWF or low levels of factor 8
What are the main types of vWD?
Inherited: deficiency (type 1 and 3)
VWF with abnormal function (type 2)
Acquired: due to antibody (rare)
What are the functions of Von Willebrand factor?
Binding to collagen and capturing platelets, stabilising factor 8
What are the three types of inherited disorders of vessel walls affecting haemostasis?
Hereditary haemorrhagic telangiectasia
Ehlers-Danlos syndrome
Other connective tissue disorders
What are the tree types of acquired disorders of vessel walls affecting haemostasis?
Steroid therapy
Ageing
Vasculitis
Scurvy
Are inherited or acquired disorders of vessel walls affecting haemostasis more common?
Acquired
What is ecchymosis?
Bruising > 10mm
What is petechiae?
Clinical feature of thrombocytopenia
Small spots caused by bleeding underneath the skin
What is senile purpura?
Ecchymoses that occur on elderly patients extensor surfaces due to peri vascular connective tissue atrophy
Bruising under skin
Not dangerous and no further work-up needed
What are the clinical features of disorders of primary haemostasis?
Typical primary haemostasis bleeding:
Immediate, prolonged bleeding from cuts
Nose bleeds, gum bleeding, heavy menstrual bleeding
Ecchymoses and prolonged bleeding after trauma or surgery
What is pupura?
Condition of red/purple discoloured spots on skin that do not black when pressure is applied
Normally between 3-10mm and can be found over mucosal surface e.g. gums
What types of disorders are purpura often seen in?
Platelet disorders e,g, thrombocytopenic purpura or vascular disorders
In severe VWD clinical features resemble what?
Haemophilia-like bleeding due to low factor 8
What are the tests done 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)
Outline the principles of treatment of abnormal haemostasis
Failure of production/function
-Replace missing factor/platelets e.g. VWF containing concentrates
i) Prophylactic
ii) Therapeutic
-Stop drugs e.g. aspirin/NSAIDs
•Immune destruction
-Immunosuppression (e.g. prednisolone)
-Splenectomy for ITP
•Increased consumption
-Treat cause
-Replace as necessary
What is secondary haemostasis?
Stabilisation of the platelet plug with fibrin
Coagulation cascade
Production of thrombin (2a) which converts fibrinogen to fibrin - stops blood loss
What are the three mechanisms of disorders of coagulation?
Deficiency of coagulation factor production
Dilution of coagulation factor
Increased consumption of coagulation factor
What can cause a deficiency of a coagulation factor and thus a disorder of coagulation?
Hereditary - factor 8/9, haemophilia A/B
Acquired - liver disease, anticoagulant drugs, direct oral anticoagulants
How can coagulation factors be diluted resulting in a disorder of coagulation?
Blood transfusion with insufficient plasma being given
How can increased consumption result in a disorder of coagulation?
Acquired - disseminated intravascular coagulation (DIC) (common)
Immune - antibodies (rare)
What are the main hereditary coagulation disorders?
Haemophilia A (Factor VIII deficiency)
•Haemophilia B (Factor IX deficiency)
• sex linked
•1 in 104 births
•Others are very rare (autosomal recessive)
What is the hallmark of haemophilia?
Haemarthrosis - bleeding into the joint
What does the term haemophilia mean?
Failure to generate fibrin to stabilise the platelet plug
What are the sequelae of haemarthrosis?
Chronic haemarthrosis leads to muscle wasting
Friable synovial lining bleeds spontaneously
Leads to joint deformity
Why should intramuscular injection be avoided in haemophilia patients?
Leads to extensive haematoma
Acquired coagulation disorders are more common where?
In hospital
A deficiency in coagulation factor 8 and 9 (haemophilia) causes what?
Spontaneous joint and muscle bleeding, is severe but compatible with life
Which coagulation factor deficiency is most lethal?
Prothrombin (factor 2)
A deficiency in coagulation factor 11 results in what?
The patient will not bleed spontaneously but will after trauma
A deficiency in coagulation factor 12 results in what?
No bleeding at all
How does liver failure result in coagulation disorders?
Decreased production - most coagulation factors are synthesized in the liver
What is disseminated intravascular coagulation?
Generalised activation of coagulation – Tissue factor
Widespread microthrombi resulting in ischaemia and infarction leading to more clotting
Consumption of platelets and factors results in bleeding, especially from IV sites and mucosal surfaces leading to more bleeding
DIC is a disorder of both________
More clotting and more bleeding
DIC is associated with _______
Sepsis, major tissue damage, inflammation
How does DIC cause organ failure?
Activation of fibrinolysis depletes fibrinogen – raised D-dimer
(a breakdown product of fibrin)
Deposition of fibrin in vessels causes organ failure
What are the clinical features of coagulation disorders?
•superficial cuts do not bleed (platelets)
•bruising is common, nosebleeds are rare
•spontaneous bleeding is deep, into muscles and joints
•bleeding after trauma may be delayed and is prolonged
•Bleeding frequently restarts after stopping
The shearing of vessels in DIC is treated by ______
Treating underlying cause, supportive treatment with replacement of missing coagulation factors e.g. FFP and platelets in mean time
What is the clinical distinction between bleeding due to platelet defects, or coagulation defects?
Platelet/Vascular: Superficial bleeding into skin, mucosal membranes, Bleeding immediate after injury
Coagulation: bleeding into deep tissues, muscles, joints. Delayed, but severe bleeding after injury, bleeding often prolonged
What are the 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
How is the extrinsic pathway tested?
Measured via PT
What should the prothrombin time be in the test of the extrinsic pathway?
11-15 seconds
What test is used to measure the intrinsic pathway
Measured by activated partial thromboplastin time
When measuring the activated partial thromboplastin time, what should it be in a regular intrinsic pathway? §
25-39
Is the extrinsic or intrinsic pathway more important?
Intrinsic pathway, takes longer to start
what are the clinical features of coagulation disorders?
superficial cuts do not bleed (platelets)
bruising is common, nosebleeds are rare
spontaneous bleeding is deep, into muscles and joints
bleeding after trauma may be delayed and is prolonged
Bleeding frequently restarts after stopping
What does FFP contain?
contains all coagulation factors
what does cryoprecipitate contain?
rich in fibrinogen, factor 8, VWF, factor 13
what does factor concentrates contain?
Concentrates available for all factors except factor V.
Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X
what are three novel treatments for haemophilia A?
gene therapy
bispecific antibodies
RNA silencing
what bispecific antibodies can be used to treat haemophilia A?
Emicizumab
Binds to FIXa and FX
Mimics procoagulant function of FVIII
how does RNA silencing work to treat haem A and B?
Targets natural anticoagulant - antithrombin
what are two novel treatments for haem. B?
gene therapy and RNa silencing
what is DDAVP?
Desmopressin (DDAVP)
Vasopressin analogue
2-5 fold increase in VWF (and FVIII)
what are the limitations of desmopressin?
release endogenous stores so only useful in mild disorders?
an increase in fibrinolytic factors and anticoagulant proteins (resulting in more bleeding) is exceedingly rare except when induced by:
tPA (stroke)
heparin
a deficiency in which clotting factor will result in an abnormal PT?
factor 7
a deficiency in which clotting factors, or the presence of which disorders, will result in an abnormal aPTT?
factors 11 and 12
haem A and B
a deficiency in which clotting factors will affect both PT and aPTT?
factors 5, 10, and 2
both PT and aPTT will be effected by:
severe liver disease
vitamin K deficiency
anticoagulant drugs
DIC
dilution following red cell transfusion
outline the presentation of pulmonary embolism
Tachycardia
Hypoxia
Shortness of breath
Chest pain
Haemopysis
Sudden death
outline the presentation of deep vein thrombosis (DVT)
Painful leg
Swelling
Red
Warm
May embolise to lungs
Post thrombotic syndrome
venous thrombosis is due to_____
intravascular coagulation
inappropriate coagulation
what is Virchows triad?
the 3 contributory factors to thombosis
what are the three contributory factors to thrombosis?
blood
vessel wall
blood flow
blood flow is the dominating contributory factor in which type of thrombosis?
venous thrombosis
vessel wall is the domoniating contributory factor in which type of thrombosis?
arterial thrombosis
blood flow is the dominating contributory factor in which type of thrombosis?
both arterial and venous thrombosis
what is thrombophilia?
predisposition to thrombosis secondary to a congenital or acquired disorder
what is the presentation of thrombophilia?
Thrombosis at young age
‘spontaneous thrombosis’
Multiple thromboses
Thrombosis whilst anticoagulated
normal haemostasis is a delicate balance between____
fibrinolytic factors and anticoagulant proteins vs. coagulant factors and platelets
what are the key anticoagulant factors for thombosis?
antithrombin
protein S
protein C
what is the function of protein C?
inactivates factor 5a and 8a in the presence of protein S
what is the action of antithrombin?
inactivates thrombin (2a) and 10a
what potentiates the action of antithrombin?
heparin
what are the key coagulant factors and patelets that cause venous thrombosis?
factors = increased 8,2 and V
increased platelets due to myeloproliferative disorders
an increase in factor 5 activity leading to venous thrombosis is due to _____
activated protein C resistance
what is the biggest thrombophilic trait in terms of its risk factor for venous thrombosis?
antithrombin deficiency
how does the rate ratio of DVT and PE change with age?
both increase with rapid increase from age 50, PE more than DVT
the thrombotic threshold can only be reached by cumulative risk of:
interacting genetic and acquired risk factors
what preventative methods are used for the treatment of venous thrombosis?
Prophylactic anticoagulant therapy
how do we reduce risk of recurrence/ extension of venous thrombosis?
lower procoagulant factors
e.g.: warfarin, DOACs
increase anticoagulant activity
e.g: heparin
what are the therapeutic indications for anticoagulation?
venous thrombosis and atrial fibrillation, mechanical prosthetic heart valve
what are the preventative indications for anticoagulation?
E.g. following surgery, during hospital admission, during pregnancy
what is heparin and which cells produce it?
naturally occurring glycosaminoglycan.
produced by mast cells
which type of heparin is administered intravenously?
long chain - unfractionated (UFH)
which type of heparin is administered subcutaneously?
low molecular weight (LMWH)
what is the action 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 is the action of LMWH?
enhance antithrombin but to a lower extent than unfractionated.
Contain pentasaccharide sequence for binding AT
Predictable dose response in most cases so does not require monitoring (cf UFH)
what effect does unfractionated heparin have on APTT? how does this compare to LMWH?
increases APTT more than LMWH, LMWH has a more predictable effect and does not require monitoring
how do we monitor the effect of LMWH on APTT?
measure anti-10a
what is the action of warfarin on a celular level?
bocks recycling of vit.K decreasing amounts of activated factor 2,7,9,10
which clotting factor decreases fastest following warfarin administration and why?
7 as has the shortest half life
how is the action of warfarin reversed slowly?
vit K administration
how is the action of warfarin reversed rapidly?
rapidly by infusion of coagulation factors:
PCC (Prothrombin Complex Concentrate- contains Factors II, VII, IX and X)
FFP (Fresh Frozen Plasma)
what are the side effects of warfarin?
bleeding
skin necrosis
purple toe syndrome
embryopathy - Chondrodysplasia punctata
why does warfarin cause skin necrosis?
protein C deficiency
why does warfarin cause purple toe syndrome?
Disrupted atheromatous plaques bleed
Cholesterol emboli lodge in extremities
what is chondrodysplasia punctuta?
Early fusion of epiphyses
Warfarin teratogenic in 1st trimester
how is warfarin monitored?
using the international normalised ratio
what is the international normalised ratio?
standardised measure reflecting correction for different thromboplastins which might be used to measure PT
what is the target INR time?
usually 2-3
above what INR time is there a marked risk of bleeding?
above 4
what do we measure to determine patient complience of taking warfarin?
PIVKA - proteins induced by vitamin K absence
increased metabolism of which enzyme can cause resistence to warfarin?
CYP2C9
DOACs inhibit one of which two clotting factors?
10a - rivaroxaban
2a - dabigatran
do DOACs or warfarin have a faster onset
DOACs
does dietry intake effect warfarin or DOACs?
warfarin
does warfarin or DOACs have more drug interactions?
warfarin
is monitoring required for warfarin or DOACs?
warfarin
do DOACs or warfarin have renal dependence?
DOACs
how are DOACs reversed?
Specific Antidotes available for Dabigatran and in development for FXa inhibitors
what anticoagulant is used for the initial treatment of venous thrombosis to minimise clot extension/ embolisation?
DOAC or LMWH
what anticoagulant is used for long term treatment of venous thrombosis to reduce risk of recurrence?
DOAC or warfarin
what anticoagulant is used to treat atrial fibrillation?
DOAC or warfarin
what anticoagulant is used for the therapeutic treatment of a mechanical prosthetic heart valve
Warfarin (DOACs not effective and should be avoided)
which anticoagulant is not safe for use during pregnancy?
DOACs, and warfarin in first trimester
which anticoagulant drug is use in thromboprophylaxis, surgery, during hospital admission and pregnancy?
LMWH
