Haemostasis Flashcards
stages of haemostasis
local vessel constriction → formation of unstable platelet plug (primary haemostasis) → stabilisation of plug with fibrin (secondary haemostasis) → vessel repair and clot dissolution (fibrinolysis)
what does primary haemostasis involve
platelet adhesion and platelet migration
Adhesion via Gp1a to endothelial cell or VWF and Gp1b
aggregation via release of ADP and thromboxane as well as fibrinogen and calcium ( which is sued in secondary haemostasis)
fibrinogen and GpIIb/GpIIIa links platelts
low platelet count
thrombocytopenia may be caused by
bone marrow failure → leukemia, B12 deficiency
accelerated clearance → ITP, disseminated intravascular coagulation
pooling and destruction in large spleen
immune thrombocytopenia
antiplatelet autoantibodies bind → sensitised platelet detected and removed by macrophages of reticuloendothelial system in spleen
what is glanzmann’s thrombasthenia?
hereditary defect in GpIIb/IIIa production
what is bernard soulier syndrome?
hereditary defect in GpIb production
what is storage pool disease?
hereditary issue with storage granules inside platelets
how can platelet defects be acquired? Primary haemostasis
drugs e.g. aspirin vs COX (no thromboxane A2) thus platelet aggregation decreases, clopidogrel vs ADP receptor P2Y12 on platelets
VWF functions in homeostasis?
bind to collagen and collect platelets
stabilise factor VIII
what is von willebrand disease? Primary haemostasis
usually hereditary decrease in amount or function of VWF
can rarely be acquired due to antibodies
- subtypes of hereditary variation?1, 3 → deficiency of VWF2 → VWF with abnormal function
examples of inherited disorders in vessel wall leading to haemostasis issue? Primary haemostasis
hereditary haemorrhagic telangiectasia
ehlers-danlos syndrome
acquired causes of vessel wall primary haemostasis
steroid therapy, aging ‘senile purpura’, vasculitis, vit C deficiency (scurvy)
typical bleeding characteristics in primary haemostasis disorders?
immediate, prolonged bleeding from cuts/after trauma or surgery
nosebleeds 20+ mins, prolonged gum bleeding, menorrhagia
easy or spontaneous bruising (echomysis)
Prolonged bleeding after surgery
difference between petechiae and purpura?
purpura bigger (3-10mm) vs 3mm, don’t blanche when pressure is applied
Purpura seen jn platelet (thrombocytopenia purpura) or vascular disorders
Petechiae seen in thrombocytopenia
tests for primary haemostasis disorders?
VWF assay, bleeding time, platelet count and morphology
coagulation screen (PT, APTT) normal except in severe cases of VWD where factor VIII is low
treatment for failure of production/function of platelets
replace missing factor or platelets by VWF concentrates
prophylatic
therapeutic
stop drugs e.g. NSAIDs or aspirin
treatment for immune destruction of platelts
immunosuppressants eg prednisolone
ITP → splenectomy
treatment for increased consumtipn of platelets
treat cause, replace as necessary
additional haemostatic treatments for primary haemostasis
desmopressin → mild disorders, releases endogenous stores
(Vasopressin analogue which causes a 2-5 increase in VWF and only useful in mild disorders)
tranexamic acid (antifibrinolytic)
fibrin glue/sprays
Or other approaches such as OCP for menhorrahia
what is the role of coagulation
secondary haemostasis → generate thrombin (IIa) to convert fibrinogen to insoluble fibrin
hereditary coagulation disorders → examples?
haemophilia A (factor VIII deficiency), haemophilia B (factor IX deficiency)
hallmark of haemophilia
haemarthrosis (bleeding into joint cavity)
chronic leads indirectly to muscle wasting
sex linked
must not give intravascular injections
how similar are different coagulation factor deficiencies?
potentially v different →
VIII and IX serious but survivable, II fatal, XI bleed after trauma but not spontaneous, XII no bleeding at all
how are coagulation disorders acquired?
liver failure, some anticoagulant drugs eg warfarin or DOAC
dilution in blood due to transfusion(lots of rbc given no plasma)
increased consumption e.g. disseminated intravascular coagulation (acquired),immune autoantibodies (rare)
what is disseminated intravascular coagulation?
generalised activation of coagulation by tissue factor
associated with major tissue damage, inflammation, sepsis
consumes and depletes platelets, coagulation factors
activates fibrinolysis thus depleting fibrinogen which will show raised D dimer
fibrin depostion in vessels causes organ failure
clinical features of coagulation disorders?
superficial cuts don’t bleed (taken care of by platelets)
bruising common nosebleeds rare
spontaneous bleeding = deep e.g. into muscles, joints
bleeding after trauma may be delayed, prolonged
bleeding often restarts after stopping
tests for coagulation factor disorders?
PT, APTT, FBC for platelets
coagulation factor assays
test for inhibitors
what do PT and APTT each measure?
PT = extrinsic pathway
APTT = intrinsic pathway
extrinsic: TF, factor VII
intrinsic: XII, XI, IX, VIII
common: X, V, II, fibrinogen → fibrin
normal times for PT and APTT
PT → 9.6 - 11.6
APTT → 26 - 32
how are missing coagulation factors replaced?
- plasmaall coagulation factors
- cryoprecipitateesp fibrinogen, VIII, XIII, VWF
- factor concentratesavailable for all except V
- recombinantsVIII and IX, on demand or prophylactically
can give desmopressin,tranexamic acid ,firbin glue
novel treatments for haemophilia?
gene therapy for haem A and B
bispecific antibodies mimicking factor VIII procoagulant function by binding to factor IXa and X.Emicizumab
RNA silencing targeting antithrombin for haem a and b
how do disorders of thrombosis present
pulmonary embolism
DVT
pulomonary embolism
tachycardia, hypoxia, shortness of breath, chest pain, haemoptysis,sudden death
deep vein thrombosis presentation?
painful leg, red, swollen, warm
thrombus can embolise to lungs
post thrombotic syndrome (valve damage causing long standing pain)
thrombosis
intravascular coagulation
inappropriate coagulation
venous or arterial
obstructs flow
may embolise to lungs
virchows triad
three contributory factors to thrombosis:
blood, vessel wall, blood flow
which kinds of thrombosis is each prominent in?
blood dominant in venous, vessel wall dominant in arterial, blood flow contributes to both
what is thrombophilia? presentation?
increased risk of venous thrombosis
thrombosis at young age, spontaneous, multiple,thrombosis whilst anticoagulated
prominent anticoagulant proteins?
antithrombin, protein C, protein S
how does thrombsosi arise
excess coagulant factors/platelets (increased due to activated protein c resistance or myeloproliferative disorders) (basically there is an increase in factor VIII factor II and factor V Leiden the last one being due to increased activity of protein c resistance)
decrease in anticoaglant proteins
protein c and s
inactivate factor Va and VIIIa
Protein c is activated by thrombin thrombomodulin complex and protein s acts as a cofactor helping to inactivate Ava and VIIIa
what aspect of blood flow can increase thrombosis risk?
reduced flow increases riss eg pregnancy,surgery,long haul flight
venous thrombosis prevention methods?
prophylactic anticoagulation therapy
lower procoagulant factors eg warfarin/doacs
increased anticoagulant activity eg heparin
SARS-Cov-2 relevance?
contributes to many procoagulative pathways → microthrombus, venous thrombus, arterial thrombus formation
indications for anticoagulation treatment?
venous thrombosis (inital treatment to minimise clot extension,LT to reduce risk of recurrence)
atrial fibrillation (reduce risk of embolic stroke)
mechanical prosthetic heart valve
prophylactic → post-op, during hospital stay, pregnancy as a preventative
heparin
naturally occuring glycosaminoglycans
prodcued by mast cells
porcine products used in uk
different forms of heparin
unfractionated (long chains) → IV administration,short half life
low molecular weight → subcutaneous administration
what does unfractionated heparin do?
enhances antithrombin
inactivates thrombin by binding to antithrombin and thrombin
inactvates factor Xa by binding to antithrombin
inactivates IXa,XIa,XIIa
what does LMWH do?
enhances antithrombin → inactivates factor Xa (not long enough to wrap around antithrombin and thrombin)
Contains pentasaccaride sequence to bind to AT
differences in effect on APTT?
LMWH increases clotting time by less than fractionated
normally dont monitor in LMWH if needed we can measure anti-xa
Thrombin has greater affect on APTT
what kind of drug is warfarin?
blocks recycling of vitamin K
reduces production of functional clotting factors
slowly induces anticoagulative state
what factors does warfarin inactivate
II,VII,IX,X
protein c and s
how do we reverse affects of warfarin
slowly by vit k administration which takes several hours to wrok
or rapidly by infusion of coagulation factors
Prothrombin complex concentrate contains II,VII,IX,X
fresh frozen plasma
warfarin side effects
bleeding, skin necrosis, purple toe syndrome, embryopathy-chondrodysplasia punctata
what is used for warfarin monitoring?
international normalised ratio
measures correction for different hromboplastin used
target and normal values?
normal = 1, target usually 2-3
higher INR sows higher risk of all bleeding as blood is thinner
Lower INR means thick blood
what can cause resistance to warfarin?
vit K dietary intake, increased cytochrome P450 metabolism of warfarin, reduced binding,lack of patient compliance
what do direct oral anticoagulants do?
directly target a clotting factor to inhibit
work agasint factor Xa inhibitor or IIa
compare to warfarin DOACs
faster acting, not affected by diet, fixed dose
fewer interactions, no monitoring required
some renal dependence
reversible by specific antidotes
when should DOACs be avoided?
for mechanical prosthetic heart valves
as medical prothrombo-prophylaxis (e.g. during hospital admission)
in pregnancy
choice of anticoagulant
venous thrombosis:
initital give DOAC/LMWH followed by DOAC/warfarin
long term give DOAC/warfarin
atrial fibrillation:
DOAC/warfarin
Mechanical prosthetic valve
warfarin
preventative:
after surgery give LMWH/DOAC
pregnacny LMWH
What can increase both PT APTT (secondary haemostasis)
Kivrr disease
Anti coagulation drugs
DIC
Dilution following rbc transfusion
Examples of DOAC
Targeting factor Xa we have apixaban or rivaroxaban
Or factor IIa dabigatrin
COVID coag
Antiphospholipid Syndrome (APS): A hypercoagulable state where anticardiolipin IgA antibodies and other antiphospholipid antibodies promote arterial and venous thrombosis by interfering with endothelial function, platelet activation, and coagulation pathways.
Hemophagocytic Syndrome (HPS): A severe inflammatory condition that triggers a cytokine storm, leading to microthrombosis and venous thrombosis due to excessive immune activation, endothelial damage, and coagulation dysregulation.
Sepsis-Induced Coagulopathy (SIC) and Disseminated Intravascular Coagulation (DIC): Both conditions cause widespread microthrombosis by suppressing fibrinolysis, leading to the accumulation of clots in small vessels and contributing to multi-organ dysfunction.
Thrombotic Microangiopathy (TMA): Characterized by microthrombi formation due to von Willebrand factor (VWF), which leads to small vessel occlusion, hemolysis, and organ damage, as seen in conditions like thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS).
