primary disorders of Haemostasis Flashcards
what is haemostasis?
cellular and biochemical processes that enable both the specific and regulated cessation of bleeding in response to vascular insult
what are the uses of haemostasis?
- Prevention of blood loss from intact vessels
- Arrest bleeding from injured vessels
- Enable tissue repair
what is the mechanism of hemostasis?
how does platelet adhesion and platelet aggregation work?
what can cause a decrease in coagulant factor platelets?
- Lack of specific factor
- Failure of production: congenital/ acquired
- Increased consumption/ clearance
- Defective function of a specific factor
- Genetic
- Acquired: drugs, synthetic defect, inhibition
where can disorders occur from primary haemostasis?
platelets
von willebrand factor
the vessel wall
what disorders can occur from platelet dysfunction in primary haemostasis?
low numbers: thrombocytopenia
impaired function
what can cause low numbers of platelets? (thrombocytopenia)
- Bone marrow failure e.g leukaemia, B12 deficiency
- Accelerated clearance e.g immune (ITP), disseminated intravascular coagulation (DIC)
- Pooling and destruction in an enlarged spleen
what occurs in immune thrombocytopenia purpura (ITP)?
antiplatelet autoantibodies bind to sensitised platelet and cause macrophage recreuitment
what impaired defects with platelets can cause low platelet numbers?
- Hereditary absence of glycoproteins or storage granules (Rare)
- Acquired due to drugs: aspirin, NSAIDs, clipidogrel (common)
what is Glanzmann’s thrombasthenia?
hereditary platelet defect
Glp IIb/IIIa disorder
what is Bernard Soulier syndrome?
hereditary platelet defect
Glp1b disorder
where do drugs aspirin and clopidogrel act on aggregation pathway?
inhibit production thromboxane A2 (thromboxane causes platelet aggregation)
aspirin irreversibly blocks COX
clopidogrel irreversibly blocks ADP receptor on platelets
what is a primary haemostasis disorder of vWF?
- Von Willebrand disease
- Hereditary disease of quantity +/- function (common)
- Acquired due to antibody (rare)
what is a primary haemostasis disorder of the vessel wall?
- Inherited (rare) (hereditary vascular disorders)
- hereditary haemorrhagic telangiectasia
- Ehlers-Danlos syndrome
- Other connective tissue disorders
- Acquired (common)
- Steroid therapy
- Ageing (‘senile’ purpura)
- Vasculitis
- Scurvy (vit C deficiency)
what is the function of vWF in haemostasis?
- Binding to collagen and capturing platelets
- Stabilising factor VIII
- Factor VIII may be low if VWF is very low
what can occur to VWF in von willebrand disease?
- deficiency of VWF (platelet cannot bing to VWF which have become uncoiled under sheer stress)
- Type 1= lower levels VWF
- Type 3= no VWF
- VWF with abnormal function
- Type 2= abnormal VWF
what are the clinical features of disorders of primary haemostasis?`
bleeding
thrombocytopenia
purpura ( platelet or vascular disorders)
severe VWD= haemophilia like bleeding (due to low FVIII)
what are the bleeding clinical features of disorders of primary haemostasis?
- Immediate
- Prolonged bleeding from cutes
- Nose bleeds (epistaxis): prolonged >20mins
- Gum bleeding: prolonged
- Heavy menstrual bleeding (menorrhagia)
- Bruising (ecchymosis), may be spontaneous/easy
- Prolonged bleeding after trauma or surgery
what are the clinical features of thrombocytopenia?
petechiae
what are the tests for disorders of primary haemostasis?
- Platelet count, platelet morphology
- Bleeding time (PFA100 in lab)- platelet function analysis
- Assays of VWF
- Clinical observation
- Non-coagulation screen (PT,APTT) is normal (except in more severe VWD cases FVIII is low)
what is the treatment for failure of production/function (abnormal haemostasis)?
- Reproducing missing factor/ platelets e.g VWF containing concentrates
- Prophylactic (preventative before operation)
- Therapeutic
- Stop drugs e.g aspirin/ NSAIDS
what is the treatment for primary haemostasis immune destruction?
- Immunosuppression e.g prednisolone
- Splenectomy for ITP
what is the treatment for primary haemostasis increased consumption?
- Treat cause
- Replace as necessary
what additional haemostatic treatments can be given for primary haemostasis disorders?
- Desmopressin (DDAVP)
- Vasopressin analogue
- 2-5 fold increased in VWF (and FVIII)
- Releases endogenous stores (so only useful in mild disorders)
- Tranexamic acid
- Antifibrinolytic
- Fibrin glue/ spray (in theatre during surgery)
- Other approaches (e.g hormonal (coral contraceptive pill for menorrhagia)
what is secondary haemostasis?
disorders of coagulation
what is the role of coagulation?
generate thrombin (IIa) which will convert fibrinogen to fibrin
what does a deficiency in any coagulation factor result in?
failure of thrombin generation and hence failure fibrin formation
what are the causes of deficiency of coagulation factor production?
hereditary
- factor VIII/IX: haemophilia A/B
acquired
- liver disease
- anticoagulant drugs (Warfarin, DOACs)
dilution
- acquired-blood transfusion
increased consumption
- acquired - disseminated intravacular coagulation (DIC) and immune autoantibodies
what are the symptoms of factor VIII and IX deficiency?
haemophilia= failure to generate fibrin to stabilise platelet plug
- Hallmark haemophilia= hemarthrosis
- Chronic hemarthrosis= muscle wasting
- Avoid intramuscular injections in patients with haemophilia
- haemophilia A (factor VII deficiency)
- haemophilia B (factor IX deficiency)
- sex linked
- spontaneous joint and muscle bleeding
- severe but compatible with life
what is the consequence of prothrombin (FII) deficiency?
lethal
what is the consequence of FXI deficiency?
bleeding after trauma but not spontaenously
what is the consequence of factor XII deficiency?
no bleeding at all
why does liver failure cause secondary haemostasis disorder?
- most coagulation factors are synthesised in liver (except VWF-synthesised in endothelial cells lining RCB and factor VI- synthesised In platelets)
- decreased production of coagulation factors
how does dilation coagulation disorders occur?
red cell transfusions no longer contain plasma
major haemorrhage requires transfusion of plasma as well as red cells and plasma
what is disseminated intravascular coagulation?
- generalised activation of coagulation- tissue factor
- associated with sepsis, major tissue damage (pre-eclampsia), inflammation, cancer
- consumes and depletes coagulation factors
- platelets consumed- results in thrombocytopenia
- activation of fibrinolysis depletes fibrinogen- raised D-dimer (a breakdown product of fibrin)
- deposition of fibrin in vessels causes organ failure and sheering of red blood cells that flow through these vessels causing red cell fragmentation
- treatment of underlying cause required
- give replacement factors through FFP and platelets for supportive treatment
clinical features of coagulation disorders?
- superficial cuts do not bleed (platelets working fine and platelet plug sufficient in smaller blood vessels)
- in larger blood vessels the plug breaks down causing bleeding
- 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 is the difference in bleeding due to platelet and coagulation disorders?
platelet/vascular:
superficial bleeding into skin, muscular membranes
bleeding immediate after injury
coagulation:
bleeding into deep tissue, muscles, joints
delayed, but severe bleeding after injury
bleeding often prolonged
what are the screening tests for coagulation disorders?
prothrombin time
activated partial thromboplastin time (APTT)
full blood count (platelets)
when are PT and APTT increased?
liver disease
anticoagulant drugs e.g warfarin
DIC (platelets and D dimer)
dilution following red cell transfusion
deficiency of factor of the common pathway (FX, V or II)
what are the causes of increased APTT?
haemophilia A
haemophilia B
FXI deficiency
FXII deficiency
causes of increased PT?
factor VII deficiency
what does prothrombin time measure?
extrinsic pathway
the shorter pathway of secondary hemostasis.
Once the damage to the vessel is done, the endothelial cells release tissue factor which goes on to activate factor VII to factor VIIa. Factor VIIa goes on to activate factor X into factor Xa.
what does APTT measure?
intrinsic pathway
draw the coagulation pathway
what does FFP contain?
all coagulation factor
what does cryoprecipitate contain?
rich in fibrinogen, FVIII, VWF and FXIII
what factor concentrates are available?
all except FV
prothrombin complex concentrates (PCCs) factor II, VII, IX, X
what factor recombinant forms are available?
FVIII and FIX
on demand to treat bleeds
prophylaxis: e.g haemophilia
what novel treatments are available for coagulation disorders?
- Gene therapy (haem A and B)
- Bispecific antibodies (Haem A)
- Emixizumab
- binds to FIXa and FX
- mimic procoagulant function of FVIII
- RNA silencing (Haem A and B)
- Targets natural anticoagulant- antithrombin
