haemostasis - bleeding Flashcards
what is haemostasis and what is it for?
the cellular and biochemical processes that enables both the specific and regulated cessation of bleeding in response to vascular insult
use:
Prevention of blood loss from intact vessels
Arrest bleeding from injured vessels
enable tissue repair
what are the main parts of haemostasis?
in response to injury to the endothelial lining
vessel constriction
primary haemostasis (unstable platelet plug)
secondary haemostasis (stabilisation with fibrin)
fibrinolysis
what is the mechanism of vessel constriction ofter injury?
Vascular smooth muscle cells contract locally
purpose:
Limits blood flow to injured vessel
what is the mechanism of primary haemostasis?
Formation of an unstable
platelet plug
process:
platelet adhesion
platelet aggregation
purpose:
Limits blood loss +
provides surface for coagulation
what is the mechanism of secondary haemostasis?
Stabilisation of the plug with fibrin
process:
blood coagulation
purpose:
Stops blood loss
what is the mechanism of fibrinolysis?
Vessel repair and dissolution of clot
process:
Cell migration/proliferation & fibrinolysis
purpose:
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
what is the balance involved in haemostasis?
between fibrinolytic factors, such as anticoagulant proteins, and coagulant factors, such as platelets
too much fibrinolysis leads to bleeting
too much coagulation leads to thrombosis
how can the haemostatic balance be tipped towards bleeding?
- decrease in coagulant factors (eg. platelets)
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
- increase in Fibrinolytic factors
Anticoagulant proteins
quick overview of primary haemostasis?
adhesion:
platelets bind to VWF
via Gp1b
or directly yo the endothelial wall collagen via Gp1a
this stimulates release of ADP and thromboxane (from arachadonic acid) .these are the contents of platelet’s alpha and dense granules
it activates them
aggregation:
activates GpIIb/IIIa receptors on platelets
allows them to stick together with fibrinogen in between
this is the unstable platelet plug
what are the main components that can be effected in primary haemostasis?
platelets:
number
function
von willebrand factor:
Von Willebrand disease -
Hereditary decrease of quantity +/ function (common)
Acquired due to antibody (rare)
The vessel wall:
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),
how can platelet number be effected?
low number:
thrombocytopenia
Bone marrow failure (eg. leukaemia, B12 deficiency)
Accelerated clearance eg. (immune (ITP), Disseminated Intravascular Coagulation (DIC) )
Pooling and destruction in an enlarged spleen
what is immune thrombocytopenia purpura (ITP)?
when there are antiplatelet autoantibodies present in the blood
these stick to sensitised platelets that have been produced by the bone marrow
this complex is then cleared by immune system macrophages
it is a common cause of thrombocytopenia
how can platelet function be affected?
Impaired function:
Hereditary absence of glycoproteins or storage granules (rare)
Acquired due to drugs - aspirin, NSAIDs, clopidogrel (common)
what hereditary platelet defects may effect their function?
missing surface glycoproteins:
GpIIb/IIIa (Glanzmann’s thrombasthenia)
GpIb (Bernard Soulier syndrome)
missing dense granules:
so no ADP required for aggregation
storage pool disease
Glanzmann’s thrombasthenia
Bernard Soulier syndrome
Storage Pool disease
how can aspirin and clopidogrel impair platelet function?
Antiplatelet therapy: widely used in the prevention and treatment of cardiovascular & cerebrovascular disease
aspirin and clopidogrel are the most commonly used antiplatelet drugs
aspirin revesibly blocks COX
this stops production of the prostaglandin Thromboxane A2 (from arachadonic acid)
this persists for about 7 days
clopidogrel irreversibly blocks the ADP receptor on platelets (P2Y12), so the ADP Induced conformational change in the GPIIb/IIIa can’t occur and fibrin can’t bind
these both prevent platelet aggregation
what is the role of VWF in haemostasis?
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 (disease) is usually hereditary (autosomal inheritance pattern):
Deficiency of VWF (Type 1 or 3)
VWF with abnormal function (Type 2)
without VWF the platelet plug cannot form
what is a summary of possible causes of disorders of primary haemostasis?
Platelets:
Thrombocytopenia
Drugs
Von Willebrand Factor:
Von Willebrand disease
The vessel wall:
Hereditary vascular disorders
Steroids, age, vasculitis, scurvy
what are the clinical features of disorders of primary haemostasis?
Typical 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
Thrombocytopenia – Petechiae
Purpura – platelet (thrombocytopenic purpura) or vascular disorders
Severe VWD – haemophilia-like bleeding (due to low FVIII)
Petechiae and Purpura are caused by bleeding under the skin
Purpura do not blanch when pressure is applied
how do we test for disorders of primary haemostasis?
Platelet count, platelet morphology (needs electron microscopy)
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 of treatment of primary haemostasis: 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 of treatment of primary haemostasis: Immune destruction?
Immunosuppression (e.g. prednisolone)
Splenectomy for ITP
what are the principles of treatment of primary haemostasis: Increased consumption ?
Treat cause
Replace as necessary
what are some other treatments of abnormal primary haemostasis (apply to primary and scondary haemostasis problems)?
- 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 role of coagulation/secondary haemostasis?
The role of coagulation is to generate thrombin (IIa), which will convert fibrinogen to fibrin
Deficiency of any coagulation factor results in a failure of thrombin generation and hence fibrin formation
what are some causes of disorders of coagulation?
Deficiency of coagulation factor production:
Hereditary - Factor VIII/IX: haemophilia A/B
Acquired - Liver disease Anticoagulant drugs* (Warfarin Direct Oral Anticoagulants (DOACs))
Dilution:
Acquired - Blood transfusion
Increased consumption:
Acquired -
Disseminated intravascular coagulation (DIC) – common
(Immune – autoantibodies – rare)
what are hereditary coagulation disorders?
Haemophilia: failure to generate fibrin to stabilise platelet plug
Haemophilia A (Factor VIII deficiency)
Haemophilia B (Factor IX deficiency)
sex linked
1 in 10^4 births
Others are very rare (autosomal recessive)
Intramuscular injections should be
avoided in patients with haemophilia
what is haemarthrosis?
used to be The hallmark of haemophilia.
spontaneous bleeding in joints
is now treated prophylactically with factor VIII/IX replacement
what are some differences between different coagulation factor deficiencies?
(complete absence)
Factor VIII and IX (Haemophilia):
Severe but compatible with life
Spontaneous joint and muscle bleeding
Prothrombin (Factor II):
Lethal
Factor XI:
Bleed after trauma but not spontaneously
Factor XII:
No bleeding at all
what are some causes of acquired coagulation disorders?
More common in hospital practice
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
also DIC
what is DIC?
Disseminated intravascular coagulation
Increased consumption
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
combined clotting and bleeding pattern
what are the clinical features of coagulation disorders?
superficial cuts do not bleed (platelets work fine)
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 are the differences between bleeding due to platelet and 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
either can be life threatening
how do we test for coagulation disorders?
Screening tests (‘clotting screen’): Prothrombin time (PT) (extrinsic)
Activated partial thromboplastin time (APTT) (intrinsic pathway)
Full blood count (platelets)
Coagulation factor assays (for Factor VIII etc)
Tests for inhibitors
what clotting factors does PT show problems with?
VII, X, V, II, and fibrinogen
(only VII is unique to PT)
not affected in haemophilia
extrinsic pathway
what clotting factors does APPT show problems with?
XII, XI, X, IX, VIII, V, II, and fibrinogen.
(XII,XI,IX and VIII are unique to APPT)
so affected in haemophilia
intrinsic pathway
what are the principles of treatment of abnormal haemostasis due to coagulation?
Failure of production/function:
Replace missing factor/platelets
i) Prophylactic
ii) Therapeutic
Stop drugs e.g. aspirin/NSAIDs
Increased consumption :
Treat cause
Replace as necessary
how are missing coagulation factors replaced?
factor replacement therapy
Plasma (fresh frozen plasma FFP):
Contains all coagulation factors
Cryoprecipitate:
Rich in Fibrinogen, FVIII, VWF, Factor XIII
Factor concentrates:
Concentrates available for all factors except factor V.
Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X
Recombinant forms of FVIII and FIX are available:
‘On Demand’ to treat bleeds
Prophylaxis to prevent bleeds
what is a timeline of haemophilia treatment?
1969:
Plasma-Derived Clotting Factors
Widespread viral contamination
1990s:
Currently Approved Recombinant Clotting Factors
FVIII, FIX, FVIIa
Improved Safety
Eliminated potential for transmission of blood borne pathogens
2008-present: investigational therapies Prolonged half-life (FVIII/FIX): Fc fusion, PEG, albumin fusion Gene therapy Novel agents Bispecific antibody (Emicizumab) Anti TFPI antibody Antithrombin RNAi
what are some novel treatments of haemophilia?
Gene therapy (Haem A and B)
Bispecific antibodies (Haem A)
Emicizumab
Binds to FIXa and FX
Mimics procoagulant function of FVIII
RNA silencing (Haem A and B) Targets natural anticoagulant - antithrombin
what may cause an increase in fibrinolytic factors?
Both of these are exceedingly rare except when induced by drugs:
tPA (stroke)
Heparin
