5.11 - 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? (3)
- prevention of blood loss from intact vessels
- arrest bleeding from injured vessels
- enable tissue repair
What is the overall mechanism of haemostasis?
- injury to endothelial lining
- vessel constriction, VSMCs contract locally to limit blood flow to injured vessel
- primary haemostasis - formation of an unstable platelet plug - platelet adhesion (to vessel wall via VWF) and aggregation (to each other) = limits blood loss + provides surface for coagulation
- secondary haemostasis - stabilisation of the plug with fibrin - causes blood coagulation to stop blood loss
- fibrinolysis - vessel repair and dissolution of clot - cell migration/proliferation and fibrinolysis to restore vessel integrity
Why do we need to understand haemostatic mechanisms? (5)
- diagnose and treat bleeding disorders
- control bleeding in individuals who do not have 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 haemostasis a balance between?
Bleeding (fibrinolytic factors, anticoagulant proteins) and thrombosis (coagulant factors, platelets)
When can the haemostatic balance be tipped towards bleeding?
- too many fibrinolytic factors / anticoagulant proteins
- not enough coagulant factors / platelets
What are the causes of reduced coagulant factors / platelets?
Lack of a specific factor:
- failure of production - congenital and acquired
- increased consumption/clearance
Defective function of a specific factor:
- genetic
- acquired - drugs, synthesis defect, inhibition
What is happening during platelet adhesion and aggregation?
- damage to endothelium wall
- platelets bind to exposed collagen - either directly to vessel wall through GPIa receptor, or indirectly via VWF to GPIb receptor
- platelets release granular contents (ADP which binds P2Y12 on other platelets to activate them, VWF) and become activated along with thromboxane A2 release which activates other platelets (also release Ca2+)
- leads to flip flopping and activation of GPIIb/IIIa receptors on platelets (allows fibrinogen to bind)
What about platelets can cause a problem in primary haemostasis? (2)
- low numbers - thrombocytopenia
- impaired function
What can cause a low number of platelets (thrombocytopenia)? (3)
- 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 (splenomegaly)
What is auto-ITP (autoimmune thrombocytopenic purpura)?
- antiplatelet antibodies bind to sensitised platelets
- macrophages of reticular endothelial system in spleen clear these platelets
- ITP is a very common cause of thrombocytopenia
(Treatment: splenectomy)
What can impaired function of platelets be due to? (2)
- hereditary absence of glycoproteins or storage granules (rare) - e.g. Glanzmann’s thrombasthenia, Bernard-Soulier syndrome, storage pool disease
- acquired due to drugs: aspirin, NSAIDs, clopidogrel (common)
What are some examples of hereditary platelet defects causing impaired function? (3)
- Glanzmann’s thrombasthenia - absence of GPIIb/IIIa
- Bernard Soulier syndrome - absence of GPIb
- storage pool disease - reduction in contents of dense granules of platelets (ADP, ATP, serotonin, Ca2+)
What is antiplatelet therapy used for?
Prevention and treatment of cardiovascular and cerebrovascular disease
How does aspirin work (antiplatelet)?
- irreversibly binds to COX
- reduction in thromboxane A2 production therefore reduction in platelet aggregation (platelets)
- even though prostacyclin production is inhibited too (prostacyclin inhibits platelet aggregation), the endothelial cells can produce more unlike the non-nucleated platelets
How does clopidogrel work (antiplatelet)?
Blocks ADP receptor P2Y12 on platelets (reduce platelet recruitment + aggregation etc)
What about Von Willebrand Factor can cause a problem in primary haemostasis?
Von Willebrand disease
What are the causes of Von Willebrand disease? (2)
- hereditary disease of quantity and/or function (common)
- acquired due to antibody (rare)
What are the two functions of VWF in haemostasis?
- binding to collagen and capturing platelets
- stabilising factor VIII (factor VIII may be low if VWF is very low)
Describe the inheritance of hereditary VWD?
- autosomal inheritance pattern
- deficiency of VWF is type 1 or 3
- VWF with abnormal function is type 2
What about the vessel wall can cause a problem in primary haemostasis? (2)
- inherited (rare) - e.g. hereditary haemorrhagic telangiectasia, Ehlers-Danlos syndrome and other connective tissue disorders
- acquired (common) - e.g. steroid therapy, ageing (‘senile’ purpura), vasculitis, scurvy (vitamin C deficiency)
What happens in VWD?
Failure of primary haemostasis - platelet plug cannot form
What are the clinical features of bleeding in primary haemostasis? (7)
- immediate bleeding
- prolonged bleeding from cuts
- nosebleeds (epistaxis): prolonged >20min
- gum bleeding: prolonged
- heavy menstrual bleeding (menorrhagia)
- bruising (ecchymosis), may be spontaneous/easy
- prolonged bleeding after trauma/surgery
What is a particular feature of thrombocytopenia?
Petechiae - small spots under skin caused by bleeding under skin
In what types of disorders do we see purpura?
- platelet (thrombocytopenic purpura)
- vascular disorders (wet purpura if over mucosal surfaces like gums)
How can we tell the difference between petechiae and purpura?
- both are caused by bleeding under the skin
- purpura do not blanch when pressure is applied
- petechia <3mm, purpura 3-10mm, bruise >10mm
What is the bleeding pattern like in severe VWD?
Haemophilia-like bleeding (due to low FVIII too)
What are the tests for disorders of primary haemostasis? (4)
- platelet count, platelet morphology
- bleeding time (PFA100 in lab - platelet function analysis)
- assays of VWF
- clinical observation
- note - coagulation screen (PT, APTT) is normal, except more severe VWD where FVIII is low
What are the platelet count ranges for normal and thrombocytopenia?
- normal range: 150-400 x10^9/l
- no spontaneous bleeding, but bleeding with trauma: 40-100 x10^9/l
- spontaneous bleeding common: 10-40 x10^9/l
- severe spontaneous bleeding: <10 x10^9/l
How do we treat failure of production/function in primary haemostasis?
- replace missing factors/platelets e.g. VWF containing concentrates
- can be prophylactic (e.g. before surgery) or therapeutic (e.g. after bleeding)
- stop drugs e.g. aspirin/NSAIDs
How do we treat immune destruction in primary haemostasis?
- immunosuppression e.g. prednisolone
- splenectomy for ITP
How do we treat increased consumption (e.g. in DIC) in primary haemostasis?
- treat underlying cause
- replacement therapy as necessary
What additional haemostatic treatments are there for primary haemostasis disorders? (4)
- desmopressin (ddAVP) - vasopressin analogue that causes 2-5x 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?
To generate thrombin (IIa), which will convert fibrinogen to fibrin
What would a deficiency of any coagulation factor cause?
A failure of thrombin generation and hence fibrin formation
What are the main causes of disorders of coagulation? (3)
- deficiency of coagulation factor production
- dilution
- increased consumption
What are the two types of deficiency of coagulation factor production and what makes these up?
- hereditary - factor VIII/IX (haemophilia A/B)
- acquired - liver disease, anticoagulant drugs (warfarin, DOACs)
What can dilution be caused by?
- acquired - through red blood cell transfusions that do not have plasma
- a major haemorrhage requires a transfusion of plasma as well as red cells and platelets to avoid dilutional effect with reduction in coagulation factors
What are the common and rare causes of increased consumption?
- acquired
- disseminated intravascular coagulation (DIC) - common
- immune - antibodies - rare
What is haemophilia A?
Factor VIII deficiency, sex-linked
What is haemophilia B?
Factor IX deficiency, sex-linked
What do both haemophilias A&B do mainly?
- cause a failure to generate fibrin to stabilise platelet plug
- unstable platelet plug breaks away leading to bleeding
What is the hallmark of haemophilia?
- haemarthrosis - spontaneous bleeding of joints when factors are low
- usually seen in more developing countries because factor replacement therapy is more accessible in developed countries
- long term - chronic haemoarthritis with target joints having recurrent bleeds and damaging the synovial lining leading to joint deformity and muscle wasting
What happens if an intramuscular injection is given to a haemophilia patient?
There is extensive haematoma that occurs - avoid!!
Is haemophilia (A/B) compatible with life?
Yes - severe but compatible with life, spontaneous joint and muscle bleeding
Is prothrombin (factor II) deficiency compatible with life?
No - lethal