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 aim of haemostasis?
- prevention of blood loss from intact vessels
- arrest bleeding from injured vessels
- enable tissue repair
What are the mechanisms of Haemostasis?
- vessel constriction
- formation of an unstable platelet plug
- stabilisation of the plug with fibrin
- vessel repair and dissolution of clot
What happens when vessel constriction occurs?
- vascular smooth muscle cells contract locally
- limits blood flow to injured vessel
What happens during primary haemostasis?
formation of an unstable platelet plug
- platelet adhesion
- platelet aggregation
- limits blood loss and provides surface for coagulation
What happens during secondary haemostasis?
stabilisation of the plug with fibrin
- blood coagulation
- stops blood loss
What happens during fibrinolysis?
vessel repair and dissolution of the clot
- cell migration/proliferation and fibrinolysis
- restores vessel integrity
Why is understanding of haemostatic mechanisms important?
- diagnose and treat bleeding disorders
- control bleeding
- identify thrombosis risk factors
- treat thrombotic disorders
- monitor drugs used to treat bleeding/thrombotic disorders
What is balanced in normal haemostasis?
- fibrinolytic factors and anticoagulant proteins
AND - coagulant factors
- platelets
What can cause the lack of a specific factor?
- failure of production (congenital and acquired)
- increased consumption and clearance
What can cause defective function of a specific factor?
- genetic
- acquired: drugs, synthetic defect and inhibition
What are the 3 main components of primary haemostasis?
- platelets
- Von Willebrand factor
- Vessel wall
What do platelets adhere to in platelet adhesion?
- collagen revealed in wall damage
- direct via Glp1a receptor
- VWfactor GlP1b
What activates platelets?
thromboxane
What does Thrombocytopenia mean?
low number of platelets
What are the 2 causes of Thrombocytopenia?
- bone marrow failure
- Accelerated clearance
- Pooling and destruction in an enlarged spleen
What can cause bone marrow failure?
- leukaemia
- B12 deficiency
What causes accelerated platelet clearance?
- immune (ITP)
- Disseminated Intravascular Coagulation (DIC)
(cleared in the peripheral system)
What happens in Immune Thrombocytopenic Purpura (ITP)?
- anti-platlet antibodies
- attach to sensitised platlets
- cleared by macrophages of the reticula endothelial system of the spleen
(COMMON)
What causes the impaired function of platelets?
- Hereditary absence of glycoproteins or storage granules (rare)
- Acquired due to drugs
What is an example of hereditary impaired platelet function?
Glanzmann’s thrombasthenia
- problem with: GP2a
What causes Bernard Souller syndrome?
absence of GP1b
What causes storage pool disease?
Reduction in the granular contents of platlets
What drugs are associated with causing impaired platelet function?
- aspirin
- NSAIDs
- clopidogral (common)
When are anti-platelet drugs used?
in the prevention and treatment of cardiovascular and cerebrovascular disease
How does aspirin have an anti-platelet effect?
aspirin prevents the production of Thromboxane A2 by irreversibly blocking COX causing reduced platelet aggregation
How does aspirin have an clopidogrel effect?
irreversibly blocks the ADP receptor on platelets
What can cause Von Willebrand disease?
- Hereditary: decrease of quantity +/ function (COMMON)
- Acquired: antibody (rare)
What is the effect of Von Willebrand disease?
reduced or defective Von Willebrand factor
What are the roles of Von Willebrand factor in Haemostasis?
- binding to collagen and capturing platelets
- stabilising factor VIII
What is the relationship between Von Willebrand Factor and Factor VIII?
VWF is needed for Factor VIII, so if VWF is low, so is Factor VIII
What are the 2 different types of Von Willebrand factor?
Type 1/3: deficiency of VWF
Type 2: VWF with abnormal function
What is the inheritance pattern in VWD?
autosomal basis
What can cause inherited problems with the vessel wall?
RARE
- Haemorrhagic telangiectasia
- Ehlers-Danlos syndrome
(other connective tissue disorders)
What can cause acquired problems with the vessel wall?
COMMON
- steroid therapy
- Ageing (senile purpura)
- Vasculitis
- Scurvy
What VWF to unfold/uncoil?
shear force
What does VWD impact in haemostasis?
primary haemostasis
What are the clinical features of primary haemostasis disorders?
- immediate bleeding
- prolonged bleeding from cuts/trauma/surgery
- nose bleeds (epistaxis) >20mins
- prolonged gum bleeding
- heavy menstrual bleeding (menorrhagia)
- bruising (ecchymosis), spontaneous/easy
What are the visible signs seen in primary haemostasis disorders?
Petechiae and Purpura (do not blanch under pressure)(bleeding under the skin)
What is a key symptom of thrombocytopenia?
Petechiae
When are purpura seen?
- platelet disorders (thrombocytopenic purpura)
- vascular disorders
What is a key clinic feature of severe VWD?
haemophilia-like bleeding (due to low FVIII)
What is a key symptom of immune thrombocytopenia?
ecchymosis
What are symptoms are there of Ehlers-Danlos syndrome?
- increase skin elasticity
- blue sclera
- nose abnormalities
- abnormal hypermobility
What are tests are done for primary haemostasis disorders?
- platelet count/morphology (electron)
- bleeding time (PFA100)
- VWF assays
- clinical observation
- coagulation screen
What should be the expected results from the coagulation screen?
normal (PT, APTT)
UNLESS
severe VWD cases where factor VIII
What happens when platelet count <100x109?
- no spontaneous bleeding
- bleeding with trauma
What happens when platelet count <40x109?
common spontaneous bleeding
What happens when platelet count <10x109?
severe spontaneous bleeding
How would you treat the failure of production/function in primary haemostasis disorders?
replace missing factor/platelets
- prophylactic
- therapeutic
STOP drugs (aspirin, NSAIDs)
How would you treat the immune destruction in primary haemostasis disorders?
- immunosuppression (prednisolone)
- splenectomy for ITP
How would you treat the increased consumption/clearance in primary haemostasis disorders?
- treat cause
- replace as necessary
What additional treatments can be used to support haemostasis?
- Desmopressin
- Tranexamic acid (antifibrinolytic)
- Fibrin glu/spray
- other approaches ( eg: OCP for menorrhagia)
What is Desmopressin?
Vasopressin analogue
What does Desmopressin do?
- 2-5 fold increase in VWF (+ Factor VIII)
- releases endogenous stores (only used in mild disorders)
What is another name for secondary haemostasis?
coagulation
What is the role of coagulation?
generate thrombin (Factor IIa) - which converts fibrinogen to fibrin
What is the result of a coagulation factor deficiency?
failure of thrombin generation and therefore fibrin formation
What are the 3 phases of coagulation?
- initiation
- amplification
- propagation
What can cause disorders of coagulation?
- deficiency of coagulation factor production
- dilution
- increased consumption
What hereditary causes are there for the deficiency of coagulation factor production?
Factor VIII/IX deficiency
haemophilia A/B
What acquired causes are there for the deficiency of coagulation factor production?
- liver disease
- anticoagulant drugs
(warfarin, DOACs)
What are the acquired causes of dilution?
blood transfusion
inadequate plasma replacement
What are the acquired causes of increased consumption/clearance?
COMMON: Disseminated intravascular coagulation (DIC)
RARE: immune (autoantibodies)
What are the 2 common hereditary coagulation disorders?
Haemophilia A (FVIII) + B (FIX)
What is the inheritance pattern of haemophilia A/B?
- sex linked
- 1 in 10^4 births
What is the inheritance of the rare hereditary coagulation disorders?
autosomal recessive
What happens in haemophilia?
failure to generate fibrin to stabilise the platelet plug
What is the hallmark of haemophilia?
haemarthrosis
What is Haemarthrosis?
spontanteous joint bleeding (very low FVIII and FIX)
What happens in chronic haemarthrosis?
- recurrent spontaneous bleeds
- significant joint deformity
- muscle wasting
What should be avoided in patients with haemophilia?
avoid IM injections
What is the impact of the absence of Factor VII and Factor IX?
- severe but compatible with life
- spontaneous joint and muscle bleeding
What is the impact of the absence of Factor II (Prothrombin)?
- Lethal
What is the impact of the absence of Factor XI?
bleed after trauma, but not spontaneously
What is the impact of the absence of Factor XII?
no bleeding at all
What are the main types of acquired coagulation disorders?
- liver failure
- anti-coagulant drugs
- dilution
What is the impact of liver failure on coagulation?
decreased production, as most factors are synthesised in the liver.
What is the impact of dilution on coagulation?
- red cell transfusions don’t consider plasma
- major haemorrhage requires transfusion of plasma as well as RC and platelets to prevent.
What is Disseminated intravascular coagulation?
generalised (and unregulated) activation of coagulation - Tissue factor
What can trigger Disseminated Intravascular Coagulation?
- sepsis
- major tissue damage (cancer)
- inflammation
Wjhat happens in Disseminated Intravascular Coagulation?
- consumption and depletion of coagulation factors
- consumed platelets (thrombocytopenia)
- activation of fibrinolysis depletes fibrinogen (raised D-dimer)
- fibrin deposit in vessels can cause organ failure
Why is D-dimer raised in Disseminated Intravascular Coagulation?
increased D-dimer (product of fibrin breakdown)
How do you manage Disseminated Intravascular Coagulation?
Replacemnet of missing coagulation factors
What characterises Disseminated Intravascular Coagulation?
combined clotting and bleeding pattern
What are the clinical features of coagulation disorders?
- superficial cuts do not bleed
- common: bruising, rare: nosebleeds
- spontaneous bleeding is deep (muscles or joints)
- bleeding after trauma is delayed/prolonged
- bleeding may restart after stopping
Why do superficial cuts not bleed?
small, therefore platelets can form a plug
How can you clinically distinguish between platelet and coagulation defects?
- where the bleeding occurs
- time for bleeding after trauma/injury
What is the difference in bleeding in platelet and coagulation defects?
Platelet:
- superficial bleeding into skin and mucosal membranes
Coagulation:
- bleeding into deep tissues, muscles and joints
What is the difference in time for bleeding after injury in platelet and coagulation defects?
Platelet: - bleeding immediate after surgery Coagulation - delayed, but severe after injury - often prolonged
What tests are available for coagulation disorders?
Screening - Prothrombin time (PT) - Activated partial thromboplastin time (APTT) - FBC (platelets) Coagulation factor assays Tests for inhibitors
What does prothrombin time measure?
the extrinsic pathway
What does the Activated Partial Thromboplastin Time (APTT) measure?
the intrinsic pathway
What do we use to trigger the Prothrombin Time (PT)?
Tissue factor (recombinant)
What do we use to trigger the Activated Partial Thromboplastin Time (PT)?
by contact activation with NO
What is a normal prothrombin time?
9.6-11.6 seconds
What is a normal activated partial thrmboplastin time?
26-32 seconds
What would cause a normal PT time but an prolonged Activated Partial Thromboplastin time?
- haemophilia A/B
- Factor XI deficiency
- Factor XII deficiency
Why is APTT elongated in haemophilia A/B?
many of the factors in the intrinsic pathway are affected by a deficiency
What would cause a prolonged PT time but a normal Activated Partial Thromboplastin time?
- Factor VII deficiency
What would cause a prolonged PT time and a prolonged Activated Partial Thromboplastin time?
- Liver disease
- anti-coagulant drugs
- DIC
- Dilution
(deficiency of the factors of the common pathway)
What factors are part of the common pathway?
- FX
- FV
- FII
What are the principles of abnormal secondary haemostasis?
- failure of production
- immune destruction
- increased consumption
How do you prevent the failure of factor production/function in secondary haemostasis?
replace missing factors
- prophylactic
- therapeutic
stop drugs (aspirin, NSAIDS)
How do you prevent the immune destruction in secondary haemostasis?
- immunosuppression
How do you prevent the increased consumption in secondary haemostasis?
- treat cause (eg:sepsis in DIC)
- replace when necessary
What are the 4 different types of factor replacement therapy?
- Plasma (Fresh Forzen Plasma)
- Cryoprecipitate
- Factor concentrates
- Recombinant forms of FVIII and FIX
What is in Fresh Frozen Plasma (FFP)?
contains all coagulation factors
What is in cryoprecipitate?
rich in: fibrinogen, FVIII, VWF and FXIII
What is in factor concentrates?
available for all factors apart from FV
- Prothrombin complex concentrates (FII, FVII, FIX, FX)
What are recombinant forms of FVIII and FIX used for?
- ‘on demand’ to treat bleeds
- prophylaxis
What are the future possible treatments of haemophilia?
- prolonged half life
- gene therapy
- novel agents
What are the risks of haemophilia treatment?
safety
- potential of transfer of blood borne pathogens
What are the novel treatments available?
- gene therapy (haemophilia A/B)
- bispecific antibodies (haemophilia A)
- RNA silencing (haemophilia A and B)
What is an example of Bispecific antibodies in the treatment of haemophilia A?
Emicizumab
What does Emicizumab do?
- binds to FIXa and FX
- mimics procoagulant function of FVIII
What does RNA silencing to treat haemophilia A and B do?
targets natural anti-coagulant (antithrombin)
What additional haemostatic treatments are available for anti-coagulant blood disorders?
- desmopressin
- tranexamic acid
- fibrin glue/spray
- other indirect (treat symptoms, like: OCP)
What can cause an increase in fibrinolytic factors and anti-coagulant proteins?
induced by drugs:
- tPA - tissue plasminogen activator (stroke)
- Heparin
How does a pulmonary embolism present?
- tachycardia
- hypoxia
- shortness of breath
- chest pain
- haemoptysis (coughing blood)
- sudden death
How does deep vein thrombosis (DVT) present?
- painful leg
- swelling
- red
- warm
- post-thrombotic syndrome (pain and swelling)
- can embolise to the lungs
What is thrombosis?
- intravascular coagulation
- inappropriate coagulation
- venous (or arterial)
- obstructs flow
- may embolise to the lungs
What is Virchow’s triad?
the 3 factors that contribute to thrombosis
What is in Virchow’s triad?
- blood
- vessel wall
- blood flow
What is the impact on risk when there are changes in blood in Virchow’s triad?
dominant in venous thrombosis
What is the impact on risk when there are changes in the vessel wall in Virchow’s triad?
dominant in arterial thrombosis
What is the impact on risk when there are changes in blood flow in Virchow’s triad?
contributes to both arterial and venous thrombosis
What is thrombophilia?
increased risk of venous thrombosis
How does thrombophilia present?
- thrombosis at a young age
- spontaneous thrombosis
- multiple thromboses
- thrombosis while anti-coagulated
What factors can increase the risk of venous thrombosis?
- Reduced anticoagulant proteins
- Increased coagulant factors
(increased activity due to activated protein C resistance)
What can cause an increased platelet count?
myeloproliferative disorders
What can cause reduced anticoagulant proteins ?
nephrotic disease
What do protein C and S inactivate?
FVa
FVIIIa
What are the anticoagulant proteins?
- antithrombin
- protein C
- protein S
What are the coagulant factors?
- FVIII
- FII
- FV
What does antithrombin inactivate?
- FVIIa
- FXa
What deficiency puts you most at risk of a venous thrombosis?
antithrombin deficiency (25-50 odds ratio)
What is the effect of abnormal FVa Lieden?
increased thrombotic activity
Why is the vessel wall thought to have an effect on venous thrombosis?
many proteins are expressed on the endothelial surface and their expression changes in inflammation
What is the change in blood flow that increases the risk of thrombosis?
reduced flow (stasis) EG: surgery, long haul flight, and pregnancy
What is the effect of age on risk of thrombosis?
increases with increasing age
What is the nature of the cause of venous thrombosis?
multi-causal - interacting genetic and acquired factors
How do you prevent venous thrombosis?
- assess and prevent risks
- prophylactic anticoagulant therapy
How do you reduce the risk of recurrence/extension of venous thrombosis?
- lower procoagulant factors (warfarin, DOACs)
- increase anti-coagulant activity (heparin)
