Cardio - Haemostasis Flashcards
What is Haemostasis?
cellular + biochemical processes that enables both the specific + regulated cessation of bleeding in response to vascular insult
What is haemostasis for?
→ prevention of blood loss from intact vessels
→ arrest bleeding form injured vessels
→ enable tissue repair
What are the 4 main stages of haemostasis?
→ vessel constriction
→ primary haemostasis
→ secondary haemostasis
→ fibrinolysis
What is primary haemostasis?
→ formation of unstable platelet plug
→ platelet adhesion
→ platelet aggregation
→ limits blood loss + provides surface for coagulation
What is vessel constriction?
→ first response to injury to endothelial cell lining
→ vascular smooth muscle contracts locally
→ limits blood flow to injured vessel
What is secondary haemostasis?
→ stabilisation of the plug with fibrin
→ blood coagulation
→ stops blood loss completely
What is fibrinolysis?
→ vessel repair + dissolution of clot
→ cell migration / proliferation + fibrinolysis
→ restores vessel integrity
Why is it important to understand bleeding 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 necessary balance for normal haemostasis?
bleeding (fibrinolytic factors + anticoagulant proteins) = thrombosis (coagulant factors + platelets)
When is haemostasis tipped towards bleeding?
→ lack of a specific factor
→ defective function of a specific
Why would someone lack a specific factor that would cause them to bleed more than clot?
→ failure of production (congenital or acquired)
→ increased consumption / clearance of specific factor
Why would someone have a defective function of a specific factor that would cause them to bleed more than clot?
→ genetic
→ acquired : drugs, synthetic defect, inhibition
Summarise platelet adhesion.
→ damage to endothelium
→ platelets can adhere directly via GpIa receptors
→ platelets can adhere indirectly to VWF via GpIb receptors
Summarise platelet aggregation.
→ thromboxane release + granular content release = platelet activation
→ activates GpIIb/GpIIIa receptors
What is thrombocytopenia?
low numbers of platelets
What can cause thrombocytopenia?
→ bone marrow failure : leukaemia, B12 deficiency
→ accelerated clearance : immune (ITP), disseminated intravascular coagulation (DIC)
→ pooling + destruction of spleen : splenomegaly
What is ITP?
immune thrombocytopenia purpura
What is the pathophysiology of ITP?
→ antiplatelet autoantibodies attach to sensitised platelets
→ sensitised platelets get consumed and cleared by macrophages
What can cause impaired function of platelets?
→ hereditary absence of glycoproteins or storage granules (rare)
→ acquired impaired function : aspirin, NSAIDs, clopidogrel
How does aspirin impair the function of platelets?
→ aspirin inhibits COX
→ COX is necessary for the production of Thromboxane A2 from Arachidonic acid
→ less thromboxane A2 is produced
→ less platelet aggregation occurs
How does clopidogrel impair the function of platelets?
→ irreversibly blocks the ADP receptor on platelets
→ prevents platelet aggregation
What is VWD?
Von Willebrand Disease
What are the causes of VWD?
→ hereditary decrease of quantity or function (common)
→ acquired due to antibody (rare)
What are the 2 main function of VWF?
→ binding to collagen + capturing platelets
→ stabilising Factor VIII (8)
How is VWD usually inherited?
→ deficiency of VWF (Type 1 or 3)
→ VWF with abnormal function (Type 2)
What are the different types of vessel wall disorders that can impact primary haemostasis?
→ inherited (rare) : hereditary haemorrhagic telangiectasia Ehlers-Danlos syndrome + other connective tissues disorders
→ acquired (common) : steroid therapy, ageing (senile purpura), vasculitis, scurvy (vitamin C deficiency)
!!!!!!! What are the general clinical features of thrombocytopenia?
→ immediate
→ prolonged bleeding from the cuts
→ prolonged nose bleeds
→ gum bleeding : prolonged
→ heavy menstrual bleeding
→ bruising (spontaneous / easy)
→ prolonged bleeding after trauma or surgery
What are some clinical features of thrombocytopenia specifically?
→ petechiae (pinpoint, round spots that appear on the skin as a result of bleeding - appears red, brown or purple)
→ purpura (small blood vessels burst, causing blood to pool under the skin. This can create purple spots on the skin that range in size)
What is a unique clinical feature of severe VWD?
haemophilia-like bleeding due to low Factor VIII (8)
What are tests you can do for disorders of primary haemostasis?
→ platelet count, platelet morphology
→ bleeding time (PFA100 in lab)
→ assays of VWF
→ clinical observation
→ note - coagulation screen (PT, APTT) is normal
What does the platelet count of <10 x 10^9/L tell you about the thrombocytopenia?
severe spontaneous bleeding
What does the platelet count of 10 - 40 tell you about the thrombocytopenia?
spontaneous bleeding common
What does the platelet count of 40 - 100 tell you about the thrombocytopenia?
no spontaneous bleeding, but bleeding with trauma
How do you treat homeostasis if it’s being caused by the failure of production or function of components?
→ Replace missing factor/platelets e.g. VWF containing concentrates
i) Prophylactic
ii) Therapeutic
→ Stop drugs e.g. aspirin/NSAIDs
How do you treat homeostasis if it’s being caused by immune destruction?
→ immunosuppression (e.g. prednisolone)
→ splenectomy for ITP
How do you treat homeostasis if it’s being caused by increased consumption?
→ treat cause
→ replace as necessary
What are some additional haemostatic treatments?
→ desmopressin (DDAVP) : causes a 2-5 x increase in VWF (and factor 8), releases endogenous stores
→ tranexamic acid : antifibrinolytic
→ fibrin glue / spray
→ hormonal approaches e.g. OCP
What plays the main role in coagulation?
thrombin (Factor IIa), which converts fibrinogen into fibrin to produce the unstable fibrin clot
What are the 3 main types of coagulation disorders?
→ deficiency of coagulation factor production
→ dilution
→ increased consumption
What are the causes of coagulation factor deficiency or lack of production?
→ hereditary : haemophilia A or B (lacking factor 8 or 9)
→ acquired : liver disease, anticoagulant drugs
What anticoagulant drugs can cause deficiency in coagulation factors?
→ warfarin
→ direct oral anticoagulants
What causes dilution of blood, that results in deficiency of coagulation factors?
acquired, BLOOD TRANSFUSIONS
What causes increased consumption of coagulation factors?
acquired :
→ disseminated intravascular coagulation (DIC) - common
→ immune with autoantibodies (rare)
What are the different hereditary coagulation disorders?
→ haemophilia A (Factor VIII deficiency)
→ haemophilia B (Factor IX deficiency) : sex-linked
→ others : autosomal recessive + very rare
What is the pathophysiology of haemophilia?
→ failure to produce a fibrin
→ failure to generate a platelet plug
What are some clinical features of haemophilia?
→ haemarthrosis : articular bleeding into the joints
→ muscle wasting
What are the consequences of prothrombin (factor II) deficiency?
LETHAL
What are the consequences of Factor XI deficiency?
bleed after trauma but not spontaneously
What are the consequences of Factor XII deficiency?
no bleeding at all
What are some acquired coagulation disorders?
→ liver failure
→ anticoagulant drugs
→ dilution
→ increased consumption
How can liver failure lead to coagulant disorders?
decreased production of coagulant factors from the liver
How does blood dilution lead to coagulation disorders?
→ red cell transfusion no longer contain plasma
→ major haemorrhage requires transfusion of plasma as well as red cells + platelets
What is DIC?
disseminated intravascular consumption
What is the pathophysiology of DIC?
→ 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
What are some clinical features of coagulation disorders?
→ superficial cuts do not bleed (platelets)
→ 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 some clinical distinctions that can be made between bleeding due to platelet + coagulation defects?
platelet/vascular vs coagulation:
→ superficial bleeding into skin vs. deep bleeding into joints, tissues and muscles
→ bleeding immediately after injury vs. delayed but severe prolonged bleeding after injury
What are some tests for coagulation disorders?
→ PT (prothrombin time)
→ APTT (activated partial thromboplastin time)
→ full blood count (platelet analysis)
→ coagulation factor assays (for factor VIII)
→ test for inhibitors
What coagulation pathway does the APTT follow?
measures the intrinsic pathway
What coagulation pathway does the PT follow?
measures the extrinsic pathway
What factors does the intrinsic pathway involve?
→ factors I (fibrinogen)
→ factor II (prothrombin)
→ factor IX
→ factor X
→ factor XI (plasma thromboplastin)
→ factor XII
→ factor VIII
What factors does the extrinsic pathway involve?
→ factor I (fibrinogen)
→ factor II (prothrombin)
→ factor VII
→ factor XII
What coagulation disorders can cause prolonged APTT?
→ haemophilia A
→ haemophilia B
→ factor XI deficiency
→ factor XII deficiency
What coagulation disorders can cause prolonged PT?
→ factor VII deficiency
What coagulation disorders could cause prolonged APTT and PT?
→ liver disease
→ anticoagulant drugs e.g. warfarin
→ DIC
→ dilution following red cell transfusion
How do you treat coagulation factor deficiency?
factor replacement therapy
What are the different ways in which you can replace coagulation factors?
→ FFP (fresh frozen plasma, contains all coagulation factors)
→ cryoprecipitate (rich in fibrinogen, VIII, VWF, XIII)
→ factor concentrates (except factor V)
→ prothrombin complex concentrates (PCCs) - factors II, VII, IX, X
→ recombinant forms of FVIII and FIX (on demand to treat bleeds, prophylaxis to prevent bleeds)
What is FFP? What does is it contain?
Fresh frozen plasma, contains all factors
What is cryoprecipitate? What does it contain?
Rich in fibrinogen, Factor 8, VWF, Factor 13
What are factor concentrates?
Concentrates available for all factors except factor 5
Prothrombin complex concentrates include factor 2, factor 7, 9 and 10
What recombinant forms are available?
Factor 8, factor 9
On demand to treat bleed
Prophylaxis to prevent bleeds
What are the current haemophilia treatments?
recombinant clotting factors (factor 8, 9, 12a)
Why are recombinant clotting factors currently used better than the plasma-derived clotting factors used previously?
Plasma-derived caused widespread viral contamination of blood-borne disease such as hepatitis C or HIV
Recombinant has eliminated the potential of transmission
What are some investigational therapies for haemophilia
→ prolonged half-life for clotting factors (Fc fusion, PEG, albumin fusion)
→ gene therapy
→ bispecific antibody (emicizumab)
→ anti TFPI antibody
→ antithrombin RNAi
How does gene therapy for haemophilia A and B work?
Insert gene that can then code for Factors 8 or 9
How do bispecific antibodies work for Haemophilia A?
Binds to both Factor 9a and factor 10
Mimics the procoagulant function of factor 8
What’s an example of a bispecific antibody therapy?
Emicizumab
How does RNA silencing work for Haemophilia A and B?
Targets natural anticoagulant Antithrombin
Promotes pro coagulation
When can bleeding disorders be as a result of too many fibrinolytic factors or anticoagulant proteins?
Both of these are exceedingly rare expect when induced by drugs e.g. tPA given in strokes or Heparin
What is thrombosis?
Dkesjfb
What are some key feature of venous thrombosis?
Intravascular coagulation
Inappropriate coagulation
Obstructs blood flow
May embolism into lungs
What are two common venous thrombosis disorders?
Pulmonary embolism
Deep vein thrombosis
How does deep vein thrombosis clinically present?
Painful leg
Selling
Redness
Warm
Possible pulmonary embolism
Post thrombotic syndrome (long-standing damage to limbs due to incompetence of valves)
How does pulmonary embolism clinically present?
Tachycardia
Hypoxia
Shortness of breath
Chest pain
Haemopysis (coughing up blood)
Sudden death
How do most people die of thrombosis disorders?
Die with an haemostatic end-point
What is Virchow’s triad for the 3 contributory factors for thrombosis?
Blood = dominant in venous
Vessel wall = dominant in arterial
Blood flow = dominant in both venous and arterial
What is thrombophilia?
Increased risk of venous thormbosis
How does thrombophilia present? What are the red flag?
Thrombosis at young age
Spontaneous thrombosis with no obvious cause
Multiple thrombosis
Thrombosis whilst anticoagulated
What increases the chances of thrombosis in terms of anti/coagulant factors and platelets?
Increased Factor 8
increased Factor 2
Factor 5 Leiden (increased coagulant activity due to activated protein C)
Myeloproliferative disorders due to increase in platelets
Decreased antithrombin or protein C or S (genetic predisposition)
Which anticoagulant deficiency has the highest inherited frequency?
Protein C, Protein S
Which inherited anticoagulant deficiency has the highest odds ratio?
Antithrombin
What can cause a natural increase in Factor 8, or reduced blood flow?
Increased Factor 8 natural due to:
Pregnancy
Contraceptive pill
Post-surgery
Long haul travel
Why is the vessel wall not a huge contributor to thrombosis?
V
How do changes in blood flow increase chances of thrombosis?
Reduced blood flow increases chances of thrombosis
What are the general risk factors of thrombosis?
Lifestyle risks that are acquired e.g. pregnancy, etc.
Ageing
Genetic risks
What are the 2 main principles of venous thrombosis treatment?
Prevention
Reduce risk of recurrence + extension + embolisms
How can venous thrombosis be prevented?
Asses + prevent risks
Apply prophylactic anticoagulant therapy
How do you reduce risk of venous thrombosis recurrence or extension?
Lower the procoagulant factors e.g. DOACs or warfarin
Increase the anticoagulant activity e.g. heparin
Why is COVID-19 coagulopathy so complicated?
Overlaps with many other coagulation disorders
