haemostasis Flashcards
What is haemostasis? What is its purpose?
Cellular/biochemical process that enables regulated cessation of bleeding in response to injury.
-Purpose to prevent blood loss from intact vessels, stop bleeding from injured vessels & enable tissue repair
What is the first thing that happens as a response to endothelial cell lining injury?
Vasoconstriction - vascular smooth muscle cells contract locally to limit blood flow to injured vessel
What is primary haemostasis?
Formation of unstable platelet plug (platelet adhesion + aggregation) to limit blood loss & give surface for coagulation
What is secondary haemostasis?
Stabilisation of platelet plug with fibrin to stop blood loss
What is fibrinolysis?
Vessel repair & clot dissolution
What factors cause and stop bleeding? What is needed between them?
Anti-coagulant factors & fibrinolytic factors cause bleeding.
Coagulant factors/platelets cause potential thrombosis.
Balance is needed between the 2.
Under what conditions can the balance be tipped towards bleeding?
- lack of specific coagulant factor - failure of production, increased consumption
- defective function of factor - genetic, acquired, drug
What is the mechanism of primary haemostasis?
- Damage to endothelium exposes collagen in vessel wall.
- Platelets directly adhere to wall via glycoprotein 1a (GP1a) or indirectly via VWF via GP1b receptor (platelet adhesion).
- This binding causes release of granular contents (ADP & thromboxane), flip-flopping & activation of GPIIb/IIIa receptors on platelets causing platelet aggregation
What platelet problems can cause disorders of primary haemostasis?
- platelets - thrombocytopenia due to bone marrow failure (leukaemia, B12 deficiency) - accelerated clearance of platelets (immune thrombocytopenia ITP, disseminated intravascular coagulation DIC), pooling of platelets in enlarged spleen
- impaired function of platelets (absence of glycoproteins or storage granules, acquired drugs - aspirin, NSAIDs, clopidogrel)
What is immune thrombocytopenic purpura (ITP)?
Anti-platelet antibodies cause phagocytosis of platelets by macrophages. Causes thrombocytopenia
what are some hereditary platelet defects and what happens in each?
- glanzmann’s thromboasthenia - absence of GPIIb/IIIa receptor on platelets
- bernard soulier syndrome - absence of GPIb receptors
- storage pool disease - reduction in granular content of platelets (dense granules)
What is mechanism of aspirin? How long does the effect last?
Aspirin irreversibly blocks COX so reduced production of thromboxane A2 from arachidonic acid, reduction in platelet aggregation.
- Also prostacyclin inhibited by COX but can be generated by endothelial cell.
- Single dose aspirin lasts 7 days until platelet replaced
What is is mechanism of clopidogrel?
Irreversibly blocks ADP receptor (p2y12) on platelet cell membrane so reduced platelet aggregation
What does VWF do?
Binds to collagen so that platelets can bind.
Stabilises factor 8 (can be low if VWF very low)
What are disorders of VWF function?
Von willebrand disease VWD is hereditary disease autosomal inheritance, deficiency of VWF (type 1 or 3) or abnormal VWF (type 2)
What are disorders of the vessel wall in primary haemostasis?
- inherited haemorrhagic telangiectasia - due to enhler danlos syndrome (collagen problem) & other connective tissue disorders
- acquired - steroid therapy can cause atrophy of collagen fibres
- ageing (senile purpura)
- scurvy (vitamin C deficiency causes defective collagen synthesis & weakening of capillary walls)
- vasculitis
What is difference between purpura and petechiae and echymosis?
- Petechiae is <3mm. Petechiae usually only in thrombocytopenia
- Purpura is between 3-10mm. Purpura does not blanch when pressure applied.
- Echymosis is >10mm
What are clinical features of disorders of primary haemostasis?
- bleeding immediate, prolonged bleeding from cuts, nose bleeds prolonged >20minutes, prolonged gum bleeding, menorrhagia, bruising easy + spontaneous, prolonged bleeding after trauma/surgery.
2. thormbocytopenia (petechiae)
3. purpura - thrombocytopenic or vascular disorders, wet purpura over mucosa like gums
4. severe VWD - haemophilia like bleeding due to low F8
What are tests for disorders of primary haemostasis?
-Platelet count & morphology, bleeding time (PFA100 in lab), VWF assays, clinical observation, coagulation screen (PT, APTT) which are usually normal unless severe VWD causes low f8
What happens in disorders of primary haemostasis as platelet count gets lower?
Bleeding with trauma, spontaneous bleeding, severe spontaneous bleeding
What are treatments of abnormal primary haemostasis?
- replace missing factors/ platelets eg. VWF containing concentrates prophylactically or therapeutically
- if immune destruction immunosuppression (prednisolone) or splenectomy for ITP
- increased consumption - treat cause, replace
- desmopressin causes release of stored VWF (endogenous) for mild disorders
- tranexamic acid - anti-fibrinolytic - for trauma & strokes. 6. fibrin glue/spray for surgery
- OCP for mennorhagia
What is secondary haemostasis goal?
To generate thrombin (IIa) which will convert fibrinogen to fibrin.
What are disorders of coagulation?
- deficiency of coagulation factor (haemophilia) / liver disease, anticoagulant drugs (warfarin, direct oral anticoagulants DOACs)
- dilution - blood transfusion (inadequate replacement of blood)
- increased consumption - DIC or autoantibodies rarely
What is haemophilia A & B? what factors are deficiency? What is the inheritence?
Haemophilia A (factor 8 deficiency), haemophilia B (factor 9 deficiency). Both sex linked, x-linked.
What are clinical features of haemophilia?
- Cant generate fibrin for platelet plug stability.
- Haemarthrosis.
- Fibroid synovial lining bleeding (muscle wasting + deformity), extensive haematoma when IM injections (avoid)
What do different coagulation factor deficiencies cause (factor 8, 9, prothrombin -2, 11,12)?
- absence of F8,9 (haemophilia) - severe but compatible with life.
- Prothrombin deficiency F2 is lethal.
- Factor 11 deficiency causing bleeding after trauma but not spontaneous.
- Factor 12 deficiency causes no bleeding at all
What are some acquired coagulation disorders?
- Liver failure (most coagulation factors made in liver except factor 5 and VWF).
- Anticoagulant drugs.
- Dilution (RBC transfusions).
- DIC (increased consumption of factors).
What is DIC? (disseminated intravascular coagulation)
- Generalised activation of coagulation - TF leads to widespread activation of coagulation triggered by things like sepsis and major tissue damage/inflammation.
- Consumes and depletes coagulation factors and platelets.
- Activation of fibinolysis depletes fibrinogen so raised D dimer
- deposition of fibrin in vessels causes organ failure
What are clinical features of coagulation disorders?
- Superficial cuts don’t bleed (primary haemostasis handles it), bruising common, nosebleeds rare.
- Spontaneous bleeding is deep in muscle & joints.
- Bleeding after trauma can be delayed and is prolonged/frequently restarts after stopping
What is difference between bleeding due to platelet & coagulation disorders?
Platelet disorders cause superficial bleeding into skin & mucosal surfaces, straight after injury.
In coagulation disorders bleeding is deep into tissues, muscle, joints, bleeding delayed but severe and prolonged
What are tests done for coagulation disorders?
Clotting screen, PT, APTT, FBC, coagulation factor assays, tests for inhibitors
What does prothrombin time PT measure? What pathway + what factors?
Extrinsic pathway. Factors 1,2,5,7,10
What does activated partial thromboplastin time APTT measure? What pathway + factors?
Intrinsic pathway. Factors 1,2,5,8,9,10,11,12
What causes prolonged PT with normal APTT?
F7 deficiency
What causes both prolonged PT & APTT?
Liver disease, anticoagulant drugs, DIC, dilution, factors 1,2,5,10
What are options for replacement of missing coagulation factors and what factors do they replace?
- fresh frozen plasma FFP: all coagulation factors
- cryoprecipitate - fibrinogen, F8, VWF, F13.
- factor concentrates: available for all except factor V.
- prothrombin complex concentrates PCC: F2,7,9,10.
- recombinant forms of F8 & 9 for prophylaxis of bleeding or treatment
What are novel haemophilia treatments?
Gene therapy, bispecific antibodies (haem A- emicizumab mimics function of factor 8, binds to 9a & 10). RNA silencing - targets natural anticoagulant antithrombin
What is tPA and what can it cause?
Tissue plasminogen activator is thrombolytic that breaks down clots. Used in stroke
What does heparin do?
Anticoagulant (blood thinner)
What is presentation of pulmonary embolism?
Shortness of breath, tachycardia, hypoxia, chest pain, haemoptysis, sudden death
What is presentation of deep vain thrombosis DVT?
Painful leg, swelling, red, warm, may embolise into lungs, post-thrombotic syndrome (long standing damage to leg due to valve damage)
Why can thrombosis happen and where?
Arteries and veins.
Can embolise to lungs
Intravascular coagulation or inappropriate coagulation
What is virchows triad ?
Factors that contribute to thrombosis
- blood - dominant in venous
- vessel wall - dominant in arterial
- blood flow - in both
What disruption in balance can cause thrombosis?
increased coagulant factors/platelets, decreased anti-coagulant proteins/fibrinolytic factors
What can cause increased coagulant factors?
Genetic, can rise in cases like F8 in cancer, pregnancy. Factor 2, factor 5 leiden (increase activity due to activated protein C resistance)
What can cause increase in platelets?
Myeloproliferative disorders
What are anti-coagulant factors and when can we see reduction?
Antithrombin, protein C, protein S. nephrotic syndrome when they leak
What do anti-coagulant proteins usually do?
Antithrombin inactivates thrombin and 10a.
Protein C and co-factor S inactivate factors
Is it more common to have pro-coagulant excess or anti-coagulant reduction for thrombosis?
pro-coagulant excess
What vessel changes can occur causing thrombosis?
Proteins active in coagulation expressed on surface of endothelial cells and expression altered in inflammation (TM, EPCR, TF)
What blood flow changes can occur causing thrombosis?
Stasis - reduced flow, increases risk - surgery, long flight, pregnancy
What is treatment of venous thrombosis?
Assess/prevent risks, prophylactic anticoagulant therapy. Reduce risk of recurrence/extension - lower pro-coagulant factors (eg warfarin, DOACs), increase anticoagulant activity (heparin)
