Haemostasis

Question 1

stages of haemostasis

Answer 1

local vessel constriction → formation of unstable platelet plug (primary haemostasis) → stabilisation of plug with fibrin (secondary haemostasis) → vessel repair and clot dissolution (fibrinolysis)

Question 2

what does primary haemostasis involve

Answer 2

platelet adhesion and platelet migration
Adhesion via Gp1a to endothelial cell or VWF and Gp1b
aggregation via release of ADP and thromboxane as well as fibrinogen and calcium ( which is sued in secondary haemostasis)
fibrinogen and GpIIb/GpIIIa links platelts

Question 3

low platelet count

Answer 3

thrombocytopenia may be caused by

bone marrow failure → leukemia, B12 deficiency

accelerated clearance → ITP, disseminated intravascular coagulation

pooling and destruction in large spleen

Question 4

immune thrombocytopenia

Answer 4

antiplatelet autoantibodies bind → sensitised platelet detected and removed by macrophages of reticuloendothelial system in spleen

Question 5

what is glanzmann’s thrombasthenia?

Answer 5

hereditary defect in GpIIb/IIIa production

Question 6

what is bernard soulier syndrome?

Answer 6

hereditary defect in GpIb production

Question 7

what is storage pool disease?

Answer 7

hereditary issue with storage granules inside platelets

Question 8

how can platelet defects be acquired? Primary haemostasis

Answer 8

drugs e.g. aspirin vs COX (no thromboxane A2) thus platelet aggregation decreases, clopidogrel vs ADP receptor P2Y12 on platelets

Question 9

VWF functions in homeostasis?

Answer 9

bind to collagen and collect platelets

stabilise factor VIII

Question 10

what is von willebrand disease? Primary haemostasis

Answer 10

usually hereditary decrease in amount or function of VWF

can rarely be acquired due to antibodies

• subtypes of hereditary variation?1, 3 → deficiency of VWF2 → VWF with abnormal function

Question 11

examples of inherited disorders in vessel wall leading to haemostasis issue? Primary haemostasis

Answer 11

hereditary haemorrhagic telangiectasia

ehlers-danlos syndrome

Question 12

acquired causes of vessel wall primary haemostasis

Answer 12

steroid therapy, aging ‘senile purpura’, vasculitis, vit C deficiency (scurvy)

Question 13

typical bleeding characteristics in primary haemostasis disorders?

Answer 13

immediate, prolonged bleeding from cuts/after trauma or surgery

nosebleeds 20+ mins, prolonged gum bleeding, menorrhagia

easy or spontaneous bruising (echomysis)
Prolonged bleeding after surgery

Question 14

difference between petechiae and purpura?

Answer 14

purpura bigger (3-10mm) vs 3mm, don’t blanche when pressure is applied

Purpura seen jn platelet (thrombocytopenia purpura) or vascular disorders
Petechiae seen in thrombocytopenia

Question 15

tests for primary haemostasis disorders?

Answer 15

VWF assay, bleeding time, platelet count and morphology

coagulation screen (PT, APTT) normal except in severe cases of VWD where factor VIII is low

Question 16

treatment for failure of production/function of platelets

Answer 16

replace missing factor or platelets by VWF concentrates
prophylatic
therapeutic

stop drugs e.g. NSAIDs or aspirin

Question 17

treatment for immune destruction of platelts

Answer 17

immunosuppressants eg prednisolone

ITP → splenectomy

Question 18

treatment for increased consumtipn of platelets

Answer 18

treat cause, replace as necessary

Question 19

additional haemostatic treatments for primary haemostasis

Answer 19

desmopressin → mild disorders, releases endogenous stores
(Vasopressin analogue which causes a 2-5 increase in VWF and only useful in mild disorders)
tranexamic acid (antifibrinolytic)

fibrin glue/sprays

Or other approaches such as OCP for menhorrahia

Question 20

what is the role of coagulation

Answer 20

secondary haemostasis → generate thrombin (IIa) to convert fibrinogen to insoluble fibrin

Question 21

hereditary coagulation disorders → examples?

Answer 21

haemophilia A (factor VIII deficiency), haemophilia B (factor IX deficiency)

Question 22

hallmark of haemophilia

Answer 22

haemarthrosis (bleeding into joint cavity)

chronic leads indirectly to muscle wasting

sex linked
must not give intramuscular injections

Question 23

how similar are different coagulation factor deficiencies?

Answer 23

potentially v different →

VIII and IX serious but survivable, II fatal, XI bleed after trauma but not spontaneous, XII no bleeding at all

Question 24

how are coagulation disorders acquired?

Answer 24

liver failure, some anticoagulant drugs eg warfarin or DOAC

dilution in blood due to transfusion(lots of rbc given no plasma)

increased consumption e.g. disseminated intravascular coagulation (acquired),immune autoantibodies (rare)

Question 25

what is disseminated intravascular coagulation?

Answer 25

generalised activation of coagulation by tissue factor associated with major tissue damage, inflammation, sepsis consumes and depletes platelets, coagulation factors activates fibrinolysis thus depleting fibrinogen which will show raised D dimer fibrin depostion in vessels causes organ failure

Question 26

clinical features of coagulation disorders?

Answer 26

superficial cuts don’t bleed (taken care of by platelets) bruising common nosebleeds rare spontaneous bleeding = deep e.g. into muscles, joints bleeding after trauma may be delayed, prolonged bleeding often restarts after stopping

Question 27

tests for coagulation factor disorders?

Answer 27

PT, APTT, FBC for platelets coagulation factor assays test for inhibitors

Question 28

what do PT and APTT each measure?

Answer 28

PT = extrinsic pathway APTT = intrinsic pathway extrinsic: TF, factor VII intrinsic: XII, XI, IX, VIII common: X, V, II, fibrinogen → fibrin

Question 29

normal times for PT and APTT

Answer 29

PT → 9.6 - 11.6 APTT → 26 - 32

Question 30

how are missing coagulation factors replaced?

Answer 30

- plasma all coagulation factors - cryoprecipitate esp fibrinogen, VIII, XIII, VWF - factor concentrates available for all except V - recombinants VIII and IX, on demand or prophylactically can give desmopressin,tranexamic acid

Question 31

novel treatments for haemophilia?

Answer 31

gene therapy for haem A and B bispecific antibodies mimicking factor VIII procoagulant function by binding to factor IXa and X.Emicizumab RNA silencing targeting antithrombin for haem a and b

Question 32

how do disorders of thrombosis present

Answer 32

pulmonary embolism DVT

Question 33

pulomonary embolism

Answer 33

tachycardia, hypoxia, shortness of breath, chest pain, haemoptysis,sudden death

Question 34

deep vein thrombosis presentation?

Answer 34

painful leg, red, swollen, warm thrombus can embolise to lungs post thrombotic syndrome (valve damage causing long standing pain)

Question 35

thrombosis

Answer 35

intravascular coagulation inappropriate coagulation venous or arterial obstructs flow may embolise to lungs

Question 36

virchows triad

Answer 36

three contributory factors to thrombosis: blood, vessel wall, blood flow

Question 37

which kinds of thrombosis is each prominent in?

Answer 37

blood dominant in venous, vessel wall dominant in arterial, blood flow contributes to both

Question 38

what is thrombophilia? presentation?

Answer 38

increased risk of venous thrombosis thrombosis at young age, spontaneous, multiple,thrombosis whilst anticoagulated

Question 39

prominent anticoagulant proteins?

Answer 39

antithrombin, protein C, protein S

Question 40

how does thrombsosi arise

Answer 40

excess coagulant factors/platelets (increased due to activated protein c resistance or myeloproliferative disorders) (basically there is an increase in factor VIII factor II and factor V Leiden the last one being due to increased activity of protein c resistance) decrease in anticoaglant proteins

Question 41

protein c and s

Answer 41

inactivate factor Va and VIIIa Protein c is activated by thrombin thrombomodulin complex and protein s acts as a cofactor helping to inactivate Ava and VIIIa

Question 42

what aspect of blood flow can increase thrombosis risk?

Answer 42

reduced flow increases riss eg pregnancy,surgery,long haul flight

Question 43

venous thrombosis prevention methods?

Answer 43

prophylactic anticoagulation therapy lower procoagulant factors eg warfarin/doacs increased anticoagulant activity eg heparin

Question 44

SARS-Cov-2 relevance?

Answer 44

contributes to many procoagulative pathways → microthrombus, venous thrombus, arterial thrombus formation

Question 45

indications for anticoagulation treatment?

Answer 45

venous thrombosis (inital treatment to minimise clot extension,LT to reduce risk of recurrence) atrial fibrillation (reduce risk of embolic stroke) mechanical prosthetic heart valve prophylactic → post-op, during hospital stay, pregnancy as a preventative

Question 46

heparin

Answer 46

naturally occuring glycosaminoglycans prodcued by mast cells porcine products used in uk

Question 47

different forms of heparin

Answer 47

unfractionated (long chains) → IV administration,short half life low molecular weight → subcutaneous administration

Question 48

what does unfractionated heparin do?

Answer 48

enhances antithrombin inactivates thrombin by binding to antithrombin and thrombin inactvates factor Xa by binding to antithrombin inactivates IXa,XIa,XIIa

Question 49

what does LMWH do?

Answer 49

enhances antithrombin → inactivates factor Xa (not long enough to wrap around antithrombin and thrombin) Contains pentasaccaride sequence to bind to AT

Question 50

differences in effect on APTT?

Answer 50

LMWH increases clotting time by less than fractionated normally dont monitor in LMWH if needed we can measure anti-xa Thrombin has greater affect on APTT

Question 51

what kind of drug is warfarin?

Answer 51

blocks recycling of vitamin K reduces production of functional clotting factors slowly induces anticoagulative state

Question 52

what factors does warfarin inactivate

Answer 52

II,VII,IX,X protein c and s

Question 53

how do we reverse affects of warfarin

Answer 53

slowly by vit k administration which takes several hours to wrok or rapidly by infusion of coagulation factors Prothrombin complex concentrate contains II,VII,IX,X fresh frozen plasma

Question 54

warfarin side effects

Answer 54

bleeding skin necrosis due to severe protein c deficiency, 2-3 days after starting warfarin,thrombosis predominantly occurs jn adipose tissue purple toe syndrome (disrupted atheromatous plaques bleed and cholesterol emboli lodge in extremities embryopathy-chondrodysplasia punctata where early fusion of epiphysis occurs Warfarin teratogenic jn first trimester

Question 55

what is used for warfarin monitoring?

Answer 55

international normalised ratio measures correction for different hromboplastin used

Question 56

target and normal values?

Answer 56

normal = 1, target usually 2-3 higher INR sows higher risk of all bleeding as blood is thinner Lower INR means thick blood

Question 57

what can cause resistance to warfarin?

Answer 57

vit K dietary intake increased cytochrome P450 metabolism of warfarin, reduced binding VKORC1 lack of patient compliance (proteins induced by vitamin k absence PIVKA)

Question 58

what do direct oral anticoagulants do?

Answer 58

directly target a clotting factor to inhibit work agasint factor Xa inhibitor or IIa

Question 59

compare to warfarin DOACs

Answer 59

faster acting, not affected by diet, fixed dose fewer interactions, no monitoring required some renal dependence reversible by specific antidotes

Question 60

when should DOACs be avoided?

Answer 60

for mechanical prosthetic heart valves as medical prothrombo-prophylaxis (e.g. during hospital admission) in pregnancy

Question 61

choice of anticoagulant

Answer 61

venous thrombosis: initital give DOAC/LMWH followed by DOAC/warfarin long term give DOAC/warfarin atrial fibrillation: DOAC/warfarin Mechanical prosthetic valve warfarin preventative: after surgery give LMWH/DOAC pregnacny LMWH

Question 62

What can increase both PT APTT (secondary haemostasis)

Answer 62

Kivrr disease Anti coagulation drugs DIC Dilution following rbc transfusion

Question 63

Examples of DOAC

Answer 63

Targeting factor Xa we have apixaban or rivaroxaban or edoxaban Or factor IIa dabigatran

Question 64

COVID coag

Answer 64

Antiphospholipid Syndrome (APS): A hypercoagulable state where anticardiolipin IgA antibodies and other antiphospholipid antibodies promote arterial and venous thrombosis by interfering with endothelial function, platelet activation, and coagulation pathways. Hemophagocytic Syndrome (HPS): A severe inflammatory condition that triggers a cytokine storm, leading to microthrombosis and venous thrombosis due to excessive immune activation, endothelial damage, and coagulation dysregulation. Sepsis-Induced Coagulopathy (SIC) and Disseminated Intravascular Coagulation (DIC): Both conditions cause widespread microthrombosis by suppressing fibrinolysis, leading to the accumulation of clots in small vessels and contributing to multi-organ dysfunction. Thrombotic Microangiopathy (TMA): Characterized by microthrombi formation due to von Willebrand factor (VWF), which leads to small vessel occlusion, hemolysis, and organ damage, as seen in conditions like thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS).

Question 65

Vitamin k recycling

Answer 65

Hydroquinone is converted to epoxide via vit k dependant carboxylase Thus process donates electrons to activate clotting factors via carboxylation Warfarin blocks VKOR (vitamin k epoxide reductase) and quinone reductasestopping vitamin k regeneration