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a path 3 > HAEM: Coagulation > Flashcards

HAEM: Coagulation Flashcards

1
Q

What are the main 3 haemostatic responses to tissue injury?

A
  • Vessel constriction
  • Platelet aggregation
  • Coagulation cascade
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2
Q

What are the functions of the vascular endothelium?

A
  1. Synthesis of PGI2, vWF, plasminogen activators, thrombomodulin
  2. Maintain barrier between blood and procoagulant subendothelial structures
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3
Q

Describe the origin of platelets.

A

Stem cell precursor (2n) –> nuclear replication –> megakaryocytes (multinucleate) –> maturation with granulation –> leave bone marrow –> enter circulation

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4
Q
A
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5
Q

How many platelets can one megakaryocyte porduce? What is the life-span of megakaryocytes?

A
  • Each megakaryocyte produces ~4000 platelets.
  • Lifespan ~10 days, 1/3 stored in spleen
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6
Q

Where are 1/3 of megakaryocytes stored?

A

Spleen

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7
Q

Label this diagram of a platelet.

A

Factors which provides platelets with an increased surface area:

  • Open canalicular system
  • Microtubules and actomyosin
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8
Q

What are the two methods for platelet adhesion to the endothelium?

A

Platelets either bind:

  1. Gp1b with assistance of vWF OR
  2. Gp1a directly
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9
Q

What factors are important in platelet aggregation and activation?

A

GpIIb/IIIa –> fibrinogen binding –> platelet aggregation

Arachidonic acid release –cyclooxygenase–> thromboxane A2

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10
Q

What pathway does aspirin acct on?

A

Acts on cyclo-oxygenase enzyme, irreversibly blocking it

This stops conversion of arachidonic acid to cyclic endoperoxides, especially thromboxane A2 which is a platelet aggregator

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11
Q

What are the functions of thrombin?

A
  • Cleaves Fibrinogen
  • Activates Platelets
  • Activates procofactors (FV and FVIII)
  • Activates zymogens (FVII, FXI and FXIII)
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12
Q

What is the function of the prothrombinase complex? What does the prothrombinase complex consist of?

A

To allow efficient production of activated thrombin

FXa and FVa assembled on negatively charged phospholipid membranes in the presence of calcium ions

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13
Q

What factor is thrombin?

A

IIa

II is an inactive zymogen which the prothrombinase complex converts into IIa , an active protein aka thrombin

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14
Q

Which two pathways activate factor X which is a component of the prothrombinase complex?

A

Extrinsic pathway - FVIIa-TF complex

Intrinsic tenase - FVIIIa and FIXa

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15
Q

Describe the initiation phase of the coagulation cascade.

A
  1. Injury of vessels wall leads to contact between blood and subendothelial cells
  2. Tissue factor (TF) is exposed and binds to FVIIa or FVII which is subsequently converted to FVIIa
  3. The complex between TF and FVIIa activates FIX and FX
  4. FXa binds to FVa on the cell surface
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16
Q

Describe the amplification stage of the coagulation cascade.

A
  1. The FXa/FVa complex converts small amounts of prothrombin into thrombin
  2. The small amount of thrombin generated activates FVIII, FV, FXI and platelets locally. FXIa converts FIX to FIXa
  3. Activated platelets bind FVa, FVIIIa and FIXa
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17
Q

Describe the propagation phase of the coagulation cascade?

A
  1. The FVIIIa/FIXa complex activates FX on the surfaces of activated platelets
  2. FXa in association with FVa converts large amounts of prothrombin into thrombin creating a “thrombin burst”.
  3. The “thrombin burst” leads to the formation of a stable fibrin clot
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18
Q

What kind of effect does absence of a component of the coagulation cascade (e.g. prothrombinase) have on the relative rate of activation?

A

Based on presence/absence of components in the coagulation cascade there is a multiplicative effect which can be as large as x1000 more coagulation.

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19
Q

Which are the Vit K dependent coagulation factors? Where are they produced?

A

II, VII, IX, X = Produced in the liver

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20
Q

What happens to the vitamin K dependent factors if it is absent?

A

To activate them you need vitamin K to act as a gamma-carboxylase enzyme

  • Antibiotics can cause Vit K deficiency as gut flora is important for Vit K production
  • Biliary tract obstruction (Vit K is fat soluble vitamin) can also cause Vit K deficiency
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21
Q

What is the main role of plasmin?

A

Conversion of fibrin into fibrin degradation products

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22
Q

List some inhibitors of fibrinolyis.

A

plasminogen activator inhibitor 1 & 2 (inhibits tPA and urokinase)

alpha2-antiplasmin and alpha2-macroglobulin (inhibit plasmin)

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23
Q

Which factors are important in conversion of plasminogen to plasmin?

A
  • Factor XIa, XIIa
  • Kallikreins
  • tPA (tissue plasminogen activator)*
  • Urokinase

*used in stroke/MI

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24
Q

Summarise fibrinolysis.

A

NB: TAFI inhibits fibrin degradation

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25
Q

List 3 physiological anticoagulants.

A

Antithrombins - bind thrombin for excretion via kidney; deficiencies present in 20s.

Protein C/S pathway - deactivate FV and VIII to stop thrombin generation. Resistance to APC in FV Leiden patients.

Tissue factor pathway inhibitor (TFPI) - inhibits TF and FVII recruitment which are important for triggerring factor IX and X activation.

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26
Q

List 4 causes of haemostasis disorders causing bleeding, which are (a) acquired and (b) genetic.

A

Acquired defects:

  • liver disease (site of clotting factor synthesis)
  • vitamin K deficiency
  • autoimmune disease (platelet destruction)
  • trauma
  • anticoagulants/antiplatelets

Genetic defects:

  • platelet abnormalities
  • blood vessel wall abnormalities
  • clotting factor deficiencies (haemophilias)
  • excess clot breakdown (fibrinolysis)
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27
Q

How do prothrombotic disorders present?

A

Transient, short-term or episodic event in individuals with chronic or recurring clotting.

It is the major cause of both stroke and heart attacks.

28
Q

Name 1 cause of thrombosis which is (a) acquired, (b) genetic.

A

Acquired defects:

  • Atherosclerosis

Genetic defects:

  • clotting factor INHIBITOR deficiencies
  • decreased fibrinolysis
29
Q

How can we classify disorders of haemostasis?

A
  1. Vascular disorders –Scurvy, easy bruising,
  2. Platelet disorders –Low Number or abnormal function
  3. Coagulation disorders–Factor deficiency.
  4. Mixed/Consumption- DIC
30
Q

How does the pathophysiology of mucosal/skin petechiae/purpura differ from that of local bleeding/haematoma/joint bleeding? What about delayed vs immediate bleeding?

A

Type:

  • Mucosal/skin petechiae/purpura - due to lack of coagulation factors
  • Local bleeding/haematoma/joint bleeding – platelet disorder

Timing:

  • Immediate – lack of formation of platelet plug, so platelets are the cause
  • Delayed – coagulatioin
31
Q

What are the features of platelet vs coagulation disorders in terms of:

  1. side of bleeding
  2. petechiae presence
  3. ecchymoses
  4. haemarthrosis
  5. bleeding after cuts
  6. bleeding after surgery/trauma
A
32
Q

How low must platelets usually be to cause severe bleeding?

A

<30,000/mm3

NB: Should examine under microscope because count may be low due to pseudothrombocytopenia or false thrombocytopenia. Commonly linked to EDTA use. In these cases you would see several platelets clumped together.

33
Q

What are 3 aetiologies of platelet disorders causing bleeding?

A

Decreased Number: Thrombocytopenia due to ….

  • Decreased Production
  • Decreased Survival – Immune (ITP)
  • Increased utilization – DIC
  • Dilution effect

Defective Platelet function due to…

  • Acquired – Drugs (aspirin), chronic renal failure
  • Congenital (rare)e.g. thrombasthenia.
34
Q

Antiplatelet agents: where does clopidogrel act?

A

Inhibitor of ADP-induced platelet aggregation, irreversibly inhibiting the binding of ADP to its platelet membrane receptors.

Ultimately it inhibits the activation of the GPIIb/IIIa receptor, its binding to fibrinogen and further platelet aggregation.

35
Q

Antiplatelet agents: what is ASA aka? What is its MOA?

A

Acetylsalicylic acid (ASA) = aspirin

ASA inhibits the COX enzyme, reducing the production of prostaglandin and TXA2 from arachidonic acid.

TXA2 normally activates the GPIIb/IIIa binding site on the platelet, allowing fibrinogen to bind.

36
Q

Antiplatelet agents: what is the MOA of dipyridamole?

A

Inhibits platelet aggregation by blocking the reuptake of adenosine formed from precursors released by red blood cells following microtrauma.

37
Q

Antiplatelet agents: what is the MOA of GPIIb/IIIa blockers?

A

Competitive inhibitors of the GPIIb/IIIa receptors on the surface of platelets.

They inhibit platelet aggregation by preventing the binding of fibrinogen, vWF and other adhesive ligands to GPIIb/IIIa receptors.

38
Q

List 2 causes of immune-mediated vs non-immune mediated thrombocytopenias.

A

Immune-mediated

  • Idiopathic
  • Drug-induced – e.g. quinine
  • Connective tissue disease e.g. SLE
  • Lymphoproliferative disease
  • Sarcoidosis

Non-immune mediated

  • DIC
  • Microangiopathic hemolytic anemia
39
Q

What is the pathophysiology of ITP?

A

Immune Thrombocytopenic Purpura - anti-platelet Abs circulate in blood and tag platelets. As these platelets go through any organ they are destroyed by macrophages

40
Q

What is the difference between childhood and adult ITP?

A

NB: often in children the ITP is left untreated.

41
Q

What is the initial management of ITP based on platelet count?

A

NB: if less than 20,000, you need to give steroids irrespective of bleeding or not.

IVIG will work by competing with auto-Ab to allow platelets to survive longer and stops destruction by reticuloendothelial system.

42
Q

How can you clinically differentiate petechiae from angiomas and vasculits?

A

Angiomas - blanch with pressure

Vasculitis - palpable rash

Petechiae - non-blanching and non-palpable

43
Q

What is a macrocyte and when is it seen?

A

Large RBC

In megaloblastic anaemia (due to vit B12 or folic acid deficiency)

44
Q

What is the arrow pointing to?

A

Auer rod - presence in blasts gives a diagnosis of AML. These cells are myeloid blasts.

45
Q

Give 3 acquired and 3 inherited causes of coagulation factor disorders causing bleeding.

A

Inherited bleeding disorders

  • Haemophilia A and B
  • vonWillebrands disease
  • Other factor deficiencies

Acquired bleeding disorders

  • Liver disease
  • Vitamin K deficiency/warfarin overdose
  • DIC
46
Q

What factors are deficient in haemophilia A vs B? What does a coagulation profile show?

A
  • Congenital X-linked recessive deficiency -Factor 8 (A) or 9 (B)
  • Prolonged aPTT but normal PT.

Haemophila A is x5 more common.

47
Q

How is the severity of haemophilia categorised?

A

Related to factor level

  • <1% - Severe - spontaneous bleeding
  • 1-5% - Moderate - bleeding with mild injury
  • 5-25% - Mild - bleeding with surgery or trauma
48
Q

What are the clinical manifestations of haemophilia?

A
  • Haemarthrosis (most common) - fixed joints
  • Soft tissue haematomas (e.g., muscle) - muscle atrophy, shortened tendons
  • Other sites of bleeding - urinary tract, CNS, neck (may be life-threatening)
  • Prolonged bleeding after surgery or dental extractions

A + B indistinguishable clinically

49
Q

What is the most common cause of increased bleeding tendency due to coagulation factors?

A

vWD - 1 in 10,0000 affected

50
Q

What are the clinical features of vWD?

A

Clinical features e.g. mucocutaneous bleeding such as nosebleeds

51
Q

What is the inhheritance pattern of vWD?

A

Autosomal dominant

52
Q

What are the types of von Willebrand disease?

A
  • Type 1- Partial quantitative deficiency
  • Type 2 - Qualitative deficiency
  • Type 3 - Total quantitative deficiency
53
Q

True or false: vWF may be normal in vWD.

A

True - in type 2 there is normal vWF antigen and normal multimer formation.

54
Q

What are 2 sources of vitamin K for the body?

A
  • Green vegetables
  • Synthesised by intestinal flora
55
Q

Which coagulation components require vitamin K for synthesis?

A

Factors II, VII, IX ,X , Protein C, S and Z

56
Q

What are some causes of vitamin K deficiency?

A
  • Malnutrition
  • Biliary obstruction
  • Malabsorption
  • Antibiotic therapy
57
Q

What is the treatment for vitamin K deficiency?

A

Vitamin K

Fresh frozen plasma

58
Q

What is the pathophysiology of DIC?

A

Activation of both coagulation and fibrinolysis triggered by various issues.

59
Q

List 5 causes of DIC.

A
  • Sepsis
  • Trauma - head injury, fat embolism
  • Malignancy
  • Obstetric complications - amniotic fluid embolism, abruptio placentae
  • Vascular disorders
  • Reaction to toxin (e.g. snake venom, drugs)
  • Immunologic disorders - severe allergic reaction, transplant rejection
60
Q

What are the laboratory findings in DIC bloods?

A
  • Consumption of coagulation factors; presence of FDPs (fibrin degradation products)
  • High aPTT
  • High PT
  • High TT
  • Low Fibrinogen
  • Presence of plasmin – raised FDP
  • Intravascular clot – low Platelets, schistocytes
61
Q

What is shown?

A

Schistocytes - red cell fragments. May occur in MAHA.

62
Q

What is the management of DIC?

A
  • Treatment of underlying disorder
  • Anticoagulation with heparin?
  • Platelet transfusion
  • Fresh frozen plasma
  • Coagulation inhibitor concentrate - APC concentrate
63
Q

What is the management of haemostatic defects in liver disease including:

  1. prolonged PT/PTT
  2. low fibrinogen
  3. DIC
A

Treatment for prolonged PT/PTT -

  • Vitamin K 10 mg o.d x 3 days - usually ineffective
  • Fresh-frozen plasma infusion - 25-30% of plasma volume (1200-1500 ml); immediate but temporary effect

Treatment for low fibrinogen - cryoprecipitate (1 unit/10kg body weight)

Treatment for DIC (elevated D-dimer, low factor VIII, thrombocytopenia - replacement therapy

64
Q

How do you manage a high INR?

A

Simplified:

  • 5 - omit dose
  • 5-9 - +/- vitamin K PO
  • >9 - +/- repeat vit K PO
  • >20 - vitamin K IV, FFP, PCC. Repeat K PRN
65
Q
A

a path 3 (89 decks)

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