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(4004) Haem > Inhibition of haemostasis > Flashcards

Inhibition of haemostasis Flashcards

1
Q

What are anticoagulants

A
  • act w/in coag cascade
  • inactivate factors that have been activated
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2
Q

Describe the mechanism of Tissue factor pathway inhibitor (TFPI)

[Physiological inhibitors of 2dary haemostasis]

A
  • produced by endo.c & MK
  • TFPI alpha: K1 & K2 domains bind & inhibit FVIIa; K3 domain bind to protein S => enhances FXa inhibition (by TFPIα)
  • TFPI beta: K1 & K2 bind & inhibit FXa
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3
Q

Describe the mechanism of Antithrombin-glycosaminoglycan pathway

[Physiological inhibitors of 2dary haemostasis]

A
  • (SERPIN: Serine Protease Inhibitor)
  • antithrobmin (AT) & Heparin cofactor II (minor AT) > both inhibit thrombin = inhibit plt aggregation
  • & inhibit FIIa, FXa, FIXa, FVIIa
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4
Q

Describe Protein C in the Protein C/S system

[Physiological inhibitors of 2dary haemostasis]

A
  • Endothelial Protein C receptor (EPCR) binds to Protein C -> presents to thrombin
  • activated via thrombin => Activated Protein C (APC) = prolong clotting time
  • inactivated FVa & FVIIIa w/ protein S
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5
Q

Describe Protein S in the Protein C/S system

[Physiological inhibitors of 2dary haemostasis]

A
  • free form only has anticoag. activity (C4b-bound is inactive)
  • inactivate FVa & FVIIIa w/ protein C
  • anticoagulant activity on FVa-FXa complex
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6
Q

Describe the mechanism of Protein Z/Z dependent protease inhibitor
[Physiological inhibitors of 2dary haemostasis]

A
  • Protein Z dependent protease inhibitor (ZPI) + preotein Z (+Ca2) => inhibits FXa
  • Protein ZPI inhibits FIXa, FXIa
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7
Q

describe what a pathological inhibitor of coagulation is (pathological anticoagulant)

A
  • auto Aby or anti-phospholipid syndrome that inhibit normal coag. cascade => haemorrhagic diathesis
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8
Q

How do you dx Aquired Haemophilia A (AHA) (4 test/Ix)

[pathological inhibitors]

A
  1. Screening test: prolonged aPTT
  2. Mixing test ( to rule out deficiency)
  3. Test for anti-phospholipid Aby (to rule out antiphospholipid syndrome)
  4. Bethesda assay to confirm anti-FVIII aby
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9
Q

describe principle of the bethesda assay for testing acquired pathological inhibitors

A
  1. FVIII inhibitors quantified by mixing plasma w/ known FVIII amount
  2. incubated @ 37C for 2h
  3. amount of inhibitor = control (plasma & buffer) - results
    * 1 Bethesda unit = inhibitor that will inactivate half of the factor in the mixture (pts & normal plasma) in 2 hrs
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10
Q

What is Antiphospholipid syndrome

[pathological inhibitors]

A
  • autoimmune disorder
  • prothrombic factors interact => arterial & venous thrombosis
  • can be associated w/ other autoimmune disease = make antiphospholioid Aby
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11
Q

How do you dx Lupus anticoagulant (LA) (4 test/Ix)

[pathological inhibitors]

A
  1. Prolong phospholipid-dependent coagulation test
  2. Dilute Russell Viper Venom Test (dRVVT)
  3. Phospholipid-neutralisation test (PNT)
  4. Partial thromboplastin time (PTT)
  5. Confirm w/ LA-sensitive reagent to demonstrate phospholipid dependence
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12
Q

Describe how warfarin works

[pharmacological inhibitors]

A
  • inhibit synthesis of functional Vit-K-dependent coag factors (II, VII, IX, X)
    (- bc Vit K = carbosylation of pCoag protein = fuctional Ca2+ binding sites = activated)
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13
Q

Describe how heparin works

[pharmacological inhibitors]

A
  • unfractionated heparin (UFH) & Low MW Heparin (LMWH)
  • binds to antithrombin = anticoag activity
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14
Q

How can you monitor heparin treatment (UFH & LMWH)

[pharmacological inhibitors]

A

UFH: aPTT (ratio range 1.5-2.5)
LMWH: snti-Xa more infarmative than aPTT but has limitations

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15
Q

Which pharmacological anticoagulant is used with Venous thromboembolism (important??)

A
  • first episode treated w/ warfarin along w/ parenteral anticoag (UFH or LMWH)
  • treat for >= 5d until INR is >=2.0 for 24+hrs
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16
Q

Describe how fondaparinux works

A
  • anti-Xa activity higher than LMWH
  • & longer halflife of LMWH
17
Q

Describe how FXa inhibitors works (direct oral anticoag: DOAC)

A
  • Rivaroxiban, Apixaban, …aban
  • inhibit thrombin generation
18
Q

Describe how Thrombin inhibitors works (direct oral anticoag: DOAC)

A
  • Dabigatran, …atran
  • inhibit thrombin action (thrombiun not bind to thrombin active site)
19
Q

The difference b/w these inhibitors:
a) Physiological
b) pathological
c) Pharmocaological

A

a) prevent intravascular thrombosis/coagulation
b) ineffective coagulation => haemorrhage
c) therapeutically manipulate haemostasis e.g. for medical procedures or VTE

20
Q

What happens if there’s a deficiency in Physiological inhibitors of 2dary haemostasis?

A

predispose Venous Thromboembolism

21
Q

Give some examples of Acquired antithrombin (AT) deficiency

A

dec production (liver cirrhosis); inc loss (nephrotic syndr.); enhanced consumption (DIC & prolonged UFHeparin)

22
Q

Once aquired AT deficiency have been ruled out, what test can you use to Dx AT deficiency?

A
  • Functional AT assay
  • Antigenic AT assay
    = allows differentiation b/w type I & Type II deficiency
23
Q

What’s the purpose of mixing studies (50:50 aPTT) i.e. the indication if corrected or not

A

Corrected: deficiency is present (& inhibitor is present e.g. heparin)
Not corrected: Lupus anti-coag. is present

24
Q

What’s the purpose of the Platelet Neutralising procedure (PNP) & the indication of results i.e. short/long time

A
  • uses lysed plt suspension (excess phospholipids = use up lupus Aby) = allow remaining plts to aggregate = shorter time
  • Shorter time (<3s than control) = LAC
  • Control: use saline = lupus Aby bind to plts = shorter time
25
Q

What’s the purpose of the diluted Russell Viper Venom Time (dRVVT) & the indication of results i.e. ratio of test/normal

A
  • direct FXa from RVV bypass intrinsic factors (FVIII, IX or XI deficiency not affect result)
  • LAC prolong time by clotting to phospholipid
  • N ratio: 0.9-1.05
  • If result is >1.05 = suggest presence of LAC but could also be due to abnormality in FII, V, X or fibrinogen or another inhibitor.

(4004) Haem (18 decks)

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