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Cardiopulmonary Renal > Fibrinolysis And Hemostasis > Flashcards

Fibrinolysis And Hemostasis Flashcards

1
Q

What. are the key facts of the clotting cascade?

A
  • Conversion of fibrinogen to fibrin (4c) and stabilization of fibrin (6c) requires thrombin (IIa)
  • Thrombin formation requires factor Xa (Xa, Va, Ca2+, platelet phospholipids prothrombinase complex- 2c)

Xa generated by-

  • extrinsic pathway. (1e-3e)- through VII and III (activated on injury)
  • intrinsic pathway (1i-5i) - through XII, XI, IX and VIII
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2
Q

What are the laboratory tests fir the coagulation cascade?

A

Prothrombin time (INR)- extrinsic pathway

Activated partial thromboplastin Time (aPTT): intrinsic pathway

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3
Q

Summarize secondary hemostasis

A

Lab test: defects in clotting cascade

Extrinsic pathway defect: increased prothrombin time (INR)

Intrinsic pathway (aPTT) increased)

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4
Q

What is the role of platelet phospholipid (platelet plugs) in clotting?

A

Platelet activation exposes phospholipids on platelet surface

This leads to platelets facilitating secondary hemostasis (coagulation cascade); provide binding sites for clotting factors. Ensures clotting occurs only at site of injury (platelet plug)

Factor VIIIa, PL, Ca2+, IXa: activates factor X

Xa, Va, Ca2+, PL: prothrombinase complex converts prothrombin to thrombin

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5
Q

Explain the role of vitamin K and y-carboxylation

A
  • Vit k dependent factors: prothrombin (factor II), VII, IX, X, proteins C and S
  • y-carboxylation of glutamic acid residues of these residues of these proteins
  • Vit K (fat soluble vitamin) coenzyme for y-glutamyl carboxylase
  • Post-translational modification forms mature clotting factors that contain y-carboxyglutamate (Gla)—> released by liver and participate in clotting
  • Warfarin inhibits VKOR (vitamin K epoxides reductase): regenerates active form of vitamin K

Y-carboxyl action allows Ca2+ binding because of two adjacent negatively charged carboxylase groups

Clotting factor-Ca2+ complex binds to phospholipids on platelet membranes

INR (prothrombin time (PT): very sensitive indicator of vitamin K deficiency and for follow up of patients on warfarin therapy. Prolonged prothrombin time (INR)

Factor VII (extrinsic pathway) levels are most sensitive to vitamin K

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6
Q

What is the role of calcium in clotting?

A

Calcium ions (factor IV)

Calcium ions required for all steps that require vitamin K dependent clotting factors II, VII, IX and X

Calcium chekatirs (EDTA/ oxalate) added to blood in vitro to prevent clotting and maintain blood in fluid state(anticoagulant )—> after centrifugation, supernatant is PLASMA

Plasma: has all coagulation factors

Serum: supernatant formed after clotting (has no coagulation factors)

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7
Q

What is fibrinolysis?

A

Dissolution of the fibrin clot(tertiary clot)

Inactive plasminogen incorporated in the clot

Activated by tissue plasminogen activator + streptokinase/urokinase

This forms. Active plasmin(Proteolytic)

Antiplasmin inactivates pLasmin

PLasmin degrades fibrin to fibrin degradation products (FDP)

D-dimers

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8
Q

What is the significance of D dimer levels in deep vein thrombosis

A

D-dimer levels are elevated in patients with deep vein thrombosis. Estimate extent and rate of fibrinolysis

High elevated D-dimer levels indicate high risk of pulmonary embolism

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9
Q

Summarize control of hemostasis

A
  • endothelial cells are central regulators of hemostasis.
  • continuous blood flow prevents clotting
  • normal endothelia are anti-thrombotic
  • coagulation automatically initiates fibrinolysis
  • balance between anti-thrombic and prothrombotic factors
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10
Q

Explain the anti-coagulant factors

A
  1. Endothelial PGI2 and NO prevent platelet aggregation
    • PGI2 - increases platelet cAMP levels and inhibits platelet activation (Thromboxane antagonist)
  2. Antithrombin -III
    • Inactivates thrombin and factor Xa and prevents clotting
    • Heparin (glycosaminoglycans) activates antithrombin-III
  3. Protein C and S (vitamin k dependent)
  • binding of thrombomodulin to thrombin —> activates Protein C
  • activated. Protein C binds to protein S
  • protein C and S—> inactivate Va and VIIIa of coagulation cascade
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11
Q

Give the pharmacology of aspirin

A

Inhibits platelet Thromboxane (TXA2) formation

  • irreversible inhibitor if CIX
  • DEcreases YXA2: PGI2 ratio
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12
Q

Give the pharmacology of heparin

A

Activates antithrombin III and inactivates thrombin

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13
Q

Give the pharmacology of warfarin(oral anticoagulan)

A

Blocks vitamin K epoxides reductase (VKOR) in liver and prevents regeneration of active form of vitamin K
-inhibits synthesis of mature vitamin k dependent clotting factors

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14
Q

Give the pharmacology of steptokinase/urikinase

A

Thrombolytic agent; plasminogen activator;

Coactivator plasminogen to plasmin enabling dissolution of clots

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15
Q

Give the pharmacology of tissue plasminogen activator

A

Used to dissolve a thrombus

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16
Q

Describe bleeding time as a test for platelet function/aggregation

A

Time taken from initial injury to formation of platelet plug

  • Indicator of platelet plug formation (primary hemostasis)
  • not a reliable test
  • prolonged bleeding time is an indicator of
    • low platelet count OR
    • vWF deficiency OR
    • Platelet receptor defects
17
Q

Aside bleeding time, what other tests are used to assess platelet function / aggregation

A
  • platelet count
  • platelet aggregation/function tests measure platelet aggregation in presence of activators (ADP, thrombin, and ristocetin)
  • Ristocetin cofactors assay: von Willebrand disease. Reduced platelet aggregation in von Willebrand disease
  • flow cytometry: platelet glycoprotein defects
18
Q

What are the tests for coagulation disorders?

A
  • Prothrombin time (PT) or international normalized ratio (INR)
  • Activated partial thromboplastin time (APTT/ aPTT/PTT)
19
Q

What is the function of prothrombin (PT) or international normalized ratio (INR)?

A

Tissue factor, phospholipids, and calcium added to blood and time for formation of fibrin clot is measured

Tests extrinsic and common pathways

Measure defects in:
Tissue factor 
Factor VII
Factor V
Factor X
Prothrombin 
Fibrinogen
20
Q

What is the function of activated partial thromboplastin time (aPTT)?

A

Activate factor XII (glass beads) along with phospholipids and calcium, and time to form fibrin clot is measured

Tests intrinsic and common pathways

Measures defects in
Factor XI

Factor XII

Factor VIII

Factor IX

Factor V

Factor X

Prothrombin

Fibrinogen

21
Q

What are the effects of bleeding disorders?

A

Bleeding disorders (defects in primary or secondary hemostasis) present with increased bruising, increased bleeding following surgery, epitaxis (nose bleeds), hemostasis

22
Q

What are the disorders of clotting pathway (coagulation cascade)?

A
  • hemophilia A and B

- vitamin K deficiency (review in vit k)

23
Q

What are the defects in platelet plug formation ?

A

-Von Willebrand disease

  • Platelet defects
    • thrombocytopenia
    • Bernard- Soulier syndrome
    • Glanzmann thrombasthenia
24
Q

What are hemophilia A and B?

A

Inherited coagulation disirder- defect in intrinsic coagulation pathway

X-linked recessive inheritance (affects males and females are carriers)

Hemophilia A and B: similar presentation and difficult to distinguish clinically
-Individual factor assays to differentiate between them

25
Q

What are the clinical features of hemophilia A and B?

A

Common to both
-Easy bruising

  • Massive hemorrhage after trauma and surgical procedures
  • Spontaneous hemorrhages, particularly in joints-hemarthrosis
26
Q

Contrast hemophilia A and B

A

Hemophilia A-factor VIII

Hemophilia B- factor IX

27
Q

What are the tests for primary hemostasis?

A

Bleeding time: normal (platelet plug formation is normal)

Platelet count:normal

28
Q

What are the tests for secondary hemostasis ?

A
  • Prothrombin time (INR) Normal: normal (extrinsic and common coagulation pathway are normal)
  • APTT: Increased (defect in intrinsic pathway)
  • Individual factor assays: to determine type of hemophilia
  • Factor VIII levels are low in hemophilia A
  • Factor IX levels are low in hemophilia B
29
Q

What is von Willebrand disease?

A

Most common inherited bleeding disorder due to deficiency of vWF

-Defect in platelet plug formation

  • Also have instability of Factor VIII (may result in increased APTT)
    • remember: vWF binds to and stabilizes factor VIII in circulation
30
Q

What are the clinical features of hemophilia?

A
  • increased mucosal bleeding
  • easy bruising
  • epitaxis (bleeding from nose)
  • increased post-operative bleeding
  • prolonged bleeding following tooth extraction
31
Q

What are the lab findings of von Willebrand disease?

A

Tests for primary hemostasis:
-bleeding time- prolonged (defect in platelet plug formation)

-platelet count-normal

Ristocetin assay for platelet aggregation: abnormal

vWF levels- LOW

Tests for secondary hemostasis

APTT- prolonged (factir VIII levels may be low normal

PT (INR)- Normal (extrinsic pathway is normal )

32
Q

What is used to treat von Willebrand disease?

A

vWF

33
Q

What are the disorders of hemostasis due to platelet defects?

A
  • Increased bleeding time (defect in formation of platelet plug)
  • Platelet aggregation tests are abnormal
  • Platelet count is obtained
  • Thrombocytopenia: increased bleeding time and low platelet count
  • If platelet count is low normal (or within normal limits), flow cytometry to identify platelet receptor defects
    • GPIb defect (Bernard-Soulier syndrome)
    • GpIIb/IIIa defect (Glanzmann thrombasthenia)

Tests for secondary hemostasis:

  • APTT- normal
  • PT(INR) - normal
34
Q

Explain classifications of platelet disorders

A

Increased bleeding time can lead to quantitative defects or qualitative defects

Quantitative - low platelet count—> thrombocytopenia (low platelet count)

Qualitative defects- -> normal platelet count/ low normal

This leads to
a. GPllb defect: Bernard soulier syndrome

b. GpIIb/IIIa defect: Glanzmann thrombasthenia

Cardiopulmonary Renal (35 decks)

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