Aims and objectives Cover the following: Clotting process: PLT - - PowerPoint PPT Presentation

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Aims and objectives Cover the following: Clotting process: PLT - - PowerPoint PPT Presentation

Aug 24, 2023 310 likes •758 views

Aims and objectives Cover the following: Clotting process: PLT and coagulation cascade Bleeding disorders Fibrinolysis Thrombophilia and hypercoagulability High-yield facts that are relevant for exams Duration: 60

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Aims and objectives

  • Cover the following:
  • Clotting process: PLT and coagulation cascade
  • Bleeding disorders
  • Fibrinolysis
  • Thrombophilia and hypercoagulability
  • High-yield facts that are relevant for exams
  • Duration: 60 mins
  • Slides and recordings: app.bitemedicine.com
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History and examination

A 30-year-old man presents with a swollen left calf. Of note, he has had 2 previous DVTs and reports he has a family history of a clotting disorder. He is a smoker but otherwise reports he is fit and well. An ultrasound confirms a DVT and you start him on dabigatran.

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Case-based discussion: 1

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A 30-year-old man presents with a swollen left calf. Of note, he has had 2 previous DVTs and reports he has a family history of a clotting disorder. He is a smoker but otherwise reports he is fit and well. An ultrasound confirms a DVT and you start him on dabigatran. What is the most likely diagnosis?

Case History

Factor V Leiden Protein C deficiency Antithrombin III deficiency Prothrombin 20210A Antiphospholipid syndrome app.bitemedicine.com

Q1 Q2 Q3

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Explanations

app.bitemedicine.com What is the most likely diagnosis? Factor V Leiden The most common hereditary thrombophilia Protein C deficiency Rare hereditary thrombophilia Antithrombin III deficiency Rare hereditary thrombophilia Prothrombin 20210A Not as common as factor V Leiden Antiphospholipid syndrome An acquired cause of thrombophilia

Q1 Q2 Q3

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History and examination

A 30-year-old man presents with a swollen left calf. Of note, he has had 2 previous DVTs and reports he has a family history of a clotting disorder. He is a smoker but otherwise reports he is fit and well. An ultrasound confirms a DVT and you start him on dabigatran.

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Case-based discussion: 1

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Haemostasis recap

Haemostasis

  • Damage to the blood vessel wall is repaired by thrombus formation
  • Occurs in two stages
  • Primary haemostasis: weak platelet plug
  • Secondary haemostasis: stabilisation of the platelet plug and involves the coagulation cascade
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Pathophysiology: Primary haemostasis

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Pathophysiology: Secondary haemostasis

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Pathophysiology: Inhibition of haemostasis

  • Factor V
  • Factor VIII
  • Factor XI
  • Factor X
  • Thrombin
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Pathophysiology: Fibrinolysis

Physiologically

  • Tissue plasminogen activator (tPA)
  • Factor XII
  • Urokinase
  • Antithrombin

Pharmacologically

  • Recombinant tPA (rtPA)
  • Alteplase, reteplase
  • Streptokinase
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Pathophysiology: Summary

All the following occur simultaneously:

  • Haemostasis
  • Inhibition of haemostasis
  • Fibrinolysis

In thrombophilia, there is a shift in the equilibrium toward haemostasis (clotting)

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You have started the patient on dabigatran. Which of the following is true?

Case History

There is no reversal agent Monitoring is not required Dabigatran inhibits factor X Dabigatran activates factor II Dabigatran is an antiplatelet app.bitemedicine.com

Q2 Q1

A 30-year-old man presents with a swollen left calf. Of note, he has had 2 previous DVTs and reports he has a family history of a clotting disorder. He is a smoker but otherwise reports he is fit and well. An ultrasound confirms a DVT and you start him on dabigatran.

Q3

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Explanations

app.bitemedicine.com You have started the patient on dabigatran. Which of the following is true? There is no reversal agent Idarucizumab can reverse the effects of dabigatran Monitoring is not required DOACs do not require monitoring unlike warfarin (INR) Dabigatran inhibits factor X DaBIgatran inhibits factor II (thrombin) Dabigatran activates factor II DaBIgatran inhibits factor II (thrombin) Dabigatran is an antiplatelet It is a DOAC which is a type of anticoagulant

Q2 Q1 Q3

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Medications: Summary

Antiplatelets Anticoagulants Fibrinolytics (Thrombolytics) Mechanism Prevent platelet aggregation (Primary haemostasis) Inhibit coagulation cascade (Secondary haemostasis) Activate fibrinolytic pathway Indications

  • Primary prevention
  • ACS
  • Stroke/TIA
  • Chronic limb ischaemia
  • PE
  • DVT
  • Atrial fibrillation
  • PE
  • Acute Stroke
  • STEMI

Examples COX inhibitors

  • Aspirin

P2Y12 inhibitors

  • Clopidogrel

GpIIb/IIIa

  • Tirofiban

Vitamin K antagonist

  • Warfarin

Antithrombin III potentiator

  • Heparins and LMWH

Direct oral anticoagulants

  • Dabigatran, apixaban

rtPA

  • Alteplase, reteplase

Streptokinase

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Introduction: Thrombophilia

Definition

  • Also known as a hypercoagulable state
  • Propensity to develop thrombi due to an abnormality in the coagulation pathways
  • Divided into hereditary and acquired causes

Epidemiology

  • Inherited thrombophilia affects ~ 10% of the population
  • Up to 50% of white people with a VTE will have an inherited thrombophilia
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Classification: Thrombophilia

Hereditary Acquired Factor V Leiden Medications Protein C or S deficiency Malignancy Prothrombin 20210A Smoking Antithrombin III deficiency Obesity Antiphospholipid syndrome Nephrotic syndrome

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Clinical features: Thrombophilia

Thrombus Location VTE

  • DVT
  • PE
  • Unusual sites e.g. upper limb

Arterial

  • MI
  • Stroke
  • Acute mesenteric ischaemia
  • Acute limb ischaemia

(1)

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Investigations: General principles

Bedside

  • Observations

Bloods

  • FBC: thrombocytopaenia e.g. HIT
  • Clotting screen: deranged e.g. antiphospholipid syndrome
  • D-dimer: raised if forming thrombi
  • Thrombophilia screen: screen for hereditary conditions
  • Autoantibodies: e.g. APLS
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Factor V Leiden

Pathophysiology

  • Autosomal dominant
  • Mutated version of factor V
  • Lacks the cleavage site for protein C and S
  • Protein C and S normally inhibit the coagulation

cascade

Epidemiology

  • Most common hereditary thrombophilia
  • Prevalence ~ 5-8%

Investigations

  • Genetic test
  • Activated protein C resistance assay

Hereditary Factor V Leiden Protein C or S deficiency Prothrombin 20210A Antithrombin III deficiency

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Factor V Leiden

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Protein C or S deficiency

Pathophysiology

  • Autosomal dominant
  • Protein C and S normally inhibit the coagulation cascade

(factor V and VIII)

  • Overactivity of factors V and VIII

Epidemiology

  • Rare
  • Prevalence ~ 1% or less

Investigations

  • Genetic test
  • Enzyme assays

Hereditary Factor V Leiden Protein C or S deficiency Prothrombin 20210A Antithrombin III deficiency

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Protein C or S deficiency

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Prothrombin 20210A

Pathophysiology

  • Prothrombin is the precursor to thrombin
  • Thrombin cleaves fibrinogen to form fibrin
  • Point mutation (G20210A) leads to increased

prothrombin expression

Epidemiology

  • Prevalence ~ 1-5%

Investigations

  • Genetic test: screen for the point mutation

Hereditary Factor V Leiden Protein C or S deficiency Prothrombin 20210A Antithrombin III deficiency

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Prothrombin 20210A

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Antithrombin deficiency

Pathophysiology

  • Autosomal dominant
  • Antithrombin III inhibits the coagulation cascade (e.g.

factor IX and X)

Epidemiology

  • Rare
  • Prevalence ~ 0.1%

Investigations

  • Enzyme assays
  • No change in APTT upon giving heparin/LMWH

Hereditary Factor V Leiden Protein C or S deficiency Prothrombin 20210A Antithrombin III deficiency

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Antithrombin III deficiency

  • Factor XI
  • Factor X
  • Thrombin
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Which of the following groups should be offered thrombophilia testing?

Case History

All patients with a DVT All patients with a positive family history of thrombophilia All patients with a positive family history of DVT All patients who are on lifelong anticoagulation None of the above app.bitemedicine.com

Q2 Q1 Q3

A 30-year-old man presents with a swollen left calf. Of note, he has had 2 previous DVTs and reports he has a family history of a clotting disorder. He is a smoker but otherwise reports he is fit and well. An ultrasound confirms a DVT and you start him on dabigatran.

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Explanations

app.bitemedicine.com All patients with a DVT Not routinely offered All patients with a positive family history of thrombophilia Offered if there is an unprovoked PE/DVT AND a first-degree relative who has had PE/DVT AND there is a plan to stop anticoagulation All patients with a positive family history of DVT Offered if there is an unprovoked PE/DVT AND a first-degree relative who has had PE/DVT AND there is a plan to stop anticoagulation All patients who are on lifelong anticoagulation Thrombophilia testing may not necessarily change management in these patients None of the above Correct

Q2 Q1 Q3

Which of the following groups should be offered thrombophilia testing?

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Investigation & Management: Hereditary thrombophilia

When to test patients?

  • Not typically tested for, even if patients have a positive family history

NICE guidance

  • Hereditary thrombophilia screen: unprovoked PE/DVT AND a first-degree relative who has

had PE/DVT AND there is a plan to stop anticoagulation

Management:

  • Anticoagulation: treatment commenced if patients develop a thrombus
  • Duration of treatment is a complex decision made by a haematologist
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Which of the following is associated with antiphospholipid syndrome ?

Rapid fire questions

Beta2 microglobulin Heterophile antibodies Anti beta2-glycoprotein I Anti-GpIIb/IIIa Reduced APTT app.bitemedicine.com

Q1 Q2 Q3

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Explanations

app.bitemedicine.com Which of the following is associated with antiphospholipid syndrome ? Beta2 microglobulin Associated with myeloma Heterophile antibodies Seen in infectious mononucleosis Anti beta2-glycoprotein I Lupus anticoagulant, anti-cardiolipin and anti-beta2-glycoprotein I are seen in APLS Anti-GpIIb/IIIa Seen in idiopathic thrombocytopaenic purpura Reduced APTT Paradoxically the APTT is increased due to lupus anticoagulant

Q1 Q2 Q3

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Which of the following describes how nephrotic syndrome leads to a hypercoagulable state?

Rapid fire questions

Increased protein C Inactivation of plasmin Reduced antithrombin III Increased protein S None of the above app.bitemedicine.com

Q2 Q1 Q3

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Explanations

app.bitemedicine.com Which of the following describes how nephrotic syndrome leads to a hypercoagulable state? Increased protein C There is reduced protein C and S Inactivation of plasmin Incorrect Reduced antithrombin III Loss of ATIII in the urine Increased protein S There is reduced protein C and S None of the above Incorrect

Q2 Q1 Q3

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Which of the following is NOT vitamin K-dependent?

Rapid fire questions

Protein C Protein S Factor X Factor IX Factor V app.bitemedicine.com

Q2 Q1 Q3

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Explanations

app.bitemedicine.com Which of the following is NOT vitamin K-dependent? Protein C 1972 CS: X, IX, VII, II, C and S are all vitamin K-dependent Protein S 1972 CS Factor X 1972 CS Factor IX 1972 CS Factor V Not vitamin K-dependent

Q2 Q1 Q3

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Acquired thrombophilia

Acquired Mechanism Medications

  • COCP and HRT → increased coagulation factors and reduced protein S
  • Tranexamic acid → inhibition of plasminogen activation

Malignancy

  • Release of procoagulant factors e.g. tissue factor

Smoking

  • Endothelial damage

Obesity

  • Increased coagulation factors and inhibition of fibrinolysis

Antiphospholipid syndrome • Acquired antibodies which lead to coagulation cascade activation

  • Associated with SLE
  • Lupus anticoagulant
  • Anti-cardiolipin
  • Beta2-glycoprotein I

Nephrotic syndrome

  • Urinary loss of antithrombin III
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Top-decile question

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Explanations

app.bitemedicine.com A woman has antiphospholipid syndrome. Which of the following may she be at risk

  • f?

Teratoma Not associated Fibroma Not associated Choriocarcinoma Recurrent spontaneous abortions is a risk factor Dysgerminoma Not associated Seminoma Seen in males

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Recap

  • Haemostasis, inhibition of haemostasis and fibrinolysis all occur simultaneously
  • The balance of these processes determines whether there will be a propensity to bleed or clot
  • The most common hereditary thrombophilia is factor V Leiden
  • There are multiple causes of acquired thrombophilia
  • Investigating and managing thrombophilia is complex
  • Next session: end of topic top-decile quiz
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References

1. James Heilman, MD / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0) All other images were made by BiteMedicine and not suitable for redistribution.

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