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

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 • 2

Case-based discussion: 1 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. 3

Case History 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. Q1 Q2 Q3 What is the most likely diagnosis? Factor V Leiden Protein C deficiency Antithrombin III deficiency Prothrombin 20210A Antiphospholipid syndrome app.bitemedicine.com 4

Explanations Q1 Q2 Q3 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 app.bitemedicine.com 5

Case-based discussion: 1 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. 6

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 • 7

Pathophysiology: Primary haemostasis 8

Pathophysiology: Secondary haemostasis 9

Pathophysiology: Inhibition of haemostasis Factor XI Factor V • • Factor X Factor VIII • • Thrombin • 10

Pathophysiology: Fibrinolysis Physiologically Pharmacologically Tissue plasminogen activator (tPA) Recombinant tPA (rtPA) • • Factor XII Alteplase, reteplase • • Urokinase Streptokinase • • Antithrombin • 11

Pathophysiology: Summary All the following occur simultaneously: Haemostasis • Inhibition of haemostasis • Fibrinolysis • In thrombophilia, there is a shift in the equilibrium toward haemostasis (clotting) 12

A 30-year-old man presents with a swollen left calf. Of note, he has had 2 previous DVTs and Case History 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. Q1 Q2 Q3 You have started the patient on dabigatran. Which of the following is true? There is no reversal agent Monitoring is not required Dabigatran inhibits factor X Dabigatran activates factor II Dabigatran is an antiplatelet 13 app.bitemedicine.com

Explanations Q1 Q2 Q3 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 Da BI gatran inhibits factor II (thrombin) Dabigatran activates factor II Da BI gatran inhibits factor II (thrombin) Dabigatran is an antiplatelet It is a DOAC which is a type of anticoagulant app.bitemedicine.com 14

Medications: Summary Antiplatelets Anticoagulants Fibrinolytics (Thrombolytics) Mechanism Prevent platelet aggregation Inhibit coagulation cascade Activate fibrinolytic (Primary haemostasis) (Secondary haemostasis) pathway Indications Primary prevention PE PE • • • DVT Acute Stroke • • ACS • Atrial fibrillation STEMI • • Stroke/TIA • Chronic limb ischaemia • Examples COX inhibitors Vitamin K antagonist rtPA Aspirin Warfarin Alteplase, reteplase • • • P2Y12 inhibitors Antithrombin III potentiator Streptokinase Clopidogrel Heparins and LMWH • • GpIIb/IIIa Direct oral anticoagulants Tirofiban Dabigatran, apixaban • • 15

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 • 16

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 17

Clinical features: Thrombophilia Thrombus Location VTE DVT • PE • Unusual sites e.g. upper limb • Arterial MI • Stroke • Acute mesenteric ischaemia • Acute limb ischaemia • (1) 18

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 • 19

Factor V Leiden Hereditary Pathophysiology Autosomal dominant Factor V Leiden • Mutated version of factor V • Lacks the cleavage site for protein C and S • Protein C or S deficiency Protein C and S normally inhibit the coagulation • cascade Prothrombin 20210A Epidemiology Most common hereditary thrombophilia • Antithrombin III deficiency Prevalence ~ 5-8% • Investigations Genetic test • Activated protein C resistance assay • 20

Factor V Leiden 21

Protein C or S deficiency Hereditary Pathophysiology Autosomal dominant Factor V Leiden • Protein C and S normally inhibit the coagulation cascade • (factor V and VIII) Protein C or S deficiency Overactivity of factors V and VIII • Prothrombin 20210A Epidemiology Rare • Prevalence ~ 1% or less • Antithrombin III deficiency Investigations Genetic test • Enzyme assays • 22

Protein C or S deficiency 23

Prothrombin 20210A Hereditary Pathophysiology Prothrombin is the precursor to thrombin Factor V Leiden • Thrombin cleaves fibrinogen to form fibrin • Point mutation (G20210A) leads to increased • Protein C or S deficiency prothrombin expression Prothrombin 20210A Epidemiology Prevalence ~ 1-5% • Antithrombin III deficiency Investigations Genetic test: screen for the point mutation • 24

Prothrombin 20210A 25

Antithrombin deficiency Hereditary Pathophysiology Autosomal dominant Factor V Leiden • Antithrombin III inhibits the coagulation cascade (e.g. • factor IX and X) Protein C or S deficiency Epidemiology Prothrombin 20210A Rare • Prevalence ~ 0.1% • Antithrombin III deficiency Investigations Enzyme assays • No change in APTT upon giving heparin/LMWH • 26

Antithrombin III deficiency Factor XI • Factor X • Thrombin • 27

A 30-year-old man presents with a swollen left calf. Of note, he has had 2 previous DVTs and Case History 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. Q1 Q2 Q3 Which of the following groups should be offered thrombophilia testing? 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 28 app.bitemedicine.com

Q1 Q2 Q3 Explanations Which of the following groups should be offered thrombophilia testing? 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 app.bitemedicine.com 29

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 • 30