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: 60-70 mins • Slides and recordings: app.bitemedicine.com • 2
Case-based discussion: 1 History and examination A 6-year-old boy is brought to the GP by his mother. He has multiple pin-point haemorrhages and bruising. He had a nosebleed today which is unusual for him. His notes show he had an upper respiratory tract infection two weeks ago but is otherwise a well child. (1) 3
Case History A 6-year-old boy is brought to the GP by his mother. He has multiple pin-point haemorrhages and bruising. He had a nosebleed today which is unusual for him. His notes show he had an upper respiratory tract infection two weeks ago but is otherwise a well child. Q1 Q2 Q3 Which of the following is likely to be affected in this child? Platelets Factor VIII White blood cells Plasmin Thrombin app.bitemedicine.com 4
Explanations Q1 Q2 Q3 Which of the following is likely to be affected in this child? Platelets Petechiae and epistaxis are classical of thrombocytopaenia. The history suggests ITP Factor VIII Coagulation cascade pathology presents with deep tissue bleeding White blood cells This is a clotting problem Plasmin The history is classical of thrombocytopaenia Thrombin Coagulation cascade pathology presents with deep tissue bleeding app.bitemedicine.com 5
Case-based discussion: 1 History and examination A 6-year-old boy is brought to the GP by his mother. He has multiple pin-point haemorrhages and bruising. He had a nosebleed today which is unusual for him. His notes show he had an upper respiratory tract infection two weeks ago but is otherwise a well child. (1) 6
Introduction 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 Endothelial damage leads to exposure of subendothelial collagen • Von Willebrand factor (vWF) binds collagen • vWF is made by PLTs and endothelial cells • PLT binds vWF via the GpIb receptor • 8
Pathophysiology: Primary haemostasis Adhesion induces PLT degranulation • Release of a number of mediators which promote PLT aggregation • ADP: activates GpIIb/IIIa receptor • Thromboxane (TXA 2 ): enhances fibrinogen binding • 9
Pathophysiology: Primary haemostasis Mediators from degranulation promote aggregation • ADP: activates GpIIb/IIIa receptor • Thromboxane (TXA 2 ): enhances fibrinogen binding • PLTs aggregate via fibrinogen • Results in the formation of a platelet plug (weak) • Secondary haemostasis required for stabilisation • 10
Classification: Primary haemostasis Primary haemostasis disorders Platelet disorders • Quantitative: reduced PLT count • Qualitative: normal PLT count but impaired function • 11
Classification: Primary haemostasis Quantitative Qualitative Idiopathic thrombocytopaenic purpura Medications Thrombotic thrombocytopaenic purpura Bernard-Soulier disease Haemolytic uraemic syndrome Glanzmann disease Heparin-induced thrombocytopaenia 12
Clinical features: Primary haemostasis Symptoms Signs Early bleeding post trauma Petechiae (1-2mm) Epistaxis Purpura GI bleeding Ecchymoses Menorrhagia Bleeding from dental extraction sites Easy bruising 13
Clinical features: Primary haemostasis (1) (2) (3) 14
Investigations: Primary haemostasis Bedside Observations: ensure haemodynamic stability • Bloods FBC: anaemia and thrombocytopaenia • Blood film: assess number and size of PLTs • Bleeding time: evaluates the time taken to form the weak PLT plug • Further tests Imaging or endoscopy: visualise bleeding points • 15
A 6-year-old boy is brought to the GP by his mother. He has multiple pin-point haemorrhages and Case History bruising. He had a nosebleed today which is unusual for him. His notes show he had an upper respiratory tract infection two weeks ago but is otherwise a well child. Q1 Q2 Q3 You strongly suspect idiopathic thrombocytopaenic purpura. What is the underlying pathophysiology? Type 1 hypersensitivity Type 2 hypersensitivity Type 3 hypersensitivity Type 4 hypersensitivity Type 5 hypersensitivity 16 app.bitemedicine.com
Explanations Q1 Q2 Q3 You strongly suspect idiopathic thrombocytopaenic purpura. What is the underlying pathophysiology? Type 1 hypersensitivity IgE mediated allergic reaction Type 2 hypersensitivity IgG against PLT antigens is the underlying mechanism Type 3 hypersensitivity Antibody-antigen complexes e.g. SLE Type 4 hypersensitivity Delayed T-cell mediated response e.g. contact dermatitis Type 5 hypersensitivity Similar to type 2 hypersensitivity but specifically refers to cases where the antibody stimulates its target e.g. Graves’ disease app.bitemedicine.com 17
Idiopathic thrombocytopaenic purpura (ITP) Quantitative Pathophysiology Type II hypersensitivity reaction: IgG directed against Idiopathic thrombocytopaenic purpura • PLT antigens e.g. GpIIb/IIIa causing splenic consumption Thrombotic thrombocytopaenic purpura Clinical presentation Acute ITP: most common cause of thrombocytopaenia in • children Haemolytic uraemic syndrome Post-viral infection or immunisation • Self-limiting • Heparin-induced thrombocytopaenia Chronic ITP: seen in women of childbearing age • Relapsing-remitting course • Management Corticosteroids • IVIG • Splenectomy • 18
Thrombotic thrombocytopaenic purpura (TTP) Quantitative Pathophysiology Reduced ADAMTS13 which is normally responsible for Idiopathic thrombocytopaenic purpura • degradation of vWF Thrombotic thrombocytopaenic purpura Haemolytic uraemic syndrome Heparin-induced thrombocytopaenia 19
Thrombotic thrombocytopaenic purpura (TTP) Pathophysiology Reduced ADAMTS13 which is normally responsible for • degradation of vWF Acquired (or genetic) deficiency • Multiple platelet thrombi → thrombocytopaenia • Clinical presentation Most commonly seen in females • Pentad: fever, thrombocytopaenia, microangiopathic • haemolytic anaemia, renal failure, CNS deficits Management (4) Plasma exchange • Corticosteroids • Immunosuppression • Splenectomy • 20
Haemolytic uraemic syndrome (HUS) Quantitative Pathophysiology Endothelial damage by drugs or infection Idiopathic thrombocytopaenic purpura • E.coli O157:H7 releases shiga-like toxin → platelet • activation and endothelial damage → multiple platelet Thrombotic thrombocytopaenic purpura thrombi → thrombocytopaenia Undercooked red meat • Haemolytic uraemic syndrome Heparin-induced thrombocytopaenia 21
Case History A 6-year-old boy is brought to the GP by his mother. He has multiple pin-point haemorrhages and bruising. He had a nosebleed today which is unusual for him. His notes show he had an upper respiratory tract infection two weeks ago but is otherwise a well child. Q1 Q2 Q3 You see a different 6-year-old and suspect haemolytic uraemic syndrome. Which of the following should be avoided? IV fluids Oral fluids Antiemetics Antibiotics Blood transfusion 22 app.bitemedicine.com
Q1 Q2 Q3 Explanations You see a different 6-year-old and suspect haemolytic uraemic syndrome. Which of the following should be avoided? IV fluids Rehydration us essential Oral fluids Can be given provided the patient is able to tolerate oral intake Antiemetics Useful in preventing vomiting Antibiotics Can trigger release of further toxin from E.coli Blood transfusion May be required due to microangiopathic haemolytic anaemia app.bitemedicine.com 23
Haemolytic uraemic syndrome (HUS) Pathophysiology Endothelial damage by drugs or infection • E.coli O157:H7 releases shiga-like toxin → platelet activation and endothelial damage → • multiple platelet thrombi → thrombocytopaenia Undercooked red meat • Clinical presentation Most common cause of acute renal failure in children • Features of gastroenteritis • Triad: AKI, microangiopathic haemolytic anaemia, thrombocytopaenia • Management Avoid antibiotics: can exacerbate thrombi formation • Supportive management: fluids, electrolytes, transfusion • Plasma exchange • 24
Heparin-induced thrombocytopaenia (HIT) Quantitative Pathophysiology Heparin binds to PF4 on PLTs Idiopathic thrombocytopaenic purpura • IgG binds the complex and causes PLT destruction • Antibody-heparin-PF4 complexes can also damage • Thrombotic thrombocytopaenic purpura endothelial cells causing thrombi formation Haemolytic uraemic syndrome Clinical presentation Occurs 1-2 weeks after starting therapy • Thrombocytopaenia and/or thrombosis • Heparin-induced thrombocytopaenia HIT antibody screen required for diagnosis • Management Stop heparin and switch to an alternative anticoagulant • 25
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