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

▶
aims and objectives
SMART_READER_LITE
LIVE PREVIEW

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

Aug 29, 2022 149 likes •741 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:

slide-1
SLIDE 1
slide-2
SLIDE 2

2

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
slide-3
SLIDE 3

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.

3

Case-based discussion: 1

(1)

slide-4
SLIDE 4

4

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. Which of the following is likely to be affected in this child?

Case History

Platelets Factor VIII White blood cells Plasmin Thrombin app.bitemedicine.com

Q1 Q2 Q3

slide-5
SLIDE 5

5

Explanations

app.bitemedicine.com 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

Q1 Q2 Q3

slide-6
SLIDE 6

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.

6

Case-based discussion: 1

(1)

slide-7
SLIDE 7

7

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
slide-8
SLIDE 8

8

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
slide-9
SLIDE 9

9

Pathophysiology: Primary haemostasis

  • Adhesion induces PLT degranulation
  • Release of a number of mediators which promote PLT aggregation
  • ADP: activates GpIIb/IIIa receptor
  • Thromboxane (TXA2): enhances fibrinogen binding
slide-10
SLIDE 10

10

Pathophysiology: Primary haemostasis

  • Mediators from degranulation promote aggregation
  • ADP: activates GpIIb/IIIa receptor
  • Thromboxane (TXA2): enhances fibrinogen binding
  • PLTs aggregate via fibrinogen
  • Results in the formation of a platelet plug (weak)
  • Secondary haemostasis required for stabilisation
slide-11
SLIDE 11

11

Classification: Primary haemostasis

Primary haemostasis disorders

  • Platelet disorders
  • Quantitative: reduced PLT count
  • Qualitative: normal PLT count but impaired function
slide-12
SLIDE 12

12

Classification: Primary haemostasis

Quantitative Qualitative Idiopathic thrombocytopaenic purpura Medications Thrombotic thrombocytopaenic purpura Bernard-Soulier disease Haemolytic uraemic syndrome Glanzmann disease Heparin-induced thrombocytopaenia

slide-13
SLIDE 13

13

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

slide-14
SLIDE 14

14

Clinical features: Primary haemostasis

(1) (2) (3)

slide-15
SLIDE 15

15

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
slide-16
SLIDE 16

16

You strongly suspect idiopathic thrombocytopaenic purpura. What is the underlying pathophysiology?

Case History

Type 1 hypersensitivity Type 2 hypersensitivity Type 3 hypersensitivity Type 4 hypersensitivity Type 5 hypersensitivity app.bitemedicine.com

Q2 Q1

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.

Q3

slide-17
SLIDE 17

17

Explanations

app.bitemedicine.com 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

Q2 Q1 Q3

slide-18
SLIDE 18

18

Idiopathic thrombocytopaenic purpura (ITP)

Pathophysiology

  • Type II hypersensitivity reaction: IgG directed against

PLT antigens e.g. GpIIb/IIIa causing splenic consumption

Clinical presentation

  • Acute ITP: most common cause of thrombocytopaenia in

children

  • Post-viral infection or immunisation
  • Self-limiting
  • Chronic ITP: seen in women of childbearing age
  • Relapsing-remitting course

Management

  • Corticosteroids
  • IVIG
  • Splenectomy

Quantitative Idiopathic thrombocytopaenic purpura Thrombotic thrombocytopaenic purpura Haemolytic uraemic syndrome Heparin-induced thrombocytopaenia

slide-19
SLIDE 19

19

Thrombotic thrombocytopaenic purpura (TTP)

Pathophysiology

  • Reduced ADAMTS13 which is normally responsible for

degradation of vWF Quantitative Idiopathic thrombocytopaenic purpura Thrombotic thrombocytopaenic purpura Haemolytic uraemic syndrome Heparin-induced thrombocytopaenia

slide-20
SLIDE 20

20

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

  • Plasma exchange
  • Corticosteroids
  • Immunosuppression
  • Splenectomy

(4)

slide-21
SLIDE 21

21

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

Quantitative Idiopathic thrombocytopaenic purpura Thrombotic thrombocytopaenic purpura Haemolytic uraemic syndrome Heparin-induced thrombocytopaenia

slide-22
SLIDE 22

22

You see a different 6-year-old and suspect haemolytic uraemic syndrome. Which of the following should be avoided?

Case History

IV fluids Oral fluids Antiemetics Antibiotics Blood transfusion app.bitemedicine.com

Q2 Q1 Q3

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.

slide-23
SLIDE 23

23

Explanations

app.bitemedicine.com 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

Q2 Q1 Q3

You see a different 6-year-old and suspect haemolytic uraemic syndrome. Which of the following should be avoided?

slide-24
SLIDE 24

24

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
slide-25
SLIDE 25

25

Heparin-induced thrombocytopaenia (HIT)

Pathophysiology

  • Heparin binds to PF4 on PLTs
  • IgG binds the complex and causes PLT destruction
  • Antibody-heparin-PF4 complexes can also damage

endothelial cells causing thrombi formation

Clinical presentation

  • Occurs 1-2 weeks after starting therapy
  • Thrombocytopaenia and/or thrombosis
  • HIT antibody screen required for diagnosis

Management

  • Stop heparin and switch to an alternative anticoagulant

Quantitative Idiopathic thrombocytopaenic purpura Thrombotic thrombocytopaenic purpura Haemolytic uraemic syndrome Heparin-induced thrombocytopaenia

slide-26
SLIDE 26

26

Medications

Qualitative Medications Bernard-Soulier disease Glanzmann disease

  • Mediators from degranulation promote aggregation
  • ADP: activates GpIIb/IIIa receptor
  • Thromboxane (TXA2): enhances fibrinogen binding
  • PLTs aggregate via fibrinogen
  • Results in the formation of a platelet plug (weak)
  • Secondary haemostasis required for stabilisation
slide-27
SLIDE 27

27

Medications

Antiplatelet drugs

  • COX inhibitors inhibit TXA2 formation
  • Aspirin
  • P2Y12 inhibitors prevent ADP from activating the GpIIb/IIIa receptor
  • Clopidogrel, ticagrelor, prasugrel
  • GpIIb/IIIa inhibitors prevent binding to fibrinogen
  • Tirofiban, abciximab, eptifibatide
slide-28
SLIDE 28

28

Bernard-Soulier disease

Qualitative Medications Bernard-Soulier disease Glanzmann disease

  • Genetic deficiency of GpIb
slide-29
SLIDE 29

29

Glanzmann disease

Qualitative Medications Bernard-Soulier disease Glanzmann disease

  • Genetic deficiency of GpIIb/IIIa
slide-30
SLIDE 30

History and examination

A 25-year-old lady presents with recurrent epistaxis. She has a background of menorrhagia which is poorly controlled and says her mother suffered from the same issue.

Observations

HR 91, BP 110/78, RR 18, SpO2 98%, Temp 37

30

Case-based discussion: 2

slide-31
SLIDE 31

31

A 25-year-old lady presents with recurrent epistaxis. She has a background of menorrhagia which is poorly controlled and says her mother suffered from the same issue. Observations HR 91, BP 110/78, RR 18, SpO2 98%, Temp 37 Which of the following is the most common hereditary bleeding disorder that this patient likely has?

Case History

Haemophilia A Haemophilia B Von Willebrand disease Idiopathic thrombocytopaenic purpura Clotting inhibitor app.bitemedicine.com

Q1 Q2

slide-32
SLIDE 32

32

Explanations

app.bitemedicine.com Which of the following is the most common hereditary bleeding disorder that this patient likely has? Haemophilia A Typically seen in males and not the most common Haemophilia B Rare Von Willebrand disease The most common hereditary bleeding disorder Idiopathic thrombocytopaenic purpura Not the most common and would expect petechiae/purpura Clotting inhibitor This is an acquired disease

Q1 Q2

slide-33
SLIDE 33

33

Pathophysiology: Secondary haemostasis

  • Secondary haemostasis (coagulation cascade) converts fibrinogen to fibrin and stabilises the platelet

plug

  • Occurs on the PLT phospholipid membrane and requires calcium
  • Intrinsic pathway
  • Subendothelial collagen
  • High-molecular-weight kininogen
  • Extrinsic pathway
  • Tissue factor
slide-34
SLIDE 34

34

Pathophysiology: Secondary haemostasis

slide-35
SLIDE 35

35

Pathophysiology: Secondary haemostasis

Weak Strong

slide-36
SLIDE 36

36

Classification: Secondary haemostasis

Secondary haemostasis disorders

  • Coagulation cascade disorders
  • Acquired or hereditary factor deficiencies
slide-37
SLIDE 37

37

Classification: Secondary haemostasis

Genetic Acquired Haemophilia Medications Von Willebrand disease Coagulation factor inhibitor Disseminated intravascular coagulation Liver failure

slide-38
SLIDE 38

38

Clinical features: Secondary haemostasis

Symptoms Signs Late bleeding post trauma Deep tissue bleeding

  • Haemarthroses
  • Haematomas
  • Retroperitoneal haemorrhage

Epistaxis Post-surgical bleeding GI bleeding Ecchymoses Menorrhagia Bleeding from dental extraction sites Easy bruising

slide-39
SLIDE 39

39

Investigations: Secondary haemostasis

Bedside

  • Observations: ensure haemodynamic stability

Bloods

  • FBC: anaemia
  • Coagulation screen
  • Prothrombin time: extrinsic system
  • INR standardises PT
  • Activated partial thromboplastin time: intrinsic system

Further tests

  • Imaging or endoscopy: visualise bleeding points
slide-40
SLIDE 40

40

Haemophilia A

Genetic Haemophilia Von Willebrand disease

Pathophysiology

  • X-linked recessive factor VIII deficiency
slide-41
SLIDE 41

41

Haemophilia A

Pathophysiology

  • X-linked recessive factor VIII deficiency
  • (Note, haemophilia B refers to factor XI deficiency)

Clinical presentation

  • Typically seen in males and can present at a young age
  • Deep tissue and post-surgical bleeding
  • APTT prolonged
  • Reduced factor VIII levels

Management

  • Factor VIII concentrate
  • Desmopressin
slide-42
SLIDE 42

42

You strongly suspect Von Willebrand disease. Which of the following would you most expect?

Case History

Increased PT Reduced PT Increased APTT Reduced APTT None of the above app.bitemedicine.com

Q2 Q1

A 25-year-old lady presents with recurrent epistaxis. She has a background of menorrhagia which is poorly controlled and says her mother suffered from the same issue. Observations HR 91, BP 110/78, RR 18, SpO2 98%, Temp 37

slide-43
SLIDE 43

43

Explanations

app.bitemedicine.com You strongly suspect Von Willebrand disease. Which of the following would you most expect? Increased PT PT affected in extrinsic pathway disease Reduced PT Factor VIII affected therefore APTT increased Increased APTT Factor VIII affected therefore intrinsic pathway impaired Reduced APTT APTT should be prolonged None of the above Incorrect

Q2 Q1

slide-44
SLIDE 44

44

Von Willebrand disease

Genetic Haemophilia Von Willebrand disease

Pathophysiology

  • Autosomal dominant condition
  • Multiple different types
  • Type 1 (80%): reduced vWF
  • Type 2 (20%): qualitative defect
  • Type 3 (~1%): complete absence of vWF (autosomal recessive)
slide-45
SLIDE 45

45

Von Willebrand disease

Pathophysiology

  • Autosomal dominant condition
  • Multiple different types
  • vWF stabilises factor VIII → deficiency results in reduced VIII half-life

Clinical presentation

  • Most common hereditary coagulation disorder
  • Increased bleeding time
  • APTT prolonged
  • Reduced factor VIII levels
  • Ristocetin assay: failure of agglutination

Management

  • Desmopressin
  • Factor VIII concentrate
  • vWF concentrate
slide-46
SLIDE 46

46

Medications

Acquired Medications Coagulation factor inhibitor Disseminated intravascular coagulation Liver failure

Anticoagulants

  • Warfarin
  • Heparin
  • Direct oral anticoagulant (DOAC)
slide-47
SLIDE 47

47

Medications: warfarin

Mechanism of action

  • Vitamin K antagonist: warfarin blocks vit K activation
  • Vitamin K dependent factors: 1972 CS
  • Factors 10, 9, 7, 2 (prothrombin)
  • Protein C and S

Monitoring

  • INR (standardised prothrombin time)
slide-48
SLIDE 48

48

Medications: Heparin

Mechanism of action

  • Antithrombin III activator
  • Inhibits thrombin as well as clotting factors
  • Heparin (IV) has a short half-life
  • LMWH (subcutaneous) and has a longer half-life

Monitoring

  • APTT used to monitor IV heparin
  • LMWH does not usually need monitoring
  • Occasionally, anti-factor Xa used to monitor LMWH
slide-49
SLIDE 49

49

Medications: DOAC

Mechanism of action

  • Thrombin inhibitor: dabigatran
  • Factor Xa inhibitors: apiXaban, rivaroXaban, edoXaban

Monitoring

  • No monitoring required
  • Difficult to reverse
slide-50
SLIDE 50

50

Coagulation factor inhibitor

Acquired Medications Coagulation factor inhibitor Disseminated intravascular coagulation Liver failure

Pathophysiology

  • Acquired antibodies to coagulation factors
  • Anti-VIII is most common
  • Occurs in haemophiliacs receiving factor VIII

Clinical presentation

  • APTT/PT deranged depending on the affected factor
  • Mixing studies
  • Mix normal plasma with patient’s plasma
  • No correction of PT/APTT suggests antibodies present
  • Correction of PT/APTT suggests decreased production
slide-51
SLIDE 51

51

Top-decile question

slide-52
SLIDE 52

52

Explanations

app.bitemedicine.com Which of the following enzymes does warfarin inhibit? Gamma carboxylase Not responsible Glucose-6-phosphate dehydrogenase Reduced in G6PD deficiency Epoxide reductase This enzyme is responsible for activating vitamin K. Activated vitamin K gamma carboxylates the vitamin K dependent clotting factors Plasmin Warfarin acts on the coagulation cascade Vitamin K oxidase Fictitious

slide-53
SLIDE 53

53

Recap

  • Primary haemostasis: weak PLT plug
  • Secondary haemostasis: stabilisation of plug
  • Next session: fibrinolytic pathway and hypercoagulability

Platelet Coagulation cascade Bleeding

  • Superficial
  • Early
  • Deep
  • Late

Petechiae Yes No Purpura/ecchymoses Yes Yes Haemarthroses No Yes Epistaxis, menorrhagia, GI bleeding, easy bruising Yes Yes

slide-54
SLIDE 54
slide-55
SLIDE 55
slide-56
SLIDE 56

56

References

1. User:Hektor / CC BY-SA (http://creativecommons.org/licenses/by-sa/3.0/) 2. James Heilman, MD / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0) 3. Ribelle2289 / CC0 4. Central Hematology Laboratory Hemostasis Research Laboratory Bern University Hospital & University of Bern / CC BY-SA (https://creativecommons.org/licenses/by-sa/4.0) All other images were made by BiteMedicine and not suitable for redistribution.

slide-57
SLIDE 57

57

Further information

Stay up-to-date!

  • Website: www.bitemedicine.com
  • Facebook: ‘BiteMedicine for Students’ for all our updates
  • Instagram: @bitemedicine
  • Email: admin@bitemedicine.com

Feedback form: please provide your feedback on how we can improve our webinar integration system