S5) Haemostasis

Question 1

What are the principles of haemostasis?

Answer 1

• Prevent bleeding
• Prevent unnecessary coagulation (allow blood to flow)
• Make clot
• Control clotting
• Break it down

Question 2

What are the essentials for haemostasis?

Answer 2

• Pump: heart, venous valves, calf pump
• Blood vessels are important
• Platelets
• Coagulation factors
• Anticoagulant factors

Question 3

What are platelets?

Answer 3

Platelets are components of blood produced by megakaryocytes in the bone marrow and bud from cytoplasm

Question 4

In three steps, outline platelet adhesion

Answer 4

⇒ Damage to the vessel wall

⇒ Exposure of underlying tissues

⇒ Platelets adhere to collagen via vWF/receptor

Question 5

In 3 steps, outline platelet activation

Answer 5

⇒ Platelets secrete ADP, thromboxane, etc to become activated and activate other platelets

⇒ Involved in activation of the clotting cascade

⇒ Provide some coagulation factors by secretion from internal stores

Question 6

What does platelet aggregation involve?

Answer 6

Platelet aggregation involves the cross linking of platelets to form a platelet plug

Question 7

Identify 6 mediating factors in haemostasis

Answer 7

• Von willebrand factor
• Fibrinogen
• Collagen
• ADP
• Thromboxane
• Thrombin

Question 8

What is the clotting cascade?

Answer 8

• The clotting cascade is a controlled amplification system involving the activation of precursor proteins to generate thrombin (IIa)
• Thrombin converts soluble fibrinogen into insoluble fibrin
• Fibrin enmeshes the initial platelet plug to make stable clot

Question 9

Describe the control of the clotting cascade

Answer 9

• Natural anticoagulants inhibit activation
• Clot destroying proteins are activated by the clotting cascade

Question 10

Identify some coagulation factors

Answer 10

• Fibrinogen
• Prothrombin
• Factor V, VII - XIII
• Tissue factor

Question 11

Identify some natural anticoagulants

Answer 11

• Protein C
• Protein S
• Antithrombin
• Tissue factor pathway inhibitor

Question 12

Describe the process of initiation in the clotting cascade?

Answer 12

Question 13

Describe the process of amplification in the clotting cascade?

Answer 13

Question 14

What is the role of Von Willebrand Factor?

Answer 14

VWF carries factor VIII and mediates platelet adhesion to the endothelium

Question 15

Describe changes in the vessel wall during blood clotting

Answer 15

• Vasoconstriction
• Production of vWF (platelet adhesion, carrier of Factor 8)
• Exposure of collagen and tissue factor initiates activation of clotting factors

Question 16

What is fibrinolysis?

Answer 16

Fibrinolysis is a process which prevents blood clots from growing and becoming problematic by breaking down fibrin clot, a product of coagulation

Question 17

What is the clinical relevance of understanding haemostasis?

Answer 17

• Bleeding disorders
• Arterial thrombotic disorders
• Venous thrombotic disorders
• Abnormal blood test results
• Drug therapy for pro- or anti-thrombotic purposes

Question 18

What are bleeding disorders?

Answer 18

Bleeding disorders are inherited/acquired conditions arising due to abnormality in the vessel wall, platelets or coagulation factors

Question 19

Identify two congenital coagulation factor disorders

Answer 19

• Haemophilia A
• Haemophilia B

Question 20

In coagulation factor disorders, clinical severity correlates with extent of deficiency.

Identify 5 clinical presentations of these disorders

Answer 20

• Muscle haematomas
• Recurrent haemarthroses
• Joint pain and deformity
• Prolonged bleeding (after dental extraction, operation, trauma)
• Intracerebral haemorrhage

Question 21

What is Haemophilia A?

Answer 21

• Haemophilia A is an X-linked recessive disorder due to a congenital lack of factor VIII
• It can be mild/moderate/severe depending on amount of factor VIII present and is treated with recombinant factor VIII or DDAVP

Question 22

What is Haemophilia B?

Answer 22

Haemophilia B is an X-linked recessive disorder due to the congenital reduction in factor IX

Question 23

Identify two acquired coagulation factor disorders

Answer 23

• Liver disease
• Vitamin K deficiency

Question 24

What is Von Willebrand’s Disease?

Answer 24

• Von Willebrand’s disease is a relatively common autosomal dominant disease often due to a reduction in vWF production
• There is abnormal platelet adhesion to the blood vessel wall as well as reduced FVIII amount/activiy

Question 25

How does Von Willebrand's Disease present clinically?

Answer 25

- **Skin and mucous membrane bleeding**: epistaxis, gum bleeding, bruising - **Prolonged post-traumatic bleeding:** heavy periods, post surgery, post dental extraction

Question 26

How do blood vessel wall abnormalities present?

Answer 26

- Easy bruising - Spontaneous bleeding from small vessels (skin/mucous membranes)

Question 27

Identify some congenital conditions causing problems with vessels

Answer 27

- Hereditary Haemorrhagic Telangiectasia (HHT) - Ehlers Danlos Syndrome

Question 28

Identify some acquired conditions causing problems with vessels

Answer 28

- Senile purpura - Steroids - Infection *e.g. measles, meningococcal infection* - Scurvy

Question 29

What are the two different types of platelet disorders?

Answer 29

- Qualitative - Quantitative (thrombocytopenia)

Question 30

Describe the different causes for thrombocytopenia

Answer 30

Question 31

Describe the causes and treatment for the immune destruction of platelets

Answer 31

- **Immune thrombocytopenic purpura** is most common cause - Can be **secondary to autoimmune disease** *e.g lupus, lymphoma* - Treated with **immunosuppression** (corticosteroids or IVIg first line) as platelet transfusions do not work

Question 32

Identify two circumstances wherein the non-immune destruction of platelets occurs

Answer 32

- Microangiopathic haemolytic states *e.g. DIC* - Cardiopulmonary bypass surgery

Question 33

Identify 4 causes of the reduced production of platelet cells

Answer 33

- **B₁₂ / folate** deficiency - Infiltration of the bone marrow by **cancer cells/fibrosis** - **Drugs** (chemotherapy, some antibiotics) - **Viruses** (HIV, infective hepatitis, EBV, CMV)

Question 34

What are the consequences of severe thrombocytopenia?

Answer 34

- Easy bruising - Petechiae, purpura - Mucosal bleeding - Severe bleeding after trauma - Intracranial haemorrhage

Question 35

What is Disemminated Intravascular Coagulopathy?

Answer 35

- **DIC** is a type of microangiopathic haemolytic anaemia due to the pathological activation of coagulation - Numerous microthrombi are formed in the circulation which leads to consumption of clotting factors and platelets and a haemolytic anaemia

Question 36

How does DIC present?

Answer 36

**Symptoms are due to tissue hypoxia and infarction or haemorrhage:** - Respiratory compromise - Convulsions and neurological symptoms - Renal & hepatic failure - Shock and cardiac failure - Gangrene of the skin

Question 37

Identify six triggers of DIC

Answer 37

- Malignancy - Massive tissue injury e.g. burns - Infections (Gneg sepsis) - Massive haemorrhage and transfusion - ABO transfusion reaction - Obstetric causes (placental abruption, pre-eclampsia, amniotic fluid embolism)

Question 38

Which clotting tests are affected in DIC?

Answer 38

- Raised **PT/INR** - Raised **APTT** - Low **fibrinogen** - Raised **D dimers**

Question 39

Why does DIC present with a low fibrinogen count and a raised D-Dimer count?

Answer 39

**Fibrinogen** is consumed in microthrombi formation, which is broken down by fibrinolysis leading to the release of fibrin degradation products *e.g. **D Dimers***

Question 40

What is PT and what are its uses?

Answer 40

- **Prothrombin time** (PT) is a blood test that measures how long it takes blood to clot - It can be used to check for bleeding problems / to check if medication for bleeding problems is working

Question 41

What is INR and what are its uses?

Answer 41

- The **INR is a calculated ratio**: (patient’s PT / mean PT) - The INR (rather than PT ratio) is used for monitoring patients on warfarin

Question 42

Provide some explanations for a patient presenting with an isolated prolonged PT

Answer 42

- Warfarin use for liver disease (APTT often also prolonged in severe liver disease) - Vitamin K deficiency - Paracetamol overdose

Question 43

What are the indications for warfarin?

Answer 43

**Treatment and prophylaxis for thrombosis**, including: - Thrombotic event *e.g. PE/DVT* - Arrhythmias *e.g. AF* - Cardiac valve replacement ​

Question 44

What is warfarin's main mechanism of action?

Answer 44

Warfarin **inhibits synthesis of vitamin K dependent factors** (II, VII, IX and X)

Question 45

What is the likely explanation for a raised INR in a patient on antibiotics and warfarin (to treat a recent thrombotic event)?

Answer 45

**Antibiotics** (commonly trimethoprim, metronidazole, fluconazole, ciprofloxacin, levofloxacin, azithromycin, and clarithromycin) interfere with the metabolism of warfarin

Question 46

A 68 year old man presents with severe septicaemia, bleeding from the arterial line puncture site and has haematuria and rectal bleeding. Provide an explanation for the following abnormalities in his blood results: Haemoglobin: 115 g/L (130-180) MCV: 90 fl (80-99) WCC: 20.8 x 10⁹/l (4-11) Neutrophils: 18.0 x 10⁹/l (1.5-7.5) Lymphocytes: 2.4 x 10⁹/l (1-4) Platelets: 15 x 10⁹/l (140-400) INR: 2.5 PT: 27 secs (12-15) APTT: 70 secs (25-35) Fibrinogen: 0.5 g/L (2.0-4.0) D Dimers: 5mcg/ml (0-0.5)

Answer 46

- **Normocytic anaemia** – likely combination of microangiopathic haemolytic anaemia and bleeding - **Neutrophilia** – bacterial infection - **Thrombocytopenia** – likely due to microthrombi formation in the setting of DIC - **Combined prolongation of APTT and PT** – global reduction in clotting factors - **Reduced fibrinogen** – DIC