Lecture 14: Thrombotic disorders

Question 1

Describe virchows triad for arterial and venous thrombosis:

Answer 1

Triad:
- Stasis FLOW of blood
- Vascular injury BLOOD VESSELS
- Hypercoagulability COMPONENTS of blood

Question 2

What can cause vascular injury?

Answer 2

• Trauma
• Surgical manipulation
• Prior thrombosis
• Atherosclerosis

Question 3

What causes stasis?

Answer 3

Stasis (mainly venous thrombosis)
- Immobility
-> Post op state, debility, coma

Pressure
- Catheter, tumor obstruction

Increase viscosity
- Polycythemia
- Dehydration
- EPO

Question 4

What causes blood hypercoagulability?

Answer 4

• Increased procoagulants
• Decrease in inhibitors
• Impaired fibrinolysis (Rare)

Question 5

What generally creates a deep vein thrombosis?

Answer 5

Fibrin + RBC primarily

Question 6

What are the signs and symptoms of DVT?

Answer 6

Nonspecific and common

• Leg swelling
• Leg pain
• Oedema

-> Pain, tenderness, swelling

Notoriously hard to diagnose

Question 7

What are the signs and symptoms of PE?

Answer 7

PE:
- SOB
- Chest pain
- Tachycardia
- Tachypnoea

Malignancy common cause.

Again non-specific and common

Question 8

Describe the algorithm for DVT diagnosis:

Answer 8

Clinical score + D-dimer to determine if ultrascan sound needed.

High clinical score goes straight to US scan.

Question 9

What is D-dimer?

Answer 9

• Breakdown product of fibrin
• Positive in most DVT and PE cases
• BUT can also be positive in patients with inflam and surgery, therefore, should be considered with clinical score.

Question 10

What are the classic symptom triad of PE?

Answer 10

classic symptom triad of:
- Pleuritic pain
- SOB
- Heamoptysis (Rare, comes from lung infections, peripheral issues, doesnt change treatment)

Question 11

Write some notes on thrombophilia:

Answer 11

• Tendency to develop thrombosis.
• Acquired, inherited, or both i.e anti-phospholipid
• Manifested as VTE

Question 12

What are the causes of VTE?

Answer 12

~30-40% spontaneous

• ~50% of these have hereditary factor which increases risk: Thrombophilia

Remainder provoked events
- Surgery or trauma
- Immobility
- Hospitlisation
- Malignancy
- Pregnancy etc etc

Question 13

Describe the types of inherited thrombophilia:

Answer 13

• Abnormal factor function (i.e protein C - Factor V leiden, most common hereditary cause of thrombophilia)
• Deficiency of inhibitors (i.e Antithrombin, protein C or S)
• Increased factor levels i.e prothrombin, factor 8
• Dysfibrinogenemia (Very rare)

Question 14

What is the function of factor 5?

Answer 14

• Factor 5a enhances factor 10 activation.
• Activated protein C cleaves normal factor 5a.
• Slows 10a production.

Question 15

What happens in factor 5 leiden?

Answer 15

• Activated protein C unable to cleave factor V leiden
• Factor Xa activation continues
• Va levels ~20% higher

Question 16

Why test for APCr?

Answer 16

Heterozygotes 3-7 fold increase risk for thrombosis

Homozygotes carry a 50-100 fold increase risk of thrombosis

Question 17

Whats the value in testing for thrombophilia?

Answer 17

• Initial VTE risk increased
• BUT recurrence not increased
• Limited use for families
• Testing now reserved for young patients particularly spontaneous VTE
• NO role in arterial thrombosis

Question 18

What are the treatments for PE and DVT?

Answer 18

Anticoagulation

Initially -> Heparin
= Immediate effect
Requires antithrombin: Inactivation of Xa and 2a (thrombin)

Heparin is an inhibitor through increased antithrombin effect, APTT 1+1 is prolonged, TCT markedly prolonged, reversed with protamine.

Antithrombin deficiency does not increase APTT 1+1…

Question 19

What is the treatment following Heparin?

Answer 19

• LMWH
  -> Warfarin at the same time, minimum five days of overlap

Alternatively, now a direct oral agent preferred i.e dabigatran , inhibits coagulation, allows fibrinolytic mechanisms to operate unhindered by further clotting

Question 20

How does warfarin act?

Answer 20

Inhibits functional activation of Vit-K dependent factors i.e 2,7,9,10

Inhibits recycling of Vit K factors.

Question 21

What are some considerations of warfarin use?

Answer 21

• Needs monitoring (INR) (Prothrombin ratio)
• Risks of interactions with many drugs
  -> Antibiotics, anticonvulsants to name a few
• High INR increases bleeding risk further (INR 2-3 is therapeutic range)
• Takes time to reduce vit K availability to reduce production of active clotting factors
• Usually 5-7 days to a therapeutic level

Question 22

How do you reverse warfarin?

Answer 22

• Vit K IV

If immediate reversal required:
- Prothrombinex
- Factors 2,9,10

Question 23

What are some direct acting oral anticoagulants? and how do they act?

Answer 23

• Oral direct inhibitors of activated clotting factors
• Rivaroxaban (10a) and dabigatran (thrombin) are both the same as warfarin for the treatment of VTE

(Probs sup to warfarin for anticoagulation in atrial fibrillation - better stroke prevention with similar rates of bleeding

Question 24

What are the advantages and disadvantages of DOACs?

Answer 24

Advantages
- No monitoring needed, fixed dose
- Less intracranial heamorrhage (Compared to warfarin)

Disadvantages
- Renal excretion (especially dabigatran) retained with renal impairment

Question 25

How do DOACs impact clotting tests?

Answer 25

Dabigatran: TCT extremely sensitive; APTT prolonged at therapeutic levels (1+1 prolonged), PR prolonged if very high.

Rivaroxaban: PR prolonged to some extent, APTT less so.

Specific assay available for both.

A normal APTT and PR does not exclude some effect of these medicines….

Question 26

How are DOAC reversed?

Answer 26

Antidote for dabigatran: Idarucizumab

-> AB that binds to dabigatran very tightly (does not bind clotting factors)
-> Immediate reversal - very effective

Question 27

Whats the morbidity of DVT and PE?

Answer 27

Up to 30% of DVT patients develop post thrombotic syndrome
-> Pain, swelling/oedema, redness, venous eczma, ulceration
-> Graduated compression stockings may help

2% of PE patients may develop chronic thromboembolic pulmonary hypertension
- SOBOE, dizziness, fatigue