Haematology 5- Thrombosis: Aetiology and Management

Question 1

Consequences of Thromboembolism

Answer 1

• Recurrence
• Thrombophlebitic syndrome (recurrent pain, swelling and ulcers
• Pulmonary hypertension

Question 2

• THREE contributory factors to thrombosis

Answer 2

• Blood composition
  
  • (viscosity)
    
    • Haematocrit (high)
    • Protein/ paraprotein (high level- e.g. myeloma and paraprotein)
  • Platelet count
  • Coagulation – net excess of procoagulant activity
• Vessel wall
• Blood flow

Question 3

procoagulant and antiocgulant factors

Answer 3

• Coagulation factors push to produce thrombin and eventually fibrin

Question 4

SBA 1: The risk of thrombosis is increased by:

• Reduced prothrombin
• Thrombocytopenia
• Reduced Protein C
• Elevated anti-thrombin
• Increased fibrinolysis

Answer 4

• Reduced prothrombin
• Thrombocytopenia
• Reduced Protein C
• Elevated anti-thrombin
• Increased fibrinolysis

Question 5

The Vessel Wall is normally Antithrombotic- how?

Answer 5

expresses anticoagulant molecules

• Thrombomodulin – help activate protein C
• Endothelial Protein C receptor – help activate protein C
• Tissue factor pathway inhibitor
• Heparans- help antithrombin work
• It does NOT express tissue factor
• It secretes antiplatelet factors:
  
  • Prostacyclin (PGI₂)
  • NO

Question 6

what makes Vessel Wall Prothrombotic

Answer 6

• Stimulus:
  
  • Infection
  • Malignancy
  • Vasculitis
  • Trauma
  • Hypoxia
• Effects:
  
  • Anticoagulant molecules (e.g. thrombomodulin) are downregulated
  • Adhesion molecules upregulated
  • TF may be expressed
• Prostacyclin production reduced

This becomes procoagulant which is how the vessel wall comes into play in thrombosis

Question 7

Inflammation and Thrombosis: Malignancy

Answer 7

causes inflammation, leading to expression of tissue factor

+ can also cause obstruction

Question 8

Blood Flow: Stasis promotes Thrombosis

Answer 8

• Mechanism:
  
  • There is an accumulation of activated factors
  • This promotes platelet adhesion
  • This also promotes leukocyte adhesion and transmigration
  • Hypoxia produces inflammatory effect on endothelium
• Causes of stasis:
  
  • Immobility- surgery, paraparesis, travel
  • Compression- tumour, pregnancy
  • Viscosity- polycythaemia, paraprotein
  • Congenital- vascular abnormalities

Question 9

SBA 2: Which factor confers the highest risk of thrombosis?

• Factor V Leiden
• Antithrombin deficiency
• FHx of thrombosis
• Reduced Factor VIII level
• 3 hour plane flight

Answer 9

• Factor V Leiden
• Antithrombin deficiency
• FHx of thrombosis
• Reduced Factor VIII level
• 3 hour plane flight

Thrombotic risk factors can combine to cause a massively increased risk of thrombosis

Question 10

Heparin - is it delayed use or immediate use?

disadvantages

MOA

example

Answer 10

Heparin– increase anticoagulant activity by potentiating anti-thrombin

LMWH (SC) + unfractionated heparin - IV

Long term disadvantages

• SC injections
• Risk of osteoporosis
• Variable renal dependence

Question 11

• Direct Acting Anti-Xa and Anti-IIa (IIa- thrombin) –
• is it delayed use or immediate use?

disadvantages

MOA

example

Answer 11

immediate use - peak in 2-4 hours

Inhibit the activation of coagulation factors

Take orally not SC like LMWH

unfractionated heparin

Question 12

warfarin

• is it delayed use or immediate use?

disadvantages

MOA

example

Answer 12

• DELAYED- takes 2-3 days
• Warfarin – reduce procoagulant activity
• Vitamin K epoxide reductase inhibitor >>> inhibits coagulation factor proteins 2, 7, 9, 10
• Also causes a reduction in Protein C and S

Question 13

how is warfarin prophylactic + theraputic

Answer 13

• HIGH dose= therapeutic
• LOW dose= prophylactic

Question 14

SBA 3: Which agent has a delayed anticoagulant effect?

• Vitamin K
• Unfractionated heparin
• Warfarin
• LMWH
• Aspirin

Answer 14

• Vitamin K
• Unfractionated heparin
• Warfarin
• LMWH
• Aspirin

Question 15

Monitoring Heparin Therapy

Answer 15

• LMWH- Reliable pharmacokinetics so not usually required to monitor
• Unfractionated heparin
• Always monitors therapeutic levels with APTT (activated partial thromboplastin time) or anti-Xa

Question 16

examples of direct acting anticoagulants + do they require monitoring

Answer 16

• Anti-Xa: Direct factor Xa inhibitor
  
  • Rivaroxaban, apixaban, edoxaban
• Anti-IIa: Direct thrombin inhibitor
  
  • Dabigatran
• No monitoring

Question 17

Delayed Anticoagulation- Long Term

warfarin- mode of adminstration

MOA + how can it be reversed

Answer 17

• inhibits the synthesis of Vitamin K-dependent proteins (factors 2, 7, 9 and 10) >>> so delayed onset of action
• also reduces amount of protein C and S

reversed with:

• vitamin K - takes 12 hours
• giving factors 2, 7, 9, 10- immediate response

Question 18

How does warfarin achieve an anticoagulant effect?

• Reduce the production of Protein C and Protein S
• Blocks phospholipid synthesis
• Reduces plasma concentration of procoagulant factors
• Acts as a cofactor for antithrombin
• Inhibits Factors II, VII, IX, X

Answer 18

• Reduce the production of Protein C and Protein S
• Blocks phospholipid synthesis
• Reduces plasma concentration of procoagulant factors
• Acts as a cofactor for antithrombin
• Inhibits Factors II, VII, IX, X

Question 19

Monitoring Warfarin

Answer 19

• Measure of effect is the INR (International Normalised Ratio)-
• Derived from prothrombin time

Question 20

can warfarin + heparin + DOAC be given in pregnancy

Answer 20

• Teratogenic

Question 21

Summary of Different Anticoagulants used

Answer 21

Question 22

Patients at Increased risk of Thrombosis

Answer 22

• Medical inpatients
  
  • Infection/ inflammation
  • immobility (including stroke)
  • age
• Patients with cancer
  
  • Procoagulant molecules, inflammation, flow obstruction
• Surgical inpatients
  
  • Immobility, trauma, inflammation
• Previous VTE, FHx, genetic traits
• Obese
• Elderly

Question 23

Thromboprophylaxis + what is used

Answer 23

low dose anticoagulation to reduce the risk of clotting when in hospital or when going home

LMWH

• E.g. tinzaparin 4500U OR Clexane 40mg OD
• Not monitored

TED stockings (for surgery or if heparin is contraindicated)

Flotron (boot)- Intermittent compression (increases flow) – avoiding stasis component

Sometimes DOAC +/- aspirin (orthopaedics)

Question 24

when during hospital admission should thrombophylaxis be given

Answer 24

All admissions to hospital should be assessed for thrombotic risk and unless contraindication exists, receive heparin prophylaxis

Question 25

**Risk Assessment for VTE**

Answer 25

* _Patient_ * Age \> 60 years * Previous VTE * Active cancer * Acute or chronic lung disease * Chronic heart failure * Lower limb paralysis (excluding acute CVA) * Acute infection * BMI \> 30 * _Procedure_ * Hip or knee replacement * Hip fracture * Other major orthopaedic surgery * Surgery \> 30 mins * Plaster cast immobilisation of lower limb

Question 26

**Treatment for DVT/ PE**

Answer 26

Need to be anticoagulated IMMEDIATELY

Question 27

Thrombolysis - when is its use

Answer 27

* **Thrombolysis** is only used for **life-threatening PE** OR **limb-threatening DVT** big increase in the risk of INTRACRANIAL HAEMORRHAGE (4%)

Question 28

factors for risk of recurrence of VTE and long term coagulation

Answer 28

need to assess risk of recurrence and bleeding when considering long term coagulation risk of recurrence- factors: * If it occurred **after surgery**, it has _LOW risk_ of recurrence * If it has occurred with a **non-surgical risk** (e.g. COCP, flight), it has a _MODERATE risk_ of recurrence * If it was **idiopathic**, it has _HIGH risk_ of recurrence * They will benefit from **long term thromboprophylaxis**

Question 29

which gender has higher risk of recurrence of DVT/PE

Answer 29

* Men have a HIGHER risk of recurrence than women

Question 30

thrombosis in what part of body has higher reucrrence risk

Answer 30

* **Proximal thrombosi**s (i.e. pelvic or popliteal thrombosis) has a higher rate of recurrence than **distal thrombosis** (e.g. calf)

Question 31

when should patients be offered CT scan for thromembolic disease

Answer 31

* All patients \> 60 years old with idiopathic thromboembolic disease should be offered a CT scan to check for an underlying cause

Question 32

**SBA 5: Which patient is most likely to benefit from long term anticoagulation after their DVT?** Circumstance of DVT: * 57 y/o man after flying from Kuala Lumpur * 27 y/o woman during pregnancy * 33 y/o woman on COCP * 77 y/o man after hip replacement * 30 y/o man after a long walk

Answer 32

* 57 y/o man after flying from Kuala Lumpur * 27 y/o woman during pregnancy * 33 y/o woman on COCP * 77 y/o man after hip replacement * **30 y/o man after a long walk** **remember men have higher risk of recurrence than women** long walk- **had an unprecipitated/ idiopathic thrombosis**- unlike long flight, pregnancy, COCP, surgery

Question 33

* 32 y/o woman developed DVT after removal of ovarian cyst. Father and 2 brothers had DVT* * what should be the next step:* * Testing for antithrombin deficiency? * Recommend HRT? * Continue long term anticoagulation?

Answer 33

* **Testing for antithrombin deficiency?** * Recommend HRT * Continue long term anticoagulation There is a strong FHx so suggests something is inherited. Continuing longer term anticoagulation may be a good idea if the tests from the antithrombin deficiency come back as positive.

Question 34

*_29 y/o man, collapsed at work following PE. No family history_* *_what should be done next_* * Test for Factor V Leiden? * Daily aspirin? * Continue long-term anticoagulation? * Heparin injections for long haul flights?

Answer 34

* Test for Factor V Leiden? * Daily aspirin? * **Continue long-term anticoagulation?** * Heparin injections for long haul flights? This **man had an unprecipitated thrombosis and subsequent PE**. **Once you have had a PE once, you are likely to see it again**. Long-term anticoagulation is the most important thing as this could recur. **Aspirin is popularly used as an anticoagulant, but it is NOT good at this.**

Question 35

*_67 y/o man present with DVT and weight loss. Started on LMWH_* *_what should be done next_* * Abdo-pelvic CT scan? * Switch to DOAC? * Switch to warfarin?

Answer 35

* **Abdo-pelvic CT scan?** * Switch to DOAC? * Switch to warfarin? Cancer is an inflammatory process that can precipitate a thrombosis.

Question 36

**IMPORTANT: ANTICOAGULATION AND RECURRENCE AFTER FIRST VTE + need for long term coagulation**

Answer 36

* **_Very LOW after surgical precipitant_** * No need for long term anticoagulation * **_HIGH after idiopathic VTE (10-20% in 2 years)_** * Consider **long term anticoagulation** * **_After MINOR precipitants (COCP, flights, trauma)_** * Usually **3 months adequate** * Longer duration may be dictated by presence of thrombotic and haemorrhagic risk factors

Question 37

summary

Answer 37

* Heparin and warfarin are anticoagulants with complementary properties * **Knowledge of risks allows appropriate use of thromboprophylaxis and duration of anticoagulant therapy**