Thrombophilia

Question 1

Thrombophilia or patient has a history of (recurrent or single) DVT/PE: PRIC-MCP?

Answer 1

Establish

P: Provoked or unprovoked, where was it?

R: Risk factors for DVT/PE: immobilisation, surgery, pregnancy/OCP, long-haul flight, malignancy, smoking; + F_H of DVT/PE_ or recurrent miscarriages + Miscarriages (suggests APS)

I: Has had Thrombophilia screening? (has the clotting tendency been identified, how?), Have you had special blood tests for clotting tendencies?

C: what are the contraindication to anticoagulation? complication - chronic venous insufficiency → chronic oedema/ulceration (post-thrmobotic syndrome)

M: Any previous or current anticoagulation therapies - INR, who checks it, how often - is there any difficulties getting to the path lab (do they have home INR tester), understands food to avoid whilst taking warfarin?

C: still on them or life-long? Any residual clots, frequency of follow-up

P: importance of INR testing + target INR, when to look for medical attention, What is the most recent INR, understanding of food/drug interaction?

Question 2

What would you advise patient about the food and warfarin?

Answer 2

It is all to do with Vitamin K. if you have too much Vit-K containing food, INR can go down, if too little, can go up.

1. Key is to stay on stable amount of vitamin K containing food each week (e.g. Kale, Brocholi, Spinach, Lettuce, Brussels sprouts, cabbage - i.e. largely green vegetables).
2. No more than 1-2 glassess of Cranberry or Grapefruit juice per day.
3. Advise against drinking excessive amount of ETOH over a short period of time (can increase INR)

Question 3

What are the risk factors for DVT/PE? (8)

Answer 3

Long-haul flight

Surgery

Immobility

Smoking

Pregnancy/OCP

FH of recurrent VTE

Malignancy

Miscarriages

Question 4

Thrombophilia/DVT/PE - examination finding to report? (3)

Answer 4

Stigmata of anticoagulation - ecchymoses, abdominal wall bruising from Clexane

Evidence of chronic venous insufficiency, oedema, ulceration

Peripheral pulses - evidence of arterial obstruction

Question 5

What are the routine test available for thrombophilia? (7+1 if indicated)

Answer 5

FBC (looking for thrombocytosis, polycythaemia) and ESR

Protein C/S (deficiency)

Antithrombin III (deficiency)

APS antibodies (anti-cardiolipin, B2M, lupus-anticoagulant)

Prothrombin mutation

Factor V Leiden (Anti-Protein C resistance)

Homocysteine

plus - if indicated

Flow-cytometry for CD55, CD59 (PNH)

vWF & Factor VIII

Question 6

What is your approach to investigating thrombophilia? (3)

Answer 6

Establish a diagnosis - thrombophilia screen

Identify the underlying cause - establish FH, beta-hCG (female), investigate for malignancy if indicated

Screen for complications - guided by symptoms: consider USS venous dopplers/VQ/CTPQ/liver USS doppler, investigations for arterial thrombosis

Question 7

What are the 4 indications for thrombophilia investigations?

Answer 7

Recurrent, Young, Unusual

Recurrent venous thrombosis

Family history of VTE

VTE <45y of age

Unusual sites: portal & hepatic vein, cavernous sinus

Question 8

Factor V Leiden - pathophysiology?

How common is it?

Answer 8

This mutation causes Factor V to be resistant to activated protein C (APC), a natural anti-coagulant.

Affects 4% of general population, 50% of those with FH of recurrent VTE (i.e. very common amongst those with positive FH)

Question 9

What is the relative risk of developing VTE in those with Factor V-Leiden compared with general population?

Answer 9

Heterozygous state: 8-fold

Homozygous: 100-fold

Question 10

How common is Prothrombin Gene mutation (in Australia)

MOI?

Diagnosis?

Answer 10

3% of Australian population

4-fold increase in VTE

Autosomal dominant

Dx by DNA PCR

Question 11

What are the diagnostic criterion for Anti-phospholipid syndrome? (3)

Answer 11

1. Vascular thrombosis
2. Positive antibody (lupus anticoagulant, cardiolipin - IgG or IgM, or B2M), ≥2 occasions at least ≥12 weeks apart
3. Pregnancy-related morbidity (miscarriage, unexplained death of fetus, spontaneous abortions)

Thrombosis in any organ: either arterial or venous

Levels of ACL and ab2gp should be >40

Question 12

Does positive anti-phospholipid Abs necessarily indicate APS? What are the differentials (4)
and what is your approach to elucidate the diagnosis (or rule out APS)?

Answer 12

No. Other causes include

1. Autoimmune & Rheumatological conditions - e.g. SLE - but in absence of clinical events, their significance is unclear
2. Infection
3. Medications
4. Malignancy

If the history (e.g. recurrent thrombosis, miscarriages) is not supportive, especially if the B2M & ACL titre is low (i.e. <40), I would repeat the test in 12 weeks time to confirm/exclude the diagnosis.

Repeat the

Question 13

What medications are associated with antiphospholipid antibodies? (4)

Answer 13

4 Ps

Phenytoin

Penicillin - Amoxycillin

Procainamide

Propranolol

Many others so I would look it up.

Question 14

Duration of Anticoagulation in the following circumstances?

1. VTE - provoked by a transient major risk factor
2. Unprovoked distal DVT
3. Unprovoked proximal DVT or PE
4. Recurrent DVT or significant thrombophilia (e.g. APS)

Answer 14

1. VTE - provoked by a transient major risk factor: 3 months
2. Unprovoked distal DVT: 3 months
3. Unprovoked proximal DVT or PE: 3 months then reconsider risk vs benefit with an aim to continue if the risk of thrombosis outweigh the benefit of stopping
4. Recurrent DVT or significant thrombophilia (e.g. APS): indefinite

Question 15

What is the reasonable alternative approach to those with distal DVT or proximal DVT that are unprovoked and the risk of anticoagulation is high (e.g. major bleeding)?

Answer 15

Especially consider when patient is asymptomatic and D-dimer negative.

Surveillance USS in 2 weeks → only anticoagulate if thrombus extension detected

Question 16

What is your approach to managing this patient with recurrent VTE? (include 5 aspects of non-pharmacological Mx)

Answer 16

Goals: identify & treat reversible causes, prevent thrombosis, bleeding.

Confirm Dx

A: Screen for secondary causes - clarify FH, thrombophilia testing, cancer screening (only age-appropriate cancer screening - PSA, FOBT, mamogram…etc)

Screen for complications - consider imaging (USS, VQ, CT, arterial dopplers if pulses are weak)

T: non-pharm - education (importance of monitoring symptoms of bleeding, INR, food/drug interactions), smoking & alcohol cessation, pre-operative/pregnancy (aggressive thromboprophylaxis), air-travel (prophylaxis if >6h, frequent ambulation, hydration, calf exercises, graduated compression stockings), falls-prevention (home modifications, night lights, PT/mobility aids)

T: pharm

ICE: follow-up and reassess risk & benefit of continuing anticoagulation.

For example, if a patient with above-knee DVT (proximal) and develops significant bleeding complications 3 months into the therapy, I would carefully consider ceasing anticoagulation in discussion with the patient and other specialist involved, while closely monitoring in 2 weeks time with d.dimer + USS to ensure the patient remains a) asymptomatic, b) d.dimer -ve, c) no extension of the DVT.