Hypercoagulable states - BB

Question 1

Virchow’s triad

Answer 1

Endothelial damage

Stasis of blood

Hypercoagulability

Question 2

Natural anticoagulants made by endothelial cells

Answer 2

NO, prostaglandins, antithrombin, tPA, APC

Question 3

Reasons why malignancy may cause hypercoagulable state:

Answer 3

1. Some tumours produce pro-coagulants (TF)
   1b. Adenocarcinomas - some data that mucin is thrombogenic
2. Normal cells may produce pro-coagulants (in reaction to the presence or growth of the tumour)
3. Decreased activity, surgery and bed rest of the patient

Question 4

Why does pregnancy cause hypercoagulable state?

Answer 4

• Possible evolved to protect against blood loss at delivery
• Many clotting factor level changes
• – increased fibrinogen
• – decreased protein S
• Foetus obstructs venous return - pooling of blood in lower extremities (stasis)
• – Hence DVT common

Question 5

Why does oral contraceptive cause hypercoagulable state?

Answer 5

Oestrogen increases production of coagulation factors

Question 6

Elevated presence of which amino acid causes hypercoagulable state

Answer 6

Homocysteine

Question 7

Why does elevated homocysteine cause a hypercoagulable state?

Answer 7

High levels may cause - A+V clots

• Endothelial injury
• Activation of some clotting factors

Question 8

What causes elevated homocysteine?

Answer 8

Deficiencies:

• Folate
• B12
• B6

Homocystinuria - (cystathionine beta synthase deficiency)

Question 9

Why does nephrotic syndrome cause a hypercoagulable state?

Answer 9

Multiple mechanisms - main one is:

- loss of anti-clotting factors in the urine (antithrombin III)

Question 10

Inherited hypercoagulable states (thrombophilia)

x4

Answer 10

1. Factor V Leiden Mutation
2. Prothrombin gene mutation
3. Antithrombin deficiency
4. Protein C/S deficiency

Question 11

Factor V Leiden Mutation - how it works

Answer 11

Abnormal factor V - not inactivated by APC:S

Means that factor V remains active for longer -=> causing hypercoagulability

Question 12

Genetics of factor V leiden mutation

Answer 12

Point mutation in factor V gene

Results in:

• single amino acid substituion
• guanine to adenine change

Occurs at position 506 on factor V molecule

Question 13

Prothrombin gene mutation genetics:

Answer 13

Prothrombin 20210 gene

• guanine to adenine change in prothrombin gene
• occurs at position 20210

Heterozygous carriers have 30% increase in prothrombin
Homozygous carriers have even higher

Question 14

ATIII deficiency (antithrombin) 2 types:

Answer 14

1. Inherited due to gene mutations (number of different mutations can cause)
2. Acquired deficiency
   a- Liver disease (impaired production)
   b- Nephrotic syndrome (Protein losses including ATIII)
   c- DIC (consumption of both anti-/coagulant factors)

Question 15

Typical presentation of antithrombin III deficiency

Answer 15

Heparin resistance

• escalating dose with little to no change in PTT
• Because no ATIII for heparin to work on

Question 16

Protein C or S deficiency presentation:

Answer 16

Associated with warfarin skin necrosis (thrombosis of skin tissue)
—- Large dark purple skin lesions

• Protein C has short half life and so is first vitamin K factor to fall when warfarin is administered

Question 17

Protein C or S deficiency: (why does it occur)

Answer 17

Because of loss of inhibitory actions of APC on Va and VIIIa

Excessive activation of clotting factors

Question 18

Antiphospholipid syndrome causes

Answer 18

Antiphospholipid antibodies

Occurs either in association with lupus or primary disease

Question 19

Clinical concequences of antiphospholipid syndrome (X3)

Answer 19

1. Increased risk of V/A thrombosis
   - – Most commonly DVT but also stroke
   - – Recurrent foetal losses
2. Increased PTT
3. False positive for syphilis (RPR/VDRL)
   - - if this antibody is present

Question 20

3 Types of antiphospholipid antibodies

Answer 20

1. Anti-cardiolipin
   
   • – False positive for syphilis (because it also produces these antibodies)

2 ‘Lupus anticoagulant’
— Interferes with PTT test (intrinsic)

3. Anti-beta2 glycoprotein

Question 21

Antibody detection in antiphospholipid syndrome:

Answer 21

For anti-cardiolipin + anti-beta” glycoprotein:
— ELISA (enzyme linked immunosorbent assay testing)

For ‘Lupus anticoagulant’:
— Usually detected indirectly through coagulation assays (PTT)

Question 22

‘Lupus anticoagulant’ testing

Answer 22

1. PTT mixing test - to show the presence of an inhibitor

– Clotting factor deficiencies (e.g. hemophilia) will correct to normal in a mixing PTT test
(only 50% of patients with lupus anticoagulant have a raised PTT)

(*if still suspicious despite no raised PTT move on)

2. Dilute Russell Viper Venom Time
3. Kaolin clotting time

(in remaining tests time to clot will be prolonged if LA is present)
—- Time will not correct with mixing study

Question 23

Criteria for antiphospholipid syndrome:

Answer 23

Many patients have antiphospholipid antibodies but no syndrome

To have syndrome you must have 1 lab and 1 clinicla criteria

Lab criteria (2 positive results 12 weeks apart)

• Lupus anticoagulant
• anti-cardiolipin
• anti-beta2-glycoprotein

Clinical criteria:

• A/V thrombosis
• foetal death after 10 weeks of normal foetus
• > =3 consecutive foetal losses before 10 weeks

Question 24

Workup that can be done in patients who are hypercoagulable:

Answer 24

Antithrombin levels
Protein C and S levels
Factor V Leiden gene mutation
Prothrombin gene mutation 
Antiphospholipid antibodies 
Cancer screening (age appropriate)