Haematology JC050: Leg Swelling And Chest Pain: Deep Vein Thrombosis, Pulmonary Embolism, Thrombophilia Flashcards

1
Q

***Virchow triad: Risk factors of Venous thromboembolism

A

Thrombosis (Clot formation) is due to (either 1 of 3 or more):
1. Stasis (smallest role)
- Surgery
- Immobilisation
- Pelvic obstruction (e.g. ovarian tumours, uterine fibroids)
- Heart failure
- Stroke
- Varicose veins (∵ dilated superficial veins impair bloodflow back to central circulation)

  1. Hypercoagulability (most important)
    - **Inherited thrombophilia
    —> **
    AT, PC, PS deficiency (Antithrombin, Protein C, Protein S)
    —> **Factor 5 Leiden
    —> **
    Hyperhomocysteinaemia
    —> Prothrombin G20210A mutation
  • Acquired thrombophilia
    —> ***Antiphospholipid syndrome (by Anticardiolipin antibodies + Lupus anticoagulant)
  • Dehydration
  • Hyperviscosity
  • ***Malignancy
  • ***Nephrotic syndrome
  • ***Myeloproliferative neoplasm
  • ***Pregnancy / Estrogen therapy
  • ***PNH
  1. Endothelial injury
    - Surgery
    - Stroke
    - **Radiation (gamma rays will damage skin + underlying vessels —> induce inflammation in vessels)
    - **
    Indwelling catheter
    - ***Sepsis (∵ cytokines released + inflammatory response)
    - Tourniquet
    - Dilatation of vein due to immobility —> stretching of endothelium

(4. General
- Advanced age
- Obesity
- Family history (unknown hypercoagulability))

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2
Q

Venous thromboembolism

A
  • Blood clot in Venous system
  • Low pressure system
  • Consists of:
    1. Pulmonary embolism (PE)
    2. Deep vein thrombosis (DVT): legs / iliac veins / mesenteric veins (rare) / other unusual sites
    —> patients usually have both but only present symptoms at 1 site
    —> clot rarely develop in pulmonary circulation
    —> mostly develop in ***deep veins (leg veins / iliac veins)
    —> dislodged and embolised to pulmonary circulation
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3
Q

Superficial veins vs Deep veins

A

Clot in Superficial vs Deep veins
- Different clinical implications
- Different management
- Different prognosis

Deep veins:
- Tibial vein —> ***Popliteal vein (分界線) —> Femoral vein (aka Superficial Femoral vein) —> Iliac vein
- Proximal deep veins: Proximal to Popliteal vein
- Distal deep veins: Distal to Popliteal vein
—> Proximal vs Distal: different clinical implications, management

Superficial veins (run in SC tissue to supply skin):
- Great saphenous vein
- Small saphenous vein

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4
Q

Risk factors of ***Arterial thrombosis

A

**Different spectrum of risk factors
Examples of Arterial thrombosis: **
Stroke, ***MI

Applicable to both arterial and venous:
- Age
- Family history
- Obesity
- Smoking
- Antiphospholipid syndrome
- **
Hyperhomocysteinaemia (
only Inherited thrombophilia applicable to Arterial thrombosis)
- **
Myeloproliferative neoplasm (esp. with JAK2 mutation)
- **PNH (Paroxysmal nocturnal haemoglobinuria)
- **
Nephrotic syndrome

Arterial thrombosis only:
- Hypercholesterolaemia
- DM
- HT
- Chronic renal impairment
- Male gender

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5
Q

Antithrombin deficiency: Inherited thrombophilia

A
  • ***AD inheritance
  • Prevalence: 1 in 2000-2500

Antithrombin:
- Naturally occurring anticoagulant
- ***Digest / neutralise Thrombin, Factor 9a, 10a, 11a, 12a
- Activity enhanced by Heparin (i.e. homozygous AT deficiency is resistant to Heparin)
- Synthesised in liver

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6
Q

Protein C deficiency: Inherited thrombophilia

A
  • ***AD inheritance
  • Prevalence: 1 in 200-500

Protein C:
- Vit K dependent anticoagulant, requiring activation by **Thrombin
- **
Inactivate Factor 5a, 8a
- Synthesised in liver

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7
Q

Protein S deficiency: Inherited thrombophilia

A
  • ***AD inheritance

Protein S:
- Vit K dependent anticoagulant
- ***Cofactor of activated Protein C
- Synthesised in liver, endothelial cells, megakaryocytes, brain cells

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8
Q

Acquired deficiencies of natural anticoagulant

A

Antithrombin deficiency:
- Neonatal period
- **Liver disease
- **
Pregnancy
- Sepsis
- Acute thrombosis
- **DIC
- **
Nephrotic syndrome
- Heparin
- L-asparaginase
- Estrogen

Protein C deficiency:
- Neonatal period
- Liver disease
- Sepsis
- Acute thrombosis
- DIC
- ***Warfarin (Vit K antagonist)
- L-asparaginase

Protein S deficiency:
- Neonatal period
- Liver disease
- Pregnancy
- Sepsis
- Acute thrombosis
- DIC
- Nephrotic syndrome
- ***Warfarin (Vit K antagonist)
- L-asparaginase
- Estrogen

***Never do Thrombophilia screen during acute thrombosis / patient on warfarin!!!
- ∵ AT, PC, PS are consumed during acute thrombosis / on warfarin (in case of PC, PS) in a normal individual as well

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9
Q

Other inherited thrombophilia (less common in HK)

A
  1. Factor 5 Leiden
    - mutant Factor 5a ***resistant to inactivation by activated Protein C
    - extremely rare in Asians
  2. Prothrombin G20210A mutation
    - very rare in Asians
  3. Hyperhomocysteinaemia
    - inherited metabolic disorder / acquired from B12 deficiency / alcoholic
    - increased risk of **Atherosclerosis + **VTE
    - high level of homocysteine —> induce vascular injury, factor 5 activation?
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10
Q

***Antiphospholipid syndrome (APLS)

A

Pathophysiology:
Ab against phospholipid binding proteins: Lupus anticoagulant
1. **Anti-cardiolipin Ab (IgG / IgM)
2. **
Anti-B2 glycoprotein 1 Ab
3. **Lupus anticoagulant
—> persistence for **
>=12 weeks

  • LA / ACA can present as sole laboratory abnormality without clinical manifestation
    —> after viral / syphilis infections / after some drugs
    —> ∴ diagnosis of Antiphospholipid syndrome require ***both Laboratory + Clinical manifestations

Clinical features:
- **Recurrent arterial + venous thrombosis
- **
Livedo reticularis (wiki: caused by reduction in blood flow through arterioles, resulting in deoxygenated blood showing as blue discolouration)
- **Recurrent fetal loss
- **
Thrombocytopenia
- May have underlying SLE (i.e. Secondary Antiphospholipid syndrome)

One of the most thrombophilic clinical conditions
- **Anticoagulation should be indefinite
- **
LMWH / Warfarin in patients with APLS and VTE
- Target INR between **2-3
- NOAC is NOT recommended (shown to be inferior)
- may consider to add **
Aspirin if patients develop arterial thrombosis

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11
Q

Malignancy associated VTE

A
  • Malignancy is a **hypercoagulable state
    —> believed that tumour cells releasing **
    pro-coagulants into circulation
    —> or ***obstructing venous return e.g. ovarian tumour obstruct venous return from lower limbs
  • up to 10% of patients were found to have underlying malignancy after an “unprovoked” VTE
  • Thorough history + P/E + appropriate investigations for every patient with ***unprovoked VTE to exclude underlying malignancy
  • Universal PET-CT screening is not recommended (although some centres in HK do it)
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12
Q

Myeloproliferative neoplasm associated thrombosis

A
  • Myeloproliferative neoplasm ↑ ***both arterial + venous thrombotic risk
  • JAK2 mutation ↑ thrombosis risk
  • Particularly Mesenteric thrombosis (Budd–Chiari syndrome)
  • Beware of ***aVWD in extreme thrombocytosis (Plt >1000) —> instead of thrombosis will present with bleeding tendency

aVWD:
- acquired deficiency of vWF in extreme thrombocytosis
—> vWF bound by / consumed by Platelets

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13
Q

Pregnancy and Estrogen associated VTE

A
  • Pregnancy is a hypercoagulable state
  • Prevalence of VTE in pregnancy and puerperium 1 in 1600
  • Highest risk during ***post-partum period
  • Risk ↑ with
    —> **multiple pregnancies
    —> maternal obesity
    —> maternal DM / HT
    —> known thrombophilia
    —> advanced maternal age
    —> hospitalisation
    —> **
    C-section
    —> eclampsia
    —> ***post-partum haemorrhage
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14
Q

Nephrotic syndrome and Thrombophilia

A
  • 8x higher risk of having venous / arterial thrombosis in nephrotic syndrome patients
  • ∵ ***loss of natural anticoagulants through kidneys e.g. Antithrombin
  • ***Renal vein thrombosis itself is a cause of heavy proteinuria (have to investigate whether thrombosis is a cause / result)
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15
Q

***Clinical features of VTE

A
  1. Lower limb DVT (most common presentation)
    - leg ***swelling, pain / warmth
    - unilateral usually but can be bilateral
    - DDx of asymmetrical lower leg swelling: Lymphedema, Cellulitis, Ruptured Baker’s cyst, Haematoma
  2. Pulmonary embolism
    - **pleuritic chest pain, haemoptysis (rare), cough, **SOB, syncope / cardiac arrest
    - could be fatal (if emboli massive)
  3. Unusual site of thrombosis
    - cerebral venous thrombosis —> syncope, headache, **stroke-like features
    - mesenteric venous thrombosis —> sudden onset of **
    abdominal pain
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16
Q

History taking in VTE

A
  1. Onset of symptoms
    - calf pain, swelling, chest symptom
  2. **Screening of provocation / risk factors
    - recent operation
    - trauma
    - immobility
    - pregnancy + obstetric history
    - **
    OC pills / other hormones (∵ ↑ gene transcription of clotting factors)
  3. Family history of VTE
  4. ***Constitutional symptoms
    - thrombosis can be first manifestation of underlying malignancy!!!
17
Q

***Investigations for suspected VTE

A
  1. Baseline CBP (Hb, Plt) + Clotting profile
    - for consideration of anticoagulant commencement
  2. ***D-dimer
    - ↑ in VTE
  3. ECG
    - classical ***S1, Q3, T3 of right heart strain in PE
    - but in massive PE: may still present with sinus tachycardia
  4. ***Troponin
    - whether there is strain on heart
  5. ***USG doppler of relevant body parts
    - diagnostic of presence of blood clots
    - first doppler usually negative —> repeat doppler in a few days
  6. ***CT pulmonary angiogram
    - gold standard for diagnosing PE
  7. Ventilation perfusion (VQ) lung scan
    - less informative compared to CT but no need contrast
  8. Echocardiogram
    - assessment of RV function if diagnosed PE
18
Q

Thrombophilia screening

A
  • do NOT carry out Thrombophilia screening during acute thrombosis / on warfarin / other anticoagulant treatment
  • does NOT predict recurrence risk (whether or not patient harbour inherited thrombophilia)
  • only thing that can predict recurrence risk is whether the index episode is idiopathic / provoked
    —> provoked: very low recurrence risk
    —> unprovoked: very high recurrence risk
  • ***NOT recommended following a provoked VTE
    —> ∵ does not guide management (simply give anticoagulant for a period then stop giving)
  • only after **unprovoked VTE, ∵ knowledge of Inherited thrombophilia may allow
    —> provision of prophylaxis during subsequent at risk period e.g. pregnancy, operation
    —> identify family members at risk
    —> Screening of **
    first degree relatives if anticoagulation cannot be discontinued in the index patient
19
Q

***Treatment of VTE

A
  1. Anticoagulation
    - ***LMWH (all patients)
    - NOAC
    - Warfarin
  2. Thrombolytic
  3. Embolectomy
  4. IVC filter

Management of VTE (SpC Revision):
1. Anticoagulation
- LMWH for >=5 days then Warfarin
- Intensity of warfarinisation: INR 2-3
- Duration:
—> 3 months (provoked)
—> >3 months / Long-term (recurrent DVT, some unprovoked)

  1. DOACs
    - Direct thrombin inhibitor: Dabigatran
    - Direct Xa inhibitors: Rivaroxaban, Apixaban. Edoxaban
  2. No routine IVC filter
20
Q

Duration of anticoagulation treatment

A
  1. Provoked event
    - ***3 months
  2. Unprovoked event
    - ***6 months / long term
  3. Recurrent event
    - long term
  4. Underlying malignancy
    - as long as malignancy is active / when patient is under chemotherapy
  5. Underlying APLS
    - ***long term
21
Q

Indication of Thrombolytic therapy / Embolectomy

A
  • Rare
    1. **Haemodynamic instability: Shock, Persistent hypotension
    2. **
    Venous gangrene of limbs (Phlegmasia cerulea dolens)
22
Q

Role of IVC filter

A
  • Very limited role
  • Efficacy based on limited uncontrolled case series
  • May consider when:
    1. **Toxicity of anticoagulation is predictably + unacceptably high
    2. **
    Temporary withhold anticoagulation yet preventing embolisation of clot to pulmonary circulation
    3. Plan for removal when the bleeding risk is lowered (remove + retrieve filter asap)
    —> usually put in for ***6-8 weeks before removal (avoid endothelialisation of filter)

When IVC filter is in place:
- Anticoagulation ***still need to be given otherwise clot forms at site of filter

23
Q

Superficial VT vs Distal vs Proximal DVT

A

Superficial thrombophlebitis / VT:
- maybe manifestation of underlying malignancy (esp. when recurrent / migrating)
- Treatment: ***NSAIDs (∵ part of symptoms come from inflammation), LMWH / NOAC for 45 days

Distal DVT:
- carries ***lower risk of embolisation (than Proximal DVT)
- 3 months anticoagulation is adequate in most cases

24
Q

Post-thrombotic syndrome

A
  • Very common after DVT
  • ***Persistent swelling, pain, skin pigmentation, ulcers in the affected limb after DVT esp. Proximal DVT
  • Due to ***chronic venous insufficiency —> Poor circulation
  • Difficult to treat
  • ***Compression therapy only proven treatment

***Have to differentiate Recurrent thrombus vs Post-thrombotic syndrome:

Recurrent thrombus:
- ***↑ D-dimer (indicate acute element)

Post-thrombotic syndrome:
- same leg
- everyday
- not new onset
- tends to worsen towards the end of day (∵ swelling is affected by gravity + degree of activity in legs)
- tends to improve after lying down + raising leg