Haematology JC050: Leg Swelling And Chest Pain: Deep Vein Thrombosis, Pulmonary Embolism, Thrombophilia Flashcards
***Virchow triad: Risk factors of Venous thromboembolism
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)
- 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
- 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))
Venous thromboembolism
- 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
Superficial veins vs Deep veins
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
Risk factors of ***Arterial thrombosis
**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
Antithrombin deficiency: Inherited thrombophilia
- ***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
Protein C deficiency: Inherited thrombophilia
- ***AD inheritance
- Prevalence: 1 in 200-500
Protein C:
- Vit K dependent anticoagulant, requiring activation by **Thrombin
- **Inactivate Factor 5a, 8a
- Synthesised in liver
Protein S deficiency: Inherited thrombophilia
- ***AD inheritance
Protein S:
- Vit K dependent anticoagulant
- ***Cofactor of activated Protein C
- Synthesised in liver, endothelial cells, megakaryocytes, brain cells
Acquired deficiencies of natural anticoagulant
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
Other inherited thrombophilia (less common in HK)
- Factor 5 Leiden
- mutant Factor 5a ***resistant to inactivation by activated Protein C
- extremely rare in Asians - Prothrombin G20210A mutation
- very rare in Asians - Hyperhomocysteinaemia
- inherited metabolic disorder / acquired from B12 deficiency / alcoholic
- increased risk of **Atherosclerosis + **VTE
- high level of homocysteine —> induce vascular injury, factor 5 activation?
***Antiphospholipid syndrome (APLS)
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
Malignancy associated VTE
- 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)
Myeloproliferative neoplasm associated thrombosis
- 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
Pregnancy and Estrogen associated VTE
- 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
Nephrotic syndrome and Thrombophilia
- 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)
***Clinical features of VTE
- 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 - Pulmonary embolism
- **pleuritic chest pain, haemoptysis (rare), cough, **SOB, syncope / cardiac arrest
- could be fatal (if emboli massive) - Unusual site of thrombosis
- cerebral venous thrombosis —> syncope, headache, **stroke-like features
- mesenteric venous thrombosis —> sudden onset of **abdominal pain
History taking in VTE
- Onset of symptoms
- calf pain, swelling, chest symptom -
**Screening of provocation / risk factors
- recent operation
- trauma
- immobility
- pregnancy + obstetric history
- **OC pills / other hormones (∵ ↑ gene transcription of clotting factors) - Family history of VTE
- ***Constitutional symptoms
- thrombosis can be first manifestation of underlying malignancy!!!
***Investigations for suspected VTE
- Baseline CBP (Hb, Plt) + Clotting profile
- for consideration of anticoagulant commencement - ***D-dimer
- ↑ in VTE - ECG
- classical ***S1, Q3, T3 of right heart strain in PE
- but in massive PE: may still present with sinus tachycardia - ***Troponin
- whether there is strain on heart - ***USG doppler of relevant body parts
- diagnostic of presence of blood clots
- first doppler usually negative —> repeat doppler in a few days - ***CT pulmonary angiogram
- gold standard for diagnosing PE - Ventilation perfusion (VQ) lung scan
- less informative compared to CT but no need contrast - Echocardiogram
- assessment of RV function if diagnosed PE
Thrombophilia screening
- 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
***Treatment of VTE
- Anticoagulation
- ***LMWH (all patients)
- NOAC
- Warfarin - Thrombolytic
- Embolectomy
- 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)
- DOACs
- Direct thrombin inhibitor: Dabigatran
- Direct Xa inhibitors: Rivaroxaban, Apixaban. Edoxaban - No routine IVC filter
Duration of anticoagulation treatment
- Provoked event
- ***3 months - Unprovoked event
- ***6 months / long term - Recurrent event
- long term - Underlying malignancy
- as long as malignancy is active / when patient is under chemotherapy - Underlying APLS
- ***long term
Indication of Thrombolytic therapy / Embolectomy
- Rare
1. **Haemodynamic instability: Shock, Persistent hypotension
2. **Venous gangrene of limbs (Phlegmasia cerulea dolens)
Role of IVC filter
- 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
Superficial VT vs Distal vs Proximal DVT
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
Post-thrombotic syndrome
- 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
