Haematology - DVT, PE, Thrombophilia Flashcards
Virchow’s triad of thrombosis
Stasis
Coagulability
Endothelial injury
Risk factors of vascular stasis
Heart failure Stroke Surgery Pelvic obstruction Varicose veins Prolonged immobolization
Risk factors of hypercoagulability
Inherited and acquired thrombophilia Malignancy, esp. haematological Nephrotic syndrome Myeloproliferative neoplasm Pregnancy/ Estrogen therapy Dehydration Paroxysmal Nocturnal Haemoglobinuria
Risk factors of endothelial injury
Surgery
Radiation
Tourniquet and Indwelling catheter
Sepsis
General risk factors of thrombosis (arterial and venous) (8)
Risk factors of arterial thrombosis only (5)
Both arterial and venous thrombosis: Age Family history of thrombosis Smoking Obesity Antiphospholipid syndrome Hyperhomocysteinaemia MPN PNH
Arterial thrombosis only: Male sex Hypercholesterolemia Diabetes Mellitus Hypertension Chronic renal impairment
List inherited thrombophilia
- Antithrombin, Protein C, Protein S deficiency
- Factor V Leiden
- Hyperhomocysteinemia
- Prothrombin G20210A mutation
Anti-thrombin deficiency
- Inheritance pattern
- Antithrombin function and synthesis
- Drug C/I
- Treatment
Inheritance: AD
Antithrombin: most thrombogenic inherited cause
- Synthesis in liver
- Function: neutralize thrombin, factor IXa, Xa, XIa, XIIa
C/I:
Heparin is ineffective without antithrombin, heparin-resistant
Tx:
Higher dose of LMWH
Antithrombin concentrate in refractory VTE
Prophylaxis in pregnancy, surgery or post-VTE
Protein C deficiency
- Inheritance pattern
- Physiological Synthesis and function
- Tx
AD inheritance
Synthesis in liver
Function: Vitamin K dependent anticoagulant, need activation by thrombin, Inactivates factor Va and VIIIa
Tx:
Anticoagulation in VTE → should continue indefinitely
Prophylactic anticoagulation in pregnancy, surgery or post-VTE
Protein S deficiency
- Inheritance pattern
- Synthesis and function
- Tx
AD inheritance
Synthesis in Liver, Endothelial cells, Megakaryocytes and Brain cells
Function:
Co-factor of activated protein C to inactivate Factor Va and VIIIa
Vitamin K dependent anticoagulant
Tx:
Anticoagulation in VTE → individualize decision for indefinite anticoagulation
Prophylactic anticoagulation in pregnancy, surgery
Common ACQUIRED causes of anticoagulant deficiency (Anti-thrombin, Protein C and S)
Depletes all 3 of anti-thrombin, Protein C and Protein S:
- Neonatal period
- Liver disease
- Sepsis
- Acute thrombosis
- DIC
- L-asparaginase
Pregnancy and Estrogen, Nephrotic syndrome:
- Depletes Antithrombin and Protein S
Warfarin:
- Depletes Protein C and Protein S (both vit. K dependent)
Factor V Leiden
Prothrombin G2021A mutation
Hyperhomocysterinemia
check SN
Antiphospholipid syndrome
Cause
Manifestations
Confounding factors for positive result
Treatment
Cause:
Generation of auto-antibodies against phospholipid-binding proteins
- Anti-cardiolipin antibodies (IgG or IgM)
- Anti-B2 glycoprotein I
- Lupus anticoagulant (actually prothrombotic)
Manifestations:
- DVT, PE
- Arterial thrombosis: MI, Stroke
- Thrombocytopenia
- Pregnancy complications, Recurrent fetal loss
- Livedo reticularis
Confounding factors: Marginal and transient increase concentration, with prolong aPTT
- Viral infections
- Drugs
Tx:
- Life-long LMWH or Warfarin for VTE, Add aspirin for Arterial thrombosis
- Target INR between 2 to 3
- DOAC not recommended
Malignancy- associated VTE
Malignancy is prothrombotic state
Immobolization causes stasis
Drugs can cause thrombosis
MPN associated thrombosis
- Risk for arterial or venous thrombosis?
- High risk of thrombosis in which organ?
- Cause?
Risk of both arterial and venous thrombotic risk
Mesenteric thrombosis
Acquired vWD in extreme thrombocytosis
Pregnancy and Estrogen associated VTE
- High risk in which pregnancy period?
- Maternal risk factors
Highest risk in post-partum period
Higher risk:
- Multiple pregnancies
- Maternal obesity
- Maternal DM or HT
- Thrombophilia
- High maternal age
- Hospitalization and C-section
- Eclampsia
- Post-partum hemorrhage
Nephrotic syndrome associated VTE
- Pathogenesis
- Increase risk of arterial or venous thrombosis
Pathogenesis:
- Renal vein thrombosis and nephrotic syndrome cause proteinuria»_space; Loss of natural anticoagulants through kidneys
Risk:
- Arterial and venous thrombosis
Clinical presentation of venous thromboembolism (5 main sites in body with S/S) **
- Lower limb DVT
- asymmetrical lower limb swelling/ bilateral calf girth difference
- Dilated superficial veins
- pain, warmth, erythema - Pulmonary embolism
- Pleuritic chest pain/ central/ crushing
- Hemoptysis
- Acute cough, dyspnea, syncope
- Shock, sudden death - Cerebral venous thrombosis:
- Increase ICP: headache, papilloedema, impaired consciousness
- Seizures, focal deficit - Mesenteric venous thrombosis
- Portal vein thrombosis
- Acute abdominal pain +/- fever, diarrhea - Axillary vein thrombosis
- UL pain, swelling, heat
- Venous thoracic outlet syndrome
- Young, athletic male with prior strenuous UL exercise
Outline history taking for suspected thrombosis
- Onset of manifestations: DVT/ PE/ Cerebral thrombosis/ Mesenteric thrombosis
- Screen underlying causes:
- Recent operations
- Trauma
- Immobility
- Pregnancy and obstetric history, high estrogen exposure
- Inherited/ acquired thrombophilia conditions
- Underlying malignancies and constitutional symptoms - Family of inherited thrombophilia/ Malignancies
- Social history: risk factors of venous and arterial thrombosis
First-line investigations for VTE
Second-line screening
Blood tests:
- CBC with diff.
- Full clotting profile, D-dimer
- Troponin
Physical exam: DVT Well’s score
Radiological
- USG doppler: DVT, Mesenteric thrombosis
- CT pulmonary angiogram* or V-Q scan
- Echocardiogram
ECG
Second line - Thrombophilia screening
Do not perform during acute thrombosis
Practical function of D-dimer test
D-dimer: in low pre-test probability
Sensitive but not specific
If +ve, offer duplex USG in 4h (or else start anticoagulant first)
D-dimer positive = many confounding factors, does not rule in acute thrombosis
D-dimer negative = chance of acute thrombosis is almost zero »_space; rule out acute thrombosis
Practical function of thrombophilia screening
Prophylaxis during at-risk periods: Pregnancy, operation
Identify family members at risk: screen first-degree relatives
Treatment options for acute thrombosis
Indication for each option
Anti-coagulants: for proximal DVT and PE
- LMWH
- DOAC
- Warfarin (if renal impairment)
Catheter-directed thrombolysis:
- for haemodynamically unstable, persistent hypotension, venous gangrene of limbs
- massive iliofemoral DVT failing anticoagulation
Surgical embolectomy
IVC Filter insertion:
- temporary placement, stop embolism from reaching lungs
- If C/I anticoagulants or failed anticoagulants
Duration of anticoagulant treatment
- Provoked
- Unprovoked
- Recurrent
- Malignancy
- APS
- Pregnancy
Provoked = 3 months
Unprovoked = 6 months or long-term
Recurrent = Long-term
Malignancy-cause = LMWH (or DOAC), continue >6mo if active cancer
Anti-phospholipid syndrome = heparin followed by indefinite warfarin
Pregnancy: LMWH in 1st and 3rd trimester, Warfarin in 2nd trimester, cover 6 weeks post-partum
Treatment of lower limb DVT
- Proximal clot vs distal clot
** Superficial femoral vein is a DEEP VEIN**
Treatment of Proximal clot: NSAID, LMWH or DOAC for 45 days
Treatment of distal clot: Anticoagulants for 90 days/ optional since low risk of embolization
S/S after treatment of DVT
Cause?
Management?
Post-thrombotic syndrome (30%)
- Persistent swelling, pain, skin pigmentation, ulcer in affected limb after DVT
- Caused by chronic venous insufficiency and damage to venous valve
- Manage by compression therapy
Surgical conditions that increase risk of VTE
Long, major surgery >30 mins
Abdominal or pelvic surgery, especially for cancer
Major lower limb orthopedic surgery, e.g. hip fracture or knee replacement
Summarize Patient factors that increase risk of VTE
Old age Obesity Varicose veins Previous DVT Family history, esp. young VTE Pregnancy and high estrogen exposure Prolonged immobility IV drug use in femoral vein
Summarize Haematological disorders that increase risk of VTE
MPN:
Polycythemia vera
Essential thrombocythaemia
Myelofibrosis
Anticoagulant deficiency: Antithrombin, Protein C, Protein S
PNH
Gain-of-function mutations: Factor V Leiden, Prothrombin G20210A mutation
Summarize medical conditions that increase risk of VTE
MI/ Heart failure Pneumonia Inflammatory bowel disease Nephrotic syndrome Neurological diseases and immobility Malignancies
Ddx of Lower limb DVT
Cellulitis
Ruptured Baker’s cyst
Lymphedema
Haematoma
Ddx mesenteric thrombosis
Malignant infiltration of portal vein esp HCC
Extrinsic compression by abdominal tumours
All causes of scute generalised abdominal pain e.g. ruptured viscus, ruptured aaa, acute pancreatitis or appendicitis, ischemic colitis…
Ddx cerebral venous thrombosis
Haemorrhagic stroke
SAH
Seizure of other origin
Ddx pulmonary embolism
Stable angina or ACS Pneumothorax Aortic dissection Gastrointestinal causes Musculoskeletal causes
Drugs used for acute anticoagulation
Subcutaneous LMWH or fondaparinux for most pt.
Unfractionated heparin
- if rapid reversal (by protamine) may be required
- (eg. renal failure, ↑bleeding risk, concomitant thrombolysis)
Upfront NOAC (rivaroxaban/apixaban)
Drugs used for long-term anti-coagulation
Warfarin (or NOAC)
Continue LMWH for 6 months for patients with active cancer
Unfractionated heparin
- Indication
- Route
- MoA
- Reversal
Indication: for acute clot only
Mechanism: binds to antithrombin → enhance affinity thrombin and factor Xa → inhibits thrombin and factor Xa
RoA: IV (bolus injection followed by continuous infusion) or deep subcutaneous
Reversal: half-life ~4 hours, can be readily reversed by protamine
LMWH
- Indication
- Route
- MoA
- Indication: acute ± long-term treatment, when oral treatment not feasible
- Route: subcutaneous
- MoA: binds to antithrombin → Enhance affinity thrombin and factor Xa → inhibits thrombin and factor Xa
Fondaparinux
- Indication
- Route
- MoA
- Indication: acute ± long-term treatment
- Route; subcutaneously
- MoA: retains active pentasaccharide sequence of heparin → only binds factor Xa and inhibit its function
Warfarin
- Indication
- Route
- MoA
- Induction
- Monitoring
- Caution
- Indication: long-term treatment only
- Route: Oral only
- MoA:
inhibits vit K epoxide reductase → ↓regeneration of reduced form of vitamin K → ↓production of vitamin K-dependent factors, i.e. II, VII, IX, X → effect takes time - Induction: require overlap with heparin as takes time for depletion of vit K-dependent factors
- Monitoring; INR, usually target 2-3×
- Caution: numerous diet and drug interactions
- Inhibitors of metabolism (↓P450): cimetidine, metronidazole
- Inducers of metabolism (↑P450): barbiturates, rifampicin, phenytoin, griseofulvin (antifungal)
Direct (newer) oral anticoagulants (DOAC, NOAC)
- Examples
- Indication
- Route
- Reversal methods
factor Xa inhibitors (apixaban, edoxaban, rivaroxaban), direct thrombin inhibitors (dabigatran)
- Indication; short and long-term treatment
- Route: orally
- Reversal methods
decoy factor Xa (andexanet α) for Xa inhibitors,
idarucizumab for dabigatran
prothrombin complex concentrate (PCC) if life-threatening bleeding
Secondary prevention methods of VTE
□ Cancer and thrombophilia screen
□ Avoidance of precipitating factors, eg. OCP, HRT, prolonged immobilization
□ Graduated compression stockings or intermittent pneumatic compression during hospitalization
□ Prophylactic anticoagulation in hypercoagulable states, eg. pregnancy, surgery
□ Consider indefinite anticoagulation
→ Unprovoked VTE + low bleeding risk
→ Recurrent provoked VTE
→ Provoked VTE with irreversible RFs
Indication for thrombophilia screening
Young patient with unprovoked venous thrombosis
Recurrent venous thrombosis or superf thrombophlebitis
Unusual sites of thrombosis (mesenteric, renal, portal veins, cerebral venous sinuses)
Warfarin-induced skin necrosis
Arterial thrombosis <40y
Recurrent miscarriage
What conditions are checked in thrombophilia screening
Antiphospholipid syndrome:
Lupus anticoagulant (LA)
Anti-cardiolipin Ab (aCL)
Anti-β2-glycoprotein I Ab (anti-β2 GPI)
Inherited thrombophilias: Protein C (PC) and S (PS) Anti-thrombin (AT) Activated protein C resistance (APCR) Factor V Leiden
