L13: Thrombotic disorders Flashcards
Virchows triad
RISK FACTORS OF THROMBOSIS
- Vascular injury (blood vessels)
- Trauma
- Surgical manipulation
- Prior thrombosis
- Atherosclerosis - Stasis (flow of blood) (mainly venous)
- Immobility (post-op, coma, debility, flights)
- Pressure (catheter, tumour)
- Increased viscosity (polycythemia, dehydration, EPO) - Blood hypercoagulability (mainly venous)
- Increased procoagulants
- Decrease in inhibitors
- Impaired fibrinolysis (rare)
DVT - incidence
- 1/1000 per year
- Incidence increases with age (much greater over 80)
- Very rare in children (usually only sick)
DVT presentation and sequelae
Clot of red cells and fibrin usually in proximal leg vein -> block upward flow of blood
- Leg swelling, pitting oedema
- Venous discolouration (engorgement)
- Leg pain
Sequelae:
- Often clot breaks off -> pulmonary embolism
- If untreated, 50% will embolise
Pulmonary embolism
- 1/2000 people per year (5% fatal)
- Clot in deep vein breaks off and eventually becomes lodged in pulmonary arteries or if large in pulmonary trunk
- If pulmonary trunk obstructed very serious (right side of heart blow out)
Diagnosis of PE
Presentation:
- Classic triad: pleuritic pain, SOB, haemoptysis
- Tachycardia
- Tachypnoea
- Hypoxia
Testing:
- D-dimer (usually positive)
- CT pulmonary angiogram
- V/Q scan (ventilation normal but perfusion decreased)
Algorithm for DVT and PE
- Symptoms are non-specific and common
- Algorithm to stratify groups for further testing
Well’s score for DVT: - If high probability –> doppler US
- If low probability –> D-dimer testing (neg -> discharge, pos -> doppler US)
D-dimer testing
- Measures products of fibrin breakdown
- Positive in 83-98% of DVT, PE
- Also positive in patients without VTE e.g. inflammation, surgery, trauma
- High negative predictive value, low positive predictive value
- Should be interpreted with clinical score
Massive PE
- Sudden death (15% of these)
- > 50% mortality
- Hypotension = defining feature
- Severe right heart strain due to back pressure from pulmonary arteries
- Require thrombolysis - given TPA
Thrombophilia
- Tendency to develop thrombosis
- Acquired and/or inherited (usually referring to hereditary)
- Manifest as VTE
- Multi-hit theory
Causes of VTE
30-40 % spontaneous (~50% of these have thrombophilia)
Rest are provoked events:
- Surgery/trauma
- Immobility
- Hospitalisation
- Malignancy (up to 20%)
- Hormonal replacement therapy/OCP/pregnancy
- Other (Myeloproliferative disease, anti-phopholipid syndrome)
Inherited thrombophilia causes
- Abnormal inhibitor function: resistance to activated protein C (mutant factor V Leiden)
- Deficiency of inhibitors: antithrombin, protein C, protein S (rare but antithrombin deficiency is high risk for future thrombosis)
- Increased factor levels: prothrombin gene mutation 20210A or elevated factor VIII
- (Dysfibrinogenemia - rare)
Factor V Leiden
- Single point mutation in factor V
- Most common hereditary cause of thrombophilia
Normally: Va enhances X activation
- Activated protein C cleaves normal Va -> slows Xa production
Factor V Leiden: activated protein C unable to cleave factor V Leiden
- Xa activation continues, Va levels 20% higher = mild tendency to thrombosis
Why test for activated protein C resistance?
Heterozygote: 3-7 fold increased risk of thrombosis
Homozygous: 50-100 fold increased risk of thrombosis
Thrombophilia testing
- Measure factor V Leiden and prothrombin gene mutation (most common)
- Also measure natural inhibitors
- Anti-thrombin, protein C and S deficiencies more severe –> only situation where management changed
- Testing usually only for young people with spontaneous VTE
Heparin
- Inhibitor through increased antithrombin effect –> inactivation of Xa and IIa)
- Given initially, immediate effect
- APTT 1+1 prolonged, TCT markedly prolonged
- Reversed (lab and clinically) by protamine
LMWH
= low molecular weight heparin
- Similar to IV heparin but smaller chains
- Increased antithrombin effect (inhibits Xa)
- Subcutaneous with better bioavailability
- E.g. enoxaparin 1mg/kg twice daily
- Weight based dose
Warfarin
- Inhibits recycling of vit k –> factors II, VII, IX and X lack carboxylation –> reduced production
- Monitored with INR (therapeutic range 2-3)
- High INR = increased bleeding risk
- Interacts with many drugs: antibiotics, anticonvulsants, amiodarone, diltiazem, citalopram etc
- Lag between starting drug and effect due to vit K stores (5-7 days to therapeutic level)
Reversal of warfarin
- Vit K IV takes 12-24hrs (synthesis of clotting factors)
- Prothrombinex (gives factor II, IX, X)
- FPP not recommended (requires too much)
DOACs
= direct acting oral anticoagulants
- Direct inhibitors of activated clotting factors
- Half life 9-14hrs
- Rivaroxaban (Xa) and dabigatran (IIa) same as warfarin for treatment of VTE
- Better than warfarin for treatment of AF (better stroke prevention with similar rates of bleeding)
DOACs advantages and disadvantages
Advantages:
- No monitoring needed, fixed dose
- Less intracranial haemorrhage (compared to warfarin)
Disadvantages:
- Renal excretion (esp. dabigatran) so retained in renal impairment
DOACs and clotting tests
Dabigatran: (inhibits IIa)
- TCT extremely sensitive
- APTT prolonged at therapeutic levels (1+1)
- PR prolonged if very high
- Antidote: idarucizumab (immediate reversal, may rebound in 24-48hrs if levels high or renal impairment)
Rivaroxaban: (inhibits Xa)
- PR prolonged to some extend, APTT less so
- Antidote in development (prothrombin sometimes used)
Morbidity rates in DVT and PE
Up to 30% of DVT patients develop post-thrombotic syndrome
- Pain, swelling/oedema, redness, venous eczema, ulceration
- Graduated compression stockings may help symptoms
2% of PE patients may develop chronic thromboembolic pulmonary hypertension
- SOBOE, dizziness, fatigue
