Lecture 14: Thrombotic disorders Flashcards
Describe virchows triad for arterial and venous thrombosis:
Triad:
- Stasis FLOW of blood
- Vascular injury BLOOD VESSELS
- Hypercoagulability COMPONENTS of blood
What can cause vascular injury?
- Trauma
- Surgical manipulation
- Prior thrombosis
- Atherosclerosis
What causes stasis?
Stasis (mainly venous thrombosis)
- Immobility
-> Post op state, debility, coma
Pressure
- Catheter, tumor obstruction
Increase viscosity
- Polycythemia
- Dehydration
- EPO
What causes blood hypercoagulability?
- Increased procoagulants
- Decrease in inhibitors
- Impaired fibrinolysis (Rare)
What generally creates a deep vein thrombosis?
Fibrin + RBC primarily
What are the signs and symptoms of DVT?
Nonspecific and common
- Leg swelling
- Leg pain
- Oedema
-> Pain, tenderness, swelling
Notoriously hard to diagnose
What are the signs and symptoms of PE?
PE:
- SOB
- Chest pain
- Tachycardia
- Tachypnoea
Malignancy common cause.
Again non-specific and common
Describe the algorithm for DVT diagnosis:
Clinical score + D-dimer to determine if ultrascan sound needed.
High clinical score goes straight to US scan.
What is D-dimer?
- Breakdown product of fibrin
- Positive in most DVT and PE cases
- BUT can also be positive in patients with inflam and surgery, therefore, should be considered with clinical score.
What are the classic symptom triad of PE?
classic symptom triad of:
- Pleuritic pain
- SOB
- Heamoptysis (Rare, comes from lung infections, peripheral issues, doesnt change treatment)
Write some notes on thrombophilia:
- Tendency to develop thrombosis.
- Acquired, inherited, or both i.e anti-phospholipid
- Manifested as VTE
What are the causes of VTE?
~30-40% spontaneous
- ~50% of these have hereditary factor which increases risk: Thrombophilia
Remainder provoked events
- Surgery or trauma
- Immobility
- Hospitlisation
- Malignancy
- Pregnancy etc etc
Describe the types of inherited thrombophilia:
- Abnormal factor function (i.e protein C - Factor V leiden, most common hereditary cause of thrombophilia)
- Deficiency of inhibitors (i.e Antithrombin, protein C or S)
- Increased factor levels i.e prothrombin, factor 8
- Dysfibrinogenemia (Very rare)
What is the function of factor 5?
- Factor 5a enhances factor 10 activation.
- Activated protein C cleaves normal factor 5a.
- Slows 10a production.
What happens in factor 5 leiden?
- Activated protein C unable to cleave factor V leiden
- Factor Xa activation continues
- Va levels ~20% higher
Why test for APCr?
Heterozygotes 3-7 fold increase risk for thrombosis
Homozygotes carry a 50-100 fold increase risk of thrombosis
Whats the value in testing for thrombophilia?
- Initial VTE risk increased
- BUT recurrence not increased
- Limited use for families
- Testing now reserved for young patients particularly spontaneous VTE
- NO role in arterial thrombosis
What are the treatments for PE and DVT?
Anticoagulation
Initially -> Heparin
= Immediate effect
Requires antithrombin: Inactivation of Xa and 2a (thrombin)
Heparin is an inhibitor through increased antithrombin effect, APTT 1+1 is prolonged, TCT markedly prolonged, reversed with protamine.
Antithrombin deficiency does not increase APTT 1+1…
What is the treatment following Heparin?
- LMWH
-> Warfarin at the same time, minimum five days of overlap
Alternatively, now a direct oral agent preferred i.e dabigatran , inhibits coagulation, allows fibrinolytic mechanisms to operate unhindered by further clotting
How does warfarin act?
Inhibits functional activation of Vit-K dependent factors i.e 2,7,9,10
Inhibits recycling of Vit K factors.
What are some considerations of warfarin use?
- Needs monitoring (INR) (Prothrombin ratio)
- Risks of interactions with many drugs
-> Antibiotics, anticonvulsants to name a few - High INR increases bleeding risk further (INR 2-3 is therapeutic range)
- Takes time to reduce vit K availability to reduce production of active clotting factors
- Usually 5-7 days to a therapeutic level
How do you reverse warfarin?
- Vit K IV
If immediate reversal required:
- Prothrombinex
- Factors 2,9,10
What are some direct acting oral anticoagulants? and how do they act?
- Oral direct inhibitors of activated clotting factors
- Rivaroxaban (10a) and dabigatran (thrombin) are both the same as warfarin for the treatment of VTE
(Probs sup to warfarin for anticoagulation in atrial fibrillation - better stroke prevention with similar rates of bleeding
What are the advantages and disadvantages of DOACs?
Advantages
- No monitoring needed, fixed dose
- Less intracranial heamorrhage (Compared to warfarin)
Disadvantages
- Renal excretion (especially dabigatran) retained with renal impairment
How do DOACs impact clotting tests?
Dabigatran: TCT extremely sensitive; APTT prolonged at therapeutic levels (1+1 prolonged), PR prolonged if very high.
Rivaroxaban: PR prolonged to some extent, APTT less so.
Specific assay available for both.
A normal APTT and PR does not exclude some effect of these medicines….
How are DOAC reversed?
Antidote for dabigatran: Idarucizumab
-> AB that binds to dabigatran very tightly (does not bind clotting factors)
-> Immediate reversal - very effective
Whats the morbidity of DVT and PE?
Up to 30% of DVT patients develop post thrombotic syndrome
-> Pain, swelling/oedema, redness, venous eczma, ulceration
-> Graduated compression stockings may help
2% of PE patients may develop chronic thromboembolic pulmonary hypertension
- SOBOE, dizziness, fatigue
