Thrombotic Disorders Flashcards
Contributors of thrombotic disorders
- vessel wall injury
- hypercoagulability of blood
- stasis of blood
Arterial Thrombosis
- Interruption of blood flow causes ischemic necrosis of involved organ/limb
- Vessel wall injury (eg, atheroma) initiates most events
- Emboli may cause downstream small vessel infarction (ie. embolic stroke)
- High shear in arterial circulation → platelets play greater role than thrombin/fibrin formation in initiating thrombosis
- Antiplatelet agents preferred for prevention of arterial events in most cases (as opposed to drugs that inhibit the coagulation cascade)
- Inherited conditions that promote thrombin formation (inherited thrombophilia) are not major risk factors for arterial thrombosis
Venous Thrombosis
- Obstruction to venous outflow (not inflow) causes edema, swelling, pain, and inflammation in the area drained by the affected vein
- Most common in deep veins of the legs/pelvis, associated with venous stasis.
- Complicated by pulmonary embolism (PE), where thrombus breaks free and follows the venous return through the right side of the heart into the pulmonary arteries.
- Massive PE (typically from large proximal leg or pelvic veins) can cause hypoxemia, shock and death. Mortality rate from PE averages about 5%.
- Low shear and stasis allows accumulation of activated clotting factors, so clots are fibrin-rich.
- Drugs that slow or block thrombin generation preferred over antiplatelet drugs for prevention and treatment of venous thrombosis
- Inherited or acquired conditions that promote thrombin formation increase risk of venous thrombosis
paradoxical embolus
obstruction of a systemic artery by an embolus originating in the venous system that passes through a septal defect,patent foramen ovale, or other shunt to the arterial system
drug preferences: arterial thrombosis and venous thrombosis
arterial: Antiplatelet agents preferred for prevention of arterial events in most cases (as opposed to drugs that inhibit the coagulation cascade)
venous: Drugs that slow or block thrombin generation preferred over antiplatelet drugs for prevention and treatment of venous thrombosis
inherited or acquired conditions that promote thrombin formation affect on arterial and venous thrombosis
arterial: not much risk
venous: increase risk of venous thrombosis
Deep Vein Thrombosis (DVT)
- the formation of a clot in a large vein, generally of the lower extremity.
- While some DVTs are asymptomatic, classic signs and symptoms are unilateral leg pain, swelling, and warmth.
- The diagnosis of DVT is most commonly confirmed by compression ultrasound (venous duplex ultrasonography) of the lower extremities. Veins with DVTs will have a non-compressible venous lumen.
Causes of Venous Stasis
- Surgery or major trauma (pt layed up in bed in hospital and not moving around)
- Cancer (vessel obstruction by tumor)
- Immobilization (prolonged bedrest, paralysis, leg cast, long airplane trips, long car trips etc)
- Obesity
- Pregnancy (large uterus can obstruct flow to legs) Congestive heart failure
- Venous insufficiency or obstruction (valves in the veins have become incompetent and forward movement of blood isn’t as efficient)
Acquired hypercoagulability
- Age
- Surgery or trauma
- Cancer (and cancer chemotherapy)
- Myeloproliferative disorders (e.g., polycythemia vera) – too many RBCs made
- Pregnancy and post-partum period
- Estrogens (oral contraceptives, postmenopausal hormone replacement)
- Antiphospholipid syndrome (automimmune condition in which Ab promote thrombosis)
- Heparin-induced thrombocytopenia (next lecture?; caused by heparin)
Antiphospholipid Antibodies
Antiphospholipid antibodies (APA)
- A general term for antibodies directed against a variety of epitopes (part of antigen antibody attaches to) present on phospholipid/protein complexes.
- Examples: anticardiolipin Ab, anti-beta-2 glycoprotein I Ab
- These are relatively common. Many patients asymptomatic, more likely to be associated with disease when present in high titers
Lupus anticoagulants (LAC)
- Subset of antiphospholipid antibodies that inhibit in vitro coagulation.
- Misleading name – many patients don’t have systemic lupus erythematosous (SLE), and these antibodies much more likely to be associated with arterial or venous thrombosis than bleeding.
- Acts as an anticoagulant in vitro only – prolongs aPTT and other phospholipid-dependent clotting tests. – does not inhibit in vivo coagulation
Antiphospholipid Syndrome
- Persistently positive tests for antiphospholipid antibodies (LAC and other high titer APA)
- Uncertain pathophysiology of thrombotic disorders
- Complications:
- Arterial and/or venous thrombosis
- Recurrent fetal loss – affects woman’s ability to carry pregnancy to term
- Autoimmune thrombocytopenia or hemolytic anemia – these can be developed (just one or both) in pts with APA
- May be associated with SLE, or with no associated condition (primary antiphospholipid syndrome); many have lupus but some don’t
- Occasional “catastrophic” presentation with multiple organ failure; inflammation, vasculitis – can be life threatening
- Some patients require lifelong anticoagulation; chronic condition that results in permanent increase risk of pt to get thrombosis
Genetic Risk Factors for VTE (Venous Thromboembolism)
* gene defect does not mean disease; just risk factor that is not predictable
Deficiency of major coagulation Inhibitors: uncommon, genetically heterogeneous conditions associated with up to 20 fold increased VTE risk in some families (not everyone affected by these)
- 1) Antithrombin Deficiency
- 2) Protein C Deficiency (C and S working together to degrave Va and VIIIa)
- 3) Protein S Deficiency
Other conditions- more common but less risky (3-5 fold increased VTE risk)
- 1) Factor V Leiden (~ 5% of US population) – polymorophism in Factor V on the site where activated Protein C cleaves Factor Va – C has a harder time killing Factor Va
- 2) Prothrombin G20210A polymorphism – increased persistance of mRNA for prothrombin; more prothrombin in the blood then increases thrombotic risk
risk of recurrence in VTE
- Idiopathic VTE is more likely to recur than provoked VTE
- if can’t identify any risk factor (or identify irreversible risk factor) than risk of recurrence tends to be high
- The risk of recurrent VTE is not strongly affected by the presence of inherited thrombophilia
- occurrence of idiopathic VTE is a better predictor of recurrence than laboratory evaluation for “hypercoagulable states”
Objective Testing for DVT
D-Dimer
- sensitive but not specific
Deep Venous Thrombosis (DVT)Duplex Doppler ultrasonography
- When you squeeze the leg of a pt without DVT the vein goes away but the artery holds form (on image); if there is a clot in the vein then the vein will not compress when the leg is squeezed
- Can look at blood flow; could see blood flowing past a clot
- Can’t tell difference between an old and a new blood clot
Contrast venography or MR venography (MRI more likely)
- Detailed picture
- More accurate because they can tell us everywhere there is a clot and how big
Pulmonary Embolism (PE)
Spiral computed tomography (CT) – test of choice
- Can see dark areas in main pulmonary arteries (=blood clots)
Ventilation-perfusion scan (V/Q scan)
- Two types of radiolabeled contrast agents; one injected and the other inhaled. The inhaled one shows where air is going and the injected shows where blood is going; if there is air going to a place where no blood is going then it is probably a blood clot
- Not used so often
MR angiography
D-Dimer
- sensitive but not specific
