Thrombotic Disorders Flashcards
Describe Venous thrombi
o Most commonly involves deep venous system in lower extremities or pelvis
o Fibrin rich = “red clot”
Occur in areas of venous stasis
• Especially in large veins, by valve cusps
Induces: edema, swelling, pain, inflammation
• DVT can lead to pulmonary embolism → hypoxemia, shock, death
• Rarely = paradoxical embolus: enters arterial circulation via patent ductus arteriosis or atrial septal defect
• Post-phlebitic syndrome
• Chronic, sometimes disabling leg swelling and pain
Formation = cyclic
Describe Arterial Thrombi
Typically platelet rich = “white clot”
Formed under conditions of high shear stress (rapid flow) with underlying endothelial abnormalities
• Tightly linked to presence of underlying atherosclerotic vessel disease:
• Mediated by inflammation and endothelial injury
• Increased expression of endothelial adhesion molecules (VCAM-1):
1) Recruits inflammatory cells
2) Stimulates cytokine release, lipid oxidation, or uptake by monocytes/macrophages
3) Stimulated smooth muscle proliferation
• Plaque formation → increased turbulent flow and shear stress → platelet activation → thrombus formation
Major atherosclerosis risk factors: • Smoking • HT • Hypercholesterolemia • Diabetes • Family history • Others: age, obesity, sedentary lifestyle
Generally occlusive → infarction, ischemic necrosis
• Ex: MI, thrombotic stroke, mesenteric ischemia
Can form emboli
• Ex: atrial fibrillation, valvular disease, severe left ventricle dysfunction → thrombus
List the components of Virchow’s triad
- Venous stasis
- Endothelial/vessel wall abnormalities
- Hypercoaguable state
Virchow’s Triad: components of venous stasis
o Decreased mobility o Intrinsic or extrinsic vessel obstruction o Obesity o CHF o Age
Virchow’s Triad: components of endothelial abnormalities
o Trauma, surgery, atherosclerosis, vasculitis, smoking, pregnancy (especially post-partum)
Virchow’s Triad: components of hypercoaguable state
Inherited prothrombotic traits
• Ex: Factor V Leiden or antithrombin deficiency
Acquired factors:
• Inflammation
• Lupus anticoagulants (LAC)
• Antiphospholipid antibodies (APA)
• Consumption/loss of natural anticoagulants (DIC or nephrotic syndrome)
• Malignancy (especially adenocarcinomas)
• Pharmacologic estrogen (Oral contraceptives, hormone replacement)
• Increased platelet reactivity = myeloproliferative disease (Polycythemia vera, Essential thrombocythemia)
• Heparin-induced thrombocytopenia
Lupus anticoagulants (LAC)
- Subset of phospholipid-dependent Abs
- Inhibit in vitro coagulation
- Does NOT require diagnosis of SLE
- Associated with arterial or venous thrombosis (NOT bleeding)
- Prolong the aPTT (or other phospholipid-dependent clotting assay) in an inhibitor pattern (not corrected by mixing studies)
- Neutralized by excess lipid or platelets
Antiphospholipid antibodies (APA)
- Phospholipid-dependent Abs
- Directed against variety of epitopes (ex: anti-cardiolipin, B2-GPI Abs)
- Do not affect in vitro coagulation
Pathologic significance if:
o Present in high titers
o Associated with other autoantibodies
o In patients with antiphospholipid Ab syndrome
Hyperhomocysteinemia
• Risk factor for BOTH arterial and venous thrombosis = hyperhomocysteinemia
Severe elevations
• From homozygous cystathionine synthetase deficiency
Mild elevations
• More common
• From other inherited/acquired genetic defects
Results → induction of endothelial procoagulant activity
Multigenic etiology of VTE and risks
Gene defect ≠ disease!
• Most people with single gene defects are asymptomatic
The most common gene defects are only present in a minority of VTE cases.
• FV Leiden is present in 20-40% of VTE cases
Multiple defects interact, often synergistically.
• FV Leiden and Protein C deficiency
Ascertainment bias profoundly affects the relative risk estimates for specific gene defects.
• General population vs. thrombophilic family
• Relative risk seems high (~10-30x) but absolute risk (0.1-0.8) still low!
• Important to keep in mind when bleeding risk from long-term anticoagulation ~1-3%/year
Evaluating Venous thrombosis
Idiopathic VTE = more likely to recur than provoked VTE:
• Any event that occurs in the absence of a precipitating event or clinical risk factor for VTE
• Associated with recurrence rates in the 20-30% range
• The occurrence of idiopathic VTE is a better predictor of recurrence than laboratory evaluation for “hypercoagulable states”
Family history predicts thrombotic risk just as well as lab studies
o Without family history = presence of thrombophilia does NOT predict thrombotic risk
Result: evaluating inherited risk factors does NOT give meaningful stratification or recurrence risk for most VTE patients
• Little/no clinical utility
List five hereditary disorders that increase the risk of venous thrombosis, and briefly describe how the genetic defect in each condition increases the risk of thrombosis.
Deficiency of major coagulation inhibitors:
o Uncommon, genetically heterogeneous conditions
o Associated with up to 20x increased VTE risk in some families
Includes: Antithrombin Deficiency • Rare • Autosomal dominant • AT levels ~50% of normal Protein C Deficiency • Autosomal dominant • PC activity ~50% of normal • Homozygous form = neonatal purpura fulminans (severe thrombotic disorder) Protein S Deficiency • Rare • Autosomal dominant • Homozygous form = neonatal purpura fulminans (severe thrombotic disorder)
Other conditions
o More common but less risky (3-5 fold increased VTE risk)
Includes:
Factor V Leiden (~ 5% of US population = common)
• Autosomal dominant
• 4-5x increase risk of VTE
• Results from single base pair change in V gene → eliminates Protein C cleavage site in Va → activated protein C resistance → defective termination of coagulation by activated Protein C
Prothrombin G20210A polymorphism
• Relatively common (2% population)
• Autosomal dominant
• 15-30% higher levels of prothrombin antigen in plasma
• Due to single base pair change in 3’ untranslated region of prothrombin gene
Other candidates (many!)
Describe the major diagnostic tests for venous thromboembolism
Symptoms & physical examination
o Not sufficiently sensitive or specific to diagnose VTE
D-dimer level
o Sensitive but not specific (negative test makes VTE unlikely = good for rule-out)
Objective documentation of thrombus o Critical to establishing the diagnosis Includes: Deep Venous Thrombosis Duplex Doppler ultrasonography o Vein compressible = no DVT o Vein not compressible = DVT Contrast or MR venography
Pulmonary Embolism Ventilation-perfusion scan (V/Q scan) o Ventilation without perfusion → PE Spiral computed tomography (CT) Pulmonary angiography (rarely used)
Describe the most important laboratory findings and clinical features associated with
antiphospholipid syndrome.
• Persistently positive tests for antiphospholipid antibodies
o LAC and other high titer APA
Complications:
o Arterial and/or venous thrombosis
o Recurrent fetal loss
o Autoimmune thrombocytopenia or hemolytic anemia
May be associated with SLE, or with no associated condition (primary antiphospholipid syndrome).
Occasionally associated with “catastrophic” presentation with multiple organ failure
Some patients may require lifelong anticoagulation
Treatment of VTE:
Begin treatment ASAP with heparin or comparable rapid-acting anticoagulant (ie. Rivaroxaban)
• Continue for at least 5 days
• Recurrence rate is substantially higher if treated with vitamin K antagonist (i.e., warfarin) only
• Monitor heparin with PTT or comparable assay
Begin treatment with warfarin within 1-2 days
• Overlap with heparin at least 4 days
• INR should be therapeutic (2-3) before stopping heparin
Continue warfarin for 3-6 months, INR target of 2-3
• Idiopathic DVT = often treated for 6-12 months since higher risk of recurrence
Consider indefinite treatment for patients at highest risk for recurrence:
• History of ≥ 2 episodes VTE
• Other strong clinical risk factors for recurrence
• Antiphospholipid syndrome
Presence of other forms of thrombophilia is not an independent indication for prolonging therapy
Special cases:
Heparin-induced thrombocytopenia (HIT)
• Stop all forms of Heparin
• Direct thrombin inhibitor or fondaparinux
• Warfarin once platelets normal
Cancer-associated VTE
• Lower recurrence rate with prolonged LMWH vs. warfarin
Placement of IVC filter may be indicated when there is failure of anticoagulant therapy or a contraindication to giving it
VTE in hospitalized patients:
o Postoperative VTE = 2nd most common medical complication in hospitalized patients
o Pulmonary embolism is the most common cause of preventable hospital death
Treatment options:
• Low dose heparin, LMWH or comparable drug most effective
• Elastic stockings or pneumatic compression devices (reduce venous stasis) an alternative for patients at high risk of bleeding
o Most thrombotic events occur in 1st 2-3 weeks after hospital discharge
