255/256/258 - Thrombophilia, Thrombotic Disorders (VTE), and Anticoagulant Therapy Flashcards
Compare the relative and absolute risk of thrombosis with the inherited thrombophilias
Relative risk increases several fold
Absolute risk remains relatively low; can become higher when combined with another risk factor (OCPs, smoking), but still low enough that we don’t need to screen for thrombophilias before prescribing OCPs
What 3 antibodies are associated with antiphospholipid antibody syndrome?
- Lupus anticoagulant
- Anti-beta 2 glycoprotein antibody
- Anti-cardiolipin antibody
Antiphospholipid Antibody Syndrome:
- acquired and not inherited
- have antibodies directed against phospholipids and PL-binding proteins
- associated w/ arterial and venous thrombosis and pregnancy complications
- Dx requires lab criteria (antibodies) and clinical criteria (thrombosis or obstetric complications)
What is the inhibitor for dabigatran?
Idarucizumab
List the 2 major categories of direct acting oral anticoagulants
-
Anti-Xa agents (-xaban)
- Rivaroxaban
- Apixaban
- Endoxaban
-
Direct thrombin (IIa) inhibitors (-gat-, -rudin)
- Argatroban
- Dabigatran
- Bivalirudin
Is the following characteristic of arterial or venous thrombus?
Red (rich in RBCs)
Venous (due to stasis of blood)
What comorbidity increases bleeing risk in patients on LMWH?
Renal failure (b/ LMWH is cleared by the kidneys –> too much LMWH in the body w/ lead to bleeding)
What enzyme activates clotting factors II, VII, IX, and X?
What is the cofactor?
(Vitamin K Epoxice Reductase) VKOR
Vitamin K is the cofactor
VKOR is the target of Warfarin –> warfarin causes acquired deficiency in all Vit K dependent clotting factors
What is the most common cause of VTE?
Abnormal blood flow
- Bedrest
- After surgery
- Long flights
How long after starting therapy does it take for warfarin to achieve full therapeutic effects?
5 days
- FVII will drop first (shortest half life)
-
Not considered therapeutic until FII drops (which has the longest half life)
- Must decrease below 20%
- Use a heparin bridge if immediate anticoagulation is necessary
A clot in which veins are most likely to embolize to the lungs?
Proximal lower extremity clots are most likely to cause pulmonary embolism
proximal lower extremity DVT > distal lower extremity DVT > Upper extremity DVT
List 2 low-molecular weight heparin agents
Enoxaparin
Dalteparin
List 4 complications of VTE
- Death
- Recurrent thrombosis (VTE again)
-
Post-thrombotic syndrome (increased pressure + distension in veins –> valves are incompetent and allow reflux
- symptoms of parethesia, pain, sensation of heaviness, residual swelling, and chronic venous insufficiency
-
Chronic Thromboembolic Pulmonary hypertension (CETPH)
- pulmonary vasculature becomes attenuated due to vessel wall thickening and luminal narrowing
What is the goal INR for Warfarin therapy?
2-3
Which outpatient anticoagulant is safest to use in renal disease?
Warfarin - not excreted renally
- Of the Direct Oral Anticoagulants (DOACs), Apixaban relies least on renal excretion*
- For inpatient/acute setting, unfractionated heparin is safe in renal disease, but NOT LMWH or fondaparinux*
What inherited thrombophilia results in relative heparin resistance?
Antithrombin deficiency
Heparin works by potentiating the effects of antithrombin
List 2 demographics for whom direct oral anticoagulants should not be prescribed
Pregnant patients
Patients with renal failure
What are the indications for thrombolytic therapy in VTE?
- Systemic therapy if massive PE ( has hemodynamic instability)
- Catheter-directed therapy:
- If DVT is life or limb threatening
- If PE is submassive but high risk
What imaging method is most commonly used for suspected PE?
What method is gold standard?
- Commonly used = CT pulmonary angiogram
- Gold standard = Pulmonary Angiography
Which clotting factors are inactivated by protein C? (2)
Va, VIIIa
Protein C cleaves Va, and then V helps protein C cleave VIIIa
When would an IVC filter be used to treat VTE?
If a pt has acute PE or proximal DVT and cannot tolerate therapeutic anticoagulation
Is unfractionated heparin safe to use in patients with renal disease?
Yes
List 3 loss of functional inherited thrombophilias
- Protein C deficiency
- Protein S deficiency
- Antithrombin deficiency
What clotting factors are inhibited by antithrombin?
IIa, Xa
- Note: heparin drugs potentiate the effects of antithrombin*
- Heparin: inactivates IIa, Xa*
- LMWH: more specific for Xa*
- Fondaparinux: Most specific for Xa, minimal effects on IIa*
Which inherited thrombophilia mutation is associated with the greatest risk of thrombosis?
Factor V Leiden
- mutation in factor V where it can’t be cleaved by activated protein C (APC) anymore –> FVa remains active –> activates prothrombin –> increases thrombotic events
- Venous thrombosis most common
Is the following characteristic of arterial or venous thrombus?
Forms in high shear areas
Arterial
in places with endothelial damage
Is Factor V Leiden autosomal recessive or dominant?
Autosomal dominant
- Heterozygous: 3-5 fold increased risk of first VTE
- Homozygous: 18 fold increased risk of first VTE
FVL has the highest risk of thrombosis of the inherited thrombophilias
Which inherited thrombophilia mutation is associated with the lowest risk of thrombosis?
Heterozygous prothrombin gene mutation
- mutation leads to increased expression of prothrombin –> increased thrombotic events
- Factor V Leiden has the highst risk of thrombosis
What are the differences in location and pathogenesis of arterial vs. venous thrombi?
- Arterial
- High-shear areas
- Driven by platelets (Arterial thrombi will be platelet rich)
- Venous
- Low-flow areas
- Driven by pro-coagulant factors
Anti-platelet drugs are better at preventing arterial thrombi than venous thrombi
List 3 gain of function inherited thrombophilias
- Factor V Leiden –> factor V can’t be cleaved by APC anymore
- Prothrombin gene mutation (G20210A) –> increased expression of prothrombin
- Increased factor VIII –> increased activation of FX –> increased thrombotic events
What is responsible for the transient pro-thrombotic state after starting warfarin?
What is the consequence
- Protein C (endogenous anticoagulant) drops first –> Prothrombotic state
- can lead to widespread thrombosis of post-capillary venules in skin, muscle –> warfarin necrosis :(
Prevent by overlapping with Heparin
What are the two most common initiating events for arterial thrombus?
-
Injury to vessel wall (most common overall)
- Usually superimposed on an atherosclerotic plaque
- Embolism (rare)
List the 4 most common symptoms of VTE
- Pain
- Unilateral swelling
- Warmth
- Redness
When is it appropriate to test for an inherited thrombophilia?
Only if the test will influence the management
- Don’t test if pt has a provoked blood clot
- Don’t test during an acute event
List the 3 items in Virchow’s Triad of thrombosis
(3 things that lead to a pro-thrombotic state)
- Endothelial injury
- Abnormal blood flow
- Hypercoagulation
What anticoagulant therapy poses particular risk to people with protein C deficiency?
Warfarin
-> can lead to Warfarin-induced skin necrosis
- Warfarin inhibits II, VII, IX, X, Protein C, Protein S
- Protein C decreases before all of the other factors, resulting in a transient hypercoagulable state
- overalap with heparin in the setting of an acute clot to prevent this
What is the difference between a massive and a submassive PE?
Massive = hemodynamically unstable; pt is in shock
Submassive = Right Ventricle strain with no hemodynamic instability
When would it be contraindicated to do a CTPA in a patient with suspected PE?
(Assume the pt has a high enough Wells score to do imaging)
If the pt has renal failure:
- Contrast is contraindicated
- Use an echocardiogram instead
List 2 anatomic syndromes that would increase a patient’s risk of VTE
-
May-Thurner syndrome
- Chronic compression of the left common iliac vein between the right common iliac artery and 1st vertebral body
-
Venous thoracic outlet syndrome
- compressio of subclavian vein as it passes from lower neck to armpit.
- most likely will result in upper extremity DVT
What is the major contraindication to the direct oral anticoagulants?
Renal failure
What is the inhibitor for Heparin and LMWH?
Protamine
- cationic peptide that forms ion pair w/ heparin or LMWH –> cannot have anticoagulant activity
How does the risk of VTE change with…
- A major risk factor
- A minor risk factor
- A major risk factor: >10 fold increased risk
- A minor risk factor: 3-10 fold increased risk
List 2 herbal remedies that increase warfarin levels and 1 that decreases levels
Increase: Ginkgo, Garlik
Decrease: St. John’s Wort
Why is VTE considered a chronic disease?
Large potential for recurrence
List 3 direct thrombin inhibitors
- Bivalirudin
- Argatroban
- Dabigatran
-gat- or -rudin
List 3 indications for tPA
Tissue Plasminogen Activator (tPA) = converts plasminogen to plasmin, which is the main enzyme involved in thrombolysis
- Acute coronary thrombosis
- Massive PE (hemodynamic instability)
- Thrombotic stroke
Is the following characteristic of arterial or venous thrombus?
Platelet-rich
Arterial
How does the prothrombin gene mutation G20210A lead to increased risk of thrombosis?
Mutation is in the promotor region
-> More prothrombin synthesis, increased thrombotic events
How does Factor V Leiden increase the risk of venous thrombosis?
Factor V leiden is resistant to cleavage (and thus, inactivation) by activated protein C –> FVa activates Factor X –> increased thrombotic events
What is post-thrombotic syndrome?
- Venous occlusion by thrombi causes increased venous pressure
- -> Venous hypertension
-
Valves become incompetent; even when VTE disappears, there is reflux
- Pain, paresthesia, heaviness, swelling
- Venous insufficiency; discoloration, ulcers, dilated veins
- Can cause permanent disability
How can mutations in VKORC1 and CYP2C9 affect warfarin sensitivity?
- VKORC1 = target of warfarin
- Mutation –> increased resistance to warfarin
- CYP2C9 increase sensitivity to warfarin by decreasing warfarin clearance
Which direct oral anticoagulant is relies least on the kidney for excretion?
Apixaban (Direct Factor Xa inhibitors)
Describe the appropriate method for diagnosing a suspected PE or DVT
High clinical suspicion: (Wells score > 6 for PE or ≥3 for DVT)
- -> Immediate imaging (CTPulmonary Angiogram for PE, compression Ultrasound for DVT)
Low/intermediate clinical suspicion:
- -> D-dimer
- If low, can rule out PE/DVT
- If high, do CTPA for PE, compression US for DVT
What is the appropriate management of VTE?
Anticoagulation
- 3 months if provoked by a major transient risk factor
- Indefinite if unprovoked, or ongoing risk factor
- Balance with bleeding risk
Thrombolytic therapy only given…
- Systemically if massive PE (hemodynamic instability)
- Catheter-directed if DVT is life or limb threatening, or PE is submassive but high risk
IVC filter only if pt cannot tolerate anticoagulation
What is the inhibitor for rivaroxaban and other direct FXa inhibitors?
Andexanet alpha or 4 factor Prothrombin complex concentrate
List 3 anti-Xa agents (oral)
- Rivaroxaban
- Apixaban
- Endoxaban
(-xaban)
Describe the testing assay for lupus anticoagulant
A patient is positive for lupus anticoagulant if…
- Prolonged clot-based assay (ex: PTT)
- No correction on mixing study (mix patient plasma w/ normal plasma)
- Corrects with addition of excess phospholipid
What constitutes a high Wells score in:
- DVT:
- PE:
- DVT: ≥ 3
- PE: >6
Which anticoagulant is the only one known to be safe in pregnancy?
Low molecular weight heparin (LMWH)
Warfarin is NOT safe in pregnancy, but is safe in breastfeeding
Is malignancy a risk factor for VTE?
Yes
Up to 20% of VTE in the community is associated with malignancy
Why do patients on heparin need close monitoring?
Risk of heparin-induced thrombodytopenia
Heparin undergoes extensive protien binding
Which imaging method is most commonly used to assess DVT?
What method is gold standard?
- Commonly used = Compression ultrasound
- Most sensitive for proximal veins
- Gold standard = Venography
- Do if high clinical suspicion*
- OR*
- Low suspicion and positive D dimer*
What is INR?
INR = International Normalized Ratio (INR)
- developed to standardize PT results.
- INR = (patient PT / Control PT) ^ISI
- ISI is specific for each thromboplastin reagent
