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NOTES: Heme/Onc > 255/256/258 - Thrombophilia, Thrombotic Disorders (VTE), and Anticoagulant Therapy > Flashcards

255/256/258 - Thrombophilia, Thrombotic Disorders (VTE), and Anticoagulant Therapy Flashcards

1
Q

Compare the relative and absolute risk of thrombosis with the inherited thrombophilias

A

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

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2
Q

What 3 antibodies are associated with antiphospholipid antibody syndrome?

A
  1. Lupus anticoagulant
  2. Anti-beta 2 glycoprotein antibody
  3. 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)
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3
Q

What is the inhibitor for dabigatran?

A

Idarucizumab

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4
Q

List the 2 major categories of direct acting oral anticoagulants

A
  • Anti-Xa agents (-xaban)​
    • Rivaroxaban
    • Apixaban
    • Endoxaban
  • Direct thrombin (IIa) inhibitors (-gat-, -rudin)
    • Argatroban
    • Dabigatran
    • Bivalirudin
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5
Q

Is the following characteristic of arterial or venous thrombus?

Red (rich in RBCs)

A

Venous (due to stasis of blood)

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6
Q

What comorbidity increases bleeing risk in patients on LMWH?

A

Renal failure (b/ LMWH is cleared by the kidneys –> too much LMWH in the body w/ lead to bleeding)

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7
Q

What enzyme activates clotting factors II, VII, IX, and X?

What is the cofactor?

A

(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

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8
Q

What is the most common cause of VTE?

A

Abnormal blood flow

  • Bedrest
  • After surgery
  • Long flights
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9
Q

How long after starting therapy does it take for warfarin to achieve full therapeutic effects?

A

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
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10
Q

A clot in which veins are most likely to embolize to the lungs?

A

Proximal lower extremity clots are most likely to cause pulmonary embolism

proximal lower extremity DVT > distal lower extremity DVT > Upper extremity DVT

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11
Q

List 2 low-molecular weight heparin agents

A

Enoxaparin

Dalteparin

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12
Q

List 4 complications of VTE

A
  • 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
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13
Q

What is the goal INR for Warfarin therapy?

A

2-3

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14
Q

Which outpatient anticoagulant is safest to use in renal disease?

A

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*
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15
Q

What inherited thrombophilia results in relative heparin resistance?

A

Antithrombin deficiency

Heparin works by potentiating the effects of antithrombin

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16
Q

List 2 demographics for whom direct oral anticoagulants should not be prescribed

A

Pregnant patients

Patients with renal failure

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17
Q

What are the indications for thrombolytic therapy in VTE?

A
  • 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
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18
Q

What imaging method is most commonly used for suspected PE?

What method is gold standard?

A
  • Commonly used = CT pulmonary angiogram
  • Gold standard = Pulmonary Angiography
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19
Q

Which clotting factors are inactivated by protein C? (2)

A

Va, VIIIa

Protein C cleaves Va, and then V helps protein C cleave VIIIa

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20
Q

When would an IVC filter be used to treat VTE?

A

If a pt has acute PE or proximal DVT and cannot tolerate therapeutic anticoagulation

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21
Q

Is unfractionated heparin safe to use in patients with renal disease?

A

Yes

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22
Q

List 3 loss of functional inherited thrombophilias

A
  • Protein C deficiency
  • Protein S deficiency
  • Antithrombin deficiency
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23
Q

What clotting factors are inhibited by antithrombin?

A

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*
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24
Q

Which inherited thrombophilia mutation is associated with the greatest risk of thrombosis?

A

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
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25
Q

Is the following characteristic of arterial or venous thrombus?

Forms in high shear areas

A

Arterial

in places with endothelial damage

26
Q

Is Factor V Leiden autosomal recessive or dominant?

A

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

27
Q

Which inherited thrombophilia mutation is associated with the lowest risk of thrombosis?

A

Heterozygous prothrombin gene mutation

  • mutation leads to increased expression of prothrombin –> increased thrombotic events
  • Factor V Leiden has the highst risk of thrombosis
28
Q

What are the differences in location and pathogenesis of arterial vs. venous thrombi?

A
  • 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

29
Q

List 3 gain of function inherited thrombophilias

A
  • 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
30
Q

What is responsible for the transient pro-thrombotic state after starting warfarin?

What is the consequence

A
  • 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

31
Q

What are the two most common initiating events for arterial thrombus?

A
  • Injury to vessel wall (most common overall)
    • Usually superimposed on an atherosclerotic plaque
  • Embolism (rare)
32
Q

List the 4 most common symptoms of VTE

A
  1. Pain
  2. Unilateral swelling
  3. Warmth
  4. Redness
33
Q

When is it appropriate to test for an inherited thrombophilia?

A

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
34
Q

List the 3 items in Virchow’s Triad of thrombosis

(3 things that lead to a pro-thrombotic state)

A
  1. Endothelial injury
  2. Abnormal blood flow
  3. Hypercoagulation
35
Q

What anticoagulant therapy poses particular risk to people with protein C deficiency?

A

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
36
Q

What is the difference between a massive and a submassive PE?

A

Massive = hemodynamically unstable; pt is in shock

Submassive = Right Ventricle strain with no hemodynamic instability

37
Q

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)

A

If the pt has renal failure:

  • Contrast is contraindicated
  • Use an echocardiogram instead
38
Q

List 2 anatomic syndromes that would increase a patient’s risk of VTE

A
  • 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
39
Q

What is the major contraindication to the direct oral anticoagulants?

A

Renal failure

40
Q

What is the inhibitor for Heparin and LMWH?

A

Protamine

  • cationic peptide that forms ion pair w/ heparin or LMWH –> cannot have anticoagulant activity
41
Q

How does the risk of VTE change with…

  • A major risk factor
  • A minor risk factor
A
  • A major risk factor: >10 fold increased risk
  • A minor risk factor: 3-10 fold increased risk
42
Q

List 2 herbal remedies that increase warfarin levels and 1 that decreases levels

A

Increase: Ginkgo, Garlik

Decrease: St. John’s Wort

43
Q

Why is VTE considered a chronic disease?

A

Large potential for recurrence

44
Q

List 3 direct thrombin inhibitors

A
  1. Bivalirudin
  2. Argatroban
  3. Dabigatran

-gat- or -rudin

45
Q

List 3 indications for tPA

A

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
46
Q

Is the following characteristic of arterial or venous thrombus?

Platelet-rich

A

Arterial

47
Q

How does the prothrombin gene mutation G20210A lead to increased risk of thrombosis?

A

Mutation is in the promotor region

-> More prothrombin synthesis, increased thrombotic events

48
Q

How does Factor V Leiden increase the risk of venous thrombosis?

A

Factor V leiden is resistant to cleavage (and thus, inactivation) by activated protein C –> FVa activates Factor X –> increased thrombotic events

49
Q

What is post-thrombotic syndrome?

A
  • 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
50
Q

How can mutations in VKORC1 and CYP2C9 affect warfarin sensitivity?

A
  • VKORC1 = target of warfarin
    • Mutation –> increased resistance to warfarin
  • CYP2C9 increase sensitivity to warfarin by decreasing warfarin clearance
51
Q

Which direct oral anticoagulant is relies least on the kidney for excretion?

A

Apixaban (Direct Factor Xa inhibitors)

52
Q

Describe the appropriate method for diagnosing a suspected PE or DVT

A

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
53
Q

What is the appropriate management of VTE?

A

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

54
Q

What is the inhibitor for rivaroxaban and other direct FXa inhibitors?

A

Andexanet alpha or 4 factor Prothrombin complex concentrate

55
Q

List 3 anti-Xa agents (oral)

A
  1. Rivaroxaban
  2. Apixaban
  3. Endoxaban

(-xaban)

56
Q

Describe the testing assay for lupus anticoagulant

A

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
57
Q

What constitutes a high Wells score in:

  • DVT:
  • PE:
A
  • DVT: ≥ 3
  • PE: >6
58
Q

Which anticoagulant is the only one known to be safe in pregnancy?

A

Low molecular weight heparin (LMWH)

Warfarin is NOT safe in pregnancy, but is safe in breastfeeding

59
Q

Is malignancy a risk factor for VTE?

A

Yes

Up to 20% of VTE in the community is associated with malignancy

60
Q

Why do patients on heparin need close monitoring?

A

Risk of heparin-induced thrombodytopenia

Heparin undergoes extensive protien binding

61
Q

Which imaging method is most commonly used to assess DVT?

What method is gold standard?

A
  • Commonly used = Compression ultrasound
    • ​Most sensitive for proximal veins
  • Gold standard = Venography
  • Do if high clinical suspicion*
  • OR*
  • Low suspicion and positive D dimer*
62
Q

What is INR?

A

INR = International Normalized Ratio (INR)

  • developed to standardize PT results.
  • INR = (patient PT / Control PT) ^ISI
    • ​ISI is specific for each thromboplastin reagent

NOTES: Heme/Onc (36 decks)

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