Venous Thromboembolism Monte

What is VTE?

• Clot formation in venous circulation

• Manifests as deep vein thrombosis (DVT) or pulmonary embolism (PE)

What are VTE risk factors?

• Increasing age

• History of VTE

• Blood stasis

  • Immobility, paralysis, obesity

• Vascular injury

  • Surgery, trauma, venous catheters

• Hypercoagulability

  • Cancer, coagulation factor abnormalities, antiphospholipid antibodies, pregnancy, certain drugs

What makes up Virchow’s Triad?

• Blood stasis

• Vascular injury

• Hypercoagulability

What is clinical presentation of DVT?

• Unilateral leg swelling

• Pain

• Tenderness

• Erythema

• Warmth

What is clinical presentation of PE?

• Cough

• Chest pain/tightness

• SOB

• Palpitations

• Hemoptsis (cough up blood)

• Dizziness

• Tachypnea

• Tachycardia

• Diaphoresis (sweating)

• Cyanosis

• Hypotension

• Shock

What is VTE diagnosis?

• D-dimer (blood level)

• Compression ultrasound (non-invasive) or venography (more accurate, invasive, expensive) for DVT diagnosis

• Ventilation/perfusion (V/Q) scan (non-invasive) or computed tomography (CT) pulmonary angiography (more accurate, invasive, expensive) for PE diagnosis

What are nonpharmacologic prevention of VTE?

• Ambulation

• Compression stockings

• Intermittent pneumatic compression (IPC) devices

• Inferior vena cava (IVC) filters- if at high risk & cannot be on anticoagulation

What is pharmacologic prevention of VTE?

Anticoagulation

What is treatment of VTE?

• Anticoagulation is mainstay of VTE treatment

• Thrombolytic therapy in select cases

What are the pharmacologic therapies for VTE prophylaxis?

• UFH

• LMWH (Enoxaparin, Dalteparin)

• Factor Xa (-)s (Apixaban, Rivaroxaban, Eboxaban, Fondaparinux)

• Direct Thrombin (-) (Dabigatran)

What are the pharmacologic therapies for VTE treatment?

• UFH

• LMWH (Enoxaparin, Dalteparin)

• Factor Xa (-)s (Apixaban, Rivaroxaban, Eboxaban, Fondaparinux)

• Direct Thrombin (-) (Dabigatran)

• Vitamin K Antagonist (Warfarin)

What is dosing** of UFH?

• Prophylaxis: 5,000 units SC q8-12h

• Tx: 80 units/kg IV bolus followed by 18 units/kg/hr IV infusion

What are contraindications of UFH?

• Uncontrolled active bleeding

• Severe thrombocytopenia

• History of HIT

• Hypersensitivity to pork

What are side effects of UFH?

• Bleeding

• Thrombocytopenia

• HIT

• Hyperkalemia

What is monitoring of UFH?

• aPTT or anti-Xa

• Platelets

• Hgb

• Hct

What is dosing** of Enoxaparin (Lovenox)?

• Prophylaxis: 30 mg SC q12h or 40 mg SC daily

  • CrCl <30 mL/min: 30 mg SC daily

• Tx: 1 mg/kg SC q12h or 1.5 mg/kg SC daily

  • CrCl <30 mL/min: 1 mg/kg SC daily

What are contraindications of Enoxaparin (Lovenox)?

• History of HIT

• Active major bleed

• Hypersensitivity to pork

What are side effects of Enoxaparin (Lovenox)?

• Bleeding

• Anemia

• Thrombocytopenia

• Hyperkalemia

• Increased LFTs

What is monitoring of Enoxaparin (Lovenox)?

• Anti-Xa (pregnancy, obesity, renal function**)

• Platelets

• Hgb

• Hct

• SCr

What is dosing of Dalteparin (Fragmin)?

• Prophylaxis: 2,500-5,000 units SC daily

• Tx (off-label): 200 units/kg SC daily or 100 units/kg SC BID

What are contraindications of Dalteparin (Fragmin)?

• History of HIT

• Active major bleed

• Hypersensitivity to pork

What are side effects of Dalteparin (Fragmin)?

• Bleeding

• Anemia

• Thrombocytopenia

• Hyperkalemia

• Increased LFTs

What is monitoring of Dalteparin (Fragmin)?

• Anti-Xa

• Platelets

• Hgb

• Hct

• SCr

What is Heparin-Induced Thrombocytopenia (HIT)?

• Can occur in up to 5% of pts exposed to heparin

• Up to 50% develop thromboembolic complications, which is associated w/ a 20-30% mortality rate

• Incidence varies based on risk factors

What are the risk factors for HIT?

• Source of heparin: UFH (bovine » porcine) > LMWH

• Duration of heparin exposure: >4 days

• Past exposure: w/in 30 days » w/in 100 days

• Gender: female > male

What is HIT pathophysiology?

• Anti-heparin/PF4 IgG immune complex..

• Platelet activation

  • Positive feedback loop

  • Platelet aggregation & removal

  • Thrombosis

• Subendothelial matrix (collagen, VWF)

What are HIT complications?

• Thrombocytopenia

• Venous thrombosis

• Arterial thrombosis

• Limb gangrene

• Skin lesions/necrosis

• Disseminated intravascular coagulation

• Death

What is HIT diagnosis based on?

• </= 3- low probability for HIT

• 4-5- intermediate probability for HIT

• >/= 6- high probability for HIT

What give 2 points?

• Thrombocytopenia

  • Platelet count fall >50% & platelet nadir >/= 20,000

• Timing of platelet count fall

  • Clear onset b/w days 5-10 OR

  • Platelet fall </= 1 day (prior heparin exposure w/in 30 days)

• Thrombosis/ other sequelae

  • New thrombosis or skin necrosis at heparin injection/ acute systemic rxn after IV heparin bolus

What gives 1 point?

• Thrombocytopenia

  • Platelet count fall 30-50% & platelet nadir 10-19,000

• Timing of platelet count fall

  • Consistent w/ days 5-10 fall, but not clear/onset after day 10 OR

  • Fall </= 1 day (prior heparin exposure 30-100 days ago)

• Thrombosis/ other sequelae

  • Progressive or recurrent thrombosis or nonnecrotizing (erythematous) skin lesions or suspected thrombosis

What are the HIT lab tests?

• Enzyme-linked immunosorbent assay (ELISA)

  • Immunoassay detects PF4 antibodies in serum sample

  • High sensitivity but low specificity

• Functional assays

  • Serotonin release assay (SRA): gold standard, expensive

    • Measures platelet activation by detecting release of serotonin from test platelets; takes 1-2 days for results

    • High sensitivity & specificity

  • Heparin-induced platelet aggregation (HIPA)

    • Measures platelet aggregation of healthy & suspected pts in presence & absence of low-dose heparin

    • High specificity but low sensitivity

What is HIT tx?

• Stop all forms of heparin & LMWH

• Argatroban is recommended for anticoagulation

  • If urgent cardiac surgery/PCI is required, bivalirudin is preferred anticoagulant

• Do not start warfarin until plateltes are at least 150,000/mm³ & overlap w/ a non-heparin anticoagulant for min of 5 days & until INR is w/in target range for 24 hours

  • Argatroban falsely elevates INR

What is the duration of therapy for HIT tx?

• 3 months for pts w/ HIT & thrombosis

• 1 month for pts w/ HIT & NO thrombosis

What is dosing (HIT) of Argatroban?

• 2 mcg/kg/min IV infusion (max 10 mcg/kg/min)

• Decrease dose in hepatic impairment

What are contraindications of Argatroban?

Active major bleeding

What are side effects of Argatroban?

• Bleeding

• Anemia

• Hematoma

What is monitoring of Argatroban?

• aPTT

• Platelets

• Hgb

• Hct

• Liver function

What is dosing (HIT: off label) of Bivalirudin (Angiomax)?

• 0.15-0.2 mg/kg/hr IV infusion

• Decrease dose when CrCl <30 mL/min

What are contraindications of Bivalirudin (Angiomax)?

Active major bleeding

What are side effects of Bivalirudin (Angiomax)?

• Bleeding

• Anemia

• Hematoma

What is monitoring of Bivalirudin (Angiomax)?

• ACT

• Platelets

• Hgb

• Hct

• Renal function

What is dosing of Apixaban (Eliquis)?

• Prophylaxis (after knee/hip replacement): 2.5 mg PO BID x 12 days after knee or 35 days after hip replacement surgery

• Tx: 10 mg PO BID x 7 mg, then 5 mg PO BID

What are contraindications of Apixaban (Eliquis)?

• Active pathological bleeding

• Avoid use w/ strong dual inducers of CYP3A4 & P-gp

What are side effects of Apixaban (Eliquis)?

• Bleeding

• Anemia

What is monitoring of Apixaban (Eliquis)?

• Hgb

• Hct

• SCr

• LFTs

What is dosing of Rivaroxaban (Xarelto)?

• Prophylaxis:

  • After knee/hip replacement: 10 mg PO daily x 12 days after knee or 35 days after hip replacement surgery

  • Acutely ill medical pts: 10 mg PO daily x 31-39 days

• Tx: 15 mg PO BID x 21 days, then 20 mg PO daily

  • CrCl <30 mL/min: avoid use

What are contraindications of Rivaroxaban (Xarelto)?

• Active pathological bleeding

• Avoid use w/ strong dual inducers/inhibitors of CYP3A4 & P-gp

What are side effects of Rivaroxaban (Xarelto)?

• Bleeding

• Anemia

What is monitoring of Rivaroxaban (Xarelto)?

• Hgb

• Hct

• SCr

• LFTs

What is dosing of Edoxaban (Savaysa)?

Tx: 60 mg PO daily (start after 5-10 days of parenteral anticoagulation)

• CrCl 15-50mL/min or </= 60 kg or on certain P-gp inhibitors: 30 mg daily

• CrCl <15mL/min: use not recommended

What are contraindications of Edoxaban (Savaysa)?

Active pathological bleeding

What are side effects of Edoxaban (Savaysa)?

• Bleeding

• Anemia

• Rash

• Increased LFTs

What is monitoring of Edoxaban (Savaysa)?

• Hgb

• Hct

• SCr

• LFTs

What is dosing of Fondaparinux (Arixtra)?

• Prophylaxis: >/=50 kg: 2.5 SC daily (<50 kg: contraindicated)

• Tx:

  • <50 kg: 5 mg SC daily

  • 50-100 kg: 7.5 mg SC daily

  • >100 kg: 10 mg SC daily

• Both indications:

  • CrCl 30-50mL/min: use caution

  • CrCl <30mL/min: contraindicated

What are contraindications of Fondaparinux (Arixtra)?

• Active major bleed

• CrCl <30mL/min

• <50 kg (prophylaxis)

• Thrombocytopenia

• Bacterial endocarditis

What are side effects of Fondaparinux (Arixtra)?

• Bleeding

• Anemia

• Thrombocytopenia

• Hypokalemia

• Hypotension

What is monitoring of Fondaparinux (Arixtra)?

• Anti-Xa

• Platelets

• Hgb

• Hct

• SCr

What is dosing of Dabigatran (Pradaxa)?

• Prophylaxis (after hip replacement, off-label for knee): 110 mg PO x 1 on day 1, then 220 mg PO daily

  • CrCl <50mL/min & P-go inhibitor: avoid use

• Tx: 150 mg PO BID (start after 5-10 days of parenteral anticoagulation)

  • CrCl <50mL/min & P-gp inhibitor: avoid use

What are contraindications of Dabigatran (Pradaxa)?

• Active pathological bleeding

• Mechanical prosthetic heart valve(s)

What are side effects of Dabigatran (Pradaxa)?

• Bleeding (more GI)

• Dyspepsia

• Gastritis-like symptoms

What is monitoring of Dabigatran (Pradaxa)?

• Hgb

• Hct

• SCr

What is dosing of Warfarin (Jantoven)?

Tx: 10 mg daily for first 2 days, then adjust dose per INR values (goal 2-3) in healthy outpatients

• Lower doses (</=5 mg) for elderly, malnourished, liver disease, HF, high risk of bleeding, or drug-drug interactions

• W/ acute DVT/PE, start warfarin on same day as parenternal anticoagulant & continue both for min of 5 days until INR is 2-3 for at least 24 hours

What are contraindications of Warfarin (Jantoven)?

• Pregnancy (except w/ mechanical heart valves)

• Malignant HTN

• Hemorrhagic tendencies

• Eye/CNS surgery

What are side effects of Warfarin (Jantoven)?

• Bleeding

• Skin necrosis

• Purple toe syndrome

What is monitoring of Warfarin (Jantoven)?

• INR

• Hgb

• Hct

What is Warfarin counseling?

• Indication/dosing

• INR monitoring

• Drug-drug interactions

  • Increased bleeding risk: NSAIDs, antithrombotic agents, garlic, ginger, ginkgo, ginseng, & glucosamine, alcohol

  • Decreased effectiveness: alfalfa, green tea, coenzyme Q10, & St. John’s wort

  • Major substrate of CYP2C9 (inducers can decrease INR & inhibitors can increase INR)

• Consistent diet of vitamin K-containing foods

• Side effects

What to convert to from warfarin to a DOAC?

Stop warfarin & convert to:

• Rivaroxaban when INR is <3

• Edoxaban when INR is </=2.5

• Apixaban when INR is <2

• Dabigatran when INR <2

What to convert to from DOAC to warfarin?

Start parenteral AC & warfarin at next scheduled dose of DOAC

• Start warfarin 1-3 days before stopping Dabigatran (determined by renal function)

What is activated partial thromboplastin time (aPTT) lab test?

• Time to generate fibrin from start of intrinsic pathway

• Requires citrated plasma (activating agent) & calcium

What is anti-factor Xa (anti-Xa) lab test?

• Looks only at functional activity of heparin

• More consistent & reliable results; expensive

What is activated clotting time (ACT) lab test?

Preferred in cath lab due to shorter time for result & smaller blood sample required

What is international normalized ratio (INR) lab test?

• INR: patient PT/control PT

• Monitor effects of warfarin

What are the warfarin dosing guidelines - maintenance?

• Adjustments in total weekly dosage (once at steady state) range from 5-20%

• Clinical judgement of other issues may result in dose changes outside of these general recommendations:

  • Consider pt’s previous response to current dosage & trending INR values

  • Consider missed/extra doses

  • Consider changes in dietary factors (vitamin K intake, alcohol use)

  • Consider potential for numerous drug interactions

What is the action w/ warfarin when INR <2 (goal INR 2-3)?

• Consider giving additional dose

• Increase weekly dose by 5-15%

What is the action w/ warfarin when INR 2-3 (goal INR 2-3)?

No change

What is the action w/ warfarin when INR 3.1-3.5 (goal INR 2-3)?

Decrease weekly dose by 0-15%

What is the action w/ warfarin when INR 3.6-4 (goal INR 2-3)?

• Hold 1 or no doses

• Decrease weekly dose by 0-15%

What is the action w/ warfarin when INR >4 (goal INR 2-3)?

• Hold until therapeutic

• Decrease weekly dose by 10-20%

What is the reversal agent of UFH & LMWH?

Protamine sulfate

What is the reversal agent of Dabigatran?

Idarucizumab (Praxbind)

What is the reversal agent of Apixaban & Rivaroxaban?

Andexanet alfa (Andexxa)

What is the reversal agent of Warfarin?

Phytonadione/Vitamin K (Mephyton) & Prothrombin Complex Concentrate (Kcentra)

What is the VTE antithrombotic therapy based on?

2021 CHEST guidelines

What is preferred for pts w/ VTE & w/o cancer?

DOACs preferred over warfarin

• Warfarin preferred over LMWH if DOAC not selected

• If recurrent VTE on oral anticoagulation, consider switching to LMWH

What is preferred for pts w/ VTE & w/ cancer?

DOACs preferred over LMWH

• Apixaban or LMWH preferred in pts w/ gastrointestinal malignancies

What is the duration of therapy w/ prevention?

• Give throughout period of increased VTE risk

• General surgical procedures: once ambulating regularly & other risk factors gone, prophylaxis can be discontinued

• 15-42 days following total knee/hip replacement surgery

What is the duration of therapy w/ tx?

• Provoked: 3 months

• Unprovoked: at least 3 months (if low-moderate bleeding risk)

What are key points about thrombolytic therapy**?

• Anticoagulation alone is preferred over thrombolytic therapy for acute leg/upper extremity DVT & acute PE w/o hypotension

• Systemic thrombolytic therapy is recommended for pts w/ acute PE associated w/ hypotension who do not have a high bleeding risk

• Catheter-directed thrombolysis is recommended for acute PE associated w/ hypotension & a high bleeding risk, failed systemic thrombolysis, or shock that is likely to lead to death before systemic thrombolysis can take effect

When the pt has confirmed VTE, what will they receive if they have PE w/ severe cardiopulmonary compromise or DVT w/ high risk of limb loss?

Thrombolytic therapy followed by anticoagulant w/ UFH or LMWH

When the pt has confirmed VTE, what will they receive if they have active bleeding or contraindication to anticoagulation?

If VTE is lower extremity DVT

• Place IVC filter

• Initiate anticoagulation when bleeding or contraindication resolves

• Resolve IVC filter as soon as clinically acceptable

When the pt has confirmed VTE, what will they receive if they have PE w/ poor prognosis or DVT unsuitable for outpatient treatment?

If hospitalized for VTE tx & CrCl <30mL/min

• UFH x 5 days overlap w/ warfarin & INR >2

When the pt has confirmed VTE, what will they receive if they need outpatient VTE tx?

• Rivaroxaban

• Apixaban

• LMWH/fondaparinux x 5 days THEN dabigatran or Edoxaban

• LMWH/fondaparinux x 5 days OVERLAP w/ warfarin & INR >2

What if started on Apixaban?

• Apixaban 10 mg PO BID x 7 days

• Apixaban 5 mg PO BID

• Optional: reduce apixaban 2.5 mg PO BID after 6 months

What if started on Rivaroxaban?

• Rivaroxaban 15 mg PO BID x 21 days

• Rivaroxaban 20 mg PO daily

• Optional: reduce to Rivaroxaban 10 mg PO daily after 6 months

What if started on UFH, LMWH, or Fondaparinux (all SC) and switching?

• UFH/LMWH/Fondaparinux SC x 5 days

• Dabigatran 150 mg PO BID OR Edoxaban 60 mg PO daily

What if started on UFH, LMWH, or Fondaparinux (all SC) and overlapping?

• UFH/LMWH/Fondaparinux SC

• Warfarin PO daily, overlapped w/ parenteral anticoagulant for at least 5 days & INR >/=2, then dose adjusted to INR target 2.5 (range 2-3)