Brian Locke

VTE

Considerations around initial anticoagulant and monitoring : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715843/

Massive PE:

If a patient receives catheter directed lytics: give heparin on top?

Yes, probably - though there has not been a clear trial of how to do this.

  • need at least some to prevent clot on the sheath
  • probably need more, but not clear if you need treatment dose, intermediate dose, or just low dose. Ask pharm and interventionalists.

IMC - follows European cardiology guidelines: https://academic.oup.com/eurheartj/article/41/4/543/5556136

Intermediate-High risk: (Not shock but signs of RH strain based on CT, TTE, or Troponin) AC only and monitoring. Generally only do advanced therapies if they have deranged vital signs (tacky 140+, 100% HFNC, no improvement with heparin and you think it's this). Then, do low dose systemic TPA (alteplase 10mg boluses up to 50mg) a la MOPETT if they are low bleed risk (e.g. Age <65), or mechanical thrombectomy (if age over 65 or contra to TPA).

TTE in intermediate risk - what is the negative predictive value of no heart strain on an TTE

High risk = shock with PE, sustained for 15 minutes or requiring pressers for that duration: systemic thrombolysis or catheter thrombolysis. Other options are US-assisted thrombus fragmentation, Suction embolectomy, or mechanical thrombectomy, Surgical embolectomy, VA ECMO.

Advanced therapies

Systemic TPA

8 person 1995 RCT is the best evidence (=basically no evidence). Meta-analyses only including patients with shock OR death 0.59. In Intermediate-High risk, mortality estimate is OR 1.09.

Thus, first line if patient has acceptable bleed risk. EMPEROR registry suggests this is very under-used.

Contraindications:
Absolute

  • History of haemorrhagic stroke or stroke of unknown origin
  • Ischaemic stroke in previous 6 months
  • Central nervous system neoplasm
  • Major trauma, surgery, or head injury in previous 3 weeks
  • Bleeding diathesis
  • Active bleeding

Relative

  • Transient ischaemic attack in previous 6 months

  • Oral anticoagulation (**debatable, often this is not viewed in that way)

  • Pregnancy or first post-partum week

  • Non-compressible puncture sites

  • Traumatic resuscitation

  • Refractory hypertension (systolic BP >180 mmHg)

  • Advanced liver disease

  • Infective endocarditis

  • Active peptic ulcer

  • Alteplase 100 mg over 2 hours, continue IV heparin fusion (ESC) or pause during the infusion (Uptodate) if a patient has a pulse

  • If arrest: Accelerated protocol 0.6-1.0 mg/kg to max 50kg bolus over 10 minutes (won't be around for 2h). Can give a second 50mg 30 minutes later if still arresting.

PEITHO study, NEJM 2014 = in intermediate-risk PE using tenecteplase (available in Europe, not here), equivalent to full dose of alteplase (60-100mg) and did not interrupt heparin. Benefit in preventing hemodynamic compensation or rescue thrombolysis. Risk of intracranial and major extra cranial bleeding. Per 100 patients: prevent decomposition in 3, 2 hemorrhagic strokes, 5 major extra cranial bleeding. => sum, do not give.

MOPETT: AJC 2013. "Safe Dose" tPA - enrolled 121 patients with large thrombus burden, VS abnormalities but not shock. Alteplase 50mg total (10mg up front, then 40mg), received uninterrupted anticoagulation with maximal rate. But no bleeding.

In sum, it seems that bleed risk increases largely as age increases over 65. Relatively lower harm risk under.

Does not decrease risk of CTEPH (because the body will catch up in thrombolysis by day 7.. it just accelerates it up front - difference at 24h by V/Q)

Catheter treatments

  • Thrombolysis (uncommon, no good data, shaky biologic rationale)
  • Thrombolysis with ultrasound assistance (Ekos, US; Ultima, Seattle 2, Optalyse studies but all are severely limited in using surrogate TTE parameters or no control arm).
  • Thrombolysis with mechanical assistance (not much
  • Embolectomy (mechanical or suction) without thrombolysis (FLARE study - single arm with 106 patients RV/LV ratio change improves, 1/2 patients didn't require ICU). Catheter out at end of procedure.

Surgical Embolectomy

Old data suggests low mortality, but it's a rare situation you'd need to do it. Not clear there is a role for this nowadays.

VA ECMO

Means of supportive care for refractory obstructive shock. Often, combine with another modality (e.g. thrombectomy.

Peripheral VA-ECMO through bifemoral access sites. Having received thrombolysis is not a contraindication for cannulation

Data limited to case series with significant selection biases. 50% mortality.

IVC Filter

PREPIC 2 - no difference in recurrent PE in patients who can be anti coagulated. Thus, only use if patients cannot be anti coagulated who have proximal DVT.

Thrombophilia workup?

ACP 2016, ESC 2019 both recommend indefinite anticoagulation after single unprovoked VTE unless unacceptable bleed risk. THus, doesn't usually change

Provoked?

If they might have APS, it may make sense to test to know if they need warfarin. Test for it:

  • Young (<50) and unprovoked
  • Thrombosis in unusual site
  • mild thrombocytopenia (50k-100k)
  • baseline prolonged aptt (might be LA)

HIT

PF4 released when platelets are activated. If you get antibodies that bind to that (PF4-heparin complex), it further activates the platelets and makes big complexes -> very hypercoagulable.

Risk of developing is much higher with normal unfractional heparin. Surgical and trauma patients are at higher risk of getting this.

5-10 day after exposure to heparin if first. Faster if already developed ab's from prior exposure.

Screen with anti-PF4, then confirm with SRA. Switch to argatroban and stop ALL heparin exposure. (Bivalrudin might work but is not approved and thus no protocol exists. DOACs might work, some weak evidence. Would need parenteral anticoagulation first. Fondaparinoux could work if they don't have renal failure... but rarely associated with HIT still).

Argatroban: metabolized in liver, reaches steady state in 1-3 hours. monitored with aptt levels. Will raise INR level. Start Warfarin once platelets 150k.

CHEST: treat HIT for 3 months if there was thrombosis, 1 month if not. For whatever reason, they do not generate memory to heparin-PF4... so theoretically you could use it down the line if they really needed it (e.g. bypass)

Antiphospholipid syndrome

In triple positive patients:

  • Rivaroxaban vs warfarin - Xarelto was inferior
  • Apixaban trial ongoing but not promising
  • Thus, generally use Warfarin. (even for non-triple positive, because we don't exactly know why)

Order:

  • LA (if they are not yet on anticoagulants - may get false positive if they are on any anticoagulant (due to step 1). Steps: 1. prolonged aptt or dilute russel viper venom, 2. mix with normal plasma to exclude deficiency and suggest inhibitor, 3. add phospholipids to see if it normalizes aptt = the inhibitor is a antiphospholipid ab as opposed to some other inhibitor )
  • Cardiolipin ab (IgG and IgM - do NOT test for IgA, not correlated)
  • betaglycoprotein (IgG and IgM - do NOT test for IgA, not correlated)

There are other antiphospholipid antibodies that could lead to + LA but they have not been as strongly correlated with outcomes to know if they should be treated the same.

needs repeat in 12 weeks to confirm

Heparin resistance

Def: 35,000 units/day or more, or 25 u/kg/hr or more

DDx:

  • most commonly AT3 deficiency ( normally functions at a low level as the body's natural anticoagulant): can be consumptive (e.g. DIC, long-term heparin use, bypass/ECMO) or production problem (e.g. liver failure). -> can give FFP or antithrombin concentrate (mostly in OR by anesthesiology in cardiac surgery). Beware of rebound once the AT3 comes back up if consumptive process is removed.
  • but could be a heparin binding ab
  • can be interference with the assay -> switch to monitoring for Xa to exclude elevated factor VI or fibrinogen interfering with the assay

Management:

Switch to argatroban if antithrombin deficiency: because it's a direct thrombin inhibitor