In a patient with recurrent deep vein thrombosis (acute distal right femoral vein DVT and chronic left popliteal vein DVT) who was restarted on apixaban (Eliquis) and now has a falling hemoglobin from 10 g/dL to 7.7 g/dL, how should I manage the anticoagulation and anemia?

Management of Recurrent DVT with Falling Hemoglobin on Apixaban

Stop apixaban immediately and investigate for the bleeding source, then switch to therapeutic-dose LMWH (enoxaparin 1 mg/kg twice daily) after bleeding is controlled, because this patient has both anticoagulant-associated bleeding (hemoglobin drop from 10 to 7.7 g/dL) and breakthrough thrombosis on a DOAC. 1, 2

Immediate Management of Bleeding

• Discontinue apixaban now because a hemoglobin decrease ≥2 g/dL meets the American College of Cardiology definition of major bleeding. 1

• Provide hemodynamic support, volume resuscitation, and apply local compression measures if a bleeding site is identified. 1, 3

• Transfuse red blood cells using a restrictive threshold (hemoglobin trigger 70 g/L, target 70-90 g/L) unless the patient has cardiovascular disease, in which case use a higher threshold (hemoglobin trigger 80 g/L, target 100 g/L). 1

• Discontinue any concomitant antiplatelet agents (aspirin, clopidogrel) immediately. 1

• Consider andexanet alfa only if bleeding is severe or life-threatening (e.g., intracranial, retroperitoneal, or hemodynamically unstable). 1, 3

Diagnostic Workup for Bleeding Source

• Perform CT angiography to localize the bleeding site, especially if the patient is hemodynamically unstable or has active bleeding. 1

• If CT angiography is negative and the patient remains unstable, proceed immediately to upper endoscopy to rule out gastrointestinal bleeding. 1

• Check hemoglobin/hematocrit serially to assess for ongoing occult blood loss. 3

• Monitor platelet counts every 2-3 days for the first 14 days to rule out heparin-induced thrombocytopenia (HIT) if the patient has recently received unfractionated heparin or LMWH. 2

Anticoagulation Strategy After Bleeding Control

Switch to therapeutic-dose LMWH (enoxaparin 1 mg/kg subcutaneously twice daily or dalteparin 200 U/kg once daily) rather than restarting apixaban, because the American College of Chest Physicians recommends switching from DOACs to LMWH for at least one month when DVT recurs despite therapeutic anticoagulation. 2

• Do not restart another DOAC after documented DOAC failure; the American Society of Hematology recommends LMWH over DOACs for breakthrough thrombotic events. 2

• Do not maintain the patient on standard-intensity warfarin (INR 2.0-3.0) because this is insufficient after multiple anticoagulant failures. 2

Timing of Anticoagulation Resumption

• Restart anticoagulation within 7 days after bleeding has stopped if the patient has high thrombotic risk (recent recurrent VTE qualifies as high risk). 1, 3

• Delay restarting anticoagulation if bleeding occurred at a critical site (intracranial, intraspinal, intraocular, pericardial, intra-abdominal, retroperitoneal), if the patient is at high risk of rebleeding, or if the bleeding source has not been definitively treated. 3

Mandatory Pre-Treatment Evaluation

Before finalizing the anticoagulation plan, complete three essential evaluations:

• Screen for occult malignancy because a cancer diagnosis mandates switching to LMWH monotherapy (dalteparin 200 U/kg daily for 30 days, then 150 U/kg daily indefinitely while cancer is active). 2, 4

• Test for antiphospholipid syndrome (APS) because APS contraindicates DOACs and favors LMWH or warfarin. 2

• Verify medication compliance objectively because non-adherence is a frequent cause of apparent anticoagulant failure. 2

Long-Term Anticoagulation Options

If LMWH alone fails after one month, consider one of two intensified strategies:

• High-intensity warfarin (target INR 3.0-3.5) with bridging using therapeutic LMWH for a minimum of 5 days and until INR ≥2.5 on two consecutive days. 2

• Escalate LMWH dose by 25-33% above the standard therapeutic regimen (e.g., increase enoxaparin from 1 mg/kg twice daily to 1.25-1.33 mg/kg twice daily) and monitor anti-factor Xa levels targeting peak levels of 1.0-2.0 IU/mL drawn 4 hours post-injection. 2

Special Considerations

• If occult malignancy is identified, immediately switch to therapeutic LMWH monotherapy and continue indefinitely while cancer remains active, metastatic, or the patient is receiving chemotherapy, because LMWH is superior to warfarin for cancer-associated VTE. 2, 4

• Do not place an inferior vena cava (IVC) filter unless pulmonary embolism recurs despite maximal anticoagulation (high-intensity warfarin or escalated LMWH) or an absolute contraindication to anticoagulation exists (active major bleeding or severe thrombocytopenia <20 × 10³/µL). 2

Monitoring Requirements

• Monitor hemoglobin, hematocrit, and platelet counts every 2-3 days for the first 14 days, then every 2 weeks thereafter to detect bleeding or HIT. 2

• Perform annual reassessment for all patients on indefinite anticoagulation, evaluating bleeding complications, changes in cancer status, medication adherence, new bleeding risk factors, and patient preference. 2

Common Pitfalls to Avoid

• Do not assume the chronic left popliteal DVT is irrelevant—the acute right femoral DVT represents true recurrence despite recent apixaban therapy. 2

• Do not overlook drug-drug interactions with warfarin if that route is chosen, especially antibiotics, antifungals, amiodarone, and NSAIDs that cause dangerous INR fluctuations. 2

• Do not restart apixaban at the same dose because the FDA label indicates apixaban should be restarted "as soon as adequate hemostasis has been established," but this patient has demonstrated both bleeding and breakthrough thrombosis on apixaban, mandating a switch. 5