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cardio.dvt.nephrotic-syndrome.v1PRODUCTION
cardio.dvt.nephrotic-syndrome.v1

Nephrotic-syndrome DVT (urinary AT-III/protein S loss; LMWH preferred over DOAC)

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11/12 authored

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Current phase

Frame

Detailed

Nephrotic syndrome = acquired hypercoagulable state from urinary AT-III + protein S/C loss + hepatic up-regulation of fibrinogen / factor V/VIII / vWF; LMWH preferred over DOAC while heavy proteinuria persists; concurrent RVT surveillance in membranous nephropathy; primary prophylaxis if albumin <2.5 g/dL + MN per KDIGO 2021

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NS-DVT phenotype framed

Patient inputs (12)

AT-III activity <70% indicates urinary loss; predicts heparin resistance (heparin requires AT-III cofactor); supports LMWH or DOAC over UFH; severe AT-III deficiency may justify AT-III concentrate replacement

Older NS patients (membranous nephropathy peaks 50-70 yr) have additive VTE risk; lifelong-AC tolerance considerations dominate

Female patients with NS face OCP / pregnancy planning decisions; estrogen contraception must be discontinued; pregnancy in active NS is a high-risk overlap

Membranous nephropathy carries the highest VTE risk; FSGS, minimal-change, lupus nephritis, and amyloid each carry distinct VTE risk profiles and treatment implications

Steroids, rituximab, calcineurin inhibitors, cyclophosphamide — interactions with warfarin (cyclophosphamide), rituximab-related infusion reactions, and steroid-driven hyperglycaemia all influence AC plan

Severity marker; <2.5 g/dL = highest VTE risk band; predicts free-DOAC fraction perturbation (apixaban + rivaroxaban are 87-92% albumin-bound)

Quantifies proteinuria; UPCR >3.5 (or 24-h urinary protein >3.5 g) defines nephrotic-range; >10 g/day is severe and shifts strongly toward LMWH over DOAC

Cardinal symptom of proximal DVT; bilateral edema in NS may obscure unilateral DVT — measure calf circumferences and look for asymmetry

First-line imaging confirmation of DVT; assess proximal vs distal extent

Baseline platelet for AC; thrombocytosis is common in NS and adds to thrombotic risk

HAS-BLED + biopsy timing (post-renal-biopsy AC needs ≥5-7 d delay) drives AC eligibility

eGFR for LMWH dose adjustment (CrCl <30 → 1 mg/kg SC daily instead of BID); informs IV UFH alternative

* = hard-required. Engine cannot meaningfully run until these are filled.

Severity triggers (5)

5 need judgement
  • informationalsevereconcurrent_renal_vein_thrombosis_in_membranous_nephropathy
    Membranous nephropathy patient with new flank pain, gross hematuria, AKI, or asymmetric proteinuria — concurrent renal vein thrombosis (RVT) suspected; bilateral RVT can cause acute renal failure
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseveredoac_inadvertently_started_in_active_ns
    NS patient with proteinuria >3.5 g/day or albumin <2.5 g/dL found to be on rivaroxaban, apixaban, edoxaban, or dabigatran — must transition to LMWH or warfarin given unreliable DOAC PK in active NS
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereheparin_resistance_with_at_iii_below_50_percent
    NS patient on therapeutic UFH with refractory aPTT despite escalating doses — AT-III deficiency from urinary loss; heparin requires AT-III as cofactor
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverepregnancy_planning_in_woman_with_active_nephrotic_syndrome
    Woman of reproductive age with active NS planning pregnancy — high-risk pregnancy requiring LMWH antepartum + 6-wk postpartum + low-dose ASA + nephrology + MFM co-management; estrogen contraception must be discontinued
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderateprimary_prophylaxis_decision_for_membranous_nephropathy_with_albumin_below_2_5
    Newly diagnosed or active membranous nephropathy with serum albumin <2.5 g/dL and no current VTE — Lee CJASN 2014 Markov decision analysis supports primary prophylactic AC if bleed risk acceptable
    Trigger could not be auto-evaluated — needs clinician judgement.

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Recommended regimen

Nephrotic-syndrome DVT anticoagulation — LMWH preferred (urinary DOAC loss + albumin-binding shift); warfarin acceptable after LMWH bridge; DOAC avoided while proteinuria >3.5 g/day or albumin <2.5 g/dL (KDIGO 2021; ISN 2021)
axis: nephrotic_syndrome_anticoagulation_lmwh_first_doac_avoided
Selected axis "Nephrotic-syndrome DVT anticoagulation — LMWH preferred (urinary DOAC loss + albumin-binding shift); warfarin acceptable after LMWH bridge; DOAC avoided while proteinuria >3.5 g/day or albumin <2.5 g/dL (KDIGO 2021; ISN 2021)" by default fallback (first axis)
  • enoxaparin
    first line
    lmwh
    1 mg/kg SC BID (reduce to 1 mg/kg SC daily if CrCl <30) • SC • BID; continue while proteinuria >3.5 g/day or albumin <2.5 g/dL
    triggers: ns_dvt_initial_treatment, heavy_proteinuria_with_acute_dvt, membranous_nephropathy_dvt
    ASH 2020 (PMID 33007077); ISN 2021 + KDIGO 2021 — LMWH preferred over DOAC in heavy-proteinuria NS due to unreliable PK + free-fraction shifts; predictable subcutaneous absorption; AT-III independent of urinary loss when monitored by anti-Xa
    rxcui 67108
  • warfarin
    second line
    vitamin_k_antagonist
    5 mg PO daily; target INR 2-3 • PO • daily; AC duration tied to NS activity (continue while heavy proteinuria persists)
    triggers: ns_dvt_long_term_oral_AC_after_lmwh_bridge, patient_unable_to_self_inject_long_term, cost_constraint
    Acceptable long-term oral AC after LMWH bridge once NS activity moderating; not protein-bound so free-fraction concerns are less; INR-monitored (note vitamin-K losses in nephrotic urine may shift INR variability — narrow-band INR monitoring needed); ACCP 2021 framework
    rxcui 11289
  • heparin
    comorbidity specific
    unfractionated_heparin
    80 U/kg IV bolus + 18 U/kg/h targeting aPTT 1.5-2.5× (use anti-Xa 0.3-0.7 IU/mL if AT-III deficiency causing aPTT-resistance) • IV • continuous
    triggers: ns_dvt_with_severe_renal_impairment_egfr_below_15, peri_procedural_bridge, ns_dvt_with_at_iii_deficiency_on_lmwh_failure
    Reversibility for peri-procedural management (renal biopsy planning); UFH requires AT-III as cofactor — heparin resistance possible if AT-III <50%; consider AT-III concentrate replacement (50 IU/kg) if refractory aPTT despite escalating UFH per ASH 2020
    rxcui 235473
  • AVOID rivaroxaban during heavy proteinuria
    contraindication substitute
    do_not_use
    AVOID • N/A • N/A
    triggers: ns_with_proteinuria_above_3_5_g_per_day, ns_with_albumin_below_2_5
    Sexton CJASN 2018 — variable apixaban PK in NS; rivaroxaban (87% albumin-bound) similarly affected; case-series reports of recurrent VTE on DOAC in active NS; ISN 2021 + KDIGO 2021 advise against DOAC during heavy proteinuria; revisit only when proteinuria <3.5 g/day or albumin >2.5 g/dL sustained ≥3 mo
  • AVOID apixaban during heavy proteinuria
    contraindication substitute
    do_not_use
    AVOID • N/A • N/A
    triggers: ns_with_proteinuria_above_3_5_g_per_day, ns_with_albumin_below_2_5
    Sexton CJASN 2018 PK study — wide apixaban variability in NS patients; high albumin binding (87%) makes free-fraction unpredictable in hypoalbuminemia; ISN 2021 + KDIGO 2021 — DOAC avoided
  • apixaban (AFTER NS remission)
    add on
    doac_factor_xa_direct
    apixaban 5 mg PO BID once proteinuria <3.5 g/day AND albumin >2.5 g/dL sustained ≥3 mo • PO • BID after sustained NS remission
    triggers: ns_in_partial_or_complete_remission, transition_from_lmwh_to_oral_doac_after_ns_quiescence
    AMPLIFY (Agnelli NEJM 2013 PMID 23808982) — apixaban first-line outside NS; once NS proteinuria resolves, DOAC PK normalises and routine outpatient AC framework applies
    rxcui 1364430
  • aspirin
    add on
    antiplatelet_cox1
    81 mg PO daily • PO • daily
    triggers: ns_with_concurrent_atherosclerotic_disease, ns_pregnancy_planning_low_dose_asa_antepartum
    NS-driven dyslipidaemia + endothelial dysfunction accelerates atherosclerosis; low-dose ASA reasonable in NS patients with established ASCVD; antepartum low-dose ASA in NS-pregnancy reduces preeclampsia risk
    rxcui 243670
  • antithrombin III concentrate
    rescue
    plasma_derived_concentrate
    50 IU/kg IV (target AT-III activity >80%) when refractory heparin resistance from severe NS-driven AT-III loss • IV • one-time, repeat as guided by AT-III activity
    triggers: heparin_resistance_with_at_iii_below_50_percent, severe_at_iii_deficiency_with_active_thrombosis
    Heparin requires AT-III as cofactor; severe NS-driven AT-III deficiency blunts UFH response; AT-III concentrate replacement restores cofactor activity; case-series + ASH 2020 framework

outpatient playbook — drug actions (4)

  1. 1. maintenance LMWH while NS active
    rxcui 67108
    enoxaparin 1 mg/kg SC BID • SC • BID
    trigger: Active NS
    KDIGO 2021; ISN 2021
  2. 2. switch to LMWH if pregnancy
    rxcui 67108
    enoxaparin 1 mg/kg SC BID antepartum + 6 wk postpartum + low-dose ASA antepartum • SC + PO • BID
    trigger: Pregnancy with active NS
    ASH 2018 pregnancy; KDIGO 2021
  3. 3. transition to apixaban once sustained NS remission
    rxcui 1364430
    apixaban 5 mg PO BID (or 2.5 mg BID extended-low-dose if continuing indefinite) • PO • BID
    trigger: Sustained NS remission ≥3 mo (proteinuria <3.5, albumin >2.5)
    AMPLIFY; KDIGO 2021 transition criteria
  4. 4. statin for CV risk reduction (NS dyslipidaemia + accelerated atherosclerosis)
    rxcui 83367
    atorvastatin 20-80 mg PO daily • PO • daily
    trigger: NS with hyperlipidaemia + ASCVD risk
    AHA ASCVD prevention; NS dyslipidaemia drives accelerated atherosclerosis

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: Unilateral leg swelling/pain in a patient with known nephrotic syndrome (proteinuria >3.5 g/day, hypoalbuminemia, edema, hyperlipidemia) — VTE pretest probability sharply elevated; Serum albumin <2.5 g/dL + UPCR >3.5 (or 24-h urinary protein >3.5 g) — high-risk VTE substrate; surveillance + prophylaxis decision triggered; Biopsy-proven membranous nephropathy patient with new leg symptoms — highest-risk glomerular disease for DVT (~30% lifetime VTE per Kerlin CJASN 2012).

Objective

- No vitals, labs, or imaging entered for this encounter.

Assessment

**Nephrotic-syndrome DVT (urinary AT-III/protein S loss; LMWH preferred over DOAC)** (cardio.dvt.nephrotic-syndrome.v1).
Scope: Nephrotic syndrome = acquired hypercoagulable state from urinary AT-III + protein S/C loss + hepatic up-regulation of fibrinogen / factor V/VIII / vWF; LMWH preferred over DOAC while heavy proteinuria persists; concurrent RVT surveillance in membranous nephropathy; primary prophylaxis if albumin <2.5 g/dL + MN per KDIGO 2021

No severity triggers fired against current inputs.

Plan

Regimen axis: **Nephrotic-syndrome DVT anticoagulation — LMWH preferred (urinary DOAC loss + albumin-binding shift); warfarin acceptable after LMWH bridge; DOAC avoided while proteinuria >3.5 g/day or albumin <2.5 g/dL (KDIGO 2021; ISN 2021)**.
1. enoxaparin 1 mg/kg SC BID (reduce to 1 mg/kg SC daily if CrCl <30) SC BID; continue while proteinuria >3.5 g/day or albumin <2.5 g/dL (lmwh, first line) — ASH 2020 (PMID 33007077); ISN 2021 + KDIGO 2021 — LMWH preferred over DOAC in heavy-proteinuria NS due to unreliable PK + free-fraction shifts; predictable subcutaneous absorption; AT-III independent of urinary loss when monitored by anti-Xa
2. warfarin 5 mg PO daily; target INR 2-3 PO daily; AC duration tied to NS activity (continue while heavy proteinuria persists) (vitamin_k_antagonist, second line) — Acceptable long-term oral AC after LMWH bridge once NS activity moderating; not protein-bound so free-fraction concerns are less; INR-monitored (note vitamin-K losses in nephrotic urine may shift INR variability — narrow-band INR monitoring needed); ACCP 2021 framework
3. heparin 80 U/kg IV bolus + 18 U/kg/h targeting aPTT 1.5-2.5× (use anti-Xa 0.3-0.7 IU/mL if AT-III deficiency causing aPTT-resistance) IV continuous (unfractionated_heparin, comorbidity specific) — Reversibility for peri-procedural management (renal biopsy planning); UFH requires AT-III as cofactor — heparin resistance possible if AT-III <50%; consider AT-III concentrate replacement (50 IU/kg) if refractory aPTT despite escalating UFH per ASH 2020
4. AVOID rivaroxaban during heavy proteinuria AVOID N/A N/A (do_not_use, contraindication substitute) — Sexton CJASN 2018 — variable apixaban PK in NS; rivaroxaban (87% albumin-bound) similarly affected; case-series reports of recurrent VTE on DOAC in active NS; ISN 2021 + KDIGO 2021 advise against DOAC during heavy proteinuria; revisit only when proteinuria <3.5 g/day or albumin >2.5 g/dL sustained ≥3 mo
5. AVOID apixaban during heavy proteinuria AVOID N/A N/A (do_not_use, contraindication substitute) — Sexton CJASN 2018 PK study — wide apixaban variability in NS patients; high albumin binding (87%) makes free-fraction unpredictable in hypoalbuminemia; ISN 2021 + KDIGO 2021 — DOAC avoided
6. apixaban (AFTER NS remission) apixaban 5 mg PO BID once proteinuria <3.5 g/day AND albumin >2.5 g/dL sustained ≥3 mo PO BID after sustained NS remission (doac_factor_xa_direct, add on) — AMPLIFY (Agnelli NEJM 2013 PMID 23808982) — apixaban first-line outside NS; once NS proteinuria resolves, DOAC PK normalises and routine outpatient AC framework applies
7. aspirin 81 mg PO daily PO daily (antiplatelet_cox1, add on) — NS-driven dyslipidaemia + endothelial dysfunction accelerates atherosclerosis; low-dose ASA reasonable in NS patients with established ASCVD; antepartum low-dose ASA in NS-pregnancy reduces preeclampsia risk
8. antithrombin III concentrate 50 IU/kg IV (target AT-III activity >80%) when refractory heparin resistance from severe NS-driven AT-III loss IV one-time, repeat as guided by AT-III activity (plasma_derived_concentrate, rescue) — Heparin requires AT-III as cofactor; severe NS-driven AT-III deficiency blunts UFH response; AT-III concentrate replacement restores cofactor activity; case-series + ASH 2020 framework

Setting playbook (outpatient) — Long-term NS-conditional AC management with annual reassessment; nephrology co-management of underlying glomerulonephritis; reproductive planning for women with active NS; cardiovascular risk reduction (NS-driven accelerated atherosclerosis); recurrence-prevention
9. maintenance LMWH while NS active enoxaparin 1 mg/kg SC BID SC BID — Active NS (KDIGO 2021; ISN 2021)
10. switch to LMWH if pregnancy enoxaparin 1 mg/kg SC BID antepartum + 6 wk postpartum + low-dose ASA antepartum SC + PO BID — Pregnancy with active NS (ASH 2018 pregnancy; KDIGO 2021)
11. transition to apixaban once sustained NS remission apixaban 5 mg PO BID (or 2.5 mg BID extended-low-dose if continuing indefinite) PO BID — Sustained NS remission ≥3 mo (proteinuria <3.5, albumin >2.5) (AMPLIFY; KDIGO 2021 transition criteria)
12. statin for CV risk reduction (NS dyslipidaemia + accelerated atherosclerosis) atorvastatin 20-80 mg PO daily PO daily — NS with hyperlipidaemia + ASCVD risk (AHA ASCVD prevention; NS dyslipidaemia drives accelerated atherosclerosis)

Non-pharmacologic actions:
- Estrogen/OCP avoidance while NS active
- Smoking cessation
- Cardiovascular risk modification
- Pre-procedure AC management plan documented (especially for renal biopsy ≥5-7 d hold)
- Patient carries NS + AC card
- EHR DOAC-avoidance flag annually verified

AVOID / contraindication checks:
- Doac_avoid_in_active_ns_with_proteinuria_above_3_5_g_per_day (KDIGO 2021; ISN 2021)
- Doac_avoid_when_serum_albumin_below_2_5 (Sexton CJASN 2018 PK)
- Lmwh_renal_dose_reduction_below_egfr_30 (FDA label)
- Warfarin_avoid_pregnancy_use_lmwh (ASH 2018 pregnancy)
- Ufh_at_iii_dependent_check_at_iii_if_aptt_resistant (ASH 2020)
- Decision:lmwh_first_line_in_ns_dvt_while_heavy_proteinuria_persists (ISN 2021)
- Decision:warfarin_acceptable_after_lmwh_bridge_if_long_term_oral_needed (ACCP 2021)
- Decision:transition_lmwh_to_doac_only_when_proteinuria_below_3_5_and_albumin_above_2_5_sustained_3mo
- Decision:primary_prophylaxis_with_lmwh_or_warfarin_if_membranous_nephropathy_with_albumin_below_2_5_and_low_bleed_risk (Lee CJASN 2014; KDIGO 2021)
- Decision:rvt_screen_with_contrast_ct_or_mr_venography_for_membranous_with_flank_pain_or_hematuria (KDIGO 2021)
- Decision:hold_AC_5_to_7d_after_renal_biopsy (procedural safety)
- Decision:ehr_flag_doac_avoidance_during_active_ns (operational safety)
- Decision:ns_dvt_AC_duration_tied_to_NS_activity_not_calendar_3mo_rule

Monitoring

Regimen monitoring:
- serum albumin and upcr every 2-4 weeks during NS treatment (drives AC continuation decision)
- cbc creatinine quarterly during lmwh or warfarin (FDA labels)
- inr weekly during warfarin init then q2-4 weeks (ACCP 2021; vitamin-K urinary losses can drive INR variability)
- at iii activity recheck if heparin resistance suspected (ASH 2020)
- pts villalta at 3 6 12mo (Kahn Lancet 2014)
- rvt surveillance imaging for membranous with new flank pain or hematuria or aki (KDIGO 2021)
- transition criteria check at 3mo for lmwh to doac switch (proteinuria <3.5, albumin >2.5)
- pre pregnancy lmwh dose planning for women with active ns (ASH 2018 pregnancy)

Setting (outpatient) monitoring:
- Quarterly albumin + UPCR + CBC + creatinine while NS active
- Annual lipid + A1c
- Annual HAS-BLED
- Annual reproductive counseling for women
- Annual nephrology

Follow-up plan: Co-management with nephrology for NS treatment (steroids ± rituximab ± CNI per histology); annual reassessment of AC continuation tied to NS activity; pre-conception planning for women (LMWH antepartum + 6-wk postpartum if active NS); estrogen avoidance lifelong while NS active; EHR flag against DOAC use during heavy proteinuria; PT/OT for deconditioning if prolonged inpatient
- Close-out criterion: NS-specific AC continuation + reproductive plan + DOAC-avoidance EHR flag documented

Monitoring phase: Albumin + UPCR every 2-4 weeks during NS treatment (drive AC continuation decision); CBC + creatinine quarterly; bleed surveillance; AT-III rechecked if heparin resistance suspected; PTS Villalta at 3/6/12 mo; reassess transition LMWH → DOAC if proteinuria <3.5 g/day or albumin >2.5 g/dL sustained ≥3 mo

Disposition

Current setting: outpatient — Long-term NS-conditional AC management with annual reassessment; nephrology co-management of underlying glomerulonephritis; reproductive planning for women with active NS; cardiovascular risk reduction (NS-driven accelerated atherosclerosis); recurrence-prevention

Disposition criteria:
- Indefinite continuation while NS active; cross-reference with chronic-AC clinic + nephrology

Escalation triggers (move to higher acuity):
- Recurrent VTE on therapeutic AC → reassess AC adequacy + NS activity + AT-III status
- Pregnancy → switch to LMWH + ASA
- Major bleed → reverse, hold, reassess AC intensity
- NS flare → escalate immunosuppression + maintain LMWH

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [SEVERE] Membranous nephropathy patient with new flank pain, gross hematuria, AKI, or asymmetric proteinuria — concurrent renal vein thrombosis (RVT) suspected; bilateral RVT can cause acute renal failure
- [SEVERE] NS patient with proteinuria >3.5 g/day or albumin <2.5 g/dL found to be on rivaroxaban, apixaban, edoxaban, or dabigatran — must transition to LMWH or warfarin given unreliable DOAC PK in active NS
- [SEVERE] NS patient on therapeutic UFH with refractory aPTT despite escalating doses — AT-III deficiency from urinary loss; heparin requires AT-III as cofactor

Citations

- KDIGO 2021 Glomerular Diseases + ISN 2021 NS-VTE position + ASH 2020 VTE Treatment + ACCP/CHEST 2021 [PMID:34352295](https://pubmed.ncbi.nlm.nih.gov/34352295/)
- Cited evidence (PMID 33007077) [PMID:33007077](https://pubmed.ncbi.nlm.nih.gov/33007077/)
- Cited evidence (PMID 30482764) [PMID:30482764](https://pubmed.ncbi.nlm.nih.gov/30482764/)
- Cited evidence (PMID 30482767) [PMID:30482767](https://pubmed.ncbi.nlm.nih.gov/30482767/)
- Cited evidence (PMID 22516287) [PMID:22516287](https://pubmed.ncbi.nlm.nih.gov/22516287/)

Last reconciled with current guidelines: 2026-05-15.
References