What diagnosis is suggested by intermittent hemoglobinuria (urine dipstick positive for blood without red blood cells), mild transient anemia, normal creatine kinase, normal lactate dehydrogenase and haptoglobin, negative direct antiglobulin test (DAT), negative paroxysmal nocturnal hemoglobinuria (PNH) flow, low‑normal complement C4, in a woman with recurrent miscarriages, postpartum hypertension, psychiatric decompensation, and a family history of kidney disease?

Clinical Presentation Suggests Paroxysmal Cold Hemoglobinuria or Complement-Mediated Hemolysis

This constellation of findings—intermittent hemoglobinuria triggered by infection, dipstick-positive blood without RBCs on microscopy, transient multi-lineage cytopenias, normal LDH/haptoglobin 24 hours post-episode, negative PNH flow, negative DAT, low-normal C4, recurrent pregnancy loss, postpartum psychiatric decompensation, and family history of complement-related disease (CFH Y402H homozygosity)—most strongly suggests an episodic complement-mediated hemolytic process, likely paroxysmal cold hemoglobinuria (PCH) or atypical hemolytic uremic syndrome (aHUS) variant with subclinical manifestations.

Why Standard PNH Testing Was Negative

• PNH flow cytometry detects deficiency of GPI-anchored proteins (CD55/CD59) on blood cells, which results from PIG-A gene mutations in hematopoietic stem cells 1, 2
• Your negative PNH flow effectively rules out classic paroxysmal nocturnal hemoglobinuria as the cause 2
• The negative DAT excludes warm autoimmune hemolytic anemia and most cold agglutinin disease 3

The Critical Clue: Hemoglobinuria Without RBCs

• Dipstick-positive blood (1+ occult blood, 3+ lysed) with no intact RBCs on microscopy indicates free hemoglobin or myoglobin in urine, not hematuria 3
• Your low-normal creatine kinase excludes rhabdomyolysis as the source of myoglobinuria 3
• This pattern is pathognomonic for intravascular hemolysis with hemoglobinuria 3
• Normal LDH and haptoglobin 24 hours after the episode indicate the hemolytic event was brief and self-limited, explaining why markers normalized by the time of testing 4, 5

The Complement Connection

Your Genetic Risk Profile

• Homozygous CFH Y402H (complement factor H polymorphism) dramatically increases risk of complement dysregulation 3
• Low-normal C4 (21 mg/dL) suggests chronic low-grade complement consumption 3
• Normal C3 (89 mg/dL) does not exclude episodic complement activation, as levels can normalize between attacks 3

The Infection Trigger

• Your cold/URI immediately preceded the dark urine episode—infections are classic triggers for complement-mediated hemolysis 5
• Paroxysmal cold hemoglobinuria (PCH) classically presents with hemoglobinuria triggered by cold exposure or viral illness 5
• The Donath-Landsteiner antibody (biphasic hemolysin) causes complement-mediated RBC lysis in PCH, but this test was not performed in your workup 5

Explaining the Hematologic Pattern

The Multi-Lineage Drops on the Episode Date

• RBC dropped from 4.78 to 4.38 (×10⁶/μL)
• Hemoglobin dropped from 14.6 to 13.4 g/dL
• Hematocrit dropped from 41% to 38%
• These drops represent acute intravascular hemolysis during the episode 4, 5

Why LDH and Haptoglobin Were Normal 24 Hours Later

• Intravascular hemolysis releases LDH and consumes haptoglobin acutely 4
• Both markers have short half-lives and normalize within 24–48 hours after hemolysis stops 4
• Your testing occurred after the hemolytic event resolved, missing the diagnostic window 4

The Chronic Low-Grade Pattern

• Intermittent 1+ occult blood without RBCs for 5 months represents subclinical hemoglobinuria between acute episodes 3
• Occasional small bilirubin elevations reflect ongoing low-grade hemolysis 3
• Ferritin 36 ng/mL with transferrin saturation 44% suggests iron loss through chronic hemoglobinuria (renal tubular iron deposition) 6

The Pregnancy and Postpartum Connection

Obstetric History Red Flags

• Multiple miscarriages and blighted ovum are associated with complement dysregulation and aHUS 3
• Failed NIPT due to low fetal fraction suggests abnormal maternal cell populations 3
• MCV rising from 85–87 to 95 fL during pregnancy indicates reticulocytosis (hemolytic response) 3
• Spontaneous hemorrhage with hemoglobinuria (blood in catheter bag) suggests acute complement-mediated hemolysis during labor 3, 6

Postpartum Psychiatric Decompensation

• Severe psychiatric symptoms (rage, hypersexuality, paranoia, delusions) immediately postpartum with only partial SSRI response 3
• Dramatic improvement with progesterone one year later is highly significant 3
• This pattern suggests complement-mediated microangiopathy affecting the CNS, similar to aHUS neurologic manifestations 3
• Progesterone has complement-regulatory effects and may have stabilized subclinical complement activation 3

Postpartum Hypertension

• Blood pressure 140/110 one month postpartum, then 145/97 for one week after the recent dark urine episode 3
• Hypertension accompanying hemolytic episodes suggests complement-mediated endothelial injury 3
• This mirrors the hypertensive crises in your paternal aunt with end-stage kidney disease 3

Family History Supports Complement-Mediated Disease

• Paternal aunt: preeclampsia (both pregnancies), end-stage kidney failure, severe anemia (Hb 4), hypertensive crises—classic for aHUS 3
• Father: mild anemia despite normal iron panel—possible subclinical complement-mediated hemolysis 3
• Mother: early-onset macular degeneration with CFH Y402H homozygosity—complement dysregulation in the eye 3

What Testing Should Have Been Done (and Still Needs to Be Done)

During an Acute Episode (Next Time Dark Urine Occurs)

• Immediate serum LDH, haptoglobin, indirect bilirubin, and reticulocyte count—must be drawn during or within 6 hours of hemoglobinuria 4, 5
• Urine hemosiderin (Prussian blue stain on urine sediment)—remains positive for weeks after hemolysis 6
• Plasma-free hemoglobin—elevated during acute intravascular hemolysis 5
• Direct antiglobulin test (DAT) with polyspecific and monospecific (IgG, C3d) reagents—may detect complement fragments transiently 4

Specialized Complement Testing (Send Now)

• Donath-Landsteiner antibody (biphasic hemolysin)—diagnostic for paroxysmal cold hemoglobinuria 5
• Complement functional assays: CH50 (classical pathway) and AH50 (alternative pathway)—may be low during or after attacks 5
• Genetic testing for complement regulatory genes: CFH, CFI, MCP (CD46), CFB, C3—given your CFH polymorphism and family history 3
• Soluble C5b-9 (membrane attack complex)—elevated during complement activation 5

Additional Workup

• Cold agglutinin titer—although DAT was negative, biphasic hemolysins can cause hemolysis without positive DAT 5
• Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I)—given recurrent pregnancy loss and possible thrombotic tendency (platelet clumping) 3
• Renal biopsy if proteinuria develops—would show complement deposition and hemosiderin in tubules 6

Why This Matters Clinically

Risk of Progression

• Your paternal aunt's progression to end-stage kidney disease with severe anemia demonstrates the potential trajectory 3
• Chronic hemoglobinuria causes renal tubular iron deposition and progressive kidney injury 6
• Complement-mediated thrombotic microangiopathy can cause acute renal failure 6

Pregnancy Implications

• Future pregnancies carry high risk of recurrent pregnancy loss, preeclampsia, and hemolytic crises 3
• Complement activation is a known mechanism in recurrent miscarriage and preeclampsia 3
• Progesterone supplementation may be protective based on your response 3

Infection Triggers

• Any future infection (URI, UTI, gastroenteritis) may trigger acute hemolysis 5
• Avoid cold exposure if Donath-Landsteiner antibody is positive 5

Immediate Management Recommendations

During Future Hemolytic Episodes

• Maintain hydration aggressively (target urine output >100 mL/hour) to prevent acute tubular necrosis from hemoglobin precipitation 6
• Alkalinize urine (sodium bicarbonate) to increase hemoglobin solubility and reduce tubular toxicity 6
• Monitor renal function (creatinine, BUN) closely during episodes 6
• Avoid nephrotoxic medications during episodes 6

Chronic Monitoring

• Urinalysis every 3 months to detect subclinical hemoglobinuria 3
• Serum creatinine and blood pressure every 3 months to detect early kidney injury 3
• CBC every 3 months to monitor for progressive anemia 3
• Ferritin and iron studies annually—may need iron supplementation for chronic urinary iron loss 6

Potential Therapeutic Options (Discuss with Hematology/Nephrology)

• Eculizumab (anti-C5 monoclonal antibody)—FDA-approved for PNH and aHUS, blocks terminal complement activation 4, 5
• Ravulizumab (long-acting anti-C5)—alternative to eculizumab with less frequent dosing 5
• Pegcetacoplan (C3 inhibitor)—may be superior if C3-mediated extravascular hemolysis is occurring 5
• Immunosuppression (corticosteroids, rituximab)—if autoantibody-mediated (Donath-Landsteiner positive) 5

Critical Pitfalls to Avoid

• Do not assume normal LDH/haptoglobin 24 hours post-episode excludes hemolysis—these markers normalize rapidly after acute events stop 4
• Do not attribute hemoglobinuria to "benign hematuria"—absence of RBCs on microscopy with positive dipstick is never benign 3
• Do not dismiss psychiatric symptoms as purely psychiatric—complement-mediated CNS microangiopathy can cause severe neuropsychiatric manifestations 3
• Do not delay complement workup—your genetic risk (CFH Y402H homozygous) and family history mandate comprehensive evaluation 3

Urgent Referrals Needed

• Hematology—for Donath-Landsteiner testing, complement functional assays, and consideration of complement inhibitor therapy 5
• Nephrology—for complement genetic testing, renal protection strategies, and monitoring for progressive kidney disease 3, 6
• Maternal-Fetal Medicine (if considering future pregnancy)—for high-risk pregnancy management and complement monitoring 3