Complement Deficiencies: Locate the Break and the Overactive Brake
Use pathway tests, timing and tissue findings to distinguish missing complement defense from runaway activation in infection, swelling, blood and kidney disease.
A low complement result does not name a gene. Ask first whether a pathway fails to work, is being consumed, or has been deliberately blocked. Missing defense favors infection and immune-complex persistence; a lost regulator can instead injure the host. The same alternative-pathway fault can affect a vessel or leave deposits in a glomerulus, so the tissue pattern matters as much as the blood test. This entire lesson and its practice are free to read.
Localize a failed pathway before naming a protein
Classical activation begins with C1 recognition of antibody-containing complexes; lectin recognition uses microbial carbohydrate and MASP enzymes. Both make the C4b2a C3 convertase (also called C4b2b in harmonized notation). The alternative route amplifies C3b on a permissive surface through factor B and factor D; properdin helps stabilize C3bBb. All three require downstream C3 and terminal C5 through C9 to produce full hemolytic activity. A low protein concentration and a low functional result measure different things. [1]
Inspect why an early classical break lowers CH50 alone, an alternative break lowers AH50 alone, and a common downstream break can lower both. [1] Image: Bone Wizardry.
CH50 interrogates classical entry through the terminal lytic pathway; AH50 interrogates alternative entry through the same terminal endpoint. A reproducibly absent CH50 with preserved AH50 suggests an early classical component; the reverse suggests an alternative component such as properdin, B, or D. Both low suggests C3 or a terminal component, but can also reflect consumption or inhibition. Lectin-only defects may escape both tests and need directed assessment. A C9 defect may retain measurable hemolysis rather than showing an absolutely flat value. [1]
Confirm the pattern on a properly collected specimen and measure targeted components and functions. Complement degrades with mishandling; active lupus or infection can consume several proteins; C5 inhibitors depress both endpoint assays without a germline defect. Compare serial results and medication history. An isolated low C3 or C4 is not proof of an inherited deficiency, and normal component concentration does not guarantee function. In a controlled addback experiment, preserved bacterial C3b deposition with failure of both lytic assays rescued by C7 localizes a terminal defect; preserved C4 antigen cannot substitute for a test of C2 function. Factor D cleaves C3b-bound factor B to generate the Bb-containing alternative convertase, whereas properdin stabilizes the formed complex. [1][10]
If CH50 is absent and AH50 preserved, what would loss of C2 change?
Classical entry would fail, while the alternative entry could still reach C3 and terminal lysis.
Match missing defense to the organism and assay
C3 fragments tag encapsulated bacteria for uptake. Severe recurrent pneumococcal and other pyogenic infection plus impaired activity in both assays can point to C3 loss; immune complexes also clear poorly. Early classical C1q, C2, or C4 defects can produce infections and lupus-like disease because clearance of immune complexes and dying cells is impaired. They do not all produce the same measured C4 concentration: isolated C2 loss can leave C4 antigen present. [1]
Terminal C5 through C9 components assemble a pore in the bacterial membrane, not the cell wall. Repeated invasive meningococcal disease raises concern for terminal deficiency, but properdin loss can give similar susceptibility with an alternative-pathway rather than a shared terminal assay pattern. A second meningococcal infection is a reason to investigate, not a molecular diagnosis. Test the individual components after excluding consumption, specimen problems, and drugs. [1]
Patients receiving C5 blockade and other complement inhibitors also face substantial meningococcal risk. CDC recommends both MenACWY and MenB vaccination for inhibitor recipients; vaccination is incomplete protection, and clinicians may consider antibiotic prophylaxis. Even after both precautions, possible meningococcal symptoms call for prompt assessment and emergency management. Vaccine-induced antibodies cannot restore C5-dependent terminal killing during blockade. Do not confuse a suppressed CH50 during treatment with evidence of inherited C5 loss. [2]
In repeated meningococcal disease with normal CH50 and low AH50, which branch deserves attention?
The alternative branch, including properdin, deserves directed functional and component testing.
Why a clearance defect can resemble lupus
Antibody-bound material activates classical complement. C3b decorates immune complexes; erythrocyte CR1 carries complexes toward liver and spleen for removal without requiring red-cell lysis. Early classical components also help dispose of dying cells. When that entry pathway is deficient, persistent debris and complexes can promote a lupus-like rash, arthritis, or renal inflammation. Active acquired lupus can itself consume C3 and C4. A low CH50 does not distinguish these directions without component studies, clinical timing, and repeat measurements. [1]
Consider two patients with photosensitivity and proteinuria. One has persistently absent CH50, normal AH50, absent C2 function, and stable C3/C4 concentrations even when clinically well. The other has falling C3 and C4 during an inflammatory flare and recovery afterward. The first favors an early classical defect; the second favors consumption. Neither is proven from a single C4 measurement. [1]
If immune-complex disease becomes quiet but CH50 remains absent, what should be checked?
Repeat a properly handled functional sample and measure early classical components before inferring an inherited defect.
Deep swelling: locate the mediator, then test the inhibitor
The paired inhibitor measurements below follow the 2021 WAO/EAACI diagnostic pathway. The 2025 WAO guideline, published in 2026, groups the traditional quantitative and qualitative patterns under HAE with C1-INH deficiency and prioritizes functional testing in a reliable specialist laboratory. Antigen and function still describe different properties of the protein. [14]
C1 inhibitor restrains activated C1 and, crucially for swelling, factor XIIa and plasma kallikrein. Kallikrein releases bradykinin from high-molecular-weight kininogen. Bradykinin increases vascular permeability through its B2 receptor. Thus C1 inhibitor dysfunction causes recurrent deep skin, gut, or airway swelling without the typical itchy wheals of histamine release. Lack of hives alone is not definitive: mast-cell angioedema sometimes has no wheals. Timing, response history and tests contribute. Airway or tongue involvement warrants emergency evaluation and treatment, not waiting for laboratory confirmation. [3]
Inspect where loss of C1 inhibitor increases contact-system signaling before bradykinin raises leak. [3] Image: Bone Wizardry.
Measure C1-INH antigen, C1-INH function and C4; repeat abnormal or discordant diagnostic results. Type 1 hereditary disease has low antigen and function; type 2 can have normal or high antigen but low function. C4 is often low, but normal C4 alone does not rule out hereditary angioedema. Late onset without family history and low C1q suggests acquired C1-INH deficiency, often associated with a lymphoproliferative condition, though C1q is not an absolute classifier. Histaminergic swelling is favored by itchy wheals, rapid onset after exposure and response to antihistamine therapy; when anaphylaxis is possible, manage it urgently rather than withholding epinephrine based on an uncertain mechanism. [3]
For current anaphylaxis with rapid wheals, wheeze or hypotension, give intramuscular epinephrine immediately while arranging emergency airway, breathing and circulation support. H1 antihistamines address mainly skin symptoms; inhaled beta-2 agonists are adjuncts for persistent bronchospasm, not treatment for hypotension; glucocorticoids do not replace prompt epinephrine. A prior nonurticarial episode must not delay anaphylaxis care. [7]
Selected on-demand HAE therapies target the actual pathway: C1-INH replacement, plasma kallikrein inhibition, or bradykinin B2 receptor antagonism. A planned procedure may call for specialist short-term prevention; long-term prevention is individualized. Do not assume steroids or antihistamines reverse proven bradykinin attacks. An ACE inhibitor reduces bradykinin breakdown and can provoke a distinct acquired angioedema mechanism; exposure alone does not diagnose inherited C1-INH deficiency. [3]
Why can normal C1-INH antigen coexist with recurrent bradykinin swelling?
The protein may be present but functionally defective, as in type 2 hereditary angioedema.
Pregnancy changes the choice among otherwise relevant on-demand HAE therapies. The cited WAO/EAACI guidance favors intravenous plasma-derived C1 inhibitor during pregnancy and lactation. This preference does not replace emergency airway management for a progressing upper-airway attack. [3]
Acquired loss can reflect an antibody that interferes with inhibitor function, followed by cleavage of the inhibitor. These are distinct from making too little protein. Experiments on supplied normal inhibitor separate a circulating antibody effect from a production defect. [12]
Planning matters even when swelling is absent. Upper-airway instrumentation may trigger an attack, so specialist short-term prophylaxis should be arranged before the procedure when indicated, with rescue treatment available afterward. During pregnancy, plasma-derived C1-INH is preferred. Prevention does not replace a plan for breakthrough swelling or emergency airway care. [3][14]
PNH: a missing anchor leaves blood cells exposed
An acquired PIGA variant in a hematopoietic stem-cell clone prevents assembly of the glycosylphosphatidylinositol (GPI) anchor. Its progeny lose multiple surface proteins including CD55, which accelerates convertase decay, and CD59, which prevents terminal pore assembly. This is not inherited global complement deficiency. Complement-sensitive red cells can lyse inside vessels, causing elevated LDH, depleted haptoglobin and sometimes hemoglobinuria. Thrombosis, including unusual venous sites, and marrow failure are further reasons to investigate. Dark morning urine is possible, not required. [4]
Compare intact GPI-linked surface brakes with the exposed PNH clone and predict terminal lysis. [4] Image: Bone Wizardry.
Diagnosis uses flow cytometry for GPI-linked antigens in blood cells, with FLAER on granulocytes and monocytes and relevant red-cell markers such as CD55/CD59. A recently transfused patient's red-cell fraction may underestimate clone size, so leukocyte assessment matters. A negative direct antiglobulin test supports investigation but is not itself diagnostic. Older acid hemolysis tests are not preferred. [4]
Terminal C5 inhibition can reduce intravascular hemolysis, but CD55 remains absent: C3 fragments still accumulate on some surviving PNH cells, which macrophages remove outside vessels. Persistent anemia despite a fall in LDH therefore needs evaluation for C3-mediated extravascular clearance, marrow insufficiency, and other causes rather than assuming C5 blockade failed. Hill and colleagues found C3 coating of PNH red cells during eculizumab treatment and evidence of extravascular clearance in some patients; marrow insufficiency and other causes still require assessment. Specialist management also addresses thrombosis and infection prevention. [8][4][2]
Why may LDH improve while anemia persists after C5 blockade?
C5 blockade limits intravascular pore formation but does not restore CD55, so C3-coated cells may still be removed outside vessels.
Kidney injury: microvascular clots or glomerular deposits?
A thrombotic microangiopathy (TMA) fragments red cells in small vessels and consumes platelets, often with acute kidney injury. A complement-mediated TMA can follow failed regulation of the alternative pathway on endothelium, including factor H, factor I or CD46 changes, factor H autoantibodies or activation-promoting C3/factor B variants. This is different from congenital complete absence of C3. Normal serum C3 does not exclude endothelial complement dysregulation. Factor H can retain fluid-phase C3b cofactor activity yet bind a sialylated host-like surface poorly: in a paired experiment with otherwise identical reagents, normal solution cleavage but increased surface C3b deposition rescued by control factor H supports a surface-specific protection defect. That experiment localizes a mechanism; it does not alone establish the clinical cause of TMA. [9][1][5]
Do not diagnose complement-mediated TMA from absence of diarrhea alone. Send ADAMTS13 testing promptly for possible TTP, ideally before plasma exchange; activity below 10% strongly supports TTP. Test stool for Shiga toxin and culture for STEC when HUS is possible, including when diarrhea is absent or resolving. Review pregnancy, drugs, severe hypertension, transplant and other secondary triggers. If TTP is suspected, urgent treatment must not wait for the assay. A specialist may use C5 inhibition for a complement-mediated TMA while etiologic investigation proceeds; avoid treating a serum C3 number in isolation. [5]
A different alternative-pathway disorder accumulates C3-dominant glomerular deposits and causes hematuria and proteinuria: C3 glomerulopathy. C3 nephritic factor is an autoantibody that stabilizes alternative C3 convertase and may accompany it, often with low C3 and preserved C4. Dense deposit disease is the electron-microscopy-defined subtype with distinctive intramembranous deposits; a membranoproliferative pattern alone does not establish that subtype. Postinfectious glomerulonephritis can also show dominant C3 initially; clinical course, serial complement and tissue findings separate them. C3 glomerulopathy and complement TMA share an overactive pathway, not identical lesions. [6]
Ask which object is damaged: endothelial small vessels yield schistocytes plus low platelets; a C3-dominant glomerular deposit yields a urinary and biopsy pattern. Next ask whether the alternative pathway is constitutively active in fluid or inappropriately active on a host surface. Neither one low C3 nor one gene variant alone establishes the complete clinical diagnosis. [5][6]
If C3 is normal but schistocytes, falling platelets and kidney injury persist, can complement TMA be dismissed?
No. Normal circulating C3 cannot rule out inappropriate complement activity on the endothelial surface.
In immune thrombotic thrombocytopenic purpura, severe ADAMTS13 loss and an inhibitor create two treatment tasks. Urgent plasma exchange supplies functional plasma protein and removes inhibitor; immune-directed treatment addresses the process producing the inhibitor. These tasks form part of specialist-led acute care, not a complete dosing or treatment protocol. [13]
Apply the localization to clinical evidence
Read the lead-in before the options. Separate deficient defense, acquired consumption, and lost surface regulation, then use the finding that excludes the nearest rival. All practice remains free.
Case 1
Show answer and explanations for case 1
A. Reduced factor B cleavage with preserved classical initiation (Why this does not fit)
Impaired cleavage can lower alternative-pathway activity. Normal initial C3bBb formation shows that cleavage and assembly occurred.
B. Preserved convertase persistence with impaired classical initiation (Why this does not fit)
It can reduce antibody-triggered C4b generation. Early C4b is normal while the assembled alternative enzyme decays rapidly.
C. Reduced convertase persistence with preserved classical initiation (Best answer)
The sample can assemble the alternative convertase. The assembled enzyme lacks normal stabilization. The early classical route remains functional.
D. Reduced C3b deposition with preserved terminal pore assembly (Why this does not fit)
Insufficient surface C3b limits alternative convertase assembly. The normal initial amount of surface C3bBb places the demonstrated loss after assembly.
Takeaway: Compare enzyme assembly with enzyme survival before assigning the defect.
A. Complement-directed neutrophil recruitment but not complement-assisted phagocytic uptake (Why this does not fit)
Active C5a generation supports a chemotactic signal. The supplied C3 tags and phagocyte receptors are both preserved.
B. Complement-directed neutrophil recruitment and complement-assisted phagocytic uptake (Best answer)
C5a can still provide a recruitment signal. Normal phagocytes can recognize complement-tagged targets. Pore assembly is a separate downstream effector function.
C. Complement-assisted phagocytic uptake but not complement-directed recruitment (Why this does not fit)
Bacterial complement deposition is preserved. C5 cleavage still produces an active small soluble fragment.
D. Neither complement-directed recruitment nor complement-assisted phagocytic uptake (Why this does not fit)
A major upstream C3 activation defect can impair several complement outputs. Independent assays document preserved tags and a preserved C5-derived signal.
Takeaway: Loss of pores does not automatically remove upstream signals or tags.
A. Replace patient phagocytes after incubation with patient serum (Why this does not fit)
They could recognize a tag that patient cells cannot recognize. Patient phagocytes already ingest donor-pretagged bacteria normally.
B. Increase erythrocyte CR1 without changing serum-dependent tagging (Why this does not fit)
CR1 binds complement-tagged immune complexes. Normal receptor abundance cannot supply the deficient ligand or repair bacterial tagging.
C. Supply only terminal pore-forming proteins after the target wash (Why this does not fit)
They participate in membrane attack against susceptible targets. Terminal proteins do not replace the upstream tags required for uptake and CR1 carriage.
D. Supply functional serum complement during target tagging before the wash (Best answer)
The demonstrated limitation is in serum-dependent target preparation rather than phagocyte recognition. Complement fragments tag immune complexes for CR1 binding. Restoring complement tagging before washing supplies ligands for both clearance routes.
Takeaway: Correct the missing target tag before replacing receptors that already work.
A. CH50 recovers; AH50 remains absent (Why this does not fit)
It supplies functional C2 for classical conversion. The patient sample supplies functional factor B, so alternative activity can also recover.
B. CH50 and AH50 both recover (Best answer)
Functional C2 from the second reagent restores the missing classical conversion step. Functional factor B from patient serum supplies the second reagent's missing component. The mixture has sufficient functional components and no inhibitor.
C. AH50 recovers; CH50 remains absent (Why this does not fit)
Patient serum supplies functional factor B. The second reagent also supplies sufficient functional C2.
D. Neither CH50 nor AH50 recovers (Why this does not fit)
Two samples missing the same required component would not complement each other. They lack different components and each supplies the other's missing function.
Takeaway: Locate both defects before predicting the mixed sample.
A. Activation has ceased; the antibody leaves C3b coating unchanged (Why this does not fit)
The circulating C3 pool has returned to the reference interval. Elevated cleavage fragments and excess target coating still demonstrate C3 activation.
B. Activation continues; the antibody directly stops further C3b coating (Why this does not fit)
C3 activation continues despite a restored circulating pool. It does not inhibit the C3 convertases that generate new C3b.
C. Activation continues; C3b coating can continue during C5 blockade (Best answer)
C3 activation remains detectable. Concentration measures the pool present, not the separate rates of production and consumption. The selective antibody leaves upstream C3 convertase activity intact.
D. Activation has ceased; the antibody directly stops further C3b coating (Why this does not fit)
The pool has normalized after treatment. The independent fragment and coating assays remain abnormal. It does not directly inhibit C3 cleavage.
Takeaway: Interpret the circulating pool separately from the inhibited reaction.
A. Handling explains the additional broad loss; confirm the lectin-specific abnormality in a new properly handled sample (Best answer)
Both aliquots began with the same in vivo complement state. Its isolated lectin-triggered abnormality is not assessed by the normal classical and alternative screens. Repeat targeted functional testing with validated specimen handling.
B. A common terminal deficiency is established; sequence terminal genes from the overnight panel (Why this does not fit)
They depend on shared downstream components. The properly handled aliquot preserves classical and alternative function.
C. The fresh normal screens exclude complement disease; no lectin follow-up is needed (Why this does not fit)
They begin through classical and alternative triggers. Lectin-triggered activity is reduced in the properly handled sample.
D. In vivo consumption explains the difference; repeat only total C3 concentration (Why this does not fit)
An in vivo change would be shared by the simultaneously collected aliquots. It neither explains postcollection loss nor confirms the isolated functional lectin abnormality.
Takeaway: A damaged specimen cannot localize a defect, and normal CH50/AH50 do not test every entry route.
A. An acquired block of C5 activation rather than absence of a downstream pore component (Best answer)
It lies downstream of C3 activation. C5 antigen is present but its cleavage is inhibited. The functional suppression is reversible and linked to the administered antibody.
B. An acquired block of alternative C3 convertase assembly alone (Why this does not fit)
It could prevent alternative C3 amplification. C3b deposition persists while the supplied assay specifically loses C5 cleavage.
C. Complete congenital absence of C6 with preserved C5 cleavage (Why this does not fit)
It can impair their shared terminal lysis endpoint. C5 cleavage is blocked after previously normal function and returns after antibody removal.
D. Depletion of circulating C3 and C5 during global consumption (Why this does not fit)
It can deplete components required by multiple pathways. C3b deposition and C5 antigen persist, and removing one antibody restores activity.
Takeaway: Normal protein amount can coexist with reversible blockade of its activation.
A. The isolate is unrecognized by patient antibody, so antibody mismatch alone explains the results (Why this does not fit)
Antibodies may not recognize a circulating strain adequately. Patient IgG supports killing of the same isolate with donor complement.
B. Patient antibody lacks any useful effector capacity, even with functional complement (Why this does not fit)
It would not support the demonstrated complement-dependent killing. The patient preparation works when donor complement replaces the patient complement sample.
C. Antibody can recognize the isolate, but more recognition cannot replace the impaired complement effector (Best answer)
The antibody can support recognition and killing when an effective complement system is supplied. More antibody alone does not restore the impaired effector step. A vaccine response does not guarantee protection when complement function remains inhibited.
D. Insufficient antibody quantity alone explains the failure in the patient complement sample (Why this does not fit)
More target recognition can strengthen initiation when antibody availability is limiting. Additional IgG fails with patient complement but works with donor complement.
Takeaway: Test recognition and effector function separately; vaccination does not remove the need for urgent assessment.
A. Ba is released and Bb remains with C3b; formation increases without prolonging the measured enzyme lifetime (Best answer)
It cleaves factor B after factor B binds C3b. Bb remains associated with C3b while Ba is released. The rescue corrects formation rather than an abnormal lifetime of assembled enzyme.
B. Bb is released and Ba remains with C3b; formation increases without prolonging lifetime (Why this does not fit)
It attributes the rescue to factor B cleavage. Bb, not Ba, is the factor B fragment retained in C3bBb.
C. Ba is released and Bb remains with C3b; rescue acts only by prolonging assembled enzyme lifetime (Why this does not fit)
Factor D cleavage releases Ba and retains Bb with C3b. The rescued complexes have normal decay once new assembly is prevented.
D. Uncleaved factor B remains with C3b; rescue prolongs proconvertase lifetime without generating Bb (Why this does not fit)
C3bB is the proconvertase before factor D cleavage. Factor D must generate retained Bb to form active C3bBb. Successfully rescued enzymes already decay at the normal rate.
Takeaway: Factor D enables formation of C3bBb; stabilization is a separate role.
A. Assess C8 quantity and function; residual screening lysis does not exclude severe C8 deficiency (Why this does not fit)
Both pathways share the terminal lysis machinery. Patient serum restores the C8-deficient reagent but not the C9-deficient reagent.
B. Assess C2 quantity and function; the complementation tests localize an early classical defect (Why this does not fit)
It would impair classical function while sparing the alternative screening route. The selective failure to complement a C9-deficient reagent identifies a terminal activity question.
C. Assess C9 quantity and function; residual screening lysis does not exclude severe C9 deficiency (Best answer)
The patient serum supplies functional C8. Neither mixture partner supplies adequate C9 function. Residual hemolysis has been documented in human C9 deficiency.
D. Exclude terminal deficiency; any measurable hemolysis establishes intact C8 and C9 (Why this does not fit)
Some terminal defects retain measurable activity under particular assay conditions. The C9-deficient reagent is not rescued while the C8-deficient reagent is.
Takeaway: Complementation localizes the missing activity; a nonzero screen is not an absolute exclusion.
A. Excess upstream kininogen cleavage can persist while the endothelial permeability response decreases (Best answer)
The inhibitor is present but does not provide normal functional restraint. Kallikrein-dependent bradykinin generation occurs in the plasma reaction. It can reduce the endothelial response without restoring upstream inhibitor function.
B. Kininogen cleavage normalizes and inhibitor function returns to the reference range (Why this does not fit)
It could restore regulation of upstream protease activity. The antagonist acts on endothelial B2 receptors rather than on the plasma inhibitor.
C. Kininogen cleavage stops but the endothelial bradykinin response remains unchanged (Why this does not fit)
It would act upstream on mediator generation. The specified antagonist blocks the endothelial receptor, not plasma kallikrein.
D. Both plasma cleavage and endothelial response increase because C1-INH antigen is normal (Why this does not fit)
No, the confirmed functional assay demonstrates deficient activity. Blocking B2 reduces the receptor-mediated response rather than increasing it.
Takeaway: Blocking the receptor can reduce an output without repairing excess mediator generation.
A. A qualitative inhibitor defect; perform inhibitor antigen and function testing in her brother (Why this does not fit)
It would retain normal or increased C1-INH antigen despite low function. Her antigen is markedly reduced on both samples. An asymptomatic first-degree relative should still undergo inhibitor evaluation.
B. A quantitative inhibitor defect; defer further testing of her brother until an attack (Why this does not fit)
Both inhibitor quantity and function are reduced. Inherited deficiency may be present before recognized swelling attacks.
C. A quantitative inhibitor defect; perform inhibitor antigen and function testing in her brother (Best answer)
It supports a quantitative type 1 C1-INH defect. A single normal C4 does not exclude C1-INH-associated disease. C1-INH antigen and functional testing are still needed.
D. A qualitative inhibitor defect; defer further testing of her brother until an attack (Why this does not fit)
Repeated antigen concentrations are markedly low. First-degree family screening should not depend on a first swelling attack.
Takeaway: Classify the paired inhibitor results, then screen relatives beyond C4 alone.
A. Reduced synthesis of inhibitor, followed by consumption of the smaller circulating pool (Why this does not fit)
It can reduce the amount of newly produced inhibitor. The assay contains supplied normal donor protein and no protein synthesis.
B. Antibody interference with inhibitory binding, followed by proteolytic inactivation (Best answer)
A transferable antibody-dependent effect interferes with inhibitor function. The inhibitor undergoes proteolytic inactivation after the binding defect. The experiment begins with normal donor inhibitor and changes only the added IgG.
C. Proteolytic inactivation before IgG exposure, followed by incidental antibody binding (Why this does not fit)
Proteolysis can make an inhibitor inactive. Normal donor inhibitor fails only after patient IgG is introduced, and IgG removal prevents the effect.
D. Accelerated binding of inhibitor to C1s, followed by consumption of effective complexes (Why this does not fit)
Effective inhibitor-protease complexes remove inhibitor from the available pool. Patient IgG prevents the inhibitory complex from forming before the inactive fragment appears.
Takeaway: Separate neutralization of function from subsequent destruction of the inhibitor.
A. Confirm dysfunctional C1-INH disease from the first low value and investigate SERPING1 as an established type 2 case (Why this does not fit)
The first report combines normal antigen with low function. The compromised sample is contradicted by two properly handled normal functional results.
B. Do not confirm C1-INH deficiency; continue specialist evaluation for other causes, including normal-C1-INH forms (Best answer)
They do not confirm persistent C1-INH deficiency or dysfunction. Some bradykinin-mediated and hereditary forms have normal C1-INH assays. Specialist assessment of medication-related, hereditary normal-C1-INH and other causes remains appropriate.
C. Use the normal C4 to exclude bradykinin-mediated disease and stop the complement-related evaluation (Why this does not fit)
C4 often falls in C1-INH-associated disease. C4 is not an absolute exclusion test for the wider bradykinin-mediated swelling differential.
D. Confirm acquired inhibitor deficiency from the discordance and investigate a B-cell disorder as its established cause (Why this does not fit)
It can cause a persistent functional C1-INH deficit. Properly handled repeated testing does not confirm that deficit. It can evaluate the unresolved phenotype without presupposing acquired inhibitor deficiency.
Takeaway: Reject an unconfirmed abnormal assay without dismissing the unresolved phenotype.
A. Give intravenous plasma-derived C1-INH before instrumentation and retain on-demand treatment (Best answer)
Upper-airway instrumentation can trigger a subsequent HAE attack. Plasma-derived C1-INH is the preferred preparation in the cited guidance. Short-term prophylaxis reduces risk but does not guarantee that no attack will occur.
B. Reserve plasma-derived C1-INH for an attack after instrumentation without short-term prophylaxis (Why this does not fit)
Plasma-derived C1-INH is an appropriate pregnancy-preferred treatment. Planned endotracheal instrumentation warrants short-term prophylaxis even during an asymptomatic interval.
C. Give intravenous recombinant C1-INH before instrumentation and retain on-demand treatment (Why this does not fit)
Preprocedural C1-INH can provide short-term prevention of a trigger-related attack. Pregnancy-specific guidance favors the plasma-derived preparation when it is available.
D. Reserve recombinant C1-INH for an attack after instrumentation without short-term prophylaxis (Why this does not fit)
There is no current swelling. Mechanical upper-airway manipulation can provoke a later attack. Pregnancy favors plasma-derived C1-INH in the cited recommendations.
Takeaway: Prevent the procedural trigger with the pregnancy-preferred preparation and keep rescue ready.
Rapid wheals, respiratory compromise and hypotension support anaphylaxis now. Intramuscular epinephrine is the first-line medication while emergency support continues.
B. Intravenous epinephrine bolus (Why this does not fit)
It treats the circulatory and respiratory effects of anaphylaxis. Intravenous boluses carry greater arrhythmia risk and are not recommended as initial treatment of a spontaneously perfusing patient. A monitored infusion by experienced clinicians may be used for refractory anaphylaxis.
C. Intravenous antihistamine with an inhaled beta-2 agonist (Why this does not fit)
It may reduce wheals and bronchospasm. It does not replace epinephrine for the systemic circulatory compromise.
D. Intravenous glucocorticoid with crystalloid (Why this does not fit)
Fluid supports circulation during anaphylactic shock. Glucocorticoids do not provide the immediate vascular and respiratory effects of epinephrine.
E. Subcutaneous bradykinin B2 antagonist (Why this does not fit)
Prolonged isolated nonurticarial swelling can involve bradykinin. Food-associated wheals, wheeze and hypotension indicate a systemic anaphylactic pattern.
Takeaway: Treat the current anaphylaxis pattern promptly with intramuscular epinephrine.
A. Expansion of the stem-cell clone; a new inherited terminal-component deficiency (Why this does not fit)
A parallel change in the leukocyte clone fractions would support that interpretation. Both independently measured leukocyte fractions remain near 70%. It follows the introduction of a drug that suppresses terminal complement function.
B. Correction of the GPI-anchor defect; suppression of terminal function by treatment (Why this does not fit)
Effective C5 inhibition can suppress this terminal-dependent assay. The surviving red cells still belong to the measured GPI-deficient population.
C. Dilution by donor red cells; suppression of terminal function by treatment (Why this does not fit)
Recent transfusion adds GPI-normal donor red cells. No transfusion occurred, and the GPI-deficient fraction rises rather than becoming diluted.
D. Improved survival of deficient red cells; suppression of terminal function by treatment (Best answer)
Intravascular hemolysis has decreased. C5 blockade allows more vulnerable GPI-deficient red cells to survive in circulation. The treatment inhibits the terminal reaction required for that assay.
Takeaway: Red-cell survival and a drug-suppressed assay can change while the stem clone remains similar.
A. A rapid contraction of the GPI-deficient stem-cell clone (Why this does not fit)
A stem-cell clone change could eventually alter both red and white lineages. Stable granulocyte and monocyte fractions over one day argue against rapid clone contraction.
B. New selective lysis of most circulating PNH red cells (Why this does not fit)
Selective complement lysis can deplete PNH red cells. Stable LDH without a new hemolytic episode and immediate donor red-cell input favor dilution instead.
C. An isolated CD59 staining artifact across all lineages (Why this does not fit)
Marker-specific technical artifacts can mislead one flow measurement. Concordant other GPI markers and stable leukocyte measurements argue against isolated CD59 artifact.
D. Dilution by transfused normal red cells (Best answer)
Transfused red cells carry normal GPI-linked markers. Their influx lowers the measured percentage of abnormal circulating red cells while leukocyte clone estimates stay stable.
Takeaway: Recent transfusion can underestimate PNH clone size on red cells; inspect leukocytes.
A. Extravascular removal of C3-coated PNH red cells (Best answer)
C5 blockade reduces terminal intravascular hemolysis but does not restore CD55 to PNH cells. C3-coated survivors can be cleared extravascularly, though marrow insufficiency or other causes can also contribute to anemia.
B. Marrow failure without peripheral red-cell clearance (Why this does not fit)
Marrow failure can cause persistent anemia in PNH. It does not by itself explain new C3 coating on surviving cells and ongoing indirect bilirubin elevation.
C. Breakthrough terminal intravascular lysis despite therapy (Why this does not fit)
Breakthrough terminal lysis can recur if blockade is incomplete. LDH near reference with C3-coated survivors favors extravascular clearance rather than dominant ongoing intravascular pore injury.
D. Warm IgG-mediated clearance of antibody-coated red cells (Why this does not fit)
Warm IgG antibodies can promote extravascular clearance. IgG-negative but C3-positive surviving clone cells and C5-blocked terminal lysis point instead to complement-fragment opsonization.
Takeaway: C5 inhibition can spare intravascular lysis while leaving CD55-related C3 opsonization.
A. A technical artifact despite concordant leukocyte markers (Why this does not fit)
One anomalous flow marker can be a technical artifact. Concordant GPI-marker loss in two leukocyte lineages supports a real small clone.
B. Active hemolytic PNH as the dominant cause of anemia (Why this does not fit)
Hemolytic PNH can cause anemia and thrombosis. Normal hemolysis markers with hypocellular marrow more strongly favor marrow failure as the main current anemia mechanism.
C. Treated hemolytic PNH with biochemical remission (Why this does not fit)
C5 therapy can normalize LDH in hemolytic PNH. This untreated patient has no drug-mediated biochemical suppression to explain normal markers.
D. A subclinical PNH clone alongside marrow failure (Best answer)
Small GPI-deficient clones may accompany aplastic anemia without active hemolysis. Concordant flow detects the clone while marrow failure better explains the present anemia.
Takeaway: PNH clones may be subclinical, especially with marrow failure; LDH gauges activity, not existence.
A. Replace complement components and suppress anti-complement antibody formation (Why this does not fit)
It is below the reference interval. Severe ADAMTS13 loss and its neutralizing inhibitor identify a different treatment target.
B. Use plasma exchange to replace enzyme and remove inhibitor, with treatment that suppresses the immune process (Best answer)
ADAMTS13-mediated control of von Willebrand factor multimers is severely impaired. It establishes an immune mechanism rather than isolated inherited enzyme underproduction. Exchange supplies functional plasma protein and removes inhibitor, while immune-directed treatment targets the process producing the inhibitor.
C. Replace ADAMTS13 while treating the episode as an inherited deficiency without an immune target (Why this does not fit)
It addresses inherited ADAMTS13 deficiency without a demonstrated inhibitor. The pretreatment neutralizing anti-ADAMTS13 inhibitor identifies an active immune mechanism.
D. Suppress terminal complement while using immune-directed treatment as the enzyme-replacement strategy (Why this does not fit)
Some microangiopathies are complement mediated. It would not replace the severely deficient ADAMTS13 activity. It targets the immune process rather than directly supplying active plasma enzyme.
Takeaway: Treat the missing function and its demonstrated immune cause together.
A. Rely on post-plasma ADAMTS13 to exclude TTP and obtain stool Shiga toxin testing (Why this does not fit)
Stool testing evaluates a Shiga toxin-producing trigger. The ADAMTS13 value was obtained after plasma treatment rather than before it.
B. Test pretreatment ADAMTS13 and use complement genetics instead of stool testing (Why this does not fit)
It allows assessment of ADAMTS13 before plasma exposure. A complement gene panel does not directly test the suspected diarrheal Shiga toxin trigger.
C. Rely on post-plasma ADAMTS13 and use low C3 to establish complement-mediated TMA (Why this does not fit)
Low C3 is not specific enough to establish complement-mediated TMA. The post-plasma ADAMTS13 result does not settle the pretreatment deficiency question.
D. Test ADAMTS13 in the pretreatment aliquot and obtain stool Shiga toxin testing (Best answer)
Administered plasma can alter the measured ADAMTS13 activity. The stored pretreatment aliquot precedes that confounding intervention. Bloody diarrhea warrants direct evaluation for Shiga toxin-producing infection.
Takeaway: Resolve treatment-confounded ADAMTS13 and the infectious trigger independently.
A. Global loss of factor H cofactor activity in fluid phase (Why this does not fit)
Fluid-phase cofactor loss would reduce solution C3b cleavage. Matched normal solution activity instead confines the measured difference to the host-like surface.
B. Impaired factor H recognition and protection of host surfaces (Best answer)
Factor H retains solution cofactor activity in the paired test. Reduced host-surface binding and rescue with control factor H support a surface-recognition defect.
C. Enhanced alternative activation equally in fluid and on surfaces (Why this does not fit)
They are different measurements. Reduced surface binding and rescue by control factor H support impaired host-surface recognition. The experiment does not exclude every additional change in fluid-phase complement activation.
D. An intrinsic CD46 defect in the test surface (Why this does not fit)
CD46 deficiency can impair protection on patient cells. Identical test surfaces supplied with patient versus control factor H isolate a soluble regulator difference rather than an intrinsic surface-cell defect.
Takeaway: Normal serum C3 is compatible with endothelial complement dysregulation.
A. Immune-complex-mediated membranoproliferative glomerulonephritis (Why this does not fit)
Immune-complex GN can cause hematuria and proteinuria. Predominant C3 staining together with dense intramembranous deposits more specifically identifies the dense-deposit C3G pattern.
B. Complement-mediated endothelial thrombotic microangiopathy (Why this does not fit)
Complement TMA can injure kidney microvessels and may coexist with GN. Glomerular C3-dominant staining and highly dense intramembranous deposits point to a deposit disorder rather than a primarily endothelial lesion.
C. Dense deposit disease within C3 glomerulopathy (Best answer)
D. C3 glomerulonephritis without dense intramembranous deposits (Why this does not fit)
C3GN can show dominant glomerular C3. The specific highly dense intramembranous ultrastructure supports dense deposit disease instead of the nondense C3GN subtype.
Takeaway: Electron-dense intramembranous deposits distinguish dense deposit disease from a vascular TMA.
A. Complement-mediated TMA with renal microvascular injury (Why this does not fit)
Complement TMA can cause renal injury with alternative dysregulation. The C3-dominant deposit biopsy and recovering C3 with improving urine findings instead support a resolving glomerulonephritis.
B. Dense deposit disease with persistent intramembranous deposits (Why this does not fit)
DDD can produce C3-dominant glomerular deposits. The absence of characteristic dense intramembranous deposits and clinical resolution argue against that subtype.
C. Persistent C3 glomerulonephritis requiring continued evaluation (Why this does not fit)
Persistent C3GN can follow C3-dominant staining and ongoing low C3. C3 normalization by ten weeks and resolving urinary findings favor a transient postinfectious process, although follow-up matters.
D. Resolving infection-associated glomerulonephritis rather than persistent C3G (Best answer)
Infection-associated GN can initially produce C3-dominant deposits and low serum C3. Normalization by ten weeks with urinary improvement supports resolution over persistent C3G, subject to ongoing clinical follow-up.
Takeaway: Follow serial C3 and renal findings before labeling postinfectious C3 deposition as persistent C3 glomerulopathy.
