NOTES

NOTES
COMPLEMENT DEFICIENCIES

GENERALLY, WHAT ARE THEY?

▪ Complement component serum levels
PATHOLOGY & CAUSES ▫ Level ↓ correlates with specific protein
deficiency
▪ Genetic diseases: a protein of the 30+ in
▫ Overactive pathway consumption
complement system missing → abnormal
→ protein level ↓ (i.e. decreased C2/
inflammatory/immune response-prone
C4 ↓ indicates classical pathway
individual
overactivation—as in C1 inhibitor
deficiency)
SIGNS & SYMPTOMS
TREATMENT
▪ Recurrent bacterial infection (i.e.
pneumonia, tonsillitis, otitis), especially
MEDICATIONS
encapsulated bacteria
▪ Bacterial infection prevention: vaccination
▪ Rheumatologic/autoimmune disorders
▫ Meningococcal, pneumococcal,
▫ Can be systemic lupus erythematosus
Haemophilus influenzae b (Hib) vaccines
(SLE)-like (fever, rash, arthritis,
(conjugated vaccines preferred for Hib
glomerulonephritis)
pneumococcal)
▪ Bacterial infection-suspicious symptoms →
DIAGNOSIS swift antibiotic management

LAB RESULTS
▪ Screening based on recurrent infection/
autoimmune familial/individual history
▫ Genetic screening
▫ Total hemolytic complement (THC/
CH50) testing < 11% (measures
individual serum’s ability to lyse sheep
red blood cells (RBCs) coated with anti-
RBC rabbit antibody → activates serum
complement proteins; AH50 alternative
pathway evaluation test)

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C1 ESTERASE
INHIBITOR DEFICIENCY
osms.it/complement_deficiency

PATHOLOGY & CAUSES DIAGNOSIS

▪ Autosomal dominant disorder: C1 inhibitor LAB RESULTS
protein missing → clinical hereditary ▪ Low C1 esterase inhibitor, C4 levels
angioedema (HAE) syndrome
▪ C1 esterase inhibitor role: inhibits C1
OTHER DIAGNOSTICS
protein cleavage in complement cascade
▫ C1 esterase inhibitor deficiency → History
overactive C1 cleavage → ↑ classical ▪ Recurrent, self-resolving angioedema
complement pathway activation → episodes with/without colicky, abdominal
proinflammatory, ↑ immune responsive pain
state → ↑ downstream anaphylatoxin ▪ No concurrent angiotensin-converting
production (C2a, C4a) enzyme (ACE) inhibitors/nonsteroidal anti-
▪ C1 esterase inhibitor also mediates inflammatory drug (NSAIDs) use
bradykinin production → hereditary ▪ Positive angioedema family history
angioedema (HAE)
▫ C1 esterase inhibitor absence → ↑ Physical examination
kallikrein, factor XII → unchecked ▪ Nondependent (i.e. head/neck), non-pitting
bradykinin production → vasodilation → edema areas without urticaria/pruritis
severe angioedema

TREATMENT
SIGNS & SYMPTOMS
MEDICATIONS
Angioedema episodes ▪ Therapies: purified C1 inhibitor concentrate,
▪ Commonly last 24–72 hours, without kallikrein inhibitor, bradykinin-B2-receptor
urticaria/pruritis antagonist
▫ Frequent prodromal symptoms: fatigue, ▪ If above targeted therapy interventions
nausea, gastrointestinal (GI) symptoms, unavailable → fresh frozen plasma
myalgias present ▪ Avoid angiotensin-converting-enzyme
▫ Individuals may report stress (physical/ (ACE) inhibitors
mental) as episode triggers

Edematous episodes SURGERY

▪ Nondependent areas, non-pitting ▪ Acute episodes → intubation for airway
▫ Most common locations: upper management
respiratory/GI tract skin/mucosal tissue
▫ GI bowel edema → nonspecific GI
distress symptoms (abdominal pain,
colic)
▫ Laryngeal edema most feared → closed
airway → asphyxiation

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 C2 DEFICIENCY
osms.it/complement_deficiency

PATHOLOGY & CAUSES DIAGNOSIS

▪ Autosomal recessive disorder: involves C2 LAB RESULTS
protein absence in classical complement ▪ Recurrent SLE-like episodes: CH50 testing
cascade
▫ Most common complement deficiency
OTHER DIAGNOSTICS
disorder
▪ Clinical/family recurrent, bacterial infection
▫ Symptoms commonly present in early
history
childhood
▪ Associated with IgG deficiency
TREATMENT
SIGNS & SYMPTOMS MEDICATIONS
▪ Bacterial infection vigilance: prompt
▪ Individuals sometimes present with SLE-
antibiotic therapy
like symptoms
▪ SLE-like episodes: corticosteroids, other
▫ Fever, rash, arthritis, glomerulonephritis
immunosuppressants
▪ ↑ infection risk from encapsulated bacteria
▫ Streptococcus pneumoniae,
Haemophilus influenza type b, Neisseria
meningitidis

C3 DEFICIENCY
osms.it/complement_deficiency
→ type III hypersensitivity reaction
PATHOLOGY & CAUSES ▫ Inability to opsonize underlies frequently
encountered sinopulmonary diseases
▪ Autosomal recessive disorder: involving (see bacterial infections below)
protein C3 (vital protein connecting three
▪ Inability to form C5 convertase → deficient
complement activation pathways—
membrane attack complex (MAC) formation
classical, alternative, lectin—to final,
common pathway) ▫ Inability to complete complement
cascade underlies (primarily meningitis-
▫ Presents with severe infections shortly
related) septic presentation
after birth
▪ Abnormal C3 protein levels → abnormal
▫ Rarest complement deficiency disorder
three complement pathway activation
▪ Cleavage product: C3b (major opsonin) → abnormal pathway byproduct
▫ Inability to effectively opsonize without concentrations (i.e. anaphylatoxins C2a,
C3b → antigen-antibody complex C4a) → abnormal immune cell response
unable to be phagocytosed → excess to immune insult → abnormal neutrophil
immune complex formation, deposition response → abscess formation

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 Chapter 31 Complement Deficiencies

SIGNS & SYMPTOMS TREATMENT

▪ Severe, recurrent encapsulated bacterial MEDICATIONS
infections shortly after birth ▪ Bacterial infection vigilance: prompt
▫ Particularly Streptococcus pneumoniae antibiotic therapy
▪ Children who survive severe infections ▪ Bacterial infection prophylaxis: vaccination
develop problems secondary to immune ▫ Pneumococcal vaccination
complex deposition, reaction ▫ Meningococcal vaccination (for resulting
▫ Especially membranoproliferative dysfunctional C5–C9 MAC formation)
glomerulonephritis

DIAGNOSIS
LAB RESULTS
▪ Clinical/family history of recurrent, bacterial
infections (especially Streptococcus
pneumoniae) → CH50 testing

C5-C9 DEFICIENCY
osms.it/complement_deficiency

PATHOLOGY & CAUSES DIAGNOSIS

▪ Autosomal recessive disorder group: LAB RESULTS
involving any protein (C5–C9) involved ▪ Clinical recurrent, bacterial infection history
in MAC formation (part of final, common (especially Neisseria species) → CH50
complement pathway) testing
▪ MAC-forming inability: precludes ability to
create osmotic gradient for cellular lysis
TREATMENT
SIGNS & SYMPTOMS MEDICATIONS
▪ Bacterial infection vigilance: prompt
▪ Frequent, recurrent bacterial infection antibiotic therapy
▫ Propensity for Neisseria gonorrhoeae, ▪ Severe bacterial infection mitigation:
meningitidis infections (thin cell walls meningococcal vaccination
→ especially complement destruction-
vulnerable)

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 PAROXYSMAL NOCTURNAL
HEMOGLOBINURIA (PNH)
osms.it/pnh

▪ Splenomegaly may present in severe

PATHOLOGY & CAUSES hemolysis setting
▪ Venous, arterial thrombosis
▪ Acquired genetic disorder: hematopoietic
stem cells produce cells that lack cell-
membrane protein CD55 (AKA decay- DIAGNOSIS
accelerating factor (DAF)) or CD59 that
predispose cells to complement-mediated
LAB RESULTS
lysis
▪ Normochromic, normocytic anemia;
▫ Involved gene (on X chromosome)
pancytopenia; ↑ lactate dehydrogenase
is phosphatidylinositol glycan
(LDH) tests
complementation group A (PIGA)
▫ Biologically-male individuals in early 20s Sugar water test
(most common) ▪ Serum mixed in sucrose (isotonic solution,
▪ CD59: anchor protein for low ionic strength) → predisposes to
glycosylphosphatidylinositol (GPI), a complement-mediated lysis → CD55/59-
marker of ‘self’ antigenicity on erythrocytes, deficient cells hemolyze
leukocytes
▫ CD59 deficiency → cells sensitive Acid hemolysis test (Ham test)
to complement-mediated lysis → ▪ Alternative complement cascade triggered
intravascular hemolysis in acidified serum conditions → CD55/59-
▫ Nocturnal: relative hypoventilation deficient cells hemolyze
during sleep → slightly ↑ serum CD55/59 protein flow cytometry
CO2 → slightly acidic serum pH → ↑
▪ Most sensitive, specific test
complement activity → ↑ nighttime
hemolysis
TREATMENT
COMPLICATIONS
▪ Potentially fatal venous (Budd–Chiari MEDICATIONS
syndrome), arterial thrombosis ▪ Glucocorticoids (prednisone; typically poor
▪ Aplastic anemia, myelodysplasia, response)
myelofibrosis, acute leukemia evolution ▪ Eculizumab: monoclonal antibody binds
C5 cleavage → prevents MAC formation,
complement-mediated cell lysis
SIGNS & SYMPTOMS
▪ Episodic crises triggers include infection,
SURGERY
dietary iron supplementation, menstruation ▪ Bone marrow transplantation
▪ Nocturnal hemoglobinuria (upon waking)
▪ Lumbar, abdominal, general
musculoskeletal pain

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