6. Moschcowitz’ Disease
1924-
Girl who presented with an
abrupt onset of petechiae and
pallor followed rapidly by
paralysis, coma and death.
Pathological examination
revealed small arterioles and
capillaries with thrombi
consisting mainly of platelets
“a powerful poison which has
both agglutinative and
hemolytic properties”
Proceedings of the New York Pathological Society 1924,24:21
Archives of Internal Medicine 1925, 36:89
8. Cleavage of Unusually Large Multimers of von Willebrand Factor on Endothelial Cells by the von
Willebrand Factor–Cleaving Metalloprotease, ADAMTS 13.
(A Disintegrin-like And Metalloprotease w Thrombospondin Type 1 motif 13)
Moake JL. N Engl J Med 2002;347:589-600.
9. Proposed Relation among the Absence of ADAMTS 13 Activity in Vivo, Excessive Adhesion and
Aggregation of Platelets, and Thrombotic Thrombocytopenic Purpura.
Moake JL. N Engl J Med 2002;347:589-600.
10. Relation between Defects in Plasma von Willebrand Factor–Cleaving Metalloprotease, ADAMTS
13, and Thrombotic Thrombocytopenic Purpura (TTP).
(Upshaw-Schulman Syndrome)
Moake JL. N Engl J Med 2002;347:589-600.
11. Treatment
Replacement of a deficient component
Plasma infusion
Metalloprotease
Plasma exchange Normal vWF multimers
Immunosuppressants Removal of a harmful plasma
component
Steroids Auto antibodies
Rituximab Unusually high multimers vWF
Immune regulation
17. Proposed Mechanisms of Platelet–Fibrin Formation in the Hemolytic–Uremic Syndrome.
Moake JL. N Engl J Med 2002;347:589-600.
18. aHUS:
A Rare, Genetic, Devastating and
Life-threatening Disease
Many patients cannot have a specific mutation identified and all still have
chronic uncontrolled complement activation
Complement-mediated TMA leads to systemic, progressive organ damage and
sudden death
One year after diagnosis, >50% of all patients have died, require dialysis, or
have permanent renal damage despite plasma exchange
Diagnosis of early signs and symptoms is the critical first step to fundamentally
transform the lives of aHUS patients
Genetic deficiency in complement regulatory genes causes chronic uncontrolled
complement activation
19. Genetic Loss of Natural Inhibitors Leads to Chronic Uncontrolled
Complement Activation
Lectin Pathway Classical Pathway Alternative Pathway
Proximal
C3 + H2O - ALWAYS ACTIVE
Immune Complex Clearance
Microbial Opsonization C3 (Chronic)
Amplification
Natural
–
Inhibitors
Terminal
C5
C5a C5b-9
Membrane Attack
Complex
Potent
Anaphylaxis Cell Lysis Cell Destructio
Anaphylatoxin
Proinflammatory
Inflammation Consequences Chemotaxis ConsequencesInflammation
Platelet Activation
Proinflammatory
Thrombosis Leukocyte/Monocyt Thrombosis
Leukocyte/Monocy
e Activation
te Activation
Endothelial
Endothelial
Activation
Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4:359-395; Walport MJ. N Engl J Med. 2001;344:1058-1066; Rother RP et al. Nature Biotech. 2007;25:1256-1264; Meyers G et al. Blood.
Activation
2007;110:Abstract 3683; Hill A et al. Br. J. Hematol. 2010;149:414-425; Hillmen P et al. Am J Hematol 2010; 85:553-559, International PNH Interest Group. Blood. 2005;106:3699-3709; Hillmen P et
Prothrombotic
al. N Engl J Med. 1995;333:1253; Nishimura J et al. Medicine.2004;83:193-207; Caprioli J et al. Blood 2006;108:1267-1279; Noris M, et al. Clin J Am Soc Nephrol. 2010;5:1844-1859; George JN et
Prothrombotic
al. Blood. 2010;116:4060-4069; Loirat C, et al. Pediatr Nephrol. 2008;23:1957-1972; Stahl A, et al Blood. 2008;111:5307-5315; Hosler GA, et al Arch Pathol Lab Med. 2003; 127;834-839; Ariceta G
et al. Pediatr Nephrol. 2009; 24:687-696.
20. Alternative Pathway of Complement Activation and Regulation.
Membrane Attack Complex
Delvaeye M et al. N Engl J Med 2009;361:345-357.
21. Model for the Mechanisms Leading from Impaired Regulation of the Alternative Pathway to
Thrombotic Microangiopathy.
Noris M, Remuzzi G. N Engl J Med 2009;361:1676-1687.
22. Classification of Atypical Hemolytic–Uremic Syndrome.
Noris M, Remuzzi G. N Engl J Med 2009;361:1676-1687.
23. Genetic Abnormalities and Clinical Outcome in Patients with Atypical Hemolytic–Uremic
Syndrome.
Noris M, Remuzzi G. N Engl J Med 2009;361:1676-1687.
24. Chronic Uncontrolled Complement Activation Causes
Platelet, Endothelial, Leukocyte/Monocyte Activation Leading to
Inflammation and Systemic Small Vessel Occlusion
Endothelial Platelet
Swelling and Consumption
Disruption
Mechanical
Hemolysis
Uncontrolled
Complement Endothelium (Schistocytes)
Activation Activation
Platelet
Activation Neutrophil
Platelet Platelet
Activation Aggregation
Blood Clots
Inflammation
Neutrophil
Occlusion
Ischemia
Hypoxia
Modified from Desch K et al. JASN. 2007;18:2457-60. Modified from Licht C et al. Blood. 2009;114:4538-4545. Modified from Noris M et al. NEJM. 2009;
361:1676-87. Modified from Stahl A, et al. Blood 2008;111:5307-15. Modified from Camous L et al. Blood. 2011;117:1340-9.
25. Systemic Organ Damage
Systemic Organ Damage CNS
CNS Kidney
Kidney GI System
GI System Heart
Heart Others
Others
Complement-Mediated TMA Leads to the
Morbidities and Mortality in aHUS
Cardiovascular2,3,4,6 CNS1,2,3,4,5
Myocardial infarction Confusion
Thromboembolism Seizures
Cardiomyopathy Stroke
Diffuse vasculopathy Encephalopathy
Complement-
Renal 7,8,9,11,12
Mediated Gastrointestinal2,3,5,10,11,12
Elevated creatinine Thrombotic Liver necrosis
Edema, malignant Pancreatitis, DM
Microangiopathy Colitis, Diarrhea
hypertension
Nausea/vomiting
Renal failure Abdominal pain
Dialysis, transplant
Pulmonary1 Impaired Quality of Life1
Dyspnea Blood11 Fatigue
Pulmonary edema Hemolysis Pain/Anxiety
Pulmonary embolism Decreased platelets Reduced mobility
Fatigue
Transfusions
1. George et al. Blood. 2010;116:4060-69. 2. Hosler et al. Arch Pathol Lab Med. 2003;127:834-39. 3. Noris et al. CJASN. 2010;10:1844-59. 4. Neuhaus et al.
Arch Dis Chilid. 1997;76:518-21. 5. Vesely et al Blood. 2003;102:60-8. 6. Sallee et al. Nephron Dial Trans. 2010; 25:2028-32. 7. Kose et al. Semin Thromb
Hemost. 2010;36:669-72. 8. Davin et al. Am J Kid Dis. 2010;55:708-77. 9. Caprioli et al. Blood. 2006;108:1267-7. 10. Dragon-Durey et al. J Am Soc Nephrol.
2010;21:2180-87. 11. Loirat et al. Pediatr Nephrol. 2008;23:1957-72. 12. Stahl et al. Blood. 2008;111:5307-15.
26. Early Signs and Symptoms of aHUS Signal the
Underlying Threat of Catastrophic Consequences
Platelet1,2
Platelet Confusion4 Edema5
Proteinuria 2
Early Signs
LDH / Haptoglobin
LDH Haptoglobin Diarrhea3 Fatigue6
of TMA
Anemia / Schistocytes
1
Nausea5 / Vomiting
Elevated creatinine3
Abdominal pain
Encephalopathy4
Acute
renal failure1
Pulmonary
complications4
Complications
ERSD1
Clinical TMA
Transplant failure1 Liver necrosis1,4
Death1
Pancreatitis7
Stroke 1
Seizures12 Malignant
hypertension4
Ischemic bowel11
Myocardial infarction10
1. Loirat C et al. Pediatr Nephrol. 2008;23:1957-1972. 3. Stahl A, et al Blood. 2008;111:5307-5315. 4. Hosler GA, et al. Arch Pathol Lab Med. 2003;127:834-839. 6. Ariceta G et al. Pediatr Nephrol. 2009;24:687-696. 7.
Caprioli J et al. Blood. 2006;108:1267-1279. 8.Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844-1859. 9. George JN et al. Blood. 2010;116:4060-4069. 10. Sallee et al. Nephron Dial Trans. 2010;25:2028-2032. 11.
Ohanian M et al. Clinical Pharmacology: Advances and Applications. 2011:3 5–12 . 12. Davin et al. Am J Kid Dis. 2010;55:708-777.
27. Differential Diagnosis for Thrombotic Microangiopathies (TMAs)
Thrombocytopenia1,7 Microangiopathic Hemolysis2,7
Platelet count <150,000 Elevated LDH and/or
Or
>25% Decrease from baseline ± Decreased Haptoglobin and/or
Schistocytes and/or
Decreased Hemoglobin
Plus One or More of the Following:
Neurological Symptoms3,4,9,12 Renal Impairment5,6,7 Gastrointestinal Symptoms7,8,9
Confusion3,4 and/or Elevated Creatinine6 and/or Diarrhea +/- Blood8 and/or
Seizures9,12 and/or Decreased eGFR6,7 and/or Nausea/Vomiting9 and/or
Cerebral convulsions3 Abnormal Urinalysis5 Abdominal Pain9and/or
Gastroenteritis7,8
Evaluate ADAMTS13 Activity and Shiga-toxin/EHEC*Test10,11
≤5% ADAMTS13 Activity >5% ADAMTS13 Activity Shiga-toxin/EHEC Positive
TTP aHUS STEC-HUS**
*Shiga-toxin/EHEC test is warranted in history/presence of GI symptoms
**Need for high clinical suspicion of aHUS in all patients with systemic TMA, even if shiga-toxin positive
1. Data on file. Alexion Pharmaceuticals, Inc. 2. Noris et al. NEJM. 2009;361:1676-1687. 3. Neuhaus et al. Arch Dis Chilid. 1997;76:518-21. 4. Noris et al. JASN. 2005;16:
1177-1183. 5. Al-Akash et al. Pediatr Nephrol. 2011;26:613-619. 6. Sellier-Leclerc AL. JASN. 2007;18:2392-2400. 7. Caprioli et al Blood. 2006; 108(4)1267-7. 8. Noris M et al.
Clin J Am Soc Nephrol. 2010;5:1844-1859. 9. Dragon-Durey et al. J Am Soc Nephrol. 2010;21:2180-2187. 10.Tsai H-M. Int J Hematol. 2010;91:1-19.11. Bitzan M. Semin Thromb
Hemost. 2010;36:594-610. 12. Davin et al. Am J Kid Dis. 2010;55:708-777.
28.
29.
30.
31. aHUS
Trigger
aHUS
Common Genetic Variants Rare Genetics Variant
32. Response to Eculizumab Therapy in Three Children with STEC-HUS and Progressive Central
Nervous System Involvement.
Lapeyraque A et al. N Engl J Med 2011;364:2561-2563.