ADAMTS13 Presentation

Case presentation 42 y/o man. No prior medical problems. Evaluated due to leg celulitis. 6/2011-

AML-biphenotypic. FLT-3 mutated. Induction: Ara-C/Ida (7+3). Persistent blasts. Re-induction with High dose Ara-C. Clinical remission.

8/16/2011- Allograft-

Preparative regimen: Busulfan/Cytoxan. Donor : HLA matched brother. Blood type: O/O

Laboratories Flow Sheet

8/30 9/9 9/16 9/20 9/30 10/7 10/14 10/21 10/28

+14 +24 +31 +35 +45 +52 +59 +66 +7320.6 7.4 6.1 10.4 5.8 12.8 10.5 8.8 6.5

9.1 11.3 11.6 11.6 9.2 12.1 14.2 11.4 10.7

25.6 32.5 33.5 33.3 27.5 36.8 42.8 32.0 29.7

287 122 23 10 62 17 34 35 19

0 0 0 0 2+ 2+ 2+

1 0 5 4 1 14

11 12 10 33 103 60 72 68 110

1.0 0.9 0.9 1.9 2.2 1.5 1.6 1.2 2.0

0.3 0.5 0.5 2.2 17.6 24.9 23.8 22.5 24.8

124 101 106 92 66 82 100 110 186

54 57 68 3169 89 50 39 71 102

56 101 96 2827 123 52 41 44 91

1392 491 320 1620 945 435 333 325 349

<1 <1 2 4 25

Date

Post BMT

WBC

Hgb

Hct

Plt

Schistocytes

NRBC

BUN

Creat

Bili

Alk phos

SGOT

SGPT

LDH

Haptoglobin

Case 9/20- Admission

Acute liver injury. Hepatology consult. Viral studies: negative. Given Mucomyst for possible Acetaminophen toxicity. Sonogram: Non-revealing. Not suggestive of VOD. +Ascites. Transjugular liver biopsy: - GVHD. Areas of necrosis. Extramedullary hematopoiesis? Therapeutic paracentesis.

9/26 Renal insufficiency- Renal consult. Hepatorenal syndrome?

9/28 Altered mental status- hepatic encephalopathy? Sepsis? Hypotensive/Hypoxic/Agitated. Transferred

to ICU. Abdominal pain. GI bleeding. Treated with broad spectrum antibiotics/pressors. Abdomen CT scan: pancreatitis. Amylase and lipase elevated. Pneumatosis intestinales. Surgery consult.

9/29 Exploratory laparotomy- hemicolectomy for necrotic bowel. Extensive ischemic damage. No GVHD

Liver biopsy: no change. Immature hematopoietic cells seen ? BM biopsy and flow: negative for leukemia. Chimeric studies: 100% donor cells.

10/1 2nd look laparotomy. Anastomosis. Liver biopsy: flow negative for leukemia. No GVHD. Pulmonary

consult. 10/3

Clinical improvement

Laboratories Flow Sheet

8/30 9/9 9/16 9/20 9/30 10/7 10/14 10/21 10/28

+14 +24 +31 +35 +45 +52 +59 +66 +7320.6 7.4 6.1 10.4 5.8 12.8 10.5 8.8 6.5

9.1 11.3 11.6 11.6 9.2 12.1 14.2 11.4 10.7

25.6 32.5 33.5 33.3 27.5 36.8 42.8 32.0 29.7

287 122 23 10 62 17 34 35 19

0 0 0 0 2+ 2+ 2+

1 0 5 4 1 14

11 12 10 33 103 60 72 68 110

1.0 0.9 0.9 1.9 2.2 1.5 1.6 1.2 2.0

0.3 0.5 0.5 2.2 17.6 24.9 23.8 22.5 24.8

124 101 106 92 66 82 100 110 186

54 57 68 3169 89 50 39 71 102

56 101 96 2827 123 52 41 44 91

1392 491 320 1620 945 435 333 325 349

<1 <1 2 4 25

Date

Post BMT

WBC

Hgb

Hct

Plt

Schistocytes

NRBC

BUN

Creat

Bili

Alk phos

SGOT

SGPT

LDH

Haptoglobin

Case 10/7

Eculizumab treatment initiated. Bacteremia. Fungemia. 10/9

Re-intubation. Pressors.Sepsis- enterococcus faecium 10/11

Extubated. CMV +. Clinical improvement. BK viruria. + galactomanan assay. Peritonitis. ID consult 10/27

Progressive renal insufficiency. Hypotension. Hypoxemia. 10/31

Re-intubation. Withdrawal of support. AUTOPSY

Heart: sub-endocardial hemorrhage Lungs: Organizing acute lung injury. Negative for fungal elements/cultures. Cultures: enterococcus faecium Liver:Centrilobular perivenular and sinusoidal fibrosis.---VOD. No GVHD Bowel: Microvascular thrombosis. Pancreas: interstitial fibrosis. Enzymatic necrosis Kidneys: Recent ischemic changes. Spleen: Intravascular thrombi. BM: NO leukemia

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

History

1924-Moschowitz 1936-hyaline occlusion

of small vessels 1958- Term TTP 1966- Clinical pentad

Microangiopathic hemolytic anemia Thrombocytopenia Neurological abnormalities Renal involvement Fever

1959-blood exchange 1976-plasma exchange

albumin plasma

1977-plasma infusion washed RBC +albumin fresh plasma

Cleavage of Unusually Large Multimers of von Willebrand Factor on Endothelial Cells by the von Willebrand Factor–Cleaving Metalloprotease, ADAMTS 13.

Moake JL. N Engl J Med 2002;347:589-600.

(A Disintegrin-like And Metalloprotease w Thrombospondin Type 1 motif 13)

Proposed Relation among the Absence of ADAMTS 13 Activity in Vivo, Excessive Adhesion and Aggregation of Platelets, and Thrombotic Thrombocytopenic Purpura.


Relation between Defects in Plasma von Willebrand Factor–Cleaving Metalloprotease, ADAMTS 13, and Thrombotic Thrombocytopenic Purpura (TTP).


(Upshaw-Schulman Syndrome)

Treatment

Plasma infusion Plasma exchange Immunosuppressants

Steroids Rituximab

Replacement of a deficient component Metalloprotease Normal vWF multimers

Removal of a harmful plasma component Auto antibodies Unusually high multimers vWF

Immune regulation

(A) Effect of treatment on median ADAMTS13 activity and IgG antibody levels in box-whisper format from admission to 1 year of follow-up in the rituximab group.

Scully M et al. Blood 2011;118:1746-1753

©2011 by American Society of Hematology

The clinical course of patients with TTP may be complex and cannot be easily represented by a single diagram.

George J N Blood 2010;116:4060-4069©2010 by American Society of Hematology

Baylor 2010Plasma exchanges: 616TTP: 292

35% at .3-13.9 yrs

Mortality 20%

Clinical Presentation

1925-1964 1964-1980 1982-1989

Microangiopathic Hemolytic Anemia

96 98 100

Thrombocytopenia 96 96 100

Neurologic Symptoms 92 84 63

Renal Disease 88 76 59

Fever 98 59 24

Clinical categories of TTP and reduced ADAMTS 13 activity

Allogeneic stem cell transplant 10 1 (10%) Pregnancy/postpartum 15 3 (21%) Drug associated

Quinine 20 0 Chemotherapy/calcineurin inh 12 0 Other 6 0

Bloody diarrhea 25 2 (8%) Other disorders

SLE 21 2 (10%) Other autoimmune 16 1 (7%) Infectious 23 4 (17%) Malignancies 10 1 (10%) Hypertension 6 0 Other 12 0

Idiopathic 107 51 (48%)

All patients: 283. Only 65 (23%) w ADAMTS 13 <10%Blood 116:4060, 2010

Thrombotic Microangiopathies.


TTP/HUS

Proposed Mechanisms of Platelet–Fibrin Formation in the Hemolytic–Uremic Syndrome.


Many patients cannot have a specific mutation identified and all still have Many patients cannot have a specific mutation identified and all still have chronic uncontrolled complement activationchronic uncontrolled complement activation

Complement-mediated TMA leads to systemic, progressive organ damage and Complement-mediated TMA leads to systemic, progressive organ damage and sudden deathsudden death

One year after diagnosis, >50% of all patients have died, require dialysis, or One year after diagnosis, >50% of all patients have died, require dialysis, or have permanent renal damage despite plasma exchangehave permanent renal damage despite plasma exchange

Diagnosis of early signs and symptoms is the critical first step to fundamentally Diagnosis of early signs and symptoms is the critical first step to fundamentally transform the lives of aHUS patientstransform the lives of aHUS patients

Genetic deficiency in complement regulatory genes causes chronic uncontrolled Genetic deficiency in complement regulatory genes causes chronic uncontrolled complement activationcomplement activation

aHUS: aHUS: A Rare, Genetic, Devastating and A Rare, Genetic, Devastating and Life-threatening DiseaseLife-threatening Disease

Cell Destruction

Inflammation

Thrombosis

ConsequencesConsequencesConsequencesConsequences

Genetic Loss of Natural Inhibitors Leads to Chronic Uncontrolled Genetic Loss of Natural Inhibitors Leads to Chronic Uncontrolled Complement ActivationComplement Activation

Pro

xim

alP

roxi

mal

Ter

min

alT

erm

inal

C3C3

C5C5

C5a

Potent Anaphylatoxin

Chemotaxis Proinflammatory Leukocyte/Monocy

te Activation Endothelial

Activation Prothrombotic

C5b-9 Membrane Attack

Complex

Cell Lysis Proinflammatory Platelet Activation Leukocyte/Monocyt

e Activation Endothelial

Activation Prothrombotic

AmplificationAmplification

Natural Inhibitors

–

Immune Complex ClearanceMicrobial Opsonization

Anaphylaxis

Inflammation

Thrombosis

C3 + HC3 + H22O - O - ALWAYS ACTIVE ALWAYS ACTIVE

(Chronic) (Chronic)

Lectin Pathway Alternative PathwayClassical Pathway

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. 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 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 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.

Alternative Pathway of Complement Activation and Regulation.

Delvaeye M et al. N Engl J Med 2009;361:345-357.

Membrane Attack Complex

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.

Classification of Atypical Hemolytic–Uremic Syndrome.


Genetic Abnormalities and Clinical Outcome in Patients with Atypical Hemolytic–Uremic Syndrome.


Chronic Uncontrolled Complement Activation CausesChronic Uncontrolled Complement Activation CausesPlatelet, Endothelial, Leukocyte/Monocyte Activation Leading to Platelet, Endothelial, Leukocyte/Monocyte Activation Leading to Inflammation and Systemic Small Vessel OcclusionInflammation and Systemic Small Vessel Occlusion

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.

Endothelium Activation

Endothelial Swelling and

Disruption

PlateletAggregation

Platelet

PlateletActivation

UncontrolledComplement

Activation

Neutrophil

NeutrophilActivation

Platelet Consumption

MechanicalHemolysis

(Schistocytes)

Blood Clots

Inflammation

Occlusion

Ischemia

Hypoxia

Complement-Mediated TMA Leads to the Complement-Mediated TMA Leads to the Morbidities and Mortality in aHUSMorbidities and Mortality in aHUS

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.

RenalRenal7,8,9,11,127,8,9,11,12

Elevated creatinineElevated creatinine

Edema, malignantEdema, malignanthypertensionhypertension

Renal failureRenal failure

Dialysis, transplantDialysis, transplant

GastrointestinalGastrointestinal2,3,5,10,11,122,3,5,10,11,12

Liver necrosisLiver necrosisPancreatitis, DMPancreatitis, DMColitis, DiarrheaColitis, DiarrheaNausea/vomitingNausea/vomitingAbdominal painAbdominal pain

BloodBlood1111

HemolysisHemolysisDecreased plateletsDecreased platelets

FatigueFatigueTransfusionsTransfusions

Impaired Quality of LifeImpaired Quality of Life11

FatigueFatiguePain/AnxietyPain/AnxietyReduced mobilityReduced mobility

PulmonaryPulmonary11

DyspneaDyspneaPulmonary edemaPulmonary edemaPulmonary embolismPulmonary embolism

CardiovascularCardiovascular2,3,4,62,3,4,6

Myocardial infarctionMyocardial infarctionThromboembolismThromboembolismCardiomyopathyCardiomyopathyDiffuse vasculopathyDiffuse vasculopathy

CNSCNS1,2,3,4,51,2,3,4,5

ConfusionConfusionSeizuresSeizuresStrokeStrokeEncephalopathyEncephalopathy

Complement-Complement-MediatedMediated

Thrombotic Thrombotic MicroangiopathyMicroangiopathy

Systemic Organ DamageSystemic Organ Damage CNSCNS KidneyKidney GI SystemGI System HeartHeart OthersOthers

Early Signs and Symptoms of aHUS Signal the Early Signs and Symptoms of aHUS Signal the Underlying Threat of Catastrophic ConsequencesUnderlying Threat of Catastrophic Consequences

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.

FatigueFatigue66

PlateletPlatelet1,21,2 ConfusionConfusion44

LDHLDH22 / Haptoglobin / Haptoglobin DiarrheaDiarrhea33

NauseaNausea55 / Vomiting / VomitingAnemiaAnemia11 / Schistocytes / Schistocytes

EdemaEdema55

Elevated creatinineElevated creatinine33

Ear

ly S

ign

so

f T

MA

ERSD1

Pulmonary complications4

Acuterenal failure1

Transplant failure1

Death1

Stroke1

Encephalopathy4

Liver necrosis1,4

Pancreatitis7

Malignanthypertension4

Cli

nic

al T

MA

C

om

pli

cati

on

s

Abdominal painAbdominal pain

ProteinuriaProteinuria

Seizures12

Myocardial infarction10

Ischemic bowel11

STEC-HUS**TTP

>5% ADAMTS13 Activity>5% ADAMTS13 Activity≤≤5% ADAMTS13 Activity5% ADAMTS13 Activity Shiga-toxin/EHEC PositiveShiga-toxin/EHEC Positive

aHUS

Differential Diagnosis for Thrombotic Microangiopathies (TMAs)Differential Diagnosis for Thrombotic Microangiopathies (TMAs)

ThrombocytopeniaThrombocytopenia1,71,7

Platelet count <150,000Platelet count <150,000OrOr

>25% Decrease from baseline>25% Decrease from baseline

Renal ImpairmentRenal Impairment5,6,75,6,7

Elevated Creatinine6 and/orDecreased eGFR6,7 and/or

Abnormal Urinalysis5

Neurological SymptomsNeurological Symptoms3,4,9,123,4,9,12

Confusion3,4 and/orSeizures9,12 and/or

Cerebral convulsions3

Evaluate ADAMTS13 Activity and Shiga-toxin/EHEC*Test10,11

Plus One or More of the Following:Plus One or More of the Following:

Gastrointestinal SymptomsGastrointestinal Symptoms7,8,97,8,9

Diarrhea +/- Blood8 and/or Nausea/Vomiting9 and/orAbdominal Pain9and/or

Gastroenteritis7,8

*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.

Microangiopathic HemolysisMicroangiopathic Hemolysis2,72,7

Elevated LDH and/orElevated LDH and/orDecreased Haptoglobin and/orDecreased Haptoglobin and/or

Schistocytes and/orSchistocytes and/orDecreased Hemoglobin Decreased Hemoglobin

±

aHUS

Trigger

Rare Genetics VariantCommon Genetic Variants

aHUS

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.

Health & Medicine

ADAMTS13 Presentation