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           St. Jude Leukemia/Lymphoma Board:                              St. Jude Leukemia/Lymphoma Board:
                     23 November 2004                                               23 November 2004

          A Review of TTP with a                                         A Review of TTP with a
        Special Focus on Congenital                                    Special Focus on Congenital
                 Deficiency                                                     Deficiency

                              Justin Baker, MD                  Justin Baker, MD
                                                                St. Jude Children’s Research Hospital

         Case presentation                                             Case presentation
CC: “swelling since several days ago”                                      Hx:
                                                              Past Medical Hx:
                                                                  Full Term
HPI:                                                              SVD
    10 month old AA baby boy with 2 d h/o                         Birth weight 7#
        Diffuse swelling
                                                                  D/C after 48hrs
                                                                  No h/o hyperbilirubinemia
        Abdominal distention and diarrhea (watery)
                                                                  Chronic diarrhea (watery) thought to be related to
                                                                  protein allergy
        Low grade fever (38.5C)
        Dry cough
                                                                  No h/o multiple infections, rash, bronchiolitis,
                                                                  pneumonias, etc.
                                                                  Adequate weight gain and development

         Case presentation                                             Case presentation
Hospital Admissions:
    June 04 for 1month                                        Physical Exam
    Signs and symptoms                                            V/S: T 38.6C RR 45 HR 130 BP 110/58 Wgt 10.6kg(75%) HT
        Diarrhea                                                  Gen: awake, alert, irritable, diffuse edema (mainly in lower ext.
        Cough                                                                              bilat.)
                                                                  and periorbital areas bilat.)
        Low grade fever                                                                 swelling,
                                                                  HEENT: periorbital swelling, PERRLA, EOMI, clear rhinorrhea, no
                                                                  erythema in TM, no effusions, no exudates or erythema in post.
        Proteinuria                                               pharynx
        Hematuria                                                 HEART: RRR, SEM grade 2/6
        Hypoalbuminemia                                                             ronchi,    crackes,
                                                                  LUNGS: diffuse ronchi, no crackes, no wheezing, mild IC
        Prolonged PT and aPTT                                     Abdomen: abdominal swelling, BS +, distended, splenomegaly
        Thrombocytopenia                                          (6cm below LT costal margin)
        Anemia                                                    EXT: diffuse swelling in lower ext. , pitting edema +2, no
        HTN                                                       Skin: no rashes, no lesions, no changes in pigmentation
    Etiology thought to be infectious – elevated EBV titers       Neuro: irritable, DTR’s +2, no meningismus
                                                                  LNs: Bilat cervical and inguinal (<1 cm)
    Discharge x 1 month


                         Case presentation
                                                                                                   Case presentation
                                  9/14             9/17         9/25     10/21
             Hgb             8.2              8.7         7.5          9.5
                                                                                             MCV 87
             Plts            82               107         93           99                    MCH 29
                                                                                             MCHC 32
             WBC             8.1              14.4        9.0          14.3
                                                                                             MPV 10.7
             retic           3.7                                       2.0                   Neu. Lymp.
                                                                                             Neu. 43 Lymp. 40                 Mono. 12
             PT              16.2             14          13                            U/A:
                                                                                             Protein +1
             aPTT            50               36          36                                 Blood +2
                                                                                             Specific gravity 1.020
             Fib                              150         250
             D-                                                                              normal

                          Case presentation
        BMA (9/24)
              No evidence of leukemic or malignant cells
             Head MRI
                        Normal study
             Abdominal CT

                                Kidney Biopsy                                         Thrombotic Microangiopathy

 •Thrombotic microangiopathy (TMA)
       •Prominent mesangiolysis
       •Glomerular capillary wall damage images/florquin19.jpg                             Moake, JL. Thrombotic Microangiopathies. NEJM. (347) 587-600. Aug 2002.


  Thrombotic Microangiopathy                                                       Case presentation
                                                                             Money Lab
                                                                             vWF cleaving protease (ADAMTS 13)
                                                                              < 4% activity (>67%)
                                                                              No inhibitor

•HUS typically a triad
                   Microangiopathic hemolytic anemia
     Renal insufficiency
    Moake, JL. Thrombotic Microangiopathies. NEJM. (347) 587-600. Aug 2002

             Case presentation                                                Upshaw-Schulman Syndrome
Summary:                                                                      Historical Background
  10 month AA baby boy with history of recurrent diffuse
  swelling, low grade fever, chronic diarrhea, abdominal                        Dacie et al 1953
  distention, splenomegaly, and abnormal labs (anemia,                             12 cases of atypical congenital hemolytic anemia
  thrombocytopenia, hypoalbuminemia,                                               Case 12 = 6 yo girl with repeated episode of severe
  proteinuria/hematuria)                                                           jaundice, thrombocytopenia, MAHA
  First episode one month ago diagnosed as infectious                                 Died at age 7 of renal failure
  process                                                                             Sibling jaundiced at birth and died of hemorrhage at age 2
  Now with thrombotic microangiopathy and unmeasurable
  ADAMTS13 level
Working Diagnosis
  Congenital Thrombotic Thrombocytopenic Purpura
  Upshaw-Schulman Syndrome

                                                                               Thrombotic Thrombocytopenic
 Upshaw-Schulman Syndrome                                                                Purpura
                                                                               A classic pentad of signs:
 Historical Background
                                                                                 Microangiopathic hemolytic anemia
   Schulman 1960
      8 yo girl with repeated episode of bleeding, thrombocytopenia              Thrombocytopenia
      and MAHA                                                                   Neurologic dysfunction
      Symptoms traced to immediate postpartum period
      Symptoms temporarily resolved with infusion of FFP                         Renal failure
   Upshaw 1978                                                                   Fever
      29 yo female with h/o 6 to 7 episodes per year of
      thrombocytopenia and MAHA from age 6 months to 12 years
   Rennard and Abe 1979
      Proposed Upshaw-Schulman syndrome nomenclature
      Intermittent decreased level of plasma cold-insoluble globulin


                               TTP clinical picture
                                                                                             TTP clinical picture
                                Pediatric Cases

         Case series of 7 children with TTP among
         543 referred for thrombocytopenia
         Ages 12 months to 16 years, avg 9.4
         4 male: 3 female
         5/7 had a preceding illness
         Presented with petechiae, purpura,
         epistaxis or hematuria

Horton et al, Journal of Pediatric Hematology/Oncology, 2003
                                                               Horton et al, Journal of Pediatric Hematology/Oncology, 2003

                 TTP clinical picture                                         Thrombotic Thrombocytopenic
             Upshaw-Schulman Syndrome                                                   Purpura
         Chronic relapsing TTP                                                  Idiopathic
               Previously mentioned clinical presentation                       Nonidiopathic
         Hyperbilirubinemia at birth                                                  Pregnancy
         May remain silent after infancy and                                          CVD
         present again in young adulthood
                                                                                      Drugs – ie Ticlopidine
         May progress to renal failure at a young                                     Bone marrow transplant
                                                                                      Metastatic neoplasm
                                                                                Congential – Upshaw-Schulman Syndrome
                                                                                ADAMTS13 inhibitor formation

                         Epidemiology of TTP                                             TTP - Histopathology
         Incidence 3.7/1,000,000                                          Microvascular thrombi
                                                                          rich in platelets and
         Women:men 3:2                                                    Thrombi partially
                                                                          occlude the vessel
                                                                          Proliferation of
         Peak incidence 30 – 40 years                                     overlying endothelial


                                                                                 HUS pathophysiology as a model
                      TTP - Pathophysiology
          Related to VWF
          VWF is synthesized in endothelial cells
          and megakaryocytes
          2 main functions
                Carrier protein for Factor VIII
                Ligand that binds glycoprotein 1b receptor on
                platelets to initiate platelet adhesion to
                damaged blood vessel walls

                                                                          Moake, JL. Thrombotic Microangiopathies. NEJM. (347) 587-600. Aug 2002.

                       TTP - Pathophysiology                                             VWF Multimers in TTP
                                                                                       Endothelial                                     Normal
                                                                                          Cell     Active                    Remission Plasma

                                                                                                                                                    “Unusually large”

Moake, JL. Thrombotic Microangiopathies. NEJM. (347) 587-600. Aug 2002.                          Moake JL et al, NEJM 307:1432, 1982

                VWF Cleaving Protease in                                               VWF Cleaving Protease
                       Plasma                                                              (ADAMTS13)
      •   Discovered in 1996 by Tsai and by Furlan                        Metalloprotease                  Thrombospondin 1

      •   Requires Ca2+ and Zn2+ ions                                       SP        M           D 1       Cys Spacer        2 3 4 5 6 7 8               CUB CUB

      •   Cleaves VWF between Tyr1605- Met1606
      •   Activated by shear stress, mild denaturants

      •   Absent in children with congenital TTP                                 A Disintegrin-like And Metalloprotease
      •   Absent in most adults with idiopathic TTP                                 with ThromboSpondin-1 repeats
            (acquired IgG autoantibody inhibitor)
     Tsai, HM. Blood vol 87, 4235-4244 (1996)                                             Zheng, C et al, J Biol Chem 276:41059-63, 2001
                                                                                              Levy et al, Nature 413:488-494, 2001
     Furlan M et al. Blood vol 87, 4223-4234 (1996)


                       TTP - Pathophysiology                                                       TTP - pathophysiology
                                                                                               Normally, the VWF protease will cleave
                                                                                               the large multimers and prevent thrombus
                                                                                               from growing

                                                                                               When protease is lacking, thrombi
                                                                                               continue to grow and widespread thrombi
                                                                                               form in the microcirculation

                                                                                               Leads to tissue ischemia and infarction
                                                                                               and hemolysis of RBCs
Ritz, Journal of the American Society of Nephrology, April 2003

                       Von Willebrand Factor                                                       TTP - pathophysiology
                                                                                               Normally VWF is in globular form
                                                                                               In the presence of high shear forces the
                                                                                               VWF unfolds
                                                                                               This unfolded from is better capable of
                                                                                               aggregating platelets than the globular
                                                                                               Ability to unfold is size dependent – the
                                                                                               large multimers but not the small exhibit
                                                                                               increased unfolding in response to shear
                                            Atomic force microscopy
    Fujimura et al. International Journal of Hematology 75 (2002) 25-34.                       stress

                    VWF Cleaving Complex                                                          VWF Cleaving Complex

                                    A1 A2                                                                     A2

                                                      M D 1 CysSpacer 2 3 4   5678   CUB CUB
                                                                                                GPIb           M D 1 CysSpacer 2 3 4   5678   CUB CUB



    VWF Cleaving Complex                                                         VWF Protease
                                                       ret           Tsai et al, NEJM, 1998
                                                                    Study the activity of VWF Protease and
                        M D    1 Cys Spacer 2 3 4 5 6 7 8 CUB CUB   the presence of inhibitor in patients with
         A1                                                         acute TTP

  GPIb                                  ?


             VWF Protease                                                        VWF Protease
39 samples from 37 pts during acute TTP                             Subjects without TTP, mean VWF
episodes                                                            Protease activity
  38 no detectable activity
  1 had 3% activity
  Inhibitor present in 67%                                            Normal subjects: 102%
                                                                      Miscellaneous autoimmune or blood
7 pts with TTP were studied in both acute phase                       disorders:101%
and in remission                                                      Heparin induced thrombocytopenia:106%
  Activity rose to normal or nearly normal level at

             VWF Protease                                                        VWF Protease
                                                                     Furlan et al, NEJM, 1998

Protease deficiency is specific for TTP                             Retrospective study of the prevalence of
Inhibitory antibodies occur in patients with                        VWF protease deficiency in patients with
acute TTP                                                           TTP or HUS
Does not rule out that other diseases may                           53 patients met clinical and lab criteria for
be associated with it                                               TTP or HUS


             VWF Protease                                VWF Protease
                                              24 nonfamilial TTP
24 nonfamilial TTP, 6 familial TTP              20 severe ADAMTS13 deficiency
                                                4 moderate deficiency
                                                20 had inhibitor to ADAMTS13
13 Nonfamilial HUS, 10 familial HUS
                                              6 Familial TTP
                                                All had no activity
Analyzed the activity of VWF protease and
                                                None had inhibitors
the presence of an inhibitor

             VWF Protease                                VWF Protease
13 nonfamilial HUS
  11 normal ADAMTS13 activity                    Conclusion
  2 low levels                                      Nonfamilial TTP is due to an inhibitor
                                                    Familial TTP is due to a deficiency
10 familial HUS                                     Neither a deficiency or resistance to VWF
  All had normal activity                           protease is involved in the pathogenesis
                                                    of HUS
No deficiency in 120 normal subjects                Means of discriminating between TTP
                                                    and HUS

             VWF Protease                                VWF Protease
                                              111 pts with acute TMA prospectively
  Veyradier et al, Blood, 2001
   Prospective study if patients with acute     66 TTP, 45 HUS
   TMA to determine the relevance of            85 sporadic, 21 intermittent, 5 recurrent
   protease activity, specifically is there     42 idiopathic, 69 secondary
   any difference in TTP vs HUS
                                              102 healthy subjects: activity 49 – 200%


                                   VWF Protease                                                                  VWF Protease
          111 study pts                                                              65 pts with decreased activity
                Activity normal in 7 TTP and 39 HUS                                        Inhibitor in 48%
                                                                                           All were previously diagnosed as TTP and all
                Activity decreased in 59 TTP and 6 HUS
                                                                                           had undetectable activity

          42 idiopathic cases
                activity was undetectable in all 25 TTP                              89% sensitivity and 91% specificity of
                                                                                     decreased VWF protease activity in TMA
                normal in all 17 HUS                                                 presenting as TTP

                         ADAMTS13 Deficiency in
                            Idiopathic TTP
     Idiopathic, acquired TTP in adults:
          • Tsai 1998: 37/37 with undetectable ADAMTS13
          • Furlan 1998: 20/24 with undetectable ADAMTS13
          • Veyradier 2001: 22/22 with undetectable ADAMTS13
          • Mori 2002: 12/18 with undetectable ADAMTS13

     Severe ADAMTS13 deficiency correlates with
      idiopathic, acquired TTP

                                                                          Fujimura et al. International Journal of Hematology 75 (2002) 25-34.

                ADAMTS13 and corresponding
                      clinical picture                                                            TTP and ADAMTS13

Moake, JL. Thrombotic Microangiopathies. NEJM. (347) 587-600. Aug 2002.   Horton et al, Journal of Pediatric Hematology/Oncology, 2003


                TTP and ADAMTS13                                                                            Clinical Correlations
               Response to Plasma Exchange
                                                                                                     Association                            Odds Ratio
                        ADAMTS13 Deficient
         Category Number Deficient + Inhibitor Survival                                          ADAMTS13 <5% and:
                                                                                                 •   Survival b,c                                 5.4
       Idiopathic 20                  16                7                  17                    •   Idiopathic TTP a,b,c                          8
          BMT      8                   0                0                   4                    •   Female sex b,c                               3.6
     Cancer/Chemo 4                    0                0                   0                    •   African ancestry b,c                         7.5
      Peripartum   2                   0                0                   2
         Other     3                   0                0                   1
                                                                                                 ADAMTS13 Inhibitor and:
             Total        37          16                7                  24
                                                                                                 • Relapse a,b,c                                 13.5
                                                                                                             aVeyradier et al, Blood 98:1765-72, 2001
                                                                                                             bVesely et al, Blood 102:60-8, 2003

Zheng et al, Blood 103:4043-9, 2004                                                                          cZheng et al, Blood 103:4043-9, 2004

               TTP and ADAMTS13                                                                                Treatment of TTP
             Implications for Future Studies                                                                                                             Purpura
                                                                                               Attempted Passive Transfer of Thrombotic Thrombocytopenic Purpura
 • PE is relatively ineffective for “non-
   idiopathic” TTP, and inhibitors predict
                                                                                             “It has been shown that idiopathic thrombocytopenic
   relapse                                                                                   purpura can be passively transferred by the infusion of
                                                                                             plasma (Harrington et al, 1951). It seemed desirable
         •   ADAMTS13 and inhibitor assays may be                                            to attempt a similar demonstration for thrombotic
             useful to guide therapy                                                         thrombocytopenic purpura. We are reporting such an
         •   Plasma exchange could be reevaluated
             for TTP not caused by ADAMTS13                                                    T. E. Brittingham III and Hugh Chaplin, Jr. Blood 1957; 12: 480-482.

        Upshaw-Schulman Syndrome
                                                                                                     Idiopathic TTP - treatment
     FFP – 10-20 cc/kg until remission induced
           10-                                                                                  Plasma exchange
         Low levels of ADAMTS13 can induce remission                                            Plasma infusion
         Platelet transfusion may induce remission secondary to                                 Steroids
         small amount of plasma in platelet preparations
     Progress to weekly maintenance FFP
                                                                                                Vincristine, cyclosporine
     If clinically stable may attempt to wean to q
                                                                                                Cyclophosphamide and rituximab
     3-4 week FFP infusion
                                                                                                Antiplatelet medications
     Recombinant ADAMTS13
                                                                                                Supportive care
         On the horizon
         Already cloned                    Tsai, J Am Soc Nephrol 14:1072-81, 2003.

                                           Plaimauer, B et al. Blood, 100 3626-3632, 2002.


                  Pediatric TTP treatment                                     Treatment

                                                               Plasma exchange vs. FFP infusion
                                                               Prospective, randomized trial
                                                                 102 patients with TTP
                                                                   51 Plasma exchange
                                                                   51 Plasma infusion

Horton et al, Journal of Pediatric Hematology/Oncology, 2003
                                                                 Rock, et al, NEJM 1991

                                           Treatment                          Treatment
        Complete response: platelet count >150                 Rate of response after cycle 1
        on 2 consecutive days, no deterioration in               47% plasma exchange
        neurologic status                                        25% plasma infusion
                                                                 P = 0.025
                                                               Late outcome at 6 months
        One cycle: death, clinical deterioration
                                                                 78% plasma exchange
        resulting in off protocol, early response or
                                                                 49% plasma infusion
        completion of 7 days
                                                                 P = 0.002

                                           Treatment              TTP – Plasma exchange
        Survival                                               Once a day plasma exchange with one
              78% plasma exchange                              plasma volume
              63% plasma infusion                              Replace with FFP
              P = 0.036                                        If no improvement, increase the volume or
                                                               frequency of exchange
        Conclusion                                             Decision to stop is empiric
                                                                 Most continue for two days post remission
              Plasma exchange is treatment of choice for
                                                                 Remission defined as normal neuro exam,
              idiopathic TTP
                                                                 platelet count and LDH with increasing Hb


    TTP – Plasma exchange                                   TTP - treatment
 Must be instituted early                       Complications of plasma exchange
   Delay in treatment can result in treatment     Catheter related problems: thrombosis, sepsis
   failure                                        Plasma related problems: allergic reaction,
 Duration variable                                infection
 Premature cessation can result in relapse        Procedure related problems: unintentional
                                                  platelet pheresis, persistent
   Exacerbations are frequent, 29 – 82%
                                                  thrombocytopenia, hypocalcemia

        TTP and ADAMTS13                                    TTP - prognosis
             Refractory Disease
• Plasma exchange does not address the            90% prior to plasma exchange
  underlying autoimmune disorder                  Now 10 – 30%
                                                  Most occur within the first year
• Refractory disease may benefit from             Can be multiple
  immunosuppression                             Effects of ischemia
                                                  Chronic renal insufficiency – 25%

            TTP - prognosis                                 TTP - prognosis
                                                Treatment failure associated with
  Pereira et al, Annals of Hematology, 1995
                                                  Delay in initiating therapy
 Retrospective study of pretreatment              Presence of stupor or coma
 factors that predict response to plasma          High creatinine levels
 32 patients with TTP/HUS
   53% attained complete response
   69% survived


         Coming full circle                                           Coming full circle
Pt recently admitted                                Treatment
  Hb 6.9 gm/dL
         gm/dL                                         FFP
                                                            10 cc/kg day 1
  Plt count 43,000
                                                            30 cc/kg day 2
  Diarrhea – more mild                                      20 cc/kg x 3d
  Smear                                                pRBC transfusion day prior to discharge
    Shistocytes and helmet cells                                   gm/dL
                                                            Hb 8.8 gm/dL
                                                            Plt count 86,000
                                                            Less diarrhea
                                                            Fewer smearabnormalities

                                                      Genetic Mutations in Upshaw-
         Coming full circle
                                                         Schulman Syndrome
  Weekly FFP until remission induced
    Then begin maintenance schedule of q 2-3 week
    FFP infusion
  Repeat ADAMTS13 level
  Plasma exchange for exacerbations once
  physically feasible
  Test parents for ADAMTS13 level
  Gene mapping of patient’s ADAMTS13

                                                    Fujimura et al. International Journal of Hematology 75 (2002) 25-34.

              Thank You!
Caridad Martinez – Case presentation
Christine Hartford – Literature review
Entire Hematology Department - Allowing
me to share this discussion                                                          Comments



                   Justin Baker, MD

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