How to manage Thrombotic Microangiopathy

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How to manage Thrombotic Microangiopathy

• Dr Marie Scully
• Haemostasis Research Unit
• UCL.

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What is Thrombotic Thrombocytopenic Purpura? (TTP)

• Rare 4-6/million
• Female 70 cases.
• Peak incidence 4th decade
• Acute, life threatening disorder
• gt70 cases-idiopathic
• Antibody to ADAMTS 13 detected in 90 of Acquired
  cases.
• IgG primarily, IgM/IgA described.
• Mortality 15-20 ? Morbidity

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Features of TTP

• Microangiopathic Haemolytic Anaemia
• Thrombocytopenia
• X-Neurological symptoms
• X-Renal impairment
• X-Fever

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Subtypes of TTP

• Primary
• Congenital
• Acquired idiopathic (autoimmune) Acute
• Relapsing
• Secondary
• Infections HIV, E.Coli
• Pregnancy
• Drugs COCP, Ticlodipine, quinine, interferon,
  simvastatin, CSA
• Autoimmune disease
• BMT
• Malignancy

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Can ADAMTS 13 differentiate between TTP HUS?

• YES (usually)
• Pathology TTP- platelet and VWF.
• HUS-Fibrin rich
• TTP-multisystem, HUS-local
• Normal ADAMTS 13 in HUS
• Veyradier J Paeds 2003
• HUS (D) (D-)

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AUTOPSY CASES
Hosler et al Arch Path Lab Med 2003
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AUTOPSY CASES
Hosler et al Arch Path Lab Med 2003
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Management of HUS

• meticulous fluid/electrolyte balance and BP
  control
• renal dialysis as required
• FFP infusions OR therapeutic plasma exchange DOES
  NOT improve outcome (Grade C, level IV)
• anti-thrombotic or anti-platelet agents not
  helpful

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Congenital TTP

• Onset between birth and 4 years
• MaleFemale
• Rarely shows full pentad of classical symptoms
• All have thrombocytopenia
• Haemolytic anaemia common

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Allford , BJH, 2002
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HIV associated TTP

• ADAMTS 13 lt5-50. No Inhibitor
• All Heterosexual Africans (8 F1M)
• 5/9 presenting feature of HIV
• HAART therapy started ASAP
• CD 4 counts 170 (range 70-400) cells/µl
• Median viral load 74,400 copies/ml.
• Median 8 PEX (range 3-16)
• All normal ADAMTS 13 activity on follow up
• Follow-up 6-74 months.
• Miller, Int J STD AIDS, 2005

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Pregnancy associated TMA

• TTP- ? 2nd Trimester
• HELLP/Pre-eclampsia-3rd Trimester-
• Reduced ADAMTS 13 activity-31(12-43).
• No Inhibitors.
• High vWFag.
• No ULvWF multimers
• HUS- 90 post partum

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TMA in Bone Marrow transplantation

• TMA is not a specific disease entity
• George et al BMT 2004-35 autopsy reports from 35
  patients after Allo-SCT, NONE had microthrombi
  characteristic of TMA. 19 had infection as a
  common cause of death.
• Median incidence 8 post Allo SCT. Rare in
  autos
• Median time 46 days post transplantation
• Risk Factors
• MUD /- TBI
• acute GVHD gtGrade II
• CSA/Tacrolimus-Further increased if given
  steroids
• VOD
• infection-esp. CMV

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TMA in BMT

• Normal ADAMTS 13 activity and no inhibitors
• Disturbances in endothelial function.
• Treatment discontinue offending drug
• ? Defibrotide
• ? Role for PEX
• Mortality 31-70, TMA attributable mortality
  13-23

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TMA and solid organ transplant

• Usually HUS, primarily post Renal transplant
• Incidence of TMA in Renal transplants 5.6
  episodes /1000 person-years
• Risk is greatest in the first 3 months post
  transplantation
• Usually 20 to immunosuppressives. Also-viral
  infections, GVHD and rejection
• Pathogenesis endothelial cell dysfunction.
• No evidence for PEX
• Patient survival 50 at 3 years

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Treatment of acute TTP
Survival of patients with thrombotic
thrombocytopenic purpura
Rock et al, 1991
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Treatment of acute TTP

• 2nd Line therapy
• change plasma type/frequency or volume of PEX
• Vincristine
• 3rd Line therapy
• Cyclosporine
• Cyclophosphamide,
• Defibrotide
• Splenectomy

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Time to platelet count recovery plasma volumes
used in acute TTP with and without anti ADAMTS
13 antibodies
Group 1 No antibody Group 2 Antibody
present
Coppo et al BJH 2006
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RITUXIMAB in TTP

• Anti-CD 20 chimeric monoclonal antibody
• acts on B-lymphocytes
• Used in
• acute refractory / acute relapsing TTP
• electively in patients with IgG antibodies to
  ADAMTS 13
• 375mg/m2 IV
• after PEX in acute TTP
• Weekly therapy
• Give 4-8 treatments
• monitored via ADAMTS 13 activity IgG antibody
  to ADAMTS 13

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Effect of Rituximab in acute refractory TTP
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Acute and elective use of Rituximab
ADAMTS 13 activity
IgG antibodies to ADAMTS 13
Rituximab
Admission
X 4
X 4
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Platelet count Pre Rituximab Therapy
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ADAMTS 13 activity and IgG antibody to ADAMTS 13
before and 3 months following Rituximab
Anti-IgG antibodies to ADAMTS 13
ADAMTS 13 activity

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CD 19 levels before and following Rituximab in
acute TTP
CD 19 ()
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Rituximab improves Response Rate and PFS in
Relapsed/refractory TTP
Heidel, TH 2007
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In Conclusion

• ADAMTS 13 lt5 appears specific for acute acquired
  and congenital TTP
• Role of antibodie(s) to ADAMTS 13
• PEX remains the mainstay of treatment
• Targeted therapy related to subtype
• The future
• ? Recombinant ADAMTS 13
• ? Monoclonal antibody therapy

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