Clinical Spectrum and Treatment Options of Thrombotic Microangiopathies

Herbert Pichler, MD

Stem Cell Transplantation Unit

St. Anna Children‘s Hospital

Vienna, Austria

Thrombotic Microangiopathy (TMA)

Localized or generalized

microvascular thrombus formation

Microangiopathic (non-immune) hemolytic anemia

Thrombocytopenia (consumption of platelets)

Organ dysfunction

Campistol JM et al., Nefrologia 2015

HUS (C. Gasser 1955)

Non-immune hemolytic anemia (Schistocytes) Thrombocytopenia Acute renal failure

TTP (E. Moschcowitz 1924)

Thrombocytopenia, bruising Non-immune hemolytic anemia Neurological symptoms (Renal failure) Fever

Hemolytic-Uremic Syndrome (HUS) Thrombotic Thrombocytopenic Purpura (TTP)

Moake J, NEJM 2002

HUS and TTP are the „prototypic“ diseases associated with TMA

Different triggers, but similar pathomechanisms!

The Spectrum of TMA: Etiologies

Campistol JM et al., Nefrologia 2015 - Mutations in DGKE (complement-independent aHUS)

- Consumption

TMA - Current Pathogenetic Model

Goldberg R et al., Am J Kidney Dis. 2010

ultra-large vWF multimers/Toxins/Alternate pathway complement activation/Insult to endothelial cells

Formation of fibrin- and platelet-rich thrombi in the microcirculation

Platelet consumption Fragmentation of erythrocytes (Schistocytes)

Obstruction of vessels

Organ damage (kidneys, CNS, GI-tract, lungs,…)

The Role of The Complement System in aHUS

Dysfuncional regulation of complement system

Heterozygous mutations affecting complement facors (60% of aHUS)

Auto-Antibodies against CFH (10% of aHUS, Children)

Activation of Complement System

Goicoechea de Jorge E et al.; Kidney Int 2010

TMA in aHUS - Multiple Hit Hypothesis

• TMA emerges after a combination of genetic predisposition (rare and common genetic variants) and trigger factors/conditions.

• Trigger factors: Resp./GI-Infections, pregnancy, ischemia reperfusion injury, neoplasia, transplantation, malignant hypertension, immunosuppressive drugs, etc.

• Eculizumab does not alter the predisposition but increases the threshold for TMA onset.

Riedl M et al., Semin Thromb Hemost 2014 Kavanagh et al., Hematology Am Soc Hematol Educ Program 2011

HSCT-associated TMA (TA-TMA)

• Pathophysiology remains to be clarified

• Gene variants in complement regulating genes in >60% of pts. with TMA

• Various diagnostic criteria/guidelines

• Incidence approx. 40%

• 1y-NRM significantly higher in patients with TMA (43,6 vs. 7,8%; n=90 pts.)

Laskin LL, et al.; Blood 2011

Jodele S, et al.; Blood + BBMT 2014 Jodele S, et al. Blood Rev 2015

Jodele S, et al.; Blood 2016

TA-TMA – Targeted Organs

Jodele et al., Blood Rev 2015

Kidneys Lungs GI Tract CNS Others? DD GvHD/VOD/TMA might be difficult

TMA – How to establish the diagnosis?

Diagnostic Approach – Parameters

• Culture or PCR for STEC O157:H7 (stool) or S. pneumoniae (blood, CSF, pleural fluid)

• Plasma ADAMTS13 activity and screening for Anti-ADAMTS13 antibodies

• Plasma levels of complement factors: C3, C4, CFH, CFI, CFB, sC5b-9

• Screening for Anti-CFH antibodies

• Screening for mutations or variants in: CFH, CFI, MCP, C3, CFB, THBD, DGKE

• MCP (membrane cofactor protein, CD46) expression on PBMCs by FACS

• Screening for autoimmune phenomena: SLE (ANA, ANCA,...), Cardiolipin antibodies

• Screening for infecious diseases: HIV, Influenza A/H1N1, HBV, HCV, CMV

• Screening for Cobalamin-C defect: homocysteine and methylmalonic acid (high), methionine (low)

Loirat C et al., Pediatr Nephrol 2016 Campistol JM et al., Nefrologia 2015 Kavanagh D et al., Am Soc Hematol Educ Program 2011

Diagnostic Algorithm

Campistol JM et al., Nefrologia 2015

Diagnostic Criteria for TA-TMA

Laskin LL, et al.; Blood 2011

sC5b-9 (soluble MAC) - Parameter für terminale Komplementaktivierung

TA-TMA Diagnostic Algorithm

Jodele S, et al.; Blood Rev 2015

TMA requires prompt management decisions!

Does the patient need urgent plasma exchange (PEX) or plasma infusion (PI)?

Should the patient receive anti-complement therapy?

Are there any other treatment options available?

Supportive measures?

Therapeutic Options - Overview

• Plasma Exchange (PEX)/Plasma Infusions (PI) – TTP, aHUS

• „Biologicals“

Complement C5-Antibody: Eculizumab – aHUS and secondary TMAs

Anti vWF Immunoglubulin: Caplacizumab – acquired TTP

Anti CD20 Antibody: Rituximab – refractory immune mediated TTP

Proteasome Inhibitor: Bortezomib - refractory immune mediated TTP

• Other Drugs:

Steroids - TTP

Recombinant Thrombomodulin (rTM) – TA-TMA

Cyclosporine A – second line in acute or chronic relapsing TTP

Other immunosuppressive drugs (MMF, Cyclophosphamide, Vincristine,...)

• Supportive measures:

management of renal failure, hypertension, bleeding, etc.

Plasma exchange (PEX)/Plasma Infusions (PI)

Aim:

Remove mutant complement proteins and/or CFH auto-Ab.

Early Plasma Exchange reduces mortality in TTP (90% if untreated).

Benefit of PEX for antibody-mediated pediatric aHUS.

Role in other forms of TMA less clear.

Early PEX in TA-TMA might be beneficial, Response 50%

Risks:

catheter related problems (infections, thrombosis, etc.)

hemorrhage, sensitization to plasma products

“Traditionally, PEX/PI was instituted immediately in all patients with an aHUS phenotype and this can still be done while awaiting the results of tests or availability of Eculizumab. However, Eculizumab should be started in patients with no response to PEX/PI within a few days or in those cases in which the presumptive diagnosis of aHUS is more certain.”

Johnson S et al., Pediatr Nephrol 2014 McClain RS et al., Transfusion 2010

Kaplan BS et al., Intractable Rare Dis Res 2014

Jodele S, Transfusion 2013 Worel N, Tansfus Apher Sci 2007 Oran B, BBMT 2007

Sinha A, Kidney Int 2013 Khandelwal, Pediatr Nephrol 2015

Anti-complement therapy and further treatment options

Eculizumab

Zuber J. et al., Nat Rev Nephrol 2012

• Humanized hybrid IgG2/IgG4 monoclonal Antibody against C5

• FDA approved for treatment of PNH...

• ...and aHUS: n=180 pts.; 4 trials (n=100 pts.)

treatment with eculizumab efficiently arrests complement activation and progression of TMA

• Adverse effects:

Infections by encapsulated germs (Neisseria, Pneumococcus, Haemophilus) –> Vaccination, AB-Prophylaxis

(Severe) Hypertension

Fever

Legendre CM, NEJM 2013 Licht C, Kidney Int 2015 Greenbaum LA, Kidney Int 2016

Hillmen P, NEJM 2006

Eculizumab in aHUS - Trials

Legendre CM, NEJM 2013 Licht C, Kidney Int 2015

Greenbaum LA, Kidney Int 2016 Fakhouri F, J Am Soc Nephrol 2013

Loirat C, Pediatr Nephrol 2016

Eculizumab in TA – TMA

Cincinnati Experience:

• n=6 children with severe TA-TMA

• 4 allogeneic/2 autologous

• dose-adjusted Eculizumab: level >99mg/mL

• …therapeutic option for TA-TMA, but HSCT patients appear to require higher medication dosing…

• CH50 may be useful to guide eculizumab dosing in HSCT patients

Jodele S, BBMT 2014

rTM in TA – TMA/aHUS

Fujiwara H et al., Transfusion 2015

Seven of the nine patients in the rTM group recovered from TA-TMA without complications, but none in the control group recovered. The rTM group showed a significantly better overall survival after TA-TMA onset than did the control group (median, 123.0 days vs. 45.5 days, respectively; p=0.045).

Caplacizumab

• Anti–vWF humanized single-variable-domain immunoglobulin (Nanobody), that...

• ...binds to the A1 domains of vWF.

• ...antagonizes the ultra-large vWF–platelet interaction in TTP and prevents platelet adhesion and microvascular thrombosis.

• ...does not prevent de novo expansion of anti-ADAMTS13 autoantibodies.

Lämmerle B. Nat Rev Nephrol 2016

Caplacizumab

• Randomized Ph II trial for acquired TTP (n=75); Caplacizumab vs placebo.

• Median time to platelet count normalization was 3 days (95% CI 2.7–3.9 days) with Caplacizumab and 5 days (95% CI 3.2–6.6 days) with placebo (P <0.005).

• Disease exacerbation after an initial treatment response more often after placebo.

• Adverese events:

Bleeding related (mild)

Infections (sepsis, bact infections)

Nervous system disorders (dizziness, headache, dysarthria) Peyvandi F et al., NEJM 2016

Rituximab

• Chimeric monoclonal antibody

• depletes B-cells by binding CD20

• Plasmacells not targeted

• Efficacy in refractory TTP with response rates >90%

• Relapses: 10-25%

• Side effects:

Severe infections - IVIG Substitution!

Viral reactivations (CMV, HSV, etc)

Progressive multifocal encephalopathy (PML)

Fakhouri F et al., Blood 2005 Scully M et al., Br J Haematol 2007 Elliott MA et al., Eur J Haematol 2009 Chemnitz JM et al., Ann Hematol 2010

Rituximab-opsonized B cells are attacked by three mechanisms.

Taylor RP et al., Nat Clin Pract Rheumatol 2007

Bortezomib

• Proteasome Inhibitor

• Treatment of hematological malignancies or Ab-mediated autoimmune conditions

• Elimination of autoreactive plasma cells producing anti-ADAMTS13 antibodies in refractory TTP

• Side effects:

Peripheral neuropathy

Thrombocytopenia

Viral infections Shortt J et al., NEJM 2013 Patriquin CJ et al., Br J Haematol 2016 Mazepa MA et al., Br J Haematol 2014 Khandelwal P. et al., BBMT 2014

Pediatric HUS and TTP – What Type of Treatment? Loirat C, Pediatr Nephrol 2016

Summary and Conclusions

• Deeper insight into the pathomechanisms behind the subtypes of TMA paved the way for targeted therapies in aHUS, TA-TMA or TTP.

• The C5-targeting complement antibody Eculizumab has been successfully introduced as first-line therapy in children and adults with aHUS and TA-TMA.

• Caplacizumab is a valuable treatment option that antagonizes the ultra-large vWF–platelet interaction in TTP by binding to the A1 domains of vWF. It prevents platelet adhesion and microvascular thrombosis in acquired TTP of adult patients.

• Rituximab and Bortezomib are available for second line treatment of refractory TTP.

• Plasma exchange (PEX) is a well-established procedure to treat TTP or Ab-mediated aHUS in children. PEX is readily accessible and therefore should not be delayed, as early intervention could improve outcome in these patients, in particular if Eculizumab is not immediately available.

Acknowledgements

St. Anna Children‘s Hospital/Station IA

• S. Matthes-Martin

• C. Peters

• A. Lawitschka

St. Anna Children‘s Hospital/Apheresis Unit

• V. Witt

• E. Beiglböck and all operators

C. Mache (Pädiatrische Nephrologie, Univ. Kinderklinik Graz)