Ezzeddine. TTP

7/27/2019 Ezzeddine. TTP

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Thrombotic

Thrombocytopenic PurpuraSerena Ezzeddine

Morning ReportSeptember 8, 2008


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Epidemiology

Suspected TTP-HUS- 11cases/million/yr

Idiopathic TTP-HUS- 4.5 cases/million/yr

Severe ADAMTS13 deficiency- 1.7cases/million/yr

Incidence rates were greater for women

and African-Americans Prior to plasma exchange, mortality rate

was as high as 90%, now less than 20%


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Terminology

TTP and HUS (hemolytic uremic syndrome) areboth acute syndromes with abnormalities inmultiple organ systems and evidencing

microangiopathic hemolytic anemia andthrombocytopenia. Although some studiesappear to distinguish these two entities thepresenting features are essentially the same in

most adult patients. Furthermore, the pathologicchanges are the same and so is the initialtreatment.


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Definitions and Diagnosis

The Classic Pentad of TTP

Microangiopathic hemolytic anemia

Thrombocytopenia

Renal insufficiency or abnormalities Neurologic abnormalities that can be fluctuating

Fever

Most common symptoms at presentation arenonspecific and include abdominal pain, nausea,vomiting and weakness.


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Definitions and Diagnosis

In the era before effective treatment, itwas common for all five features of thepentad to be present, but now it is rare

for all to be present in same patient. Now, only thrombocytopenia and

microangiopathic hemolytic anemiaWITHOUT another clinically apparentcause is required to suspect TTP-HUS andinitiate treatment.


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Definitions Continued

MAHA-nonimmune hemolysis (negative coombs) withprominent red cell fragmentation (schistocytes) onperipheral blood smear. Will exhibit increased LDH andindirect bili.

Schistocytes-in the appropriate clinical settingschistocyte count>1% was strongly suggestive of TTP-HUS, ie 2 or more schistos in microscopic field at 100xmagnification.

Thromoboctyopenia- mean in a series was 25,300prior to treatment.

Renal disease- due to renal thromboticmicroangiopathy, which is usually associated with a UAthat is often near normal with only mild proteinuria(between 1-2 g/day) and few cells or casts


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Definitions Continued

Neurologic symptoms - most are subtle, suchas transient confusion or severe headache.Focal, objective abnormalities are less common,but grand mall seizures and coma can occur.

Fever- less frequent finding, but the presenceof chills and high spiking fever should suggestdx of sepsis or DIC.

Cardiac involvement- incidence is difficult to

determine, but diffuse platelet thrombi andassociated hemorrhage in cardiac tissues canlead to arrythmias, MIs, sudden death, shock, orheart failure.


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SCHISTOCYTES!


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Pathophysiology and ADAMTS13

Before 1998, there was a lack of knowledge of the pathophysiologyof TTP. In that year, adults with idiopathic TTP were reported tohave acquired antibodies that inhibit VWF cleaving protease, whichis normally present in plasma. In 2001, VWF cleaving protease waspurified and cloned by several groups, shown to be a new memberof the a disintegrin and metalloprotease with thrombospondin type

1 repeats-aka ADAMTS13.

In initial studies with Furlan et al, in 1997, no inhibitor of theenzyme was found, and the deficiency was ascribed to anabnormality in the production, survival or function of protease, but

then in 1998, concomitant studies showed that the protease activitywas decreased during acute episode of TTP, but returned to normalin recovery, so there was a transient autoantibody produced againstthe enzyme during acute episodes.


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Pathogenesis

VWF is synthesized in endothelial cells and assembled inlarge multimers that are present in normal plasma. Thelarge multimers, ie unusually large von willebrand factor(ULVWF) are rapidly degraded in the circulation into

normal size range of VWF multimers by ADAMTS13.

ADAMTS13 deficiency could lead to accumulation ofULVWF multimers, platelet aggregation, and plateletclumping. ULVWF multimers accumulate in patients with

TTP being found in platelet thrombi and serum. TheULVWF can attach to activated platelets therebypromoting aggregation.


11/22Copyright 2006 American Society of Hematology. Copyright restrictions may apply.

Sadler, J. E. Hematology 2006;2006:415-420

Figure 1. Pathogenesis of idiopathic thrombotic thrombocytopenic purpura (TTP) caused byADAMTS13 deficiency


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ADAMTS13

An inhibitory autoantibody to ADAMTS13 hasbeen found at varying titers among highpercentage of patients with idiopathic TTP whohave severe ADAMTS13 deficiency, and theinhibitory IgG is directed at various elements ofthe protease.

It has been suggested that levels of ADAMTS13less than 5% with or without an inhibitorantibody may be part of a larger autoimmuneresponse. Non-inhibitory antibodies to

ADAMTS13 have also been demonstrated.


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ADAMTS13 and prognosis

So usually, in acute idiopathic TTP, there is a severedeficiency in ADAMTS13 activity (undetectable or


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Treatment

PLASMA EXCHANGE -do NOT wait! Usually done daily until platelet count

has normalized (150K for 2 days) andhemolysis has largely ceased, ie

normalized LDH. Exchange 1 to 1.5plasma volumes daily

1/3 to of patients have promptexacerbation of thrombocytopenia and

hemolysis when plasma exchanged stoppedor tapered. In these cases re-institute dailyexchange, or even twice daily exchange witha planned tapering schedule


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Plasma Exchange continued

Serial observations indicate that neurologicsymptoms and serum LDH improve first, thenplatelet count, and improvement of renalfunction also occurs but is unpredictable

FFP is used usually four units per liter plasmaremoved. Most commonly used.

Cryo-poor plasma (VWF largely removed), butcan lead to deficiency of fibrinogen and Factor

VIII Plasma infusion without exchange can serveas emergencv treatment if exchange notreadily available.


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Treatment

Corticosteroids (prednisone 1mg/kg) ormethylprednisolone 125mg IV BID) eitheradjunctively immediately or if platelet counts do

not increase within several days of plasmaexchange, or if thrombocytopenia recurs whenplasma exchange treatments are diminished orstopped.

There is little evidence for this strategy, but isused on the justifiable assumption that TTP isimmune mediated.


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Treatment

RITUXIMAB Humanized monoclonal antibody against CD20, which

is expressed on B cells, and it rapidly clears B cellsfrom circulation, preventing replenishment ofpathological plasma cells.

Remission associated with disappearance ofADAMTS13 inhibitors and normalization of activitylevels

Should be considered in TTP patients who fail torespond to daily PE and corticosteroids after 7-14days

Dose 375 mg/m2 IV qweek for minimum of fourweeks and maximum of 8 weeks.


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TTP and Lupus

TTP is a known complication in SLE and 1-4% ofpatients with SLE may experience an episode of TTPduring their life.

Possibly, the occurrence of TTP in SLE pts is

underestimated because of overlapping symptoms In vast majority of SLE-related TTP, SLE dx first, 13-15%

TTP dx first, and 12-26% dx concomitantly

Pts with active vasculitis esp with severe HTN and renalinvolvement may be difficult to distinguish from ITTP,and may represent true overlap syndrome betweenTTP and SLE.


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TTP and SLE


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References

NEJM 2006; 354:1927-35 George, James MD-Thrombotic Thrombocytopenic Purpura. Uptodate. Diagnosis, Causes, and Treatment of TTP-HUS Hematology 2004:407-423.Recent Advances in Thrombotic Thrombocyotopenic

Purpura, Sadler Et al Hematology 2007. TTP and ADAMTS13: When is testing appropriate? Mannucci et al Hematology 2006.Thrombocytopenic Purpura:A moving Target. Sadler

Hoffman:Hematology: Basic Principles and Practice fourth edition. Chapters 42 and132 Swiss Med Wkly 2007;137:518-524. Rituximab for acute plasma refractory thrombotic

thrombocyotopenic purpura. Eur J Haematology 2005;75:436-440. Acquired TTP as presenting symptom of SLE.

Successful treatment with plasma exchange and immunosuppression-report of 2cases

Blood cells, Molecules and Diseases (2002) 28(3) May/June:385-391. Ritux Therapy

for Refractory TTP Thrombotic Thrombocytopenic Purpura and Systemic Lupus Erythematous:Distinct

entities or overlapping syndromes. Internet Journal of Internal Medicine; Cheung

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