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Management of thrombotic

thrombocytopenic purpura :
Current Perspective
Rangga Lunesia

Rare ( 6 cases/mill/y in UK)
Life threatening
Underlying path: def. ADAMTS13

activitycleaves ultralarge von Willebrand

Acquired : autoantibody mediated
Congenital : deletarious mutations

Aggressive form of thrombotic

microangiopathy microvascular ischemia

multiorgan dysfunction
High morbid+mortal promptly treated

Pathogenesis & Terminology

<< ADAMTS13* << cleave ULvWF**

multimer to smaller
vWF as bridge between exposed
subendothelial matrix+platelet, after vessel
Vessel injuryEndothelial cells secreted
ULvWF multimer
<< ADAMTS13 activity >> ULvWF multimer
excession bind to platelet (platelet rich
thrombi) platelet aggregation partial
vessel occlusion organ ischaemia

Severe ADAMTS13 activity deficiency

Autoantibody binds to and impairs its

function (95%)/Acquired
Primary : no overt relation to immune dysregulation
Secondary : overt relation immune dysregulation

(e.g. : SLE,HIV)

Mutations of ADAMTS13 gene


Clinical Presentation
Classic pentad : fever, thrombocytopenia,

microangiopathic hemolytic anemia, renal

dysfunction, neurological symp.

Laboratory assays
<< ADAMTS13 enzyme activity(<10%)

The other investigation that routinely performed in

Blood film, reticulocyte count, bilirubin, haptoglobin
Prothrombin time, activated partial thromboplastin time,

Liver function test, electrolytes, urea and serum creatinine,
serum troponin, calcium, thyroid function test
HIV serology, hepatitis B and C serology
Autoantibody screen
Pregnancy testing
Direct antiglobulin test, cytomegalovirus serology
CT/MRI brain, echocardiogram, EKG
Other imaging to exclude malignancy

Management of TTP

instability, sudden, rapid, unpredictable

1st, resuscitation, make sure any critical organ
dysfunction stabilized.
Then, decide, by the rarity of
TTP, consider
managed in experienced centralized institution for
ADAMTS13 test.
Once suspected, if theres any intense need(central
resuscitation required, or clinical instability within 72
hrs, consider admission to ICU/hi dependency Unit.

Plasma Exchange(PEX)

Most important for acute

Initiated w/o delay for suspected patient.
Reduced death rate
Superior to plasma infusion alone (still used for temporizing

in case of unavoidable delay to PEX)

PEX is initiated at 1.5 plasma volume (PV) (60 mL/kg). In
the case of confirmed TTP, PEX at 1.5 PV is continued for at
least the first 3 days (the regimen utilized in the initial
Canadian Apheresis trial in TTP13), with further PEX
dependent on the clinical progress of the patient
One of the considerations in the timing and intensity of PEX
over the first few days is the administration of other diseasemodifying therapies (particularly methylprednisolone and
rituximab) which may be removed by the PEX procedure
Daily PEX should be continued until 2 days after platelet
count normalizes (>150 109/L), and can be safely stopped
outright without any weaning schedule.14

Various options for replacement fluid during

PEX : cryosupernatant (CSP), fresh frozen

plasma (FFP) or solvent/detergent-treated
pooled plasma (SDP)
Our standard : Octaplas (fewer allergic
reactions than FFP/CSP)
In the case that Octaplas is not available,
FFP is usually used due to its general

Safe, effective for newly diagnosed.
PEX required to achieve remission

risk of relapse by 80%

The scheduling of rituximab is 375 mg/m2
iv/weekly for 4 week
Rituximab removed from circulation by PEX
Administer Rituximab immediately after PEX to
maximize its duration of action being removed
by subsequent PEX
Avoid PEX for > 12 hrs after administration

Rapid immunosuppression
No firm evidence base to guide the choice of

Favor : methylprednisolone IV 10 mg/kg/day.
Our standard : methylprednisolone 1 g iv/day
for 3 d (1st dose immediately administered
after 1st PEX)

Supportive Care
Platelet > 50 109/L.
Aspirin, Clopidogrel

TTP at hi risk of DVT. Administer DVT prophylaxis

(LMWH) if platelet greater than 50 109/L.

Central venous access preferable for PEX

Hepatitis B prophylaxis
Folic acid
Due to hemolytic state, 5 mg orally/day

Other Interventions
has such limited role e.g.:
Other immunosuppressant :mycophenolate mofetil,
cyclosporine, vincristine (yet no high quality data
regarding its efficacy)
Splenectomy : for relapsing disease (little good
evidence for its efficacy)

Deleterious mutations within the ADAMTS13 gene.
Autoantibodies against ADAMTS13 do not occur in

congenital TTP; therefore, immunosuppression is

not indicated.
Acute episodes in congenital TTP treated with
PEX/plasma infusion alone in a similar way to acquired
Remission : treatment depends on the phenotype of
the individual pat.
Some patient w/ congenital TTP require plasma infusions every

34 weeks in order to replace functional ADAMTS13 and

prevent symptomatic TTP episodes
Others will only require treatment in the context of inciting
factors like pregnancy or infection.

Pat w/ congenital TTP have a significant lifetime

exposure to plasma; use the safest product

regarding viral/prion transmission.
Our standard: SDP

Special Circumstances
TTP may present during pregnancy
TTP in pregnancy may represent 1 of 2 processes:
acquired TTP due to the changes in immune regulation that
occur during pregnancy
precipitation of an episode of symptomatic TTP in a patient
with congenital TTP (which may or may not have been
previously recognized)
Patient treated w/ methylprednisolone and PEX in a

similar way to pregnant patients.

Rituximab is not advocated during pregnancy due
to unknown risks to the fetus.
Delivery of the baby does not necessarily result
in the resolution of the TTP episodes.

HIV-associated TTP
important cause of secondary TTP.
Patients w/ higher viral loads at presentation

(>500,000 copies/mL) require more PEX to

achieve remission.
Highly active antiretroviral therapy +PEX
+corticosteroid is sufficient to achieve a
remission from acute TTP.
If consistent viral suppression can be
achieved, the risk of relapse is low.

Future directions
While the outcomes of patients have

improved over time, yet still significant

potential for the development of new
agents that target various aspects of the
disease process, including:
Recombinant ADAMTS13
Anti-vWF nanobody
N-acetyl cysteine
Novel immunosuppressive agents

Last decade : significant advances in

understanding pathological basis of TTP

Result in improvement therapy that are
rationally targeted.
Still, theres room for improvement in
numerous areas of patient care.