eMedicine Specialties > Neurology > Pediatric Neurology

Thrombotic Thrombocytopenic Purpura: Treatment & Medication

Author: Robert Stanley Rust Jr, MD, MA, Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, Director, Child Neurology, University of Virginia; Chair-Elect, Child Neurology Section, American Academy of Neurology
Contributor Information and Disclosures

Updated: Jan 27, 2010

Treatment

Medical Care

Plasmapheresis, plasma infusion, and plasma exchange

Plasmapheresis and plasma infusion have proven useful in the treatment of TTP, but the combination of both (ie, plasma exchange) by using fresh-frozen, platelet-poor plasma, perhaps in combination with corticosteroids, appears to be the most beneficial therapy in severe cases. Plasmapheresis may remove the large vWF multimers and other possible toxins, whereas the infused fresh-frozen plasma may contain natural circulating antioxidants (eg, prostacyclin) and the multimer-reducing factor found in plasma cryosupernatant.

Plasmapheresis may remove the large vWF multimers and circulating antibodies, while, at the same time, infused fresh-frozen plasma may contribute ADAMTS-13 and circulating antioxidants (eg, prostacyclin). They may also dilute ADAMTS-13–inhibiting immunoglobulin G (IgG).

The response to plasmapheresis and plasma infusion is often so prompt and dramatic as to suggest that these treatments are the most important factors in the greatly improved outlook for patients with TTPs.57,6,49

At present, daily plasmapheresis is probably the most widespread approach to managing TTP. It is continued until the platelet count becomes persistently normal and until the LDH level and other indicators of resolution of hemolysis indicate that that the fundamental aspect of TTP has resolved. LDH values and platelet counts are important for assessing the initial response to treatment and for timing of weaning of treatment.

Critically ill patients may be treated with infusions of fresh-frozen plasma without exchange until plasmapheresis may be commenced. In some critically ill patients, plasma exchange may be started and continued for periods of 10 days or longer. Studies have shown that only a few patients who recover from TTP with this treatment have notable permanent organ damage.28 However, other studies show a somewhat different picture (see Morbidity and Mortality).

Plasma exchange may be more effective than plasma infusion. In a controlled prospective double-blind crossover multicenter trial, survival rates were at least 80% for plasma exchange compared with 60% for plasma infusion.58 A later study showed that the benefits of plasma exchange are related to the infusion of large volumes of plasma, improving the clearance of toxins, antibodies, multimers, or immune complexes compared with plasma infusion.59

Care must be taken to avoid circulatory overload and electrolyte disturbances when plasma exchange and infusion is performed, particularly because most patients with TTP have impaired renal function. Careful orchestration of plasma therapy and dialysis greatly contributes to the avoidance of such complications.

Pregnancy-associated TTP may be uneventfully managed by the combination of plasmapheresis and plasma infusions.60

Most cases of TTP are monophasic, but in heterogeneous populations, 11-28% of patients have 1 or more recurrences. Recurrence rates are likely to increase as the follow-up interval lengthens. Relapses may occur weeks to many years after initial presentation. In some instances, chronic TTP develops.16,49,28

In 1991, plasma exchange was shown to be superior to plasma infusion in a controlled prospective double-blind crossover multicenter trial by Rock and associates. This therapy resulted in an 80% survival rate for patients randomly assigned to receive plasma exchange and a 60% survival rate for patients randomly assigned to receive plasma infusion.

The superiority of plasma exchange may be related to the infusion of large volumes of plasma or the improved clearance of toxins, antibodies, multimers, or immune complexes compared with plasma infusion. Most patients have been treated with 7 or 8 exchanges (requiring blood from >200). However, at least 60% of patients with severe TTP have had relapses after such treatment. Relapses occur weeks to years after initial remission. Plasma infusions pose the risk of transmitting of infections, including hepatitis and HIV infection.

For severe or recurrent cases, plasmapheresis and plasma infusion are useful, but the combination of both (plasma exchange) by using fresh-frozen, platelet-poor plasma appears to be the most beneficial form of therapy. This is sometimes administered in combination with corticosteroids.61,18

The risks and benefits of plasma exchange and plasmapheresis should be reviewed with experts familiar with those techniques before they are undertaken.

Platelet transfusion poses a significant risk for a precipitous decline in the patient's clinical status and should be avoided.16

Other therapies

Other therapies for TTP included selective infusion of corticosteroids or other immunosuppressive drugs; vincristine, cyclophosphamide, or azathioprine; antiplatelet agents (eg, aspirin, dipyridamole); and other treatments (eg, gamma globulin, splenectomy, infusion of prostacyclin, use of staphylococcal protein A columns). Patients whose disease is refractory to acute or long-term plasma exchange or who have frequent relapses may respond to any or a combination of these approaches.

In severe cases, the effects of vincristine, splenectomy, antiplatelet agents, vitamin E, or gamma globulin are usually not particularly impressive, particularly when plasma exchange fails to produce improvement.62,16

Promising results have been published concerning the efficacy of rituximab in acquired TTP. Rituximab is a chimeric monoclonal anti-CD20 antibody that depletes B cells from the circulation and tissues and that decreases titer of the ADAMTS-13 inhibitor antibody. It has been employed as part of a preemptive strategy in patients who show persistence of anti–ADAMTS-13 autoantibody titers after recovery from a clinical bout. This approach is intended to diminish the risk for recurrence and associated morbidity and mortality. With this approach, ADAMTS-13 inhibitors disappeared and ADAMTS-13 activity ranging from 15-75% of normal was achieved in 5 of 5 patients within 6 months.63

  • Corticosteroids
    • Corticosteroids alone are beneficial in mild cases of TTP and may be valuable adjuvants when plasma exchange is undertaken is relatively severe cases.
    • The combination of prednisone and azathioprine is useful in patients who have a relapse, probably because of the effects on both vWF multimers and circulatory endothelial-cell autoantibodies.61,18
  • Vincristine, cyclophosphamide, or azathioprine
    • Vincristine may be useful in some refractory cases, but the effects of such interventions or of antiplatelet agents, vitamin E, or gamma globulin are not impressive, particularly when plasma exchange fails to produce improvement. Therefore, they are generally not recommended.
    • Vincristine is a potent drug whose management is beyond the scope of this review. Therefore, an oncologist or others familiar with the use of this drug should be consulted concerning its risks and principles of management before it is administered.
    • Azathioprine has potential benefit in treating HUS or TTP that does not respond to corticosteroids given alone or in combination with plasmapheresis and plasma exchange. It might also benefit those who have relapses with such therapy. Whether this treatment is superior to splenectomy under these circumstances is unknown.
  • Antiplatelet agents
    • Antiplatelet agents, widely used as therapeutic adjuvants, may increase the risk for bleeding and do not appear to be beneficial when used alone.
    • Most authorities appear to regard these agents as potentially useful adjuvants.
    • Despite their wide use, antiplatelet agents sometimes increase the risk of bleeding.
    • Antiplatelet agents do not appear to be beneficial when used alone.64,65,16,49

Surgical Care

  • Splenectomy is undertaken in some intractable or severe cases of TTP.
  • In some cases of HUS, colonic ischemia may be severe enough to require resection of portions of the bowel.

Consultations

  • Consultations with renal specialists are important, particularly in cases of HUS.
  • Consultation with neonatologists, gastroenterologists, cardiologists, dermatologists, ophthalmologists, and hematologists, or surgeons may be indicated, depending on the patient's particular manifestations.
  • HUS and TTP are multisystemic illnesses whose treatment in extremely ill patients requires the expertise of many subspecialists.

Activity

The activity of patients with TTP should be advanced as tolerated to avoid deconditioning, pulmonary embolus, and other complications of prolonged disease.

Medication

Among the various medical forms of therapy that have been tried, prednisone, azathioprine, vincristine, and intravenous immunoglobulin (IVIg) are the medications for which the strongest evidence of efficacy is available. Other agents pose risks without a clear demonstration of benefits. Therefore, they are not considered further here.

Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Bell et al showed that patients with TTP, normal liver function, and no neurologic abnormalities except for headache respond to prednisone 200 mg/d PO.16 Patients with hepatic dysfunction respond to prednisolone 200 mg/d IV. With both PO and IV therapy, plasmapheresis and plasma exchange also were started in patients whose condition did not respond to corticosteroid treatment within 48 h, while they continued steroids at same dose. For patients with additional neurologic abnormalities, rapid deterioration, hematocrit <20%, platelet count < 10 X 109/L (<10,000/mm3), LDH level >600 U/L, or creatinine level > 5 mg/dL, treatment was undertaken with IV prednisolone at the dosage noted, in addition to plasmapheresis and plasma exchange.


Prednisone (Sterapred)

Immunosuppressant to treat autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Adult

200 mg/d PO; continue until laboratory values return to reference range for 3 d; then may reduce to 60 mg/d

Pediatric

Not established
<40 kg: Initial dosage of 5 mg/kg/d PO may be reasonable; then taper as recommended in adults
>40 kg: Administer as in adults

Phenytoin, phenobarbital, ephedrine, or rifampin may enhance clearance, lowering serum levels; may unpredictably alter response to warfarin (usual effect is to lower response to anticoagulation; may need to increase dose on basis of carefully determined PT); may enhance risk of hypokalemia associated with potassium-depleting diuretics; may increase requirements for hypoglycemic agents or insulin in patients with diabetes mellitus

Documented hypersensitivity; systemic fungal infection; some, but not all, patients receiving amphotericin B; concomitant cerebral malaria; latent or active amebiasis, active chickenpox, measles; active tuberculosis; recent myocardial infarction; ulcerative colitis, active or latent peptic ulcer disease, impending GI perforation, or enteric abscess

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May interfere with diagnosis of infections and ability of treated patients to contain and eliminate infectious pathogens; may cause electrolyte disturbances or worsen congestive heart failure or hypertension in susceptible patients; may result in muscle weakness, loss of muscle mass, osteoporosis, vertebral compression fractures, aseptic necrosis of femoral heads, pathologic fractures of long bones, tendon rupture, pancreatitis, ulcerative esophagitis, impaired wound healing, increased sweating, convulsions, pseudotumor cerebri, glaucoma, subcapsular cataracts, vertigo, headache, confusion or psychosis, menstrual irregularities, suppression of adrenocortical axis, expression of latent diabetes mellitus, or hirsutism
Breastfeeding should be curtailed; corticosteroids appear in breast milk and may result in growth suppression of feeding child and other potential complications noted above


Prednisolone (Delta-Cortef, Econopred, AK-Pred)

Decreases autoimmune reactions, possibly by suppressing key components of immune system. Initial IV dose should be administered under close supervision; rare instances of anaphylaxis after initial dose reported.

Adult

200 mg/d PO/IV; continue until laboratory values return to reference range for 3 d; then reduce to 60 mg/d; change to PO when feasible; for further tapering, reduce 5 mg/wk from total daily dosage; return to initial dosage if relapse or deterioration of laboratory values occurs

Pediatric

Not established
<40 kg: Initial dosage of 5 mg/kg/d PO may be reasonable; then taper dose as recommended in adults
>40 kg: Administer as in adults

Phenytoin, phenobarbital, ephedrine, or rifampin may enhance clearance, lowering serum levels; may unpredictably alter response to warfarin (usual effect is to lower response to anticoagulation; may need to increase dose on basis of carefully determined PT); may enhance risk of hypokalemia associated with potassium-depleting diuretics; may increase requirements for hypoglycemic agents or insulin in patients with diabetes mellitus

Documented hypersensitivity; systemic fungal infection; some, but not all, patients receiving amphotericin B; concomitant cerebral malaria; latent or active amebiasis, active chickenpox, measles; active tuberculosis; recent myocardial infarction; ulcerative colitis, active or latent peptic ulcer disease, impending GI perforation, or enteric abscess

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May interfere with diagnosis of infections and ability of treated patients to contain and eliminate infectious pathogens; may cause electrolyte disturbances or worsen congestive heart failure or hypertension in susceptible patients; may result in muscle weakness, loss of muscle mass, osteoporosis, vertebral compression fractures, aseptic necrosis of femoral heads, pathologic fractures of long bones, tendon rupture, pancreatitis, ulcerative esophagitis, impaired wound healing, increased sweating, convulsions, pseudotumor cerebri, glaucoma, subcapsular cataracts, vertigo, headache, confusion or psychosis, menstrual irregularities, suppression of adrenocortical axis, expression of latent diabetes mellitus, or hirsutism
Breastfeeding should be curtailed; corticosteroids appear in breast milk and may result in growth suppression of feeding child and other potential complications noted above


Vincristine (Oncovin, Vincasar)

Potential benefit in treating HUS-TTP that does not respond to corticosteroids alone or combined with plasmapheresis and plasma exchange or with relapse with such therapy. Superiority to splenectomy under such circumstances unknown. Potent drug. Management beyond scope of this review; therefore, consult oncologists or other familiar with its use concerning risks and principles of management before administration.

Adult

1.4 mg/m2 IV on days 1, 4, 7, and 10

Pediatric

Consultation with oncologists should be obtained on individual basis

Mitomycin-C may cause acute pulmonary reaction; asparaginase, cytochrome P450 (CYP) 3A4 inhibitors (eg, itraconazole, quinupristin-dalfopristin, sertraline, ritonavir), granulocyte-macrophage colony-stimulating factor (GM-CSF, eg, sargramostim, filgrastim), and nifedipine increase toxicity; CYP3A4 inducers (eg, carbamazepine, phenytoin, phenobarbital, rifampin) may decrease effects

Documented hypersensitivity; demyelinating hereditary sensorimotor neuropathies

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in severe cardiopulmonary disease, hepatic impairment (adjust dose), or preexisting neuromuscular dysfunction; numerous precautions should be reviewed with consultant who can collaborate in selection and administration for treating HUS or TTP


Methylprednisolone (Adlone, Depo-Medrol, Depopred, Medrol, Methylone, Solu-Medrol)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased permeability. Used as alternative glucocorticoid of choice for all patients with severe, life-threatening bleeding or children with platelet counts <30,000/mm3. Careful observation without medical treatment may be appropriate in some asymptomatic children.

Adult

100 mg IV or equivalent 30 min prior to rituximab infusion recommended to reduce incidence and severity of infusion reactions

Pediatric

Not established

Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics; grapefruit juice increases prednisolone concentrations; methylprednisolone and cyclosporine mutually inhibit one another resulting in increased plasma levels of each drug

Documented hypersensitivity; viral, fungal or tubercular skin infections

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use
Depo-Medrol contains benzyl alcohol, which is potentially toxic when administered locally to neural tissue; administration of Depo-Medrol by other than indicated routes, including the epidural route, has been associated with reports of serious medical events including arachnoiditis, meningitis, paraparesis/paraplegia, sensory disturbances, bowel/bladder dysfunction, seizures, visual impairment (including blindness, ocular, and periocular inflammation), and residue or slough at injection site

Immunosuppressant agents

These agents decrease autoimmune reactions, possibly by suppressing key components of immune system.


Rituximab (Rituxan)

Genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against CD20 antigen. Produced by mammalian cell (Chinese Hamster Ovary) suspension culture in nutrient medium containing antibiotic gentamicin. Gentamicin is not detectable in final product. Rituximab has approximate molecular weight of 145 kD. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM.
Available as Rituxan, a sterile, clear, colorless, preservative-free liquid concentrate for IV administration. Supplied at concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials. The product is formulated in 9 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and water for injection. The pH is 6.5.

Adult

1000 mg IV infusion for 2 doses, separated by 2 wk; administer methylprednisolone 100 mg IV (or its equivalent) 30 min before each infusion to reduce infusion-related reactions
Not to exceed infusion rate of 50 mg/h initially; if hypersensitivity or infusion-related reactions do not occur, may escalate infusion rate by 50 mg/h increments q30min; not to exceed 400 mg/h
Rituxan is given in combination with methotrexate
Premedicate before each infusion with acetaminophen and an antihistamine

Pediatric

Not established

Coadministration with cisplatin is known to cause severe renal toxicity including acute renal failure; may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 months of vaccine)

Documented hypersensitivity; IgE-mediated reaction to murine proteins

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Most important serious adverse reactions include infusion reactions, tumor lysis syndrome, mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other viral infections, serious infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation; in patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias have been reported including lymphopenia, neutropenia, leukopenia, anemia, and thrombocytopenia
Since patients with RA are at increased risk for cardiovascular events compared with the general population, patients with RA should be monitored throughout the infusion and the treatment discontinued in the event of a serious or life-threatening cardiac event
Hypophosphatemia has been reported to be more common in patients who received corticosteroids; following treatment with up to 7 courses of Rituxan, at least 1 episode of newly-occurring hypophosphatemia reported

Immune globulins

These agents may interfere with processes that promote immune reactions resulting from diverse stimuli.


Human immunoglobulin (Gammagard, Gamimune, Sandoglobulin)

Believed to treat conditions associated with inflammation and immune dysregulation by neutralizing circulating myelin antibodies by means of anti-idiotypic antibodies. May downregulate proinflammatory cytokines, including interferon (IFN)-gamma. Blocks Fc receptors on macrophages, suppresses inducer T and B cells, and augments suppressor T cells; blocks complement cascade. May promote remyelination. May increase CSF IgG modestly.

Adult

2 g/kg IV administered over 2-5 d

Pediatric

Not established

Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccination)

Documented hypersensitivity; IgA deficiency

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Check serum immunoglobulin A (IgA) level before administering IVIg (use IgA-depleted product, eg, Gammagard S/D); may increase serum viscosity and thromboembolic events; may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d after infusion to 30 d); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, or preexisting kidney disease; laboratory changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in erythrocyte sedimentation rate (ESR) for 2-3 wk, and apparent hyponatremia

More on Thrombotic Thrombocytopenic Purpura

Overview: Thrombotic Thrombocytopenic Purpura
Differential Diagnoses & Workup: Thrombotic Thrombocytopenic Purpura
Treatment & Medication: Thrombotic Thrombocytopenic Purpura
Follow-up: Thrombotic Thrombocytopenic Purpura
References
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Further Reading

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Keywords

TTP, thrombocytic acroangiothrombosis, Schulman-Upshaw syndrome, Upshaw-Schulman syndrome, constitutional TTP, severe ADAMTS13 deficiency, thrombotic microangiopathy, TMA, hemolytic uremic syndrome, HUS, TTP-HUS, TTP/HUS, ADAMTS13, ADAMTS-13, Shiga toxin, Stx

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Contributor Information and Disclosures

Author

Robert Stanley Rust Jr, MD, MA, Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, Director, Child Neurology, University of Virginia; Chair-Elect, Child Neurology Section, American Academy of Neurology
Robert Stanley Rust Jr, MD, MA is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, American Headache Society, American Neurological Association, Child Neurology Society, International Child Neurology Association, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

David A Griesemer, MD, Professor, Departments of Neuroscience and Pediatrics, Medical University of South Carolina
David A Griesemer, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Neurology, American Epilepsy Society, Child Neurology Society, and Society for Neuroscience
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Kenneth J Mack, MD, PhD, Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic
Kenneth J Mack, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, Phi Beta Kappa, and Society for Neuroscience
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD, Assistant Professor, Department of Pediatrics, Division of Pediatric Neurology, Department of Neurology, Oregon Health and Science University; Consulting Staff, Shriners Hospital for Children
Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, and Child Neurology Society
Disclosure: Nothing to disclose.

 
 
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