eMedicine Specialties > Neurology > Pediatric Neurology

Thrombotic Thrombocytopenic Purpura: Treatment & Medication

Author: Robert Rust Jr, MD, Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, University of Virginia School; Clinical and Residency Training, Child Neurology, University of Virginia Hospital and Clinics
Contributor Information and Disclosures

Updated: Jun 26, 2006

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 (Ridolfi, 1981; Bukowski 1982; Rock, 1991).

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 (Tsai, 2003). 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 (Rock, 1991). 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 (Lawlor, 1997).

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.

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 (Bell, 1991; Rock, 1991; Tsai, 2003).

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 (Moake, 1984 and 1990)

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 (Bell, 1991).

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 (Byrnes, 1977; Powell, 1984; Remuzzi, 1988; Bell, 1991).

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.

  • 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. (Moake, 1990).
  • 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 (Amorosi, 1977; Birgens, Ernst, 1979; Bell, 1991; Rock, 1991).

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 (1991) showed that patients with TTP, normal liver function, and no neurologic abnormalities except for headache respond to prednisone 200 mg/d PO. Patients with hepatic dysfunction respond to prednisolone 200 mg/d IV. With both PO and IV therapy, plasmapheresis and plasma exchange also were stared 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 (Deltasone, Orasone, Meticorten)

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 reduced 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


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


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

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
[ CLOSE WINDOW ]

References

  1. Adams RD, Cammermeyer J, Fitzgerald PJ. Neuropathological aspects of thrombotic acroagiothrombosis; clinico-anatomical study of generalized platelet thrombosis. J Neurol Neurosurg Psychiatry. 1948;11:27-43.

  2. Amorosi EL, Karpatkin S. Antiplatelet treatment of thrombotic thrombocytopenic purpura. Ann Intern Med. Jan 1977;86(1):102-6. [Medline].

  3. Baker KR, Moake JL. Thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. Curr Opin Pediatr. Feb 2000;12(1):23-8. [Medline].

  4. Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med. Aug 8 1991;325(6):398-403. [Medline].

  5. Berkowitz LR, Dalldorf FG, Blatt PM. Thrombotic thrombocytopenic purpura: a pathology review. JAMA. Apr 20 1979;241(16):1709-10. [Medline].

  6. Birgens H, Ernst P, Hansen MS. Thrombotic thrombocytopenic purpura: treatment with a combination of antiplatelet drugs. Acta Med Scand. 1979;205(5):437-9. [Medline].

  7. Blaker F, Altrogge H, Hellwege HH, et al. Treatment of severe haemolytic-uraemic syndrome by dialysis [in German]. Dtsch Med Wochenschr. Aug 4 1978;103(31):1229-32. [Medline].

  8. Bohle A, Helmchen U, Grund KE, et al. Malignant nephrosclerosis in patients with hemolytic uremic syndrome (primary malignant nephrosclerosis). Curr Top Pathol. 1977;65:81-113. [Medline].

  9. Bukowski RM, Hewlett JS, Harris JW, et al. Exchange transfusions in the treatment of thrombotic thrombocytopenic purpura. Semin Hematol. Jul 1976;13(3):219-32. [Medline].

  10. Bukowski RM. Thrombotic thrombocytopenic purpura: a review. Prog Hemost Thromb. 1982;6:287-337. [Medline].

  11. Byrnes JJ, Moake JL. Thrombotic thrombocytopenic purpura and the haemolytic-uraemic syndrome: evolving concepts of pathogenesis and therapy. Clin Haematol. May 1986;15(2):413-42. [Medline].

  12. Byrnes JJ, Khurana M. Treatment of thrombotic thrombocytopenic purpura with plasma. N Engl J Med. Dec 22 1977;297(25):1386-9. [Medline].

  13. Chin D, Chyczij H, Etches W, et al. Treatment of thrombotic thrombocytopenic purpura with intravenous gammaglobulin. Transfusion. Jan-Feb 1987;27(1):115-6. [Medline].

  14. Chow TW, Turner NA, Chintagumpala M, et al. Increased von Willebrand factor binding to platelets in single episode and recurrent types of thrombotic thrombocytopenic purpura. Am J Hematol. Apr 1998;57(4):293-302. [Medline].

  15. Cimolai N, Basalyga S, Mah DG, et al. A continuing assessment of risk factors for the development of Escherichia coli 0157:H7-associated hemolytic uremic syndrome. Clin Nephrol. Aug 1994;42(2):85-9. [Medline].

  16. Drews RE, Weinberger SE. Thrombocytopenic disorders in critically ill patients. Am J Respir Crit Care Med. Aug 2000;162(2 Pt 1):347-51. [Medline].

  17. Elliott MA, Nichols WL. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Mayo Clin Proc. Nov 2001;76(11):1154-62. [Medline].

  18. Fakhouri F, Vincent F, Legendre C. Pathological and therapeutic distinctions in HUS/TTP. Lancet. Feb 5 2000;355(9202):497; discussion 497-8. [Medline].

  19. Fiorani L, Vianelli N, Gugliotta L, et al. Brain MRI and SPET in thrombotic thrombocytopenic purpura. Ital J Neurol Sci. Apr 1995;16(3):149-51. [Medline].

  20. Fujikawa K, Suzuki H, McMullen B, Chung D. Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family. Blood. Sep 15 2001;98(6):1662-6. [Medline].

  21. Furlan AJ, Robles R. von Willebrand. n Engl J Med. 1998.

  22. Furlan M, Lammle B. Haemolytic-uraemic syndrome and thrombotic thrombocytopenic purpura-- new insights into underlying biochemical mechanisms. Nephrol Dial Transplant. Aug 2000;15(8):1112-4. [Medline].

  23. Furlan M, Robles R, Solenthaler M, Lammle B. Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura. Blood. Apr 15 1998;91(8):2839-46. [Medline].

  24. Furlan M, Robles R, Solenthaler M. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood. May 1 1997;89(9):3097-103. [Medline].

  25. Furlan M, Robles R, Galbusera M, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. Nov 26 1998;339(22):1578-84. [Medline].

  26. Galbusera M, Noris M, Rossi C, et al. Increased fragmentation of von Willebrand factor, due to abnormal cleavage of the subunit, parallels disease activity in recurrent hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and discloses predisposition in families. The Italian. Blood. Jul 15 1999;94(2):610-20. [Medline].

  27. Galbusera M, Ruggenenti P, Noris M, et al. alpha 1-Antitrypsin therapy in a case of thrombotic thrombocytopenic purpura. Lancet. Jan 28 1995;345(8944):224-5. [Medline].

  28. George JN. Idiopathic thrombocytopenic purpura in adults: current issues for pathogenesis, diagnosis and management. Hematol J. 2004;5 Suppl 3:S12-4. [Medline].

  29. George JN, Vesely SK. How can we provide the best care for our patients with immune thrombocytopenic pupura?. Mayo Clin Proc. Apr 2004;79(4):456-7. [Medline].

  30. George JN, Vesely SK, Terrell DR, George JN. The Oklahoma Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS) Registry: a community perspective of patients with clinically diagnosed TTP-HUS. Semin Hematol. Jan 2004;41(1):60-7. [Medline].

  31. George JN. How I treat patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Blood. Aug 15 2000;96(4):1223-9. [Medline].

  32. George JN, Sadler JE, Lammle B. Platelets: thrombotic thrombocytopenic purpura. Hematology (Am Soc Hematol Educ Program). 2002;315-34. [Medline].

  33. Habib R, Mathieu H, Royer P. Arteriole-capillary thrombotic disease of the kidney in children. [in French]. Rev Fr Etud Clin Biol. Oct 1958;3(8):891-4. [Medline].

  34. Hosler GA, Cusumano AM, Hutchins GM. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. A review of 56 autopsy cases. Arch Pathol Lab Med. Jul 2003;127(7):834-9. [Medline].

  35. Hovinga JA, Studt JD, Alberio L, Lammle B. von Willebrand factor-cleaving protease (ADAMTS-13) activity determination in the diagnosis of thrombotic microangiopathies: the Swiss experience. Semin Hematol. Jan 2004;41(1):75-82. [Medline].

  36. Jubinsky PT, Moraille R, Tsai HM. Thrombotic thrombocytopenic purpura in a newborn. J Perinatol. Jan 2003;23(1):85-7. [Medline].

  37. Kakishita E. Pathophysiology and treatment of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). Int J Hematol. Jun 2000;71(4):320-7. [Medline].

  38. Kaplan BS, Thomson PD. Hyperuricemia in the hemolytic-uremic syndrome. Am J Dis Child. Aug 1976;130(8):854-6. [Medline].

  39. Karlsberg RP, Lacher JW, Bartecchi CE. Adult hemolytic-uremic syndrome. Familial variant. Arch Intern Med. Sep 1977;137(9):1155-7. [Medline].

  40. Kennedy SS, Zacharski LR, Beck JR. Thrombotic thrombocytopenic purpura: analysis of 48 unselected cases. Semin Thromb Hemost. 1980;6(4):341-9. [Medline].

  41. Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood. Nov 1 2004;104(9):2623-34.

  42. Kokame K, Matsumoto M, Soejima K, et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci U S A. Sep 3 2002;99(18):11902-7. [Medline].

  43. Kovacs MJ, Roddy J, Gregoire S, et al. Thrombotic thrombocytopenic purpura following hemorrhagic colitis due to Escherichia coli 0157:H7. Am J Med. Feb 1990;88(2):177-9. [Medline].

  44. Lawlor ER, Webb DW, Hill A, Wadsworth LD. Thrombotic thrombocytopenic purpura: a treatable cause of childhood encephalopathy. J Pediatr. Feb 1997;130(2):313-6. [Medline].

  45. Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. Oct 4 2001;413(6855):488-94. [Medline].

  46. MacWhinney JB, Packer JT, Miller G, Greendyke RM. Thrombotic thrombocytopenic purpura in childhood. Blood. 1962;18:181-99.

  47. Malbrain ML, Lambrecht GL, Brans B, et al. Acute renal failure in non-fulminant hepatitis A [letter]. Clin Nephrol. Mar 1994;41(3):180-1. [Medline].

  48. Martin DL, MacDonald KL, White KE, et al. The epidemiology and clinical aspects of the hemolytic uremic syndrome in Minnesota [see comments]. N Engl J Med. Oct 25 1990;323(17):1161-7. [Medline].

  49. Meacham GC, Orbiston JL, et al. Thrombotic thrombocytopenic purpura: A disseminated disease of arterioles. Blood. 1952;6:706.

  50. Misiani R, Appiani AC, Edefonti A, et al. Haemolytic uraemic syndrome: therapeutic effect of plasma infusion. Br Med J (Clin Res Ed). Nov 6 1982;285(6351):1304-6. [Medline].

  51. Moake JL. von Willebrand factor in the pathophysiology of thrombotic thrombocytopenic purpura. Clin Lab Sci. Nov-Dec 1998;11(6):362-4. [Medline].

  52. Moake JL. TTP--desperation, empiricism, progress [editorial; comment]. N Engl J Med. Aug 8 1991;325(6):426-8. [Medline].

  53. Moake JL. Thrombotic thrombocytopenic purpura. Thromb Haemost. Jul 1995;74(1):240-5. [Medline].

  54. Moake JL. The role of von Willebrand factor (vWF) in thrombotic thrombocytopenic purpura (TTP) and the hemolytic-uremic syndrome (HUS). Prog Clin Biol Res. 1990;337:135-40. [Medline].

  55. Moake JL, McPherson PD. von Willebrand factor in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. Transfus Med Rev. Apr 1990;4(2):163-8. [Medline].

  56. Moake JL. Thrombotic microangiopathies. N Engl J Med. Aug 22 2002;347(8):589-600. [Medline].

  57. Moschowitz E. Hyaline thrombosis of the terminal arterioles and capillaries: A hitherto undescribed disease. Proc N Y Pathol Soc. 1924;24:21-4.

  58. Nair JM, Bellevue R, Bertoni M, Dosik H. Thrombotic thrombocytopenic purpura in patients with the acquired immunodeficiency syndrome (AIDS)-related complex. A report of two cases. Ann Intern Med. Aug 1 1988;109(3):209-12. [Medline].

  59. Noris M, Ruggenenti P, Perna A, et al. Hypocomplementemia discloses genetic predisposition to hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: role of factor H abnormalities. Italian Registry of Familial and Recurrent Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic P. J Am Soc Nephrol. Feb 1999;10(2):281-93. [Medline].

  60. Raife TJ. Pathogenesis of thrombotic thrombocytopenic purpura. Curr Hematol Rep. Mar 2003;2(2):133-8. [Medline].

  61. Raniele DP, Opsahl JA, Kjellstrand CM. Should intravenous immunoglobulin G be first-line treatment for acute thrombotic thrombocytopenic purpura? Case report and review of the literature. Am J Kidney Dis. Aug 1991;18(2):264-8. [Medline].

  62. Remis RS, MacDonald KL, Riley LW, et al. Sporadic cases of hemorrhagic colitis associated with Escherichia coli 0157:H7. Ann Intern Med. Nov 1984;101(5):624-6. [Medline].

  63. Remuzzi G, Ruggenenti P. The hemolytic uremic syndrome. Kidney Int. Jul 1995;48(1):2-19. [Medline].

  64. Richards A, Goodship JA, Goodship TH. The genetics and pathogenesis of haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. Curr Opin Nephrol Hypertens. Jul 2002;11(4):431-5. [Medline].

  65. Ridolfi RL, Bell WR. Thrombotic thrombocytopenic purpura. Report of 25 cases and review of the literature. Medicine (Baltimore). Nov 1981;60(6):413-28. [Medline].

  66. Rizzoni G, Claris-Appiani A, Edefonti A, et al. Plasma infusion for hemolytic-uremic syndrome in children: results of a multicenter controlled trial. J Pediatr. Feb 1988;112(2):284-90. [Medline].

  67. Robertson RJ, Gilcher R, Metz KF, et al. Hemoglobin concentration and aerobic work capacity in women following induced erythrocythemia. J Appl Physiol. Aug 1984;57(2):568-75. [Medline].

  68. Ruggenenti P, Remuzzi G. Treatment of adult hemolytic-uremic syndrome. Adv Nephrol Necker Hosp. 2000;30:83-94. [Medline].

  69. Ruggenenti P, Remuzzi G. The pathophysiology and management of thrombotic thrombocytopenic purpura. Eur J Haematol. Apr 1996;56(4):191-207. [Medline].

  70. Schwartz SG, McPherson AR, Mieler WF, et al. Bilateral combined occlusion of the central retinal artery and vein secondary to thrombotic thrombocytopenic purpura. Arch Ophthalmol. Sep 2000;118(9):1304-5. [Medline].

  71. Sheth KJ, Swick HM, Haworth N. Neurological involvement in hemolytic-uremic syndrome. Ann Neurol. Jan 1986;19(1):90-3. [Medline].

  72. Silverstein A. Thrombotic thrombocytopenic purpura. The initial neurologic manifestations. Arch Neurol. Apr 1968;18(4):358-62. [Medline].

  73. Studt JD, Hovinga JA, Antoine G, et al. Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin. Blood. Jan 15 2005;105(2):542-4. [Medline].

  74. Studt JD, Hovinga JA, Radonic R, et al. Familial acquired thrombotic thrombocytopenic purpura: ADAMTS13 inhibitory autoantibodies in identical twins. Blood. Jun 1 2004;103(11):4195-7. [Medline].

  75. Tarr PI, Neill MA, Allen J, et al. The increasing incidence of the hemolytic-uremic syndrome in King County, Washington: lack of evidence for ascertainment bias. Am J Epidemiol. Mar 1989;129(3):582-6. [Medline].

  76. Torok TJ, Holman RC, Chorba TL. Increasing mortality from thrombotic thrombocytopenic purpura in the United States--analysis of national mortality data, 1968-1991. Am J Hematol. Oct 1995;50(2):84-90. [Medline].

  77. Torok TJ, Holman RC, Chorba TL. Increasing mortality from thrombotic thrombocytopenic purpura in the United States--analysis of national mortality data, 1968-1991. Am J Hematol. Oct 1995;50(2):84-90. [Medline].

  78. Tsai HM. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. J Mol Med. Oct 2002;80(10):639-47. [Medline].

  79. Tsai HM. Shear stress and von Willebrand factor in health and disease. Semin Thromb Hemost. Oct 2003;29(5):479-88. [Medline].

  80. Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. Nov 26 1998;339(22):1585-94. [Medline].

  81. Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol. Apr 2003;14(4):1072-81. [Medline].

  82. Tsai HM, Shulman K. Rituximab induces remission of cerebral ischemia caused by thrombotic thrombocytopenic purpura. Eur J Haematol. Mar 2003;70(3):183-5. [Medline].

  83. Tsai HM, Sussman II, Ginsburg D, et al. Proteolytic cleavage of recombinant type 2A von Willebrand factor mutants R834W and R834Q: inhibition by doxycycline and by monoclonal antibody VP-1. Blood. Mar 15 1997;89(6):1954-62. [Medline].

  84. Vesely SK, Perdue JJ, Rizvi MA, et al. Management of adult patients with persistent idiopathic thrombocytopenic purpura following splenectomy: a systematic review. Ann Intern Med. Jan 20 2004;140(2):112-20. [Medline].

  85. Vesely SK, George JN, Lammle B, et al. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood. Jul 1 2003;102(1):60-8. [Medline].

  86. Zheng X, Chung D, Takayama TK, et al. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem. Nov 2 2001;276(44):41059-63. [Medline].

  87. Zhou W, Inada M, Lee TP, et al. ADAMTS13 is expressed in hepatic stellate cells. Lab Invest. Jun 2005;85(6):780-8. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

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

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Robert Rust Jr, MD, Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, University of Virginia School; Clinical and Residency Training, Child Neurology, University of Virginia Hospital and Clinics
Robert Rust Jr, MD 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 Neurology and Pediatrics, Medical University of South Carolina
David A Griesemer, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, and Child Neurology Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

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

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.