Thrombotic thrombocytopenic purpura
|Thrombotic thrombocytopenic purpura|
|Classification and external resources|
|ICD-10||M31.1 (ILDS M31.110)|
|eMedicine||emerg/579 neuro/499 med/2265|
Thrombotic thrombocytopenic purpura (TTP or Moschcowitz syndrome:822) is a rare disorder of the blood-coagulation system, causing extensive microscopic clots to form in the small blood vessels throughout the body. These small blood clots, called thrombi, can damage many organs including the kidneys, heart and brain. In the era before effective treatment with plasma exchange, the fatality rate was about 90%. With plasma exchange, this has dropped to 10% at six months. Immunosuppressants, such as glucocorticoids, rituximab, cyclophosphamide, vincristine, or cyclosporine, may also be used if a relapse or recurrence follows plasma exchange.
Most cases of TTP arise from inhibition of the enzyme ADAMTS13, a metalloprotease responsible for cleaving large multimers of von Willebrand factor (vWF) into smaller units. The increase in circulating multimers of vWF increase platelet adhesion to areas of endothelial injury, particularly at arteriole-capillary junctions.
A rarer form of TTP, called Upshaw-Schülman syndrome, is genetically inherited as a dysfunction of ADAMTS13. If large vWF multimers persist, a tendency for increased coagulation exists.
Red blood cells passing the microscopic clots are subjected to shear stress which damages their membranes, leading to intravascular hemolysis and schistocyte formation. Reduced blood flow due to thrombosis and cellular injury results in end organ damage. Current therapy is based on support and plasmapheresis to reduce circulating antibodies against ADAMTS13 and replenish blood levels of the enzyme.
Signs and symptoms
- Thrombocytopenia (low platelet count), leading to bruising or purpura
- Microangiopathic hemolytic anemia (anemia, jaundice and a blood film featuring evidence of mechanical fragmentation of red blood cells)
- Neurologic symptoms (fluctuating), such as hallucinations, bizarre behavior, altered mental status, stroke, or headaches
- Kidney failure
The symptoms of TTP may at first be subtle, starting with malaise, fever, headache, and sometimes diarrhea. As the condition progresses, clots (thrombi) form within blood vessels, and platelets (clotting cells) are consumed. Bruising, and rarely bleeding, results and may be spontaneous. The bruising often takes the form of purpura, while the most common site of bleeding, if it occurs, is from the nose or gums. Larger bruises (ecchymoses) may also develop.
Neurological symptoms are present in up to 65% of patients, and may include headache, difficulty speaking, transient paralysis, numbness, fits, or coma, the last of which is a poor prognostic indicator. This is a result of clots temporarily interrupting local blood supply. 
High blood pressure (hypertension) may be found on examination.
Causes and pathogenesis
TTP, as with other microangiopathic hemolytic anemias (MAHAs), is caused by spontaneous aggregation of platelets and activation of coagulation in the small blood vessels. Platelets are consumed in the aggregation process, and bind vWF. These platelet-vWF complexes form microthrombi which circulate in the vasculature and cause shearing of red blood cells, resulting in hemolysis.
Roughly, the two forms of TTP are idiopathic and secondary TTP. A special case is the inherited deficiency of ADAMTS13, known as the Upshaw-Schülman syndrome.
The idiopathic form of TTP was recently linked to the inhibition of the enzyme ADAMTS13 by antibodies, rendering TTP an autoimmune disease. ADAMTS13 is a metalloproteinase responsible for the breakdown of von Willebrand factor (vWF), a protein that links platelets, blood clots, and the blood vessel wall in the process of blood coagulation. Very large vWF multimers are more prone to lead to coagulation. Hence, without proper cleavage of vWF by ADAMTS13, coagulation occurs at a higher rate, especially in the microvasculature, part of the blood vessel system where vWF is most active due to high shear stress.
In idiopathic TTP, severely decreased (<5% of normal) ADAMTS13 activity can be detected in most (80%) patients, and inhibitors are often found in this subgroup (44–56%). The relationship of reduced ADAMTS13 to the pathogenesis of TTP is known as the Furlan-Tsai hypothesis, after the two independent groups of researchers who published their research in the same issue of the New England Journal of Medicine in 1998.
Secondary TTP is diagnosed when the patient's history mentions one of the known features associated with TTP. It comprises about 40% of all cases of TTP. Predisposing factors are:
- Bone marrow transplantation
- Medication use:
- HIV-1 infection
The mechanism of secondary TTP is poorly understood, as ADAMTS13 activity is generally not as depressed as in idiopathic TTP, and inhibitors cannot be detected. Probable etiology may involve, at least in some cases, endothelial damage, although the formation of thrombi resulting in vessel occlusion may not be essential in the pathogenesis of secondary TTP. These factors may also be considered a form of secondary aHUS; patients presenting with these features are, therefore, potential candidates for anticomplement therapy.
A hereditary form of TTP is called the Upshaw-Schülman syndrome; this is generally due to inherited deficiency of ADAMTS13 (frameshift and point mutations). Patients with this inherited ADAMTS13 deficiency have a surprisingly mild phenotype, but develop TTP in clinical situations with increased von Willebrand factor levels, e.g. infection. Reportedly, less than 1% of all TTP cases are due to Upshaw-Schülman syndrome. Patients with Upshaw-Schülman syndrome have 5–10% of normal ADAMTS-13 activity 
TTP is characterized by thrombotic microangiopathy (TMA), the formation of blood clots in small blood vessels throughout the body, which can lead to microangiopathic hemolytic anemia and thrombocytopenia. This characteristic is shared by two related syndromes, hemolytic-uremic syndrome (HUS) and atypical hemolytic-uremic syndrome (aHUS). Consequently, differential diagnosis of these TMA-causing diseases is essential. In addition to TMA, one or more of the following symptoms may be present in each of these diseases: neurological symptoms (e.g. confusion, cerebral convulsions seizures,); renal impairment (e.g. elevated creatinine, decreased estimated glomerular filtration rate [eGFR], abnormal urinalysis); and gastrointestinal (GI) symptoms (e.g. diarrhea nausea/vomiting, abdominal pain, gastroenteritis. Unlike HUS and aHUS, TTP is known to be caused by an acquired defect in the ADAMTS13 protein, so a lab test showing ≤5% of normal ADAMTS13 levels is indicative of TTP. ADAMTS13 levels above 5%, coupled with a positive test for shiga-toxin/enterohemorrhagic E. coli (EHEC), are more likely indicative of HUS, whereas absence of shiga-toxin/EHEC can confirm a diagnosis of aHUS.
Due to the high mortality of untreated TTP, a presumptive diagnosis of TTP is made even when only microangiopathic hemolytic anemia and thrombocytopenia are seen, and therapy is started. Transfusion is contraindicated in thrombotic TTP, as it fuels the coagulopathy. Since the early 1990s, plasmapheresis has become the treatment of choice for TTP. This is an exchange transfusion involving removal of the patient's blood plasma through apheresis and replacement with donor plasma (fresh frozen plasma or cryosupernatant); the procedure must be repeated daily to eliminate the inhibitor and abate the symptoms. If apheresis is not available, fresh frozen plasma can be infused, but the volume that can be given safely is limited due to the danger of fluid overload. 
Most patients with refractory or relapsing TTP receive additional immunosuppressive therapy, with glucocorticoid steroids (e.g. prednisolone or prednisone), vincristine, cyclophosphamide, splenectomy, rituximab or a combination of the above. 
Children with Upshaw-Schülman syndrome receive prophylactic plasma every two to three weeks; this maintains adequate levels of functioning ADAMTS13.
Measurements of LDH, platelets, and schistocytes are used to monitor disease progression or remission.
The incidence of TTP is about 4-5 cases per million people per year. Idiopathic TTP occurs more often in women and people of African descent, and TTP secondary to autoimmune disorders such as systemic lupus erythematosus occurs more frequently in people of African descent, although other secondary forms do not show this distribution. Pregnant women and women in the post partum period accounted for a notable portion (12–31%) of the cases in some studies; TTP affects about one in 25,000 pregnancies.
TTP was initially described by Dr Eli Moschcowitz at the Beth Israel Hospital in New York City in 1925. Moschcowitz ascribed the disease (incorrectly, as now known) to a toxic cause. Moschcowitz noted his patient, a 16-year-old girl, had anemia, petechiae (purpura), microscopic hematuria, and, at autopsy, disseminated microvascular thrombi. In 1966, a review of 16 new cases and 255 previously reported cases led to the formulation of the classical pentad of symptoms and findings (i.e., thrombocytopenia, microangiopathic hemolytic anemia, neurological symptoms, kidney failure, fever); in this series, mortality rates were found to be very high (90%). While response to blood transfusion had been noted before, a 1978 report and subsequent studies showed blood plasma was highly effective in improving the disease process. In 1991, plasma exchange was reported to provide better response rates compared to plasma infusion. In 1982, the disease had been linked with abnormally large von Willebrand factor multimers, and the identification of a deficient protease in people with TTP was made in the late 1990s. ADAMTS13 was identified on a molecular level in 2001.
- James, William D.; Berger, Timothy G. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.
- "Thrombotic thrombocytopenic purpura". Dorland's Medical Dictionary for Health Consumers. Philadelphia, PA: Saunders. 2007.
- Moake JL (2002). "Thrombotic microangiopathies". N. Engl. J. Med. 347 (8): 589–600. doi:10.1056/NEJMra020528. PMID 12192020.
- George JN (May 2006). "Clinical practice. Thrombotic thrombocytopenic purpura". N. Engl. J. Med. 354 (18): 1927–35. doi:10.1056/NEJMcp053024. PMID 16672704.
- Moake JL (2004). "von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura". Semin. Hematol. 41 (1): 4–14. doi:10.1053/j.seminhematol.2003.10.003. PMID 14727254.
- Amorosi EL, Ultmann JE (1966). "Thrombocytopic purpura: report of 16 cases and review of the literature". Medicine (Baltimore) 45: 139–159.
- Allford SL, Hunt BJ, Rose P, Machin SJ (February 2003). "Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias". Br. J. Haematol. 120 (4): 556–73. doi:10.1046/j.1365-2141.2003.04049.x. PMID 12588343.
- Allford S, Machin S (2005). "Thrombotic thrombocytopenic purpura". NetDoctor.co.uk.
- Moake JL (1998). "Moschcowitz, multimers, and metalloprotease". N. Engl. J. Med. 339 (22): 1629–31. doi:10.1056/NEJM199811263392210. PMID 9828253.
- Furlan M, Robles R, Galbusera M et al. (1998). "von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome". N. Engl. J. Med. 339 (22): 1578–84. doi:10.1056/NEJM199811263392202. PMID 9828245.
- Tsai HM, Lian EC (1998). "Antibodies to von Willebrand factor–cleaving protease in acute thrombotic thrombocytopenic purpura". N. Engl. J. Med. 339 (22): 1585–94. doi:10.1056/NEJM199811263392203. PMC 3159001. PMID 9828246.
- van Mourik JA, Boertjes R, Huisveld IA, et al. (July 1999). "von Willebrand factor propeptide in vascular disorders: A tool to distinguish between acute and chronic endothelial cell perturbation". Blood 94 (1): 179–85. PMID 10381511.
- Iwata H, Kami M, Hori A, Hamaki T, Takeuchi K, Mutou Y (June 2001). "An autopsy-based retrospective study of secondary thrombotic thrombocytopenic purpura". Haematologica 86 (6): 669–70. PMID 11418383.
- Schulman I, Pierce M, Lukens A, Currimbhoy Z (July 1960). "Studies on thrombopoiesis. I. A factor in normal human plasma required for platelet production; chronic thrombocytopenia due to its deficiency" (PDF). Blood 16 (1): 943–57. PMID 14443744.
- Upshaw JD (June 1978). "Congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia". N. Engl. J. Med. 298 (24): 1350–2. doi:10.1056/NEJM197806152982407. PMID 651994.
- Levy, Nichols, Lian, GG, WC, EC et al. (October 2001). "Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura". Nature 413 (6855): 488–494. doi:10.1038/35097008. PMID 11586351.
- Tsai HM (2009). "Thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, and related disorders". In Greer JP, Foerster J, Rodgers GM, et al. Wintrobe’s Clinical Hematology (12th ed.). Philadelphia PA: Lippincott, Williams, and Wilkins. pp. 1314–25.
- Kokame, K.; Matsumoto, M; Soejima, K; Yagi, H; Ishizashi, H; Funato, M; Tamai, H; Konno, M; Kamide, K; Kawano, Y; Miyata, T; Fujimura, Y (14 August 2002). "Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity". Proc. Natl. Acad. Sci. U.S.A. 99 (18): 11902–7. doi:10.1073/pnas.172277399. PMID 12181489.
- George JN (November 2010). "How I treat patients with thrombotic thrombocytopenic purpura: 2010". Blood 116 (20): 4060–9. doi:10.1182/blood-2010-07-271445. PMID 20686117.
- Noris M, Caprioli J, Bresin E, et al. (October 2010). "Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype". Clin J Am Soc Nephrol 5 (10): 1844–59. doi:10.2215/CJN.02210310. PMC 2974386. PMID 20595690.
- Neuhaus TJ, Calonder S, Leumann EP (June 1997). "Heterogeneity of atypical haemolytic uraemic syndromes". Arch. Dis. Child. 76 (6): 518–21. PMC 1717216. PMID 9245850.
- Dragon-Durey MA, Sethi SK, Bagga A, et al. (December 2010). "Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome". J. Am. Soc. Nephrol. 21 (12): 2180–7. doi:10.1681/ASN.2010030315. PMC 3014031. PMID 21051740.
- Caprioli J, Noris M, Brioschi S, et al. (August 2006). "Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome". Blood 108 (4): 1267–79. doi:10.1182/blood-2005-10-007252. PMC 1895874. PMID 16621965.
- Ariceta G, Besbas N, Johnson S, et al. (April 2009). "Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome". Pediatr. Nephrol. 24 (4): 687–96. doi:10.1007/s00467-008-0964-1. PMID 18800230.
- Al-Akash SI, Almond PS, Savell VH, Gharaybeh SI, Hogue C (April 2011). "Eculizumab induces long-term remission in recurrent post-transplant HUS associated with C3 gene mutation". Pediatr. Nephrol. 26 (4): 613–9. doi:10.1007/s00467-010-1708-6. PMID 21125405.
- Zuber J, Le Quintrec M, Sberro-Soussan R, Loirat C, Frémeaux-Bacchi V, Legendre C (January 2011). "New insights into postrenal transplant hemolytic uremic syndrome". Nat Rev Nephrol 7 (1): 23–35. doi:10.1038/nrneph.2010.155. PMID 21102542.
- Tsai HM (January 2010). "Pathophysiology of thrombotic thrombocytopenic purpura". Int. J. Hematol. 91 (1): 1–19. doi:10.1007/s12185-009-0476-1. PMC 3159000. PMID 20058209.
- Bitzan M, Schaefer F, Reymond D (September 2010). "Treatment of typical (enteropathic) hemolytic uremic syndrome". Semin. Thromb. Hemost. 36 (6): 594–610. doi:10.1055/s-0030-1262881. PMID 20865636.
- Tsai, Han-Mou (February 2006). "Current Concepts in Thrombotic Thrombocytopenic Purpura". Annual Review of Medicine (Annual Reviews) 57: 419–436. doi:10.1146/annurev.med.57.061804.084505. PMC 2426955. PMID 16409158.
- Zheng XL, Kaufman RM, Goodnough LT, Sadler JE (2004). "Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura". Blood 103 (11): 4043–9. doi:10.1182/blood-2003-11-4035. PMID 14982878.
- Terrell DR, Williams LA, Vesely SK, Lämmle B, Hovinga JA, George JN (July 2005). "The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency". J. Thromb. Haemost. 3 (7): 1432–6. doi:10.1111/j.1538-7836.2005.01436.x. PMID 15978100.
- Terrell DR, Vesely SK, Kremer Hovinga JA, Lämmle B, George JN (November 2010). "Different disparities of gender and race among the thrombotic thrombocytopenic purpura and hemolytic-uremic syndromes". Am. J. Hematol. 85 (11): 844–7. doi:10.1002/ajh.21833. PMC 3420337. PMID 20799358.
- X. Long Zheng; J. Evan Sadler (2008). "Pathogenesis of Thrombotic Microangiopathies". Annual Review of Pathology (Annual Reviews) 3: 249–277. doi:10.1146/annurev.pathmechdis.3.121806.154311. PMC 2582586. PMID 18215115.
- Moschcowitz E (1924). "An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries: an undescribed disease". Proc NY Pathol Soc 24: 21–4. Reprinted in Mt Sinai J Med 2003;70(5):322-5, PMID 14631522.
- Sadler, JE (2008). "Von Willerbrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura". Blood 112 (1): 11–18. doi:10.1182/blood-2008-02-078170. PMC 2435681. PMID 18574040.
- Rock GA, Shumak KH, Buskard NA et al. (August 1991). "Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group". N. Engl. J. Med. 325 (6): 393–7. doi:10.1056/NEJM199108083250604. PMID 2062330.