Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP or Moschcowitz disease) is a rare disorder of the blood-coagulation system, causing multiple blood clots to form in blood vessels around the body.^[1] Most cases of TTP arise from deficiency or inhibition of the enzyme ADAMTS13, which is responsible for cleaving large multimers of von Willebrand factor.^[2] This leads to hemolysis and end-organ damage, and may require plasmapheresis therapy.

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Signs and symptoms

Classically, the following five symptoms are indicative of this elusive disease:^{[citation needed]}

• Fluctuating neurological symptoms, such as bizarre behavior, altered mental status, stroke or headaches (65%);
• Kidney failure (46%);
• Fever (33%);
• Thrombocytopenia (low platelet count), leading to bruising or frank purpura;
• Microangiopathic hemolytic anemia (anemia, jaundice and a characteristic blood film).

A patient may notice dark urine from the hemolytic anemia. Because of the many small areas of ischemia produced by clots in the microvasculature, symptoms may be diffuse and fluctuating, including the classical bruising, confusion, or headache, but also nausea and vomiting (from ischemia in the GI tract or from central nervous system involvement), chest pain from cardiac ischemia, seizures, muscle and joint pain, etc.^{[citation needed]}

Causes

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 coagulation process, and bind fibrin, the end product of the coagulation pathway. These platelet-fibrin complexes form microthrombi which circulate in the vasculature and cause shearing of red blood cells, resulting in hemolysis.

Roughly, there are two forms of TTP: idiopathic and secondary TTP. A special case is the inherited deficiency of ADAMTS13, known as the Upshaw-Schulman syndrome.

Idiopathic TTP

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 the so-called 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 molecules are more prone to lead to coagulation. Hence, without proper cleavage of vWF by ADAMTS13, coagulation occurs at a higher rate, especially in the part of the blood vessel system where vWF is most active due to high shear stress: in the microvasculature.

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 researchers who published their research in the same issue of the New England Journal of Medicine in 1998.^[3][4][5] This theory is seen as insufficient to explain the etiology of TTP, since many patients with hereditary lack of ADAMTS13 activity do not manifest clinical symptoms of TTP.

Secondary TTP

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:

• Cancer
• Bone marrow transplantation
• Pregnancy
• Medication use:
  • Platelet aggregation inhibitors (ticlopidine and clopidogrel)
  • Immunosuppressants (cyclosporine, mitomycin, tacrolimus/FK506, interferon-α)
• HIV-1 infection

The mechanism of secondary TTP is poorly understood, as ADAMTS13 activity is generally not as depressed as in idiopathic TTP, and inihibitors cannot be detected. Probable etiology may involve, at least in some cases, endothelial damage.

Upshaw-Schulman syndrome

A hereditary form of TTP is called the Upshaw-Schulman 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, 5-10% of all TTP cases are due to Upshaw-Schulman syndrome.

Treatment

Since the early 1990s, plasmapheresis has become the treatment of choice for TTP.^[6] 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 has to be repeated daily to eliminate the inhibitor and ablate the symptoms. Lactate dehydrogenase levels are generally used to monitor disease activity. Plasmapheresis may need to be continued for 1-8 weeks before patients with idiopathic TTP cease to consume platelets and begin to normalize their hemoglobin. No single laboratory test (platelet count, LDH, ADAMTS13 level, or inhibitory factor) is indicative of recovery; research protocols have used improvement or normalization of LDH as a measure for ending plasmapheresis. Although patients may be critically ill with failure of multiple organ systems during the acute illness, including renal failure, myocardial ischemia, and neurologic symptoms, recovery over several months may be complete in the absence of a frank myocardial infarct, stroke, or CNS hemorrhage.^{[citation needed]}

Many TTP patients need additional immunosuppressive therapy, with glucocorticoid steroids (e.g. prednisolone or prednisone), vincristine, cyclophosphamide, splenectomy or a combination of the above. Rituximab, a monoclonal antibody targeting B cells, has been successfully used to treat patients with refractory disease.

Children with Upshaw-Schulman syndrome receive plasma every three weeks prophylactically; this maintains adequate levels of functioning ADAMTS13.

Epidemiology

The incidence of TTP is about 4-6 per million people per year. As with most other autoimmune disorders, idiopathic TTP occurs more often in women and blacks, while the secondary forms do not show this distribution.

Prognosis

The mortality rate is approximately 95% for untreated cases, but the prognosis is reasonably favorable (80-90%) for patients with idiopathic TTP diagnosed and treated early with plasmapheresis.

Approximately one-third of patients experiencing a TTP episode have a relapse within 10 years following their first attack.

Secondary TTP still has a dismal prognosis, with mortality rates despite treatment being reported as 59% to 100%.

History

TTP was initially described in a 16-year old girl by Dr Eli Moschcowitz of New York City in 1924.^[7] Moschcowitz ascribed the disease (incorrectly) to a toxic cause. Moschcowitz noted that his 16 year-old patient had anemia; petechiae; microscopic hematuria; and at autopsy, disseminated microvascular thrombi. Since that time, the pathophysiology, etiology, and medical management of TTP has expanded.

See also

• Plasmapheresis
• Exchange transfusion
• ADAMTS13

Notes

1. ^ "MedlinePlus: Thrombotic thrombocytopenic purpura", MedlinePlus Medical Encyclopedia, 2007, webpage: NLM-552.
2. ^ Moake JL (2004). "von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura". Semin. Hematol. 41 (1): 4–14. PMID 14727254.
3. ^ Moake JL (1998). "Moschcowitz, multimers, and metalloprotease". N. Engl. J. Med. 339 (22): 1629–31. PMID 9828253.
4. ^ 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. PMID 9828245.
5. ^ 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. PMID 9828246.
6. ^ 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.
7. ^ 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.

References

• Moake JL (2002). "Thrombotic microangiopathies". N. Engl. J. Med. 347 (8): 589–600. doi:10.1056/NEJMra020528. PMID 12192020.