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Home , Bleeding, Purpura, Thrombocytopenic purpura

48 Monte Carlo Crescent Kyalami Business Park Kyalami, Johannesburg, 1684, RSA Tel: +27 (0)11 463 3260 Fax: + 27 (0)86 557 2232 Email: [email protected] www.thistle.co.za

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The Thistle QA CEU No is: MT- MTS 18/059

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DIFFERENTIAL SLIDES LEGEND CYCLE 52 SLIDE 6

THROMBOTIC THROMBOCYTOPENIC (TTP)

Thrombotic (TTP or Moschcowitz syndrome) is a rare disorder of the - 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. Immunosuppressant’s, 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 autoantibody-mediated 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 adhesion to areas of endothelial injury, particularly at arteriole- capillary junctions. A rarer form of TTP, called Upshaw–Schulman syndrome, is genetically inherited as a dysfunction of ADAMTS13, resulting in persisting large vWF multimers.

Red blood cells passing the microscopic clots are subjected to shear stress which damages their membranes, leading to rupture of red blood cells within blood vessels, which in turn leads to anaemia and schistocyte formation. Reduced blood flow due to 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 Classically, the following five features ("pentad") are indicative of TTP, in most cases, some of these are absent.  (low platelet count), leading to bruising or purpura  Microangiopathic hemolytic (anemia, jaundice and a blood film featuring evidence of mechanical fragmentation of red blood cells)  Neurologic symptoms (fluctuating), such as hallucinations, bizarre behavior, delirium, , or  Kidney failure  Fever

The symptoms of TTP may at first be subtle, starting with malaise, fever, , and sometimes diarrhea. As the condition progresses, clots form within blood vessels, and are consumed. Bruising, and rarely , 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 (ecchymosis) may also develop.

Neurological symptoms are present in up to 65% of patients, and may include headache, difficulty speaking, transient paralysis, numbness, fits, or , the last of which is a poor prognostic indicator. This is a result of

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48 Monte Carlo Crescent Kyalami Business Park Kyalami, Johannesburg, 1684, RSA Tel: +27 (0)11 463 3260 Fax: + 27 (0)86 557 2232 Email: [email protected] www.thistle.co.za clots temporarily interrupting local blood supply. High () may be found on examination.

Blood smear of a patient with TTP showing schistocytes, Purpura and Petechiae spherocytes and polychromasia

Causes TTP, as with other microangiopathic hemolytic (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 small blood clots which circulate in the blood vessels and cause shearing of red blood cells, resulting in their rupture. 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.

Unknown cause The form of TTP of unknown cause 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 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 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  marrow transplantation   Medication use:  Antiviral drugs (acyclovir)  Quinine  Oxymorphone  Platelet aggregation inhibitors (ticlopidine, , and prasugrel)  Immunosuppressants (cyclosporine, mitomycin, tacrolimus/FK506, interferon-α)  Hormone altering drugs (estrogens, contraceptives, hormone replacement therapy)  HIV-1

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48 Monte Carlo Crescent Kyalami Business Park Kyalami, Johannesburg, 1684, RSA Tel: +27 (0)11 463 3260 Fax: + 27 (0)86 557 2232 Email: [email protected] www.thistle.co.za

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 atypical hemolytic- uremic syndrome (aHUS); patients presenting with these features are, therefore, potential candidates for anticomplement therapy.

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, 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.

Differential diagnosis 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,); kidney impairment (e.g. elevated creatinine, decreased estimated glomerular filtration rate [eGFR], abnormal urinalysis); and gastrointestinal (GI) symptoms (e.g. diarrhea /vomiting, , 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.

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

Epidemiology 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 erythematosus occurs more frequently in people of African descent, although other secondary forms do not show this distribution. Pregnant women and women in the accounted for a notable portion (12–31%) of the cases in some studies; TTP affects about one in 25,000 .

References 1. https://en.wikipedia.org/wiki/ Thrombotic_thrombocytopenic_purpura 2. https://www.google.co.za/?gws_rd=ssl#q=ttp+blood+smear+images

Questions 1. What five clinical features are associated with TTP? 2. Discuss the differential diagnosis of TTP. 3. Discuss the lab findings in TTP.

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