Category: Review

Suspect Moschcowitz syndrome: how, when, why

Rosario Bottone1, Stefania Milione1, Barbara Guerrera2, Mauro Giordano1
 
1. Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
2. Internal Medicine, Clinical Hospital of Marcianise, ASL Caserta, Caserta, Italy

Abstract

Background
Thrombotic Thrombocytopenic Purpura is a rare and acute syndrome characterized by microangiopathic hemolytic anaemia and thrombocytopenia. Both congenital and acquired forms are characterized by the ADAMTS13 deficiency.
 
Methods
As in our case report, symptomatology is varied, including both hemorrhagic and thrombotic events, and nonspecific gastroenterological manifestations. The disease can be associated with new acute pancreatitis. Diagnosis is supported by laboratory tests.
 
Results
Rapid plasmapheresis or plasma infusion reduce mortality from 80-90% to 10%. Platelet transfusions precipitate thrombotic events. They are contra-indicated, unless there is life-threatening hemorrhage.
 
Conclusion
We demonstrate the importance of a rapid diagnosis and a correct treatment of these patients.
 
Keywords: Thrombotic Thrombocytopenic Purpura, microangiopathic haemolytic anaemia, thrombotic events, multiorgan damage, plasmapheresis.

Introduction

Thrombotic Thrombocytopenic Purpura (TTP) is an acute syndrome characterized by the presence of microangiopathic haemolytic anaemia and thrombocytopenia.
The first case of TTP was described by Moschowitz in 1924 [1]. Recently, between 1982 and 2001, several authors [2-5] identified in the deficiency of the metalloproteinase ADAMTS13 the primary pathogenic cause. TTP is a rare disease [6-8]. it occurs between 30 and 50 years of age, more frequently in the female sex. In the absence of treatment, mortality exceeds 90%, while it is reduced to 10-20% after adequate plasma plasmapheresis or infusion therapy. However, half the deaths are attributable to complications associated with plasmapheresis and hospitalization (sepsis, haemorrhages, thrombosis, etc.) [9]

Case report

A 36-year-old italian woman came to our observation in the emergency department for abdominal pain, menometrorrhagia and vomiting. The patient had no significant past medical history. She had no significant clinical changes. She was hemodynamically stable.
A first blood workup showed anaemia with haemoglobin (Hb) 7.7 g/dl, with a low-threshold mean corpuscular volume (MCV). A severe new-onset thrombocytopenia was found (laboratory tests of about 3 months ago were normal) with platelet count of 7000 per cubic millimeter. A laboratory framework of haemolysis was also associated, with indirect hyperbilirubinemia of 3.17 mg/dl and lactate dehydrogenase (LDH) of 1649 IU/L. Creatinine was 1.23 mg/dl with azotemia of 67 mg/dl and a mild hyperamylasemia 117 mg/dl. Coagulation tests were normal.The patient did not show any clinical signs and laboratory tests suggestive of infections, presenting normal number of white blood cells (WBC/mmc) and WBC differential. C-reactive Protein was 4.7 mg/dl with a negative procalcitonin (<0.50 ng/ml). The human chorionic gonadotropin (hCG) blood test was negative. Considering the clinical examinations, a therapy based on methylprednisolone (60 mg with 250 ml physiological saline solution iv), tranexamic acid (500 mg in 500 ml 0,9 % saline iv) was performed. Moreover, a transfusion of blood and platelets was carried out. 
The patient underwent to abdominal and transvaginal ultrasound, which exclude active bleeding and/or pelvic onset diseases, showing a small amount of fluid in the pouch of Douglas. A computed tomography scan (CT) of the abdomen and pelvis was performed with contrast agent and showed “no active bleeding. An increase in pancreatic volume is present with adjacent adenopathies and pervisceral fluid. CT images are suggestive of mild acute pancreatitis and duodenitis.” (Fig. 1, Fig. 2)
 
 
 MILIONE_fig1A.jpg
 
 Figure 1
 
 
MILIONE_fig2A.jpg
 
 Figure 2
 
Moreover, considering the onset of neurological symptoms, such as blurred vision and bilateral intermittent transient hypoacusia, the patient was transferred to a second-level structure and admitted to the complex operative unit of haematology, in the suspect of a microangiopathic disorder.

Discussion

Two different forms of TTP have been classified: Congenital and Acquired forms. Both cases, genetic mutations and immune-mediated mechanisms, are responsable of the ADAMTS13 protein deficiency. The ultralarge multimeter of the von-Willebrand factor (ULvWF) is not appropriately cleaved, causing spontaneous and massive platelet aggregation for intense endothelial stress, especially in the cerebral, cardiac and renal microcirculation. Some predisposing factors are: occult neoplasia or metastatic condition, the intake of drugs, among which the quinidine and ticlopidine [10], and HIV infection [11]. Acquired TTP usually occurs in a previously healthy individual, more commonly in young females as evident in our case report.
The presence of microangiopathic haemolytic anaemia and thrombocytopenia is ample for the diagnosis in the absence of other evident causes [12]. Our patient also presented two of the other three elements of the classical pentade (acute renal failure, neurological changes and fever). These signs are no longer necessary and are associated to advanced organ damage [13]. As in our case, symptomatology can be quite varied, including hemorrhagic events and the most fearful thrombotic manifestations (cardiovascular, renal and neurological). Non specific gastroenterological manifestations, such as fever, abdominal pain, diarrhoea and vomiting are very frequent. Recently McDonald et. [14] described the association with new acute pancreatitis.
Sometimes, the identification of the syndrome can be difficult, being often in overlap conditions with hemolytic-uraemic syndrome (HUS) and autoimmune disorders (antiphospholipid antibody syndrome, Evans syndrome).
Rapid diagnosis must be supported by laboratory tests; the presence of≥1schistocytes on a peripheral blood smearschistocytes is considered suggestive for diagnostic purposes [15, 16]. 
TTP treatment involves the use of plasmapheresis [17] or, in alternative, plasma infusion by evaluating the individual fluid load tolerance [18]. These therapeutic approaches reduce mortality from 80-90% to 10% [9]. The effectiveness of plasma exchange therapy is due to the removal from the circulation of anti-ADAMTS13 antibodies in the immune-mediated forms and the correction of protease deficiency in congenital forms. A delay (over 24 hours) of treatment can compromise its effectiveness. 
The use of glucocorticoids for autoimmune etiology seems to be rational in the event of poor response to initial treatment with plasmapheresis [16, 19]. It is also useful when the platelet count does not rise after several days of plasmapheresis or if it returns to fall when treatment sessions are reduced or suspended [12]. In recent years there has been an increase in the use of anti-CD20 monoclonal antibodies (Rituximab) to suppress the production of anti-ADAMTS13 antibodies by depletion of B lymphocytes [20, 21].
Several studies suggest a complete clinical and laboratory response within 1-3 weeks of starting Rituximab treatment, in about 95% of patients with idiopathic PTT, refractory to plasma exchange and corticosteroid treatments, or relapsing [22]. Intravenous immunoglobulin administration may be effective. Splenectomy may actually be considered in chronic recurrent PTT forms that are refractory to other therapeutic approaches. Its effectiveness is based on the removal of an important production site of anti-ADAMTS13 autoantibodies. Platelet aggregation inhibitors such as ticlopidine, clopidogrel, acetylsalicylic acid, and dipyridamole have no indication [9]; they are unable to inhibit platelets aggregation induced by ULvWF multimers [23]. Blood transfusions, folic acid supplements, and possible antithrombotic prophylaxis with low molecular weight heparin may be useful support therapy. For such a fearful pathology, it is right to perform a follow-up with blood count and LDH dose. In fact, several cases of recurrence are described within 30 days of the disease remission. At the moment, validated maintenance therapies are not described.

Conclusion

Our case report demonstrates the importance of the rapidity in setting the diagnosis and the treatment of PTT.
Therapy greatly reduces patient mortality. So far, the treatment performed by more physicians is not valid and nonconforming to the guidelines. Platelet transfusions are still administered by many increasing the risk of precipitating further thrombotic events. Their use is contra-indicated in TTP, unless there is life-threatening haemorrhage. 
The symptomatology is often nonspecific and the diagnosis is posed with the presence of both microangiopathic hemolytic anaemia and thrombocytopenia. Multi-organ involvement, with the onset of acute pancreatitis, may be present.
However, symptoms demonstrating a multi-organ pathological involvement may be an expression of iatrogenic damage.
References 
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