INTRODUCTION

A group of serious diseases known as microangiopathic hemolytic anemia, represented by hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), is characterized by the triad: microangiopathic hemolytic anemia, microvascular occlusion and thrombocytopenia⁽¹⁾; and due to the similarity of the clinical manifestations, in the past, they were considered one single disease⁽²⁾. TTP is associated with fever and neurological signs, although both are clinically indistinguishable. The clinical suspicion in favor of TTP or HUS is due to the presence of neurological changes or acute kidney injury, respectively. Differential diagnosis should be performed with disseminated intravascular coagulation (DIC) and consumptive thrombohemorrhagic diseases⁽³⁾. Despite the great clinical and histological similarity between TTP and HUS, the diagnosis must be performed, since both present independent and differentiated treatment and evolution⁽⁴⁾.

The diagnostic criteria for previously defined microangiopathic hemolytic anemia were based on the presence of: 1) microangiopathic hemolytic anemia; 2) thrombocytopenia; and 3) organic disorders without signs of DIC⁽⁵⁾; these are detailed in the Table. In TTP, the intermittent formation of microthrombi and its deposition in the SNC are characterized by fluctuating neurological conditions, predominantly in adulthood⁽²⁾, incidence of 3.7 cases per 1,000,000 inhabitants⁽⁶⁾ and peak in the third decade of life with the female/male ratio of 3:2⁽²⁾.

The etiopathogenesis of TTP is mainly based on the deficiency or inhibition, congenital or acquired, of a metalloproteinase responsible for the degradation of the von Willebrand factor (vWF) polymers, called multimers. The acquired form can be explained by the presence of immunoglobulin class G (IgG) anti-metalloproteinase antibodies; the congenital form is a consequence of the mutation in the ADAMTS-13 gene (a disintegrin and metalloproteinase with eight thrombospondin-1-like), leading to enzymatic deficiency⁽⁷⁾. Endothelial dysfunction is the key pathophysiological element for the occurrence of microangiopathy, resulting in microvascular thrombosis with formation of fibrin and inhibition of fibrinolysis⁽⁸⁾. Several etiologic agents may be involved, such as viruses, bacterial toxins and drugs, such as antiplatelet agents and cyclosporine⁽⁹⁾.

The laboratory profile shows hemolytic anemia with hemoglobin values between 7-9 g/dl, platelet count below 30,000/mm³, mildly elevated indirect hyperbilirubinemia and a significant increase in lactate dehydrogenase (LDH); clotting tests are usually within normal range. The identification of schistocytes in the peripheral blood smear associated with the compatible clinical-laboratory scenario is fundamental for the diagnosis of TTP, in addition to being strongly suggestive⁽¹⁰⁾.

TTP can be classified according to its forms of presentation in: primary - acute, chronic recurring, plasmapheresisresistant, familial; and secondary - pregnancy-related, human immunodeficiency virus (HIV), autoimmune diseases, neoplasia or chemotherapy, immunosuppression or drug use. Among the primary forms, acute is classically manifested by microangiopathic hemolytic anemia, thrombocytopenia, with fever, neurological and renal and dysfunction and purpura in up to 90% of cases. The neurological condition may manifest at any time, such as confusional states, changes in the visual field, sensory and motor deficits, seizures, and lowered level of consciousness. Renal dysfunction manifests with proteinuria and microscopic hematuria and transient acute kidney injury^(2,4).

TTP treatment consists of plasmapheresis, favoring enzymatic action by removing pathogenic autoantibodies and cytokines with endothelial action⁽¹¹⁾, with a change in mortality from 90% to 10%-30%⁽¹²⁾. In severe acute or recurrent/resistant cases, the association of corticosteroids, immunosuppressants and splenectomy may be indicated. Recently, the monoclonal antibody rituximab has been reported as a therapeutic option for cases of TTP resistant to plasmapheresis^(13,14).

Plasmapheresis is essential for all patients diagnosed with TTP, but the number of sessions for clinical-laboratory remission varies⁽¹²⁾. The guidelines found in the literature for acute cases are daily sessions until normalization of platelet count and LDH level, markers of the therapeutic response⁽¹⁵⁾.

CASE REPORT

Female patient L. B. S., 41 years old, without comorbidities, sought emergency room care referring to weakness and malaise for months, worsening within five days; at that time she presented generalized bone pain, headache, visual alteration and a convulsive episode. At physical examination, she was in a regular general state, lucid and oriented, pale, hydrated, anicteric, acyanotic and afebrile. Cardiac and pulmonary auscultation and abdominal examination with no abnormalities; well perfused extremities, with no edema and no signs of venous thrombosis.

Laboratory tests order entry results: hemoglobin 4.9 g/dl with schistocytes and dacrocytes (Figures 1 and 2), leukocytes 2,600/mm³, reticulocytes 0.7%, platelets 53,000/mm³, creatinine 0.7 mg/dl, urea 20 mg/dl, total bilirubin 1.63 mg/dl, indirect bilirubin 1.07 mg/dl, LDH 3,325 UI/l, antinuclear factor, direct Coombs, indirect Coombs and serology for HIV negative. The diagnosis in peripheral blood smear was analyzed and confirmed on slide under optical microscopy. The photomicrographs were performed in Zeiss© microscope, Primo Star model, trinocular, coupled to a Sony© digital camera model Cybershot DS1. The images were edited using the ImageJ© software.

Figure 1 Peripheral blood smear showing presence of schistocytes (400×) 

Figure 2 Peripheral blood smear showing presence of dacrocytes (400×) 

In the presence of pancytopenia with etiology to clarify, the patient was hospitalized for investigation and clinical support. She initially received transfusion of two red blood cell concentrates (packed RBC). She performed complete ultrasound of the abdomen, magnetic resonance imaging (MRI) and intracranial magnetic resonance angiography with no abnormalities. The criteria for diagnosis of microangiopathic hemolytic anemia (TTP) were then fulfilled. The patient received every 8 hours 300 ml transfusion of fresh frozen plasma (FFP) and packed RBC as needed and 300 mg hydrocortisone. She was admitted to the intensive care unit (ICU) to perform therapeutic plasmapheresis, with the first session eight days after her arrival at the emergency room. During the fifth, sixth and seventh plasmapheresis sessions, she presented neuropsychiatric fluctuation with mood alteration, disorientation, psychomotor agitation and aggressive behavior, symptoms controlled with haloperidol 10 mg, quetiapine 25 mg and midazolam 3 mg.

Figures 3, 4 and 5 show the laboratory evolution of the patient regarding the respective values of hemoglobin, platelets and LDH during the 32 days of hospitalization. Point 9 in Figures 3 and 4 and point 2 in Figure 5, represent four days after the first plasmapheresis session. Nine packed RBC units, 185 FFP pockets and 13 plasmapheresis sessions were administered for assuming the disease (platelets 163,000/mm3, LDH 232 UI/l and hemoglobin 10.8 g/dl) and the hospital discharge planning. At this time, the patient was referred for follow-up at the hematology outpatient clinic with prescription of prednisone 60 mg and folic acid 5 mg daily.

Figure 3 Variation of hemoglobin concentration (g/dl) during hospital stay (g/dl) 

Figure 4 Variation of platelet count during hospital stay 

Figure 5 Variation of LDH values (UI/l) during hospital stayLDH: lactate dehydrogenase. 

DISCUSSION

Microangiopathic hemolytic anemia (TTP and HUS) is a rare, serious and potentially fatal condition, but present a recognized effective treatment⁽¹⁶⁾. However, the therapeutic success is directly related to the rapid diagnosis enabled by the simplification of its criteria, without delay the specific therapy establishment^(12,16).

The recently considered diagnostic criteria are the presence of thrombocytopenia and microangiopathic hemolytic anemia confirmed by the identification of schistocytes in the peripheral blood^{(12, 16)}, initially disregarding a probable etiology⁽¹²⁾ and the presence of organ dysfunction and fever, since the pentad classic is quite unusual⁽¹⁶⁾.

In this present case report, the clinical diagnostic criteria for TTP are completely fulfilled, including the neurological manifestation before and during the hospital stay. The specific therapy - plasmapheresis, FFP transfusion and immunosuppression with hydrocortisone - was initiated on the third day after diagnostic confirmation. Therapeutic plasma exchange is the association between plasmapheresis and FFP transfusion, since plasmapheresis removes the vWF multimers, ADAMTS-13 antimetalloproteinase antibodies^(4,12) and endothelial cytokines⁽¹¹⁾. FFP transfusion restores the ADAMTS-13 deficiency with donor enzymes^(4,12).

According to several authors, the use of immunosuppressive agents offers additional action in the treatment of TTP, especially in severe acute or the plasmapheresis-resistant cases^{(13,14, 17)} or when autoimmune disease is suspected⁽¹⁸⁾. In a prospective study, prednisone at a dose of 200 mg/day was shown to induce complete remission in 55% of cases of microangiopathic hemolytic anemia associated with mild neurological dysfunction⁽¹⁹⁾.

There is no defined treatment time in the literature, but the authors indicate that therapy should be sustained until the platelet count reaches 100,000/mm³ and the LDH levels are below 400 UI/l, and these are the most sensitive markers for evaluate the therapeutic response⁽²⁰⁾. In this case, hemoglobin and LDH values improved significantly after 72 hours from the start of Plasma Exchange (hemoglobin: 4.9 g/dl to 10.7 g/dl and LDH: 3,325 UI/l to 699 UI/l), but the platelet count only reached acceptable values after 12 days of treatment.

There is a consensual doubt in the literature about the complete remission of the disease in the long term⁽²¹⁾, but in this case, the patient was discharged from hospital with laboratory values within the parameters previously defined (platelets 163,000/mm³ and LDH 232 UI/l). Keeping corticosteroids administration can support complete remission of the disease and outpatient followup is essential to monitor remission or detect recurrent chronic form, with mortality rate around 15%⁽²²⁾.

CONCLUSION

This is a serious disease, which diagnosis and the early establishment of the therapy is capable of improving the prognosis, including the possibility of cure. Therefore, every physician who provides assistance in the emergency room units should be aware of it. The possibility of the wide differential diagnosis with conditions also serious, such as consumption coagulopathy and intravascular hemolysis, evidences the need for efficient daily clinical practice.