A case of infection-induced thrombotic thrombocytopenic purpura

Abstract

Background:

Thrombotic thrombocytopenic purpura (TTP) are a group of microvascular thrombohemorrhagic syndromes with low incidence and high mortality, which are characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, neuropsychiatric disorders, and renal involvement. In addition, TTP has a high rate of misdiagnosis and underdiagnosis due to the lack of specific clinical manifestations.

Case report:

A male patient aged 47 years was admitted to our hospital with complaints of dizziness and nausea for 2 days and soy-colored urine for 1 day. The patient had caught a cold and suffered from fever, dizziness, and nausea 2 days before admission. These symptoms were relieved by self-administration of berberine 1 day before admission. Later, the patient found that the urine was scanty and soy-colored. Physical examination on admission showed that the patient developed apathy, with occasional babbling, yellowing skin and sclera, and scattered bleeding spots on the anterior chest area. Based on auxiliary tests combined with clinical manifestations, the patient was diagnosed with TTP and administered plasma exchange, hemofiltration, hormone, and anti-platelet therapies. The patient recovered and was discharged after 3 weeks. The patient regularly took aspirin and was followed up one year later with no recurrence.

Conclusion:

TTP is an acute severe disease with complex etiology, abrupt onset, and dangerous conditions. In this patient with TTP, an important cause of the disease may have been an acute gastrointestinal infection. The plasma examination in another hospital revealed positive results for ADAMTS13 inhibitors, providing strong evidence for the diagnosis of this case. Multiple plasma exchanges and glucocorticoids yielded favorable treatment results and were critical measures of successful treatment of TTP.

Keywords

Microangiopathic hemolytic anemia thrombocytopenia thrombotic thrombocytopenic purpura

1 Introduction

Thrombotic thrombocytopenic purpura (TTP) in adults is rare thrombotic microangiopathy (TMA), as a group of microvascular thrombohemorrhagic syndromes, TTP feature thrombocytopenia, microangiopathic hemolytic anemia, fever, neuropsychiatric disorders, and renal involvement [1 –5]. The pathogenesis of TTP is predominantly attributed to the absence of von Willebrand factor (VWF)-cleaving protease (ADAMTS-like 3 [ADAMTSl3]) activity, the abnormal release of VWF from vascular endothelial cells, and the aberrant activation of platelets [6]. TTP has low morbidity and high mortality. In addition, TTP lacks specific clinical manifestations, which results in high rates of misdiagnosis and underdiagnosis. In this paper, we present a retrospective analysis of a recent case of TTP and review the literature on the diagnosis and management of the disease.

Clinical data:

1. General data

Two days prior to admission to our hospital, a male patient aged 47 years caught a cold and had a fever of up to 38.4°C, accompanied by dizziness, nausea, vomiting (vomitus was stomach contents), and diarrhea (watery stools without melena and mucopurulent bloody stool), 4–5 times/day, about 100–200 mL/time. The patient self-administered berberine and the vomiting and diarrhea were alleviated 1 day before admission. Later, the patient felt an acidic bile sensation at and below the waist and observed that his urine was sparse and soy-colored, but did not record the urine volume. Then, the patient visited our emergency department and was admitted for “thrombocytopenia of unknown origin and renal insufficiency.” Since the onset of the disease, the patient had poor mental health, diet, and sleep quality, and drained watery stools and reduced quantities of urine of soy color, with no significant weight loss. The patient had a history of type 2 diabetes mellitus for more than 4 years and was orally taking 0.5 g metformin hydrochloride sustained release tablets, once a day, without regular blood glucose monitoring.

2. Physical examination

Physical examination results indicated that the patient had apathy and an anemic appearance, with a body temperature of 37.8°C, a pulse rate of 110 times/min, a respiration rate of 24 times/min, a blood pressure of 120/80 mmHg, occasional babbling, yellowing skin, and sclera, and scattered bleeding spots on the anterior chest area. The rest of the physical examination did not show any abnormalities.

Laboratory tests:

Several laboratory tests were performed on admission. Routine blood test results were as follows: 18.53×10⁹/L white blood cells, 88 g/L hemoglobin, 6×10⁹/L platelets, 90.4% neutrophils, 148.8 mg/L C-reactive protein, and 4.22 ng/mL procalcitonin. The biochemical test revealed 35.6 g/L albumin, 82.2μmol/L total bilirubin, 20.6μmol/L direct bilirubin, 61.6μmol/L indirect bilirubin, 3022 U/L lactate dehydrogenase, 143 U/L glutamic-pyruvic transaminase, 30.6 mmol/L fasting blood sugar, 3.72 mmol/L potassium, 128 mmol/L sodium, 21.2 mmol/L urea, and 357μmol/L creatinine. The coagulation function tests demonstrated that the D-dimer level was 4.22μmol/L, and the other indexes were normal. Both human immunodeficiency virus and hepatitis virus tests were negative. Peripheral blood smears indicated more than 1% fragmented red blood cells and 12.4% reticulocyte counts. The routine urine test suggested 3+ urinary protein, 3+ occult blood, 2+ glucose, and negative ketone. Stool smears and routine examinations revealed full fields of white blood cells; pyocytes and Charcot-Leyden crystals were found to be absent. Abdominal ultrasound illustrated that both kidneys were enlarged with enhanced renal parenchymal echoes. The computerized tomography scan of the head, chest, and abdomen showed no abnormalities.

On day 3 of admission, total rheumatoid indicators, antineutrophil cytoplasmic antibody, and anti-dsDNA antibody were all negative. In addition, the Coombs test exhibited negative results. Bone marrow aspirate smears revealed mildly active myeloproliferation, reduced platelets, and thromocytogenic megakaryocytes, with increased bone marrow erythroid proportion. The plasma examination conducted in another hospital exhibited positive results for ADAMTS13 inhibitors.

The changes in laboratory indicators during the treatment are shown in Fig. 1.

Fig. 1

Changes in laboratory indicators during treatment.

3. Diagnosis

Based on clinical manifestations and laboratory tests, the patient was diagnosed with TTP, acute gastrointestinal infection, and type 2 diabetes mellitus.

4. Treatment

After admission, TTP, acute gastrointestinal infection, and type 2 diabetes mellitus were considered in combination with the fever, thrombocytopenia, elevated lactate dehydrogenase, hemolytic anemia, renal insufficiency, and central nervous system symptoms that occurred during the course of the disease. The patient was given symptomatic and supportive treatments such as anti-infection and blood glucose control. Specifically, the patient underwent plasma exchange with continuous bedside hemofiltration and adjuvant glucocorticoid use. Three days after admission, laboratory tests showed negative results for the Coombs test, and bone marrow aspirate smears revealed mildly active myeloproliferation, thrombocytopenia, reduced platelets, and thromocytogenic megakaryocytes, and increased bone marrow erythroid proportion. In addition, the plasma examination conducted in another hospital tested positive for ADAMTS13 inhibitors. The patient was diagnosed with TTP and continued to receive plasma exchange and glucocorticoids. Moreover, routine blood, liver, and kidney function tests were conducted after each plasma exchange. On the fourth day of admission, the patient had 59×10⁹/L platelets and was given antiplatelet therapy with aspirin (0.075 g/d). The patient underwent four plasma exchanges during the course of the disease, with a total of 11,270 mL of plasma used, and 122 h of continuous bedside hemofiltration. Afterward, the patient became conscious, with normal platelet values and urine output, and slightly high creatinine values, and the rest of the laboratory indexes recovered significantly. The patient was then transferred to the hematology department from our department for continuous treatment, following which creatinine values gradually recovered. Glucocorticoids were gradually tapered and transitioned to oral prednisolone acetate. After 3 weeks, the patient’s condition improved, the hormones were discontinued, and the patient was discharged. After discharge, the patient was instructed to consistently take aspirin to prevent a recurrence.

5. Treatment outcomes, follow-up, and disease improvement

The patient regained consciousness; there was no yellow staining of the skin or of the sclera; the patient exhibited alleviated anemia, and had normal levels of platelet count, creatinine, lactate dehydrogenase, and urine output. The patient was discharged from the hospital on long-term aspirin and was followed up 1 year after discharge without recurrence.

2 Discussion

TTP is a microvascular thrombohemorrhagic syndrome, whose main clinical features include microangiopathic hemolytic anemia, thrombocytopenia, neuropsychiatric disorders, fever, and renal involvement. TTP is classified into hereditary and acquired forms; the latter form is categorized into idiopathic and secondary diseases according to the presence or absence of the primary disease. Hereditary TTP results from ADAMTSl3 mutation-induced reduced or deficient enzyme activity and often occurs in response to predisposing factors, such as infection, stress, or pregnancy. Idiopathic TTP is the main clinical type of TTP, which is caused by the presence of anti-ADAMTSl3 autoantibodies (inhibitors) that result in downregulated or deficient ADAMTSl3. Secondary TTP is attributable to infections, drugs, tumors, autoimmune diseases, and hematopoietic stem cell transplantation, with complex pathogenesis and poor prognosis [7]. In this case, an acute gastrointestinal infection may be an important contributor to TTP.

Currently, no specific index is available for the diagnosis of TTP. The recommendations of Chinese expert consensuses are as follows:

(1) TTP can be diagnosed with clinical manifestations: the clinical manifestations of TTP include a “triad” of microangiopathic hemolytic anemia, thrombocytopenia, and neuropsychiatric symptoms, or “Reynolds’ pentad.” In this case, the patient presented with relatively obvious central nervous system symptoms.

(2) TTP can be diagnosed with laboratory tests: ding172 Thrombocytopenia and microangiopathic hemolytic anemia (especially when the percentage of fragmented red blood cells in peripheral blood is >1%) are the two most pivotal indicators of TTP [8]. ding173 Significant elevation in serum lactate dehydrogenase is vital for early diagnosis, treatment, and relapse of TTP patients. ding174 Marked reductions in plasma ADAMTS13 activity or positive ADAMTS13 inhibitors can also be used for the diagnosis of TTP. However, not all patients show reduced ADAMTS13 activity or positive ADAMTS13 inhibitors [9].

(3) When diagnosed, TTP needs to be differentiated from hemolytic uremic syndrome, Evans syndrome, disseminated intravascular coagulation, hemolysis, elevated liver enzyme, low platelet syndrome, and megaloblastic anemia. In this case, autoimmune hemolytic anemia was excluded, and the patient had normal coagulation function and increased D-D aggregates, consistent with the characteristics of microvascular thrombosis-induced secondary thrombocytopenia.

Currently, plasma exchange is the most effective treatment for TTP. Specifically, plasma exchange should be performed as soon as possible after the diagnosis of TTP since it not only replenishes a large amount of ADAMTS13 and VWF and removes anti-ADAMTS13 autoantibodies and UL-VWF from plasma, but also removes numerous cytokines that damage vascular endothelium and activate platelets [1, 10]. A prior study revealed that the mortality rate of TTP was>90% among untreated patients but was reduced to 10–20% among patients treated with plasma exchange [11]. Currently, the exchange regimen for TTP is often 40–60 mL/kg·d. According to the 2012 British Committee for Standards in Haematology Guidelines on the treatment of TTP, [12] patients are often administered daily exchange of 1.5 times the volume of fresh frozen plasma treated with virus inactivation in the early stage of the disease and then exchange of an equal volume of plasma after the clinical symptoms of patients are significantly ameliorated and laboratory tests suggest stable disease condition. Plasma exchange therapy may be discontinued if platelets of>150×10⁹/L are detected in patients and persist for at least 2 days after plasma exchange. Plasma exchange should be performed within 24 h of the diagnosis. If immediate plasma exchange cannot be made available, patients can be transfused with a large amount of fresh frozen plasma (25 mL/kg·d or 1.5–2.0 L/day for adults) until plasma exchange can be performed. Glucocorticoids and cyclosporine can stabilize platelets and endothelial cell membranes and repress ADAMTS13 autoantibody generation; this procedure has better efficacy in the treatment of acquired TTP. Plasma exchange combined with glucocorticoids has now emerged as the primary treatment option for TTP patients and can significantly reduce the mortality rate [13]. Platelet transfusion can induce thrombosis and subsequently aggravate microangiopathic hemolytic anemia. Accordingly, small amounts of platelets should only be considered in TTP patients with life-threatening bleeding. Patients with severe anemia may be appropriately transfused with concentrated red blood cells. In this case, the patient was given plasma exchange and glucocorticoids several times and showed excellent treatment outcomes. Therefore, plasma exchange and glucocorticoids are important measures for successful treatment. To reduce recurrence, patients should consistently take aspirin for 6 to 18 months after their disease has stabilized [2].

In summary, TTP is an acute severe disease with a complex etiology, rapid onset, and dangerous conditions, which may cause death at any time if not detected and treated in time. At present, the sensitivity and specificity of the diagnostic indicators of TTP need to be further improved. For TTP treatment, the high amount of plasma required poses a significant problem for patients with respect to financial constraints and availability in blood banks. Therefore, the future treatment of patients with TTP will benefit from the development and implementation of plasma substitutes (to replace some plasma). In addition, gene therapy is anticipated to be utilized as a novel treatment option for TTP as a result of the in-depth investigation into the pathophysiology of TTP.

Footnotes

Acknowledgments

We would like to acknowledge the hard and dedicated work of all the staff that implemented the intervention and evaluation components of the study.

Availability of data and materials

All relevant data to this case is reported in the manuscript.

Conflict of interest

The authors declare that they have no competing interests.

Funding

No external funding received to conduct this study.

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