Thrombotic microangiopathy as the first manifestation of disseminated malignant disease

Introduction: Thrombotic microangiopathies are a group of diseases characterized by disseminated intravascular thrombosis, thrombocytopenia and ischemic organ damage. This group includes thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome. One of the causes of thrombotic microangiopathy, although rare, can also be malignant diseases, primarily cancers of the stomach, prostate, breast and lungs.

Case report: We present a patient with thrombotic microangiopathy and disseminated malignant disease of unclear etiology.

Conclusion: This clinical entity is called carcinoma-associated thrombotic microangiopathy and was first described in 1970. However, only a few dozen cases have been described to date. Considering the high mortality, it should be considered in patients with malignant disease, microangiopathic hemolytic anemia, and thrombocytopenia.

INTRODUCTION

Thrombotic microangiopathies (TMA) are a group of diseases characterized by disseminated intravascular thrombosis, thrombocytopenia and ischemic organ damage. This group includes thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) [1].

Thrombotic thrombocytopenic purpura is a rare disease which manifests as a pentad of clinical findings, namely: thrombocytopenia, microangiopathic nonimmune hemolytic anemia, renal function impairment, elevated body temperature, and neurological deficits. It rarely occurs that the entire pentad manifests in one patient, however, thrombocytopenia and microangiopathic hemolytic anemia are always a part of the clinical finding [2]. As opposed to thrombotic thrombocytopenic purpura, wherein kidney damage is a rare and most frequently mild manifestation of disease, in patients suffering from hemolytic-uremic syndrome, kidney damage is a regular occurrence and, together with thrombocytopenia and microangiopathic hemolytic anemia, it makes up the HUS clinical triad [3].

Carcinoma-associated thrombotic microangiopathy was first described in 1970 [4]. Since then, a few dozen cases have been described wherein patients suffering from gastric, prostate, breast, and pulmonary cancer, and less frequently from carcinomas of other localization and lymphomas, also had thrombotic microangiopathy. The clinical presentation of these patients varies – from typical TTP and HUS presentation, which is rarer, to atypical clinical patient presentation, wherein patients only have microangiopathic hemolytic anemia and thrombocytopenia, without or with minimal neurological damage or renal insufficiency [5],[6].

This case report describes thrombotic microangiopathy as a complication of disseminated malignant disease of unclear etiology.

CASE REPORT

A sixty-four-year-old patient was initially referred to a hematologist due to malaise and weakness, loss of appetite, and anemia and thrombocytopenia, which was verified by laboratory tests. The hemoglobin blood level in this patient was 54 g/l, while the platelet count was 30 x 10⁹ /l. A repeated blood test, performed in the hematology laboratory, yielded a hemoglobin level of 53 g/l, an MCV index (mean cell volume index) of 98 fl, and a platelet count of 19 x 10⁹ /l, while the leukocyte count and differential were normal. After the examination, the patient was admitted to the Clinic of Hematology of the University Clinical Center of Kragujevac. In her personal history, the patient reported hypertension and diabetes, for which she was taking oral antidiabetics. Apart from pallor of the skin and mucosa, the patient’s physical exam was normal. A transfusion of two doses of deplasmatized erythrocytes was administered to the patient, upon which her hemoglobin level was 74 g/l.

Additional laboratory tests were performed. The value of lactate dehydrogenase was 5,965 IU/l (normal value: up to 241 IU/l); the level of total bilirubin was 70.7 µmol/l (normal value: 2 – 21 µmol/l); the level of direct bilirubin was 7.9 µmol/l (normal value: 1 – 5 µmol/l); the reticulocyte count was 10.5% (normal value: up to 2%); the level of haptoglobin was 0.1 g/l (normal value: 0.5 – 2.2 g/l). In the hemostasis analysis, an elevated D-dimer level of 1,298 ng/ml was registered (normal value: up to 240 ng/ml), as well as slightly prolonged prothrombin time of 14.5 s (normal value: 11 – 13.5 s). Other parameters of hemostasis, including antithrombin 3, were within the reference range. Tumor marker analyses revealed immeasurably high values of cancer antigen (CA) 19-9 and CA 72-4. Emergency therapeutic plasma exchange (TPE) was initiated, a total of two patient plasma volumes a day, with the application of 2 mg/kg of prednisone. After four days of treatment, the hemoglobin level rose to 87 g/l, while the platelet count reached 45 x 10⁹ /l. However, due to the development of respiratory insufficiency, it was not possible to perform gastroduodenoscopy. Oxygen, via oronasal mask, as well as bronchodilators, were administered to the patient.

Multislice computed tomography of the thorax, abdomen and lesser pelvis was performed, which revealed the following: multiple conglomerate masses of pathological lymph nodes in the mediastinum (the largest measuring 60 x 46 mm), intrapericardial effusion – measuring 22 mm in diameter, secondary deposits in the liver (the largest measuring 13 mm), and a secondary deposit on the left adrenal – measuring 29 x 28 mm. As far as skeletal structures are concerned, secondary deposits on the fourth right rib and the eighth left rib were detected, as well as gas inclusions in the T8 and L2 vertebrae. The gastric mucosa was not described, for technical reasons (Figure 1).

Figure 1. Multi-slice computed tomography (MSCT) of the thorax, abdomen, and lesser pelvis
A) Conglomerate masses of lymph nodes in the mediastinum; B) Metastatic lesion in the left adrenal gland; C) Metastatic lesion on the anterior end of the fourth right rib; D) Metastatic lesions on the posterior end of the eighth left rib

Seven days after the onset of disease, TPE and corticosteroid therapy were continued. At that point, the level of hemoglobin was 88 g/l, the platelet count was 49 x 10⁹ /l, the lactate dehydrogenase level was 1,720 IU/l, the value of total bilirubin was 32.2 µmol/l, while the value of direct bilirubin was 5.2 µmol/l. On the eighth day of treatment, respiratory failure occurred resulting in the lethal outcome.

DISCUSSION

The pathophysiological mechanism of the development of thrombotic thrombocytopenic purpura is the decreased activity of metalloproteinase ADAMTS13, whose most common cause is the existence of antibodies against this metalloproteinase, and, much less commonly, its congenital deficit. Since the function of ADAMTS13 is cleaving large von Willebrand factor multimers into smaller fragments, and since large von Willebrand factor multimers have great thrombogenic potential, a reduced activity of this metalloproteinase leads to disseminated intravascular organ thrombosis. Hypoperfusion of the affected organs leads to their damage, the platelet count decreases, as they are spent during disseminated thrombosis, while hemolytic anemia develops as the result of mechanical erythrocyte damage occurring during their passage through thrombosed and narrowed blood vessels [7]. The cause of HUS development are most commonly intestinal infections caused by strains of Escherichia coli and Shigella dysenteriae, which produce the Shiga toxin, thus damaging the endothelium of blood vessels, which leads to disseminated intravascular thrombosis. Less commonly, the atypical form of HUS is caused by endothelial damage due to deficient complement activation [3].

The mechanism of the development of carcinoma-associated thrombotic microangiopathy is variable, and sometimes multiple factors can contribute to its occurrence. As it most commonly occurs in mucin-producing adenocarcinomas, one of the potential pathophysiological mechanisms of the development of this type of thrombotic microangiopathy is the direct toxic effect of mucin on the blood vessel endothelium [4]. A higher incidence of thrombotic microangiopathy in patients with metastases in bone marrow has been observed. Carcinomas in bone marrow directly penetrate blood vessels leading to secondary myelofibrosis, which also damages the endothelium of blood vessels, which, in turn, results in the release of large von Willebrand factor multimers [8],[9]. Also, in some patients, the production of autoantibodies against ADAMTS13 metalloproteinase occurs, as in primary TTP [5].

Chemotherapy can also be the cause of the development of carcinoma-associated thrombotic microangiopathy, primarily through the direct toxic dose-dependent effect on the blood vessel endothelium, and less commonly, through acute immune reaction. An example of the dose-dependent toxic effect is gemcitabine-induced HUS, whose incidence is between 0.015% and 0.31% of patients treated with gemcitabine. The median cumulative dose of gemcitabine which lead to HUS, was 20 g/m² [10]. In addition to this toxic effect of gemcitabine, cases of toxic effects of gemcitabine have been described after the first or second dose of this drug. The following factors are considered to be responsible for this: deficient complement activation and complement mediated endothelial damage [11]. The incidence of HUS induced by the direct toxic effect of mitomycin C on the endothelium is even higher, and ranges between 2% and 15% [12],[13], and such an effect has been registered also in bleomycin, cisplatin, 5-fluorouracil, cytosine arabinoside, and other drugs [12]. The causes of the development of thrombotic microangiopathy as well as the necessary procedures for their diagnosis are presented in Table 1.

Table 1. Differential diagnosis of thrombotic microangiopathies (TMA) and the procedures necessary for their diagnosis [1]

1]" width="1892" height="1444">

Bearing in mind the high levels of tumor marker CA 19-9, which is associated with gastrointestinal tumors, and of CA 72-4, which is highly associated with gastric cancer, our patient was probably suffering from gastric cancer, however, due to the initially low platelet count and the development of respiratory insufficiency, it was not possible to perform gastroduodenoscopy. Also, peripheral lymph nides were nether enlarged nor accessible for biopsy. The fact that the highest percentage of patients with carcinoma-associated thrombotic microangiopathy suffer from gastric carcinoma (26.2% of all patients suffering from carcinoma-associated thrombotic microangiopathy) speaks in favor of the diagnosis of gastric cancer in this patient [6].

Due to the high mortality from carcinoma-associated thrombotic microangiopathy, which is nearly 50%, it is essential to recognize it on time and initiate treatment in the form of therapeutic plasma exchange, corticosteroid therapy, and of course causal treatment of the malignant disease [6].