Thrombotic microangiopathy (TMA) is a clinical syndrome characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and end-organ damage [1]. TMA can be mainly classified into thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). When TMA is suspected, accurate diagnosis is required, but a differential diagnosis is often difficult because each patient has varying clinical features, and the causes of triggers may overlap [2].

We report two cases of TMA that developed after surgeries in patients with the combined administration of tranexamic acid and batroxobin intraoperatively. We obtained informed consent from the patients for the publication of this case report.

TMA is a rare disease that should be considered if a patient exhibits MAHA, thrombocytopenia, and ischemic end-organ damage [3]. MAHA is characterized by fragmented erythrocytes; laboratory findings of hemolysis, such as elevated serum LDH levels, decreased haptoglobin; and a negative Coombs test, which indicates the immune-mediated hemolysis of red blood cells [2].

In the cases described in this report, the patients had the typical triad of MAHA, thrombocytopenia, and acute kidney injury; these features were consistent with TMA. Once a diagnosis of TMA was established, it was essential to differentiate it from other causes of TMA. In order to rule out the TTP and Shiga toxin-producing E. coli (STEC)-HUS, an ADAMTS-13 activity test, and PCR were performed on the patient’s stool samples, the results of which were negative. Therefore, TTP and STEC-HUS were ruled out. There was no evidence of coagulation factor deficiency, and the results of the Coombs test were negative. Therefore, disseminated intravascular coagulation and autoimmune disease were ruled out [4]. Besides, a low level of C3 and normal level of C4; suggest activation of the complement system and complement consumption; there is the possibility of atypical HUS (aHUS). The complement system’s genetic testing may help an accurate diagnosis, but it was not conducted in these cases. But it is known that only about half of the patients who meet the clinical findings of aHUS have genetic abnormalities, aHUS cannot be excluded even if there is no genetic abnormality [5].

It is also necessary to rule out secondary TMA caused by malignant tumors, surgery, medications, transplantation, and malignant hypertension [4]. The patients described in this report had solid organ cancer, which had been surgically removed; there was no metastasis to other organs, and chemotherapy was not administered before or after surgery. Therefore, it was considered that the possibility of secondary TMA would be more likely due to the surgery, rather than cancer itself or the chemotherapeutic agents.

In the patients of this report, there is the possibility of the postsurgical TMA as the cause of secondary TMA. According to Sridharan et al. [6], the mechanism of postsurgical TMA involves an imbalance of von Willebrand factor (vWF) and ADAMTS13 due to endothelial damage, which is a feature of TTP, as well as the dysregulation of the complement pathway, which is a feature of aHUS. Indeed, cardiovascular surgery often causes a large amount of endothelial damage, resulting in an imbalance of vWF and ADAMTS13. By comparison, the underlying cause of TMA following less invasive surgery may be more directly attributed to the dysregulation of the complement pathway. As the patients in this report underwent relatively less invasive surgeries, the dysregulation of the complement pathway was considered to be the primary cause of postsurgical TMA. Nevertheless, it was difficult to clearly distinguish between aHUS and postsurgical TMA in two patients without genetic testing for aHUS in that they showed complement dysregulation in common.

In these cases, 500 mg of tranexamic acid and 2 KU of batroxobin were administered simultaneously to reduce intraoperative bleeding. Nagabhushan et al. [7] reported that the intraoperative administration of a combination of batroxobin (1 KU intravenously 15 minutes before skin incision, followed by 0.5 KU intramuscularly) and tranexamic acid (10 mg/kg bolus intravenously 15 minutes before skin incision, followed by 1 mg/kg/hr) significantly reduced blood loss during spinal surgery, without increasing the risk of thrombosis. These two agents are antifibrinolytic and induce clot formation, and seem to have a synergistic effect [8]. Previous studies have reported, rare adverse effects, such as renal cortical necrosis, with the daily administration of tranexamic acid (3 g) over a period of 4 to 5 days [9,10]. However, in our report, 500 mg of tranexamic acid and 2 KU of batroxobin were used, resulting in thrombotic complications. Furthermore, none of the underlying diseases and past history related to thrombotic events were present in the two patients in this case.

Given the potential dysregulation of the complement system among patients in this report, it was considered that microthrombi formation might have been a consequence of the synergistic effects of the concomitant tranexamic acid and batroxobin administration. Although it was not clear whether the combined use of the hemostatic agents directly affected the triggering of TMA, they may have had a role in its exacerbation.

In conclusion, for the anesthetic management of patients with a risk of thrombosis, such as those undergoing cancer surgery, we need to consider the risk of adverse effects associated with the concomitant use of tranexamic acid and batroxobin.