Anticoagulant therapy in neonatal acute infectious peritonitis based on the TAT, PIC, tPAIC, and sTM: a new case series

doi:10.21203/rs.3.rs-4712743/v1

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Case Report

Anticoagulant therapy in neonatal acute infectious peritonitis based on the TAT, PIC, tPAIC, and sTM: a new case series

https://doi.org/10.21203/rs.3.rs-4712743/v1

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Background: Neonatal acute peritonitis is a leading cause of morbidity and mortality and poses challenges that demand prompt diagnosis and treatment, particularly in infants with disseminated intravascular coagulation.

Case presentation：Here, we report a case series of four infants with acute perionitis caused by necrotising enterocolitis, gastrointestinal perforation, and meconium peritonitis. Laboratory tests for thrombin-antithrombin complex(TAT), α2-plasmin inhibitor-plasmin complex(PIC), soluble thrombomodulin (sTM), and tissue plasminogen activator-inhibitor complex (tPAIC) suggested the activation of the coagulation system followed by treatment with anticoagulant therapy in these infants.

Conclusions: Overall, thrombin-antithrombin complex, α2-plasmin inhibitor-plasmin complex, soluble thrombomodulin, and tissue plasminogen activator-inhibitor complex may guide anticoagulant therapy, offering prospects for improving the outcomes in neonates with acute peritonitis.

Thrombin-antithrombin complex

α2-plasmininhibitor-plasmin complex

soluble thrombomodulin

tissue plasminogen activator-inhibitor complex

Neonatal acute peritonitis is a major cause of neonatal acute abdomen and is a challenging problem that requires timely diagnosis and treatment. The reported morbidity rate of acute peritonitis in newborns is approximately 1.67% with causes including necrotising enterocolitis (NEC), gastrointestinal perforation, and meconial^[1]^-^[2]^[3]. Although the mortality of neonatal acute peritonitis has gradually decreased from 99% in 1939 to 33% in 1983^[2]with the improvement of medical technology, mortality remains high and varies by the conditions causing peritonitis, with NEC associated with 33%^[1]of cases and meconial peritonitis associated with 50%^[1]. Among these, microcirculation disturbances, especially disseminated intravascular coagulation (DIC), are important causes of neonatal mortality in acute peritonitis^[2]. Hayato^[4] et al. suggested that almost 30% of neonates with DIC have gastrointestinal perforations with NEC. Therefore, acute neonatal peritonitis is associated with a high risk of DIC development and high mortality. However, early standard detection and intervention for coagulation in newborns with acute peritonitis are lacking. Recognition of this special condition will enable early diagnosis and anticoagulation treatment, which could improve prognosis. Recently, the clinical efficacy of soluble thrombomodulin (sTM), thrombin-antithrombin complex (TAT), α2-plasmininhibitor-plasmin complex (PIC), and tissue plasminogen activator inhibitor complex (tPAIC) has been proven in sepsis and sepsis-induced coagulopathy^[5]^-^[6]^[7]; however, reports of these markers in the newborn are rare. We present four cases of neonatal acute infectious peritonitis from different causes that were examined for the coagulation markers TAT, PIC, tPAIC, and sTM. The diagnostic values and clinical outcomes were evaluated.

Case 1

A 3-day-old full term infant was transferred to our hospital because of "emesis, lethargy, and abdominal distension for 4 hours". The infant was resuscitated after birth. Mixed feeding was initiated at 2 days of age. The next day, he presented with bilious vomiting when 30 ml/kg of enteral feeding was achieved. He developed bloody stools, fever, and weakened bowel sounds. The diagnosis of stage IIIA NEC was confirmed using clinical signs, radiography, and ultrasonography. TAT levels markedly increased, whereas TM levels mildly increased. Additional test results are shown in Figures. He received antibiotics for 12 days and anti-coagulant therapy with enoxaparin for 14 days and was discharged without complications.

Case 2

An 8-day-old preterm infant was hospitalised with fever, abdominal distension, and haematochezia. At 7 days of age, the patient achieved full enteral feeding with breast milk plus a cow milk-based formula and developed symptoms. The full blood count, DIC clotting values, and cerebrospinal results are listed in Table 1. Ileocolic resection and ileostomy were performed, and the patient was diagnosed with stage IIIB NEC. Laboratory tests for TM, TAT, PIC, and T-PAIC suggested activation of the coagulation system and endothelial cell damage; therefore, enoxaparin was administered as an anticoagulant for 23 days. Trophic feeding began on the 5th day after operation and oral feeding was established after 14 days.

Case 3

A 3-day-old full term infant with tracheal intubation was transferred to our hospital because of "emesis and abdominal distension for 3 days". The patient started to vomit after bottle feeding 6 hours after birth, accompanied by progressive abdominal distension and failure to pass meconium. Physical examination revealed skin mottling, high abdominal distension, elevated skin temperature, slight abdominal wall discoloration, weak bowel sounds, and a capillary refill time of 4-5 seconds. The laboratory examination showed that the white blood cell count decreased, CRP slightly increased, TAT significantly increased, and TM mildly increased, indicating hypercoagulation. The patient was diagnosed with meconium peritonitis postoperatively. CRP increased to a maximum value of 178.2 mg/L. Anticoagulation therapy with enoxaparin was administered for 15 days. The length of hospital stay was 23 days.

Case 4

The newborn, aged 24 minutes, was admitted to our department because of premature birth. Non-invasive ventilation was used as primary respiratory support for the infant. On the 4th day after birth, the patient presented with vomiting, abdominal distension, tachypnoea, and groans with minimal feeding. Physical examination revealed abdominal enlargement, high abdominal distension, and the absence of bowel sounds. The patient was diagnosed with a congenital gastric wall defect postoperatively. On the first day after surgery, TAT increased, suggesting hypercoagulability, and enoxaparin was administered as an anticoagulant for 16 days. The mean time to complete enteral feeding was 11 days. At 20 days of age, the percentage of eosinophils gradually increased to 14.3%, CRP increased to 41.5 mg/L, and there were no symptoms of fever or infection. Considering food protein-induced enterocolitis syndrome, the infant was administered an amino acid-based formula instead of extensively hydrolysed milk. The length of hospital stay of the infant was 30 days.

All patients were discharged from the hospital and tolerated feed with normal coagulation test results. The clinical characteristics of the four patients are presented in Table 1. The levels of PLT and CRP are shown in Figure A. The levels of traditional coagulation markers, including prothrombin time, fibrinogen, and D-dimer are shown in Figure B. Levels of TAT, PIC, TM, and t-PAC in the four patients are shown in Figure C. Laboratory tests for TAT, PIC, TM, and t-PAC were normal in four control cases, including one case of a highly imperforate anus with ostomy surgery, two cases of intestinal stenosis surgery following NEC, and one case of food protein-induced allergic proctocolitis.

Here, we reported four cases of acute diffuse peritonitis in newborns receiving anticoagulation treatment. The pathophysiology of DIC in newborns begins with endothelial damage caused by various primary illnesses. Literature published almost 40 years ago suggested that an additional problem in neonatal peritonitis that should be noted is DIC, which could further aggravate cell and tissue injury or even death^[2]. Since non-overt DIC is the stage prior to overt DIC, early recognition and treatment of might improve prognosis. Previous studies have revealed that TAT can be used as a biomarker for non-overt DIC for early diagnosis and anticoagulation treatment, otherwise, patients might lose the therapeutic window and develop overt DIC with severe thrombocytopenia and abnormal ATPP, PT, and fibrinogen^[6]^. However, studies on the sensitivity of non-overt DIC diagnostic criteria for neonatal acute diffuse peritonitis are rare.

We monitored the changes in TAT, PIC, tPAIC, and sTM in 4 cases of acute diffuse peritonitis, and the results showed that they had the same characteristics of early elevated TAT, which suggested the onset of a hypercoagulable condition (Figure C), resulting in anticoagulant therapy administration. Conventional coagulation function markers, including PT, fibrinogen, D-dimer, and PLT, did not show obvious changes in the early stages of the disease (Figure A and B). This finding is consistent with the previous cases including in the infants with sepsis^[5]^,^[8]. Interestingly, TAT levels were normal in our patients with anal atresia or post-NEC stricture after surgery without signs of peritonitis, suggesting that surgical trauma could not induce TAT elevation. Therefore, TAT elevation may be a potential biomarker for predicting hypercoagulability with high sensitivity and specificity in the postoperative period. At present, TAT, PIC, tPAIC, and sTM are routinely performed in critically ill patients in our NICU^[9]. Low-molecular-weight heparin (LMWH) was added once TAT levels increased. The dose of LMWH was adjusted based on the level of anti-Xa to maintain the level within a range of 0.1-0.5 U/ml. These coagulation markers were examined when the patients recovered, with CRP level decreased to normal, and antibiotics were no longer required. Anticoagulant therapy with LMWH was discontinued if TAT level returned to normal. A recent clinical retrospective study demonstrated that coagulation disorders are associated with severity of NEC^[10]. Therefore, we speculated that early anticoagulation therapy could delay disease progression and avoid surgery which was similar to patient 1. The duration of gastrointestinal rest in Case 2 was only 4 days after surgery, which was significantly shorter than the recommended 7-10 days^[11]^,^[12]. Early initiation of enteral feeding (<5 days) is safe, may shorten hospital stay, and reduce the treatment costs of neonatal NEC^[13]. In case 3, enteral feeding was initiated 6 days after surgery, similar to that reported in another study^[14]. The time taken to reach full enteral feeding was 12 days, which was much shorter than the previously reported 20-38 days^[14]. The hospitalisation duration was 23 days, whereas the previously reported hospitalisation duration for neonatal meconium peritonitis was approximately 48 days on average in Canada^[15], 57-84 days in Japan14, and 71-73.5 days in Hong Kong^[16]. The reported average hospitalisation duration for congenital defects of the gastric musculature in preterm neonates with gestational age < 34 weeks was approximately 30 days (21- 36.5 days) ^[17], which was the same as in Case 4. However, the time to reach full enteral feeding was 11 days, which was much shorter than the reported 18-34 days ^[17]. We speculate that the intestinal microcirculation was significantly improved by timely surgery, early anticoagulation, and precision antibiotics, thus establishing a foundation for early enteral feeding. Altogether, our anticoagulant therapy based on the levels of TAT, PIC, tPAIC, and sTM in four cases of acute diffuse peritonitis improved disease outcomes. However, clinical trials with sufficient sample sizes are needed to evaluate the diagnostic, therapeutic, and prognostic predictive values of TAT, PIC, tPAIC, and sTM in neonatal infectious diseases. Clinical research, such as the present report, is required to study the characteristics of DIC secondary to acute diffuse peritonitis with different aetiologies and pathogens.

Due to their immature coagulation systems, neonates have a higher risk of coagulation dysfunction caused by various diseases. In neonatal infectious diseases such as acute infectious peritonitis, early recognition and treatment of the abnormal changes in the coagulation and fibrinolytic systems are important to shorten the fasting time, improve the intestinal microcirculation, and thus shorten the disease course and improve the prognosis. The coagulation markers TAT, PIC, tPAIC,

and sTM appear to predict the early phase of DIC and guide anticoagulant therapy effectively.

disseminated intravascular coagulation (DIC), Necrotising enterocolitis (NEC), α2-plasmin

inhibitor-plasmin complex (PIC), soluble thrombomodulin (sTM), thrombin-antithrombin

complex (TAT), tissue factor (TF), tissue plasminogen activator-inhibitor complex (tPAIC)

Authors’ contributions

WY and YG: data sorting and analysis, and manuscript writing. YQ: data collection. YW and GZ: review and editing. LZ and JL: review and editing. All authors reviewed and revised the manuscript and approved the final version.

Funding

This research was funded by Key research and development project of Science and Technology Department in Sichuan (grant #22ZDYF0841 to Li Zhang).

Data availability

Available on request from the corresponding author.

Declarations

Ethics approval

This study protocol was reviewed and approved by West China Second University Hospital of Sichuan University Medical Ethics Committee, approval number 22ZDYF0841.

Consent for publication

Written informed consent was obtained from the legal guardian, to participate in this study and for the publication of any potentially identifiable images or data included in this article.

Competing interests

The authors declare no competing interests.

Acknowledgement

We thank the parents for providing informed consent for the publication and sharing their cases.

We also thank Dr Xiaoping Jiang, Zhicheng Xu, and Yang Wu (Department of Pediatric Surgery,

West China Hospital, Sichuan University, Chengdu) for performing surgery on the infants.

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Anticoagulant therapy in neonatal acute infectious peritonitis based on the TAT, PIC, tPAIC, and sTM: a new case series

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