An adolescent with suspected sepsis and disseminated intravascular coagulation

CASE DESCRIPTION

A previously healthy 14-year-old boy presented to his local emergency department with a 1-day history of fever, emesis, and decreased level of consciousness. There was no history of preceding diarrhea, medication intake, substance abuse, hypertension, recurrent infections, malignancy, kidney disease, or an autoimmune disorder. Family history was noncontributory. On examination, he was hypotensive, tachycardic, confused, with mild icterus and a petechial rash. His blood work showed leukocytosis, thrombocytopenia, and hemolysis. Given the history of fever, rapid clinical decompensation and suggestive blood work findings, he was suspected to have septic shock and disseminated intravascular coagulation (DIC). Cultures were drawn and he was started on ceftriaxone, vancomycin, and acyclovir. Further clinical deterioration led to the transfer to paediatric intensive care at a tertiary care centre. Worsening consciousness and hemodynamic instability warranted invasive mechanical ventilation and inotropic support. His CT head was normal. Within 24 hours, he developed anuria and acute kidney injury, requiring continuous veno-venous hemodiafiltration (CVVHDF). The findings on admission blood work were persistent thrombocytopenia, hemolysis, deranged liver, pancreatic and cardiac markers, and mildly elevated INR and PTT (Table 1). The serum C3, C4, direct coombs test, ANA, anti-dsDNA, p-ANCA, and c-ANCA levels were normal.

Table 1.

Summary of investigations

Investigation	At presentation	At recovery	Normal range
Hemoglobin (g/L)	91	108	125–160
MCV (fL)	90	89.3	79–95
Platelets (×109/L)	20	324	150–400
LKC (×109/L)	15.5	8.5	4.0–10.0
Neutrophils (×109/L)	12.8	7.6	1.5–8.0
Reticulocyte (×109/L)	425	265	10–100
Glucose (mmol/L)	7.1	4.2	3.4–11.0
Creatinine (μmol/L)	248	52	62–120
Urea (mmol/L)	6.8	6.6	≤8
Lipase (U/L)	538	228	13–60
Amylase (U/L)	285	137	28–100
Lactate (mmol/L)	2.2	1.0	0.9–2.4
Troponin-T (ng/L)	1,715	12	≤14
INR (s)	1.7	1.0	0.9–1.1
aPTT (s)	36	17	22–30
Fibrinogen (g/L)	1.83	1.1	1.7–4.2
LDH (U/L)	1,799	291	≤300
Haptoglobin (g/L)	Undetectable	1.21	≤1.93
ALT (U/L)	114	52	≤41
AST (U/L)	193	31	≤40
GGT (U/L)	18	58	≤60
ALP (U/L)	162	117	≤468
Bilirubin (μmol/L)	103	6.5	3.4–17.1
Creatine Kinase (U/L)	450	71	≤190
ADAMTS13 Activity (%)	<1	>101	41–130

ALP Alkaline phosphatase; ALT Alanine aminotransferase; AST Aspartate aminotransferase; GGT Gamma-glutamyl transferase; LKC Leukocyte count; LDH Lactate Dehydrogenase; INR International normalized ratio; MCV Mean corpuscular volume; aPTT Activated partial thromboplastin time.

DISCUSSION

The initial presentation with hemolysis and thrombocytopenia suggested an immune-mediated etiology or thrombotic microangiopathy (TMA). Coombs negativity and marked RBC fragmentation supported TMA. In view of fever and a fulminant course, TMA was initially suspected to be secondary to sepsis and DIC. However, mild derangements in INR and PTT despite a severe presentation are atypical for overt DIC. Therefore, other etiologies of TMA were explored. There was no preceding diarrhea to suggest shiga-toxin-induced hemolytic uremic syndrome, which is the most common cause of TMA in children. Other potential TMA etiologies were ruled out including pneumococcal pneumonia, malignant hypertension, drug-induced TMA, post viral (epstein barr, cytomegalovirus, herpes simplex), post-bone marrow transplantation and malignancy. Furthermore, a normal autoimmune work-up did not favour an underlying autoimmune disorder. Though COVID was not a concern at the time of initial presentation of this case, a possibility of multisystem inflammatory syndrome in children (MIS-C) would be a consideration in current times. Given the unremarkable preliminary TMA work-up, and persistent significant neurological involvement, serum ADAMTS13 level was checked, which was found to be < 1%, with <10% level considered to be diagnostic of TTP. In the interim, blood and urine cultures obtained prior to the administration of antibiotics turned out to be negative.

The prevalence of childhood-onset acquired TTP is ~1 case per million children. The age distribution of the first TTP episode in children ranges from four months to 17 years (median: 13 years) (1). Fever is reported in 36% of children (1). Delayed diagnosis and incomplete treatment of TTP contribute to a high mortality rate, approaching 90% of all cases (1). Timely initiation of effective therapy reduces mortality rates to 10%.

TTP is caused by an underlying deficiency in ADAMTS 13 enzyme. ADAMTS 13 is responsible for cleaving von Willebrand factor (VWF) (2). Impaired VWF breakdown leads to large von Willebrand multimers, inducing intravascular platelet aggregation and microvascular thrombosis. ADAMTS 13 deficiency is acquired in 90% of cases (caused by ADAMTS13 autoantibodies), or is congenital (ADAMTS 13 gene mutation) (2). Our patient was found have ADAMTS13 autoantibodies, thereby confirming the diagnosis of acquired TTP.

Plasmapheresis removes circulating anti-ADAMTS13 antibodies, and forms the cornerstone of TTP management (1). In addition, prednisone is administered to suppress new anti-ADAMTS13 antibody production (1). Rituximab, a humanized monoclonal antibody directed against the B-cell antigen CD20, inhibits autoantibody formation and is recommended in the setting of a suboptimal response to plasmapheresis and for preventing TTP relapses (1). With the diagnosis of TTP, our patient was started on daily plasmapheresis (1.5 × plasma volume) and methyl prednisone (15 mg/kg IV daily x three), followed prednisone (60 mg/m² oral daily). Despite thrombocytopenia, platelet transfusion is contraindicated in TTP (to avoid TMA escalation), unless there is significant bleeding. After a third session of plasmapheresis, our patient showed clinical improvement, with extubation, discontinuation of inotropes, and conversion to intermittent hemodialysis. With the goal to expedite recovery and to prevent future TTP relapses, the first rituximab dose (375 mg/m²) was administered after the fourth plasmapheresis session. After a fifth session of plasmapheresis, his encephalopathy and acute kidney injury improved further, allowing a discontinuation of hemodialysis. MR brain and MR angiogram were unremarkable, with no suggestion of stroke, stenosis, or aneurysm.

Blood work at hospital discharge showed a normalizing trend of TMA markers, pancreatitis, cardiac dysfunction and ADAMTS13 level (Table 1). After discharge, prednisone was slowly weaned, and a 1-month course of weekly rituximab was completed. Paediatric TTP patients have relapse in about 24% of cases (1). Approximately 2 years later, our patient continues to be healthy with no history of TTP relapse.

CLINICAL PEARLS

1. In a child presenting with suspected sepsis and DIC, other potential etiologies of TMA should be considered until the diagnosis of sepsis is confirmed.

2. In the presence of significant neurological involvement, relatively mild INR and PTT derangement and unremarkable preliminary TMA work-up, a serum ADAMTS13 level should be checked to rule out TTP.

3. If the diagnosis of TTP is missed, mortality rate can approach 90%. Timely initiation of the effective therapy (plasmapheresis, prednisone, and rituximab) reduces mortality rates to 10%.

Funding: There are no funders to report for this submission.

Informed Consent: The patient’s mother provided informed consent for publication of this case.

Potential Conflicts of Interest: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.