Fulminant thrombotic microangiopathy in Pediatrics: Where diagnostic and therapeutic dilemmas meet
Authors: Raffaele Renella, Carolyn Stickney, Mahima Keswani, Thomas Mancuso, David Casavant, Michael Ferguson, Anupama Narla
Journal: American Journal of Hematology (2012)

We received a request to admit a previously healthy 17-month-old male infant to our tertiary critical care unit for decompensated respiratory distress, associated with fever, acute jaundice, and severe electrolyte imbalances of unknown origin. The patient had recently been treated by his primary pediatrician for acute otitis media with a 3-day course of amoxicillin. At his arrival in the outside facility's emergency department, his clinical exam revealed respiratory distress, hyperthermia, poor peripheral perfusion as well as acutely progressive icterus. Pulse oximetry was >95% on a non-rebreather oxygen mask, but decreased breath sounds were noted on the left. A chest X-ray showed diffuse left-sided opacification without effusion or pneumothorax. Laboratory tests indicated acute renal failure, severe hyperkalemia, thrombocytopenia, and anemia. The simultaneous presentation of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure suggests an acute thrombotic microangiopathy (ATM) [1]. In ATM, the formation and dissemination of platelet thrombi lead to occlusion, ischemia and necrosis of end-organs [2]. In children, the most frequent ATM is hemolytic uremic syndrome (HUS), but a similar pathophysiology is implicated in thrombotic thrombocytopenic purpura (TTP) and diffuse intravascular coagulation (DIC) [3]. A majority of pediatric cases of HUS, classified as typical, are attributable to Shiga exotoxin (Stx)-producing microbial agents acquired by ingestion of pathogenic strains of E. coli [4, 5]. These patients often present with diarrhea, a sign that was absent in our case [6]. While the absence of gastro-intestinal symptoms is not sufficient to formally exclude E. coli-associated HUS, and direct testing for the pathogen, its toxin (i.e., Stx1, Stx2), and/or indirect measurement of acute reactants (i.e., LPS-antibodies) is confirmatory, our patient unfortunately produced no stool to examine [4, 5]. More specifically, the combination of a recent history of otitis along with respiratory symptoms was in our case indicative for S. pneumoniae-associated HUS. Considering this to be the most likely diagnosis should raise immediate concern and prompt immediate action. In fact, S. pneumoniae-associated HUS constitutes an absolute emergency, which has been associated with higher acuity and unfavorable acute and long-term outcomes [7, 8]. In such setting, administration of vancomycin and a third generation cephalosporin should not to be delayed while the diagnostic process is ongoing, and transfusion of blood products is possibly contraindicated upfront. Alternative triggers to consider in the differential diagnosis, although exceedingly rare, are medications, mutations within the complement system, and metabolic disorders (i.e., methylmalonic aciduria). These are grouped under the denomination of atypical HUS (aHUS) [9-11]. As our patient was not exposed to any significant medication and we could not identify a familiar pattern suggestive for a genetic etiology and/or neonatal metabolic disease, the most likely diagnosis considered was S. pneumoniae-associated HUS. Resuscitation was initiated with crystalloid fluids and oxygen was administrated. The patient also received a platelet transfusion and empiric broad-spectrum intravenous antibiotic therapy. Prior to transport, the patient was intubated for worsening respiratory distress and started on a dopamine infusion. Transfer occurred within 2 hours of the initial request. In patients with ATM, prompt recognition of the initial diagnosis and coordinated therapy involving interdisciplinary collaboration of hematology and nephrology specialists is warranted. For our patient, the likely diagnosis of S.pneumoniae-associated HUS appropriately prompted aggressive resuscitation and immediate empiric antimicrobial therapy [7, 12]. Agents to consider include third generation cephalosporins and vancomycin, especially when a pneumococcal etiology is suspected [12], and our patient correctly received such medications. Confirming S.pneumoniae-associated HUS beyond the clinical suspicion remains difficult. In fact, an array of tests, including the Coomb's test (direct antiglobulin test, DAT) Thomsen-Friedenreich antigen activation, or peanut lectin assays can be helpful, but have neither been validated in large cohorts nor are, for some of them, universally available [9]. Platelet transfusion is indicated in patients with active bleeding, and/or when surgical intervention is required. However, transfusion should always be carefully discussed as it could contribute in aggravating the ATM cascade [6], and should possibly have been avoided in this context. Upon his arrival to our institution, the infant was unresponsive and displayed persistent poor perfusion despite vasopressors and fluid resuscitation; the addition of epinephrine and vasopressin did not elicit a significant cardiovascular response. He remained entirely anuric. Laboratory tests were significant for severe acidosis (pH 6.74, lactate 10.8 mmol/L), anemia (hemoglobin 4.9 g/dL, hematocrit 9.4%), hyperkalemia (9.7 mmol/L), and renal failure (BUN 99 mg/dL, creatinine 2.0 mg/dL). There was evidence of intravascular hemolysis (LDH 6090 U/L) and disturbed hemostasis (D-dimers 9.23). Platelets were 300 k/microl (after transfusion in the outside institution). The peripheral blood smear (Fig. 1) revealed neutrophils containing Doehle bodies and toxic inclusions. A significant amount of early myeloid forms and progenitors including meta-, pro-, and myelocytes were seen, likely representing acute stress on the bone marrow. The erythroid morphology demonstrated extreme abnormalities, with profound anisopoikilocytosis and almost no normal erythrocytes identified. Fragments and schistocytes were seen throughout. There were frequent nucleated erythrocytes, but no target cells were seen. Platelets were normal in granulation and morphology, although clear transfusional dimorphism was observed with giant platelets seen. Peripheral blood smear stained by MGG, showing prominent schistocytosis with echinocytosis. Inset shows early myeloid progenitors indicating medullary stress. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] While therapeutic management in an acute setting should be driven by a presumptive diagnosis, it ultimately remains important to distinguish between HUS, TTP, and DIC [1]. In fact, the administration of blood products and/or plasma exchange/hemodialysis require diligent consideration of the underlying ongoing pathophysiological process(es). A situation like the one presented above, where S. pneumonia-associated HUS is ranked highly in the differential, is exemplary. In this setting, exogenous plasma containing antipneumococcal antibodies could have potentially amplified the pathogenic reaction, while a fresh frozen plasma transfusion would have been indicated in the context of a strong probability of genetic aHUS or TTP [3, 6, 10]. This distinction is particularly challenging due to the considerable clinical overlap between the initial presentations of HUS/TTP/DIC, and the fact that it often requires time from laboratory perspective. Results from microbial cultures/toxin assays (i.e., Stx1-2, E. coli in typical diarrheal-HUS, or S.pneumoniae in pneumococcal HUS) or testing for enzymatic (i.e., ADAMST13 deficiency in TTP) and genetic causes (i.e., complement pathway mutations in atypical HUS) rarely can help the clinician in early diagnosis and therapy, as they are not readily available. Pragmatically, we considered DIC unlikely in our patient as the initial symptoms (e.g., jaundice, absence of fever) were not suggestive of sepsis ab initio. Equally, TTP is exceedingly rare in children [11]. The congenital form, referred to as Upshaw-Schülman syndrome is caused by genetic mutations affecting ADAMST13, a von Willebrand factor cleaving metalloprotease von Willebrand factor, could have affected this infant. The antibody-mediated form of this condition is mostly found in autoimmune associations and mostly affects children in teenage years. Both congenital and acquired TTP were deemed less likely than S.pneumoniae-associated HUS in our case. In all of the above diagnostic settings, judicious monitoring and supportive care alone are the rule initially. Ultimately, aggressive resuscitative efforts must be weighed against the risk of volume overload, secondary respiratory failure (especially in the setting of evolving acute kidney injury) and end-organ damage on a case-by-case basis. This might require multidisciplinary interaction in a tertiary center especially for the very rare group of patients with a hyperacute presentation of ATM, which represents an immediately life-threatening disorder. Persistent severe hyperkalemia was treated with intravenous calcium, bicarbonate, insulin, and albuterol. On the electrocardiogram, the QRS complex remained narrow throughout resuscitation. At that point, the patient's abdomen was noted to be hard and distended. A bedside ultrasound showed aperistaltic thickened loops of dilated and fluid-filled bowel with increasingly echogenic, hyperemic mucosa, which are findings consistent with an ischemic bowel. A small amount of ascites was seen in the subhepatic region and in the lower quadrants, but deemed inaccessible by paracentesis. Bradycardia and cardiac hypokinesia were also observed. Because of the refractory nature of the acidosis, hemodialysis was attempted using a blood/albumin prime; however, no adequate vascular flows could be achieved. Epinephrine and vasopressin infusions were titrated without effect, and the patient continued to require full code doses of epinephrine. As all attempts to correct the end-organ damage and reverse the underlying pathophysiologcal cascades of ATM by supportive measures failed, we considered the options that our patient might suffer from aHUS of a genetic origin, or have a particular vulnerability to an ATM-triggering exposure [13]. In familial cases of aHUS, several mutations have been identified in nine putative genes, all encoding for proteins of the complement pathway [14]. The majority of familial cases have mutations in CFH (complement factor H) followed by CD46 (MCP) (membrane cofactor protein), CFI (complement factor I), C3 (component of complement C3), CFB (complement factor B), and THBD (thrombomodulin). Novel therapies have recently been described for patients suffering from complement-involving disorders. Eculizumab, a humanized monoclonal antibody against the complement pathway protein C5 employed in patients with paroxystic nocturnal hemoglobinuria, has been given in situations where the suspicion for aHUS was high (recurrent/relapsing HUS of infancy), but also in cases of classic E. coli associated HUS where the evolution over several days indicated a highly likely fatal outcome [15, 16]. Although it would not formally have been required to prove complement mutations in our patient to administer eculizumab in ultima ratio, we did not elect such therapy as we deemed its potential beneficial effects to be at best limited. In fact, we interpreted the diffuse digestive ischemia to be associated to the severe systemic hypotension and hypoperfusion as well as the microthrombotic ischemic obstruction of the gut vasculature, rather than an expression of bacterial (E. coli) infection. Also, and to be consistent with our most likely etiologic source, there has been no previous report of eculizumab in patients with S. pneumoniae-associated HUS. In cases of significant acute kidney injury secondary to HUS, renal replacement therapy may be required to prevent complications of metabolic disturbances and fluid overload. Different modalities have been successfully used in this setting, including peritoneal dialysis, intermittent hemodialysis, as well as continuous renal replacement therapy (CRRT). The selection of appropriate therapy is dependent on the clinical situation as well as the goals of treatment (solute clearance and/or ultrafiltration). In patients with associated multiorgan system failure and hemodynamic instability, CRRT is typically the mode of choice. At that time, the patient's left pupil was noted to be fixed and dilated. Additionally, ventilation had become increasingly difficult with poor compliance and increasing hypercarbia (pCO2 >100 mmHg). Ongoing discussions with parents and family members were directed toward the patient's extremely poor likelihood of survival. We discussed that all attempts to reverse acidosis had failed and that cardiac arrest was inevitable since we could not reverse the underlying process. The parents nonetheless requested cardio-pulmonary resuscitation (CPR) in event of cardiac arrest. Patient became increasingly bradycardic and lost central pulses; he received CPR for 15 min. The parents—who remained at bedside throughout CPR—were advised that we would not be able to successfully resuscitate the patient and resuscitative efforts were discontinued. Blood and sputum cultures remained negative. An autopsy was declined by the family. From a pathophysiological perspective, our case evokes S. pneumoniae-associated HUS in its most acute form, while in its chronic evolution it is usually associated with recurrence and a high-risk of progression to end-stage renal disease [7-9]. This patient vignette illustrates that although rare, ATM in childhood can, in its hyperacute form, be associated with a high mortality and morbidity. Immediate recognition of the triad of acute hemolytic anemia, acute thrombocytopenia and acute renal failure should prompt aggressive evaluation, resuscitation, and supportive therapy whenever appropriate, but also interdisciplinary consultation with a pediatric nephrologist and hematologist whenever possible. In fact, transfusional support for anemia, thrombocytopenia, and coagulopathy in ATM requires careful discussion. Replacement is not always indicated and could potentially precipitate the ongoing disorder. This also applies to plasma exchange and hemodialysis for acute renal failure. Novel therapies targeting the complement (i.e., eculizumab) need to be considered whenever E. coli-associated HUS or genetically based atypical HUS is high in the differential diagnosis [17].