Delayed‐onset thrombocytopenia in a pediatric burn patient
Authors: Jin Kim, Cynthia H. Ho, Keith E. Lewis, Warren L. Garner, Randall Y. Chan
Journal: American Journal of Hematology (2016)

A 14-year-old boy presented with 36% total body surface area (TBSA) flame burns to his face, neck, and torso. On presentation to the hospital, he was endotracheally intubated for possible inhalation injury. Fluid-responsive shock was managed with Lactated Ringer's solution and albumin. Pain and agitation were managed with opiates and benzodiazepines. Aztreonam and clindamycin were started due to concern of septic shock in the setting of a history of penicillin allergy. Thermal burns are a significant cause of injury. Prehospital care involves cooling the burn with cool (but not cold) running water and covering the burn with nonadherent dressings (cling wrap) to minimize heat loss. At the hospital, initial resuscitation includes fluid resuscitation using the Parkland formula, airway protection for patients with concern for inhalation injury, pain control, and transfer to an intensive care unit. He underwent multiple escharotomies, debridements, and skin grafts during the first 2 weeks of hospitalization. His burns were dressed with topical silver sulfadiazine prior to skin debridement on day #11 (Fig.1). He was started on vancomycin when he was found to have clindamycin-resistant Streptococcus pneumoniae on respiratory culture. During his hospitalization, he developed thrombocytopenia at day #3 with a platelet nadir of 137 × 109/L at day #3 followed by normalization of the platelet count by day #6. Clinical events and platelet count during hospitalization, including all medications that may affect the platelet count. Abbreviations: IVIG—intravenous immunoglobulin, PRBC—packed red blood cells, STSG—split-thickness skin grafting. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] The most common causes of thrombocytopenia in a pediatric patient with severe burn injury include burn-induced thrombocytopenia, sepsis, disseminated intravascular coagulation (DIC), drug-induced thrombocytopenia, heparin-induced thrombocytopenia (HIT), and post-transfusion purpura (PTP) (Supporting Information Table I). Burn-induced thrombocytopenia is the most common immediately after injury. Our patient's thrombocytopenia followed by normalization within a week is consistent with the presentation of burn-induced thrombocytopenia. DIC and sepsis were unlikely since our patient was well-appearing and clinically improving at the onset of thrombocytopenia. On day #13, he underwent split-thickness skin grafting of the torso. On the same day, his platelet count again started to decline despite improvement in his wounds and resolution of pneumonia. By day #19, he had developed severe thrombocytopenia with a platelet count of <5 × 109/L. Microscopic examination of his blood smear revealed absence of platelets and normal red and white blood cell morphology. Severe thrombocytopenia, defined as platelet count <50 × 109/L, is unusual in a patient with burn-induced thrombocytopenia or sepsis. Therefore, other etiologies such as PTP, drug-induced thrombocytopenia, thrombocytopenia due to viral infection, HIT, and ITP were considered. PTP occurs 7–10 days after blood product transfusion. However, our patient did not receive his first transfusion until day 20. Drug-induced thrombocytopenia is typically associated with recovery of the platelet count 1 week after discontinuation of the offending agent. We considered several medications such as vancomycin and sulfa drugs (specifically, silver sulfadiazine); none of the medications were temporally related to the thrombocytopenia as illustrated in Fig. 1. HIT was unlikely since thrombocytopenia typically develops 5–10 days after exposure to heparin in patient who has not been previously exposed to heparin and recovers by 1 week after discontinuation of heparin. Our patient was not receiving heparin at the time of onset of thrombocytopenia. In addition, platelet counts in HIT rarely drop below 20 × 109/L. Therefore, ITP was our primary concern. Platelet transfusion was given on day #21 since thrombocytopenia. A 1-hr post-transfusion platelet count showed no change in platelet count. Intravenous immunoglobulin (IVIG) (0.8 g kg−1) was given for suspected ITP and heparin was discontinued. Antibody analysis was negative for HIT. Platelet transfusions are usually avoided in ITP unless a patient develops severe bleeding. However, our patient was given platelets since his severe thrombocytopenia was preventing routine wound care including dressing changes and debridement. In a patient with unexplained thrombocytopenia, platelet count should be assessed 1 hr after transfusion, since a platelet count refractory to transfusion may suggest immune-mediated platelet destruction. Refractoriness to platelet transfusion raised concern for drug-induced thrombocytopenia or allo-immunization from exposure to RBC antigens from previous transfusions. However, the time course made drug-induced thrombocytopenia unlikely and no allo-antibodies were identified by our blood bank. On day #23, thrombocytopenia persisted. Prednisone was started at 4 mg kg−1 day−1. Platelets started to recover 2 days after starting prednisone. He was able to resume daily dressing changes 8 days after initiation of prednisone. Thrombocytopenia is associated with increased morbidity and mortality in children with burn injuries 1, 2. Up to 60% of children with >20% total body surface area (TBSA) burns develop thrombocytopenia 1. While the differential diagnosis is broad, the etiologies of thrombocytopenia can be differentiated by the following: (1) severity of thrombocytopenia, (2) time course of onset, and (3) presence of infection. In the first 72 hr after burn injury, burn-induced thrombocytopenia, a normal physiologic response, is the most common cause 1. Burn-induced thrombocytopenia is caused by platelet activation and consumption at the injury site leading to endothelial damage and destruction of platelets in the peripheral blood 3, 4. This decline in platelets is associated with stress-induced leukocytosis in the first 48 hr followed by leukopenia. Platelet count normalizes by 1 week post-injury and a reactive thrombocytosis occurs in the second week 1. Thrombocytopenia presenting beyond the first week should raise concerns for other etiologies, in particular, sepsis 1. Other diagnoses to consider include disseminated intravascular coagulation (DIC) and drug-induced thrombocytopenia. Lack of response to platelet transfusion in our patient suggested one of the immune-mediated causes of thrombocytopenia (e.g., ITP, PTP, thrombocytopenia due to viral infection, drug-induced thrombocytopenia), except HIT which is not associated with platelet refractoriness 5. Figure 2 is a proposed algorithm for the approach to thrombocytopenia in a pediatric burn patient. Proposed algorithm for evaluation of thrombocytopenia in a pediatric burn patient. Abbreviations: DIC—disseminated intravascular coagulation, ITP—immune thrombocytopenia. A thorough medication history is important to consider drug-induced thrombocytopenia. While drugs such as sulfonamides (e.g., silver sulfadiazine) may precipitate an immune-mediated thrombocytopenia 6, the time course of thrombocytopenia did not correlate with drug exposure in our patient. Silver sulfadiazine can also induce cytopenias through bone marrow suppression; however, severe thrombocytopenia in the absence of other cytopenias is not consistent with marrow suppression 7, 8. ITP is a diagnosis of exclusion and should be considered in a well-appearing patient 9. Platelet count is often <20 × 109/L 10. Bruising, petechiae and epistaxis dominate, while severe hemorrhage is rare 11. Although thrombocytopenia refractory to a transfusion suggests immune-mediated disease, up to 42% of patients with ITP respond to platelet transfusion 12. In an otherwise well-appearing patient with no bleeding or mild bleeding, observation alone is recommended for the management of ITP; however, treatment to raise the platelet count above 50 × 109/L is indicated in patients with risk of bleeding from surgery or trauma 13. Management of severe thrombocytopenia due to ITP in the setting of burns is essential since wound debridement and skin grafting decreases mortality in burn patients with thrombocytopenia 14, 15. First-line therapy includes either (1) single-dose IVIG 0.8–1 g kg−1 and prednisone 1–2 mg kg−1 for 14 days or (2) prednisone 4 mg kg−1 for 3–4 days 13. Platelet transfusion, IVIG, and corticosteroids can be combined to control emergent bleeding 13. The benefits of raising the platelet count should be weighed against the risks IVIG and/or corticosteroids in immune compromised patients 13. There is limited experience with IVIG in burn patients. In one observational study, IVIG did not affect mortality, prevention of sepsis, or length of stay 16. Corticosteroids should be used cautiously since complications such as impaired wound healing, adrenal insufficiency, and hyperglycemia are associated with poor prognosis 17. It is unclear why our patient developed ITP. Because extensive burns cause immune dysregulation 18, the resultant proinflammatory environment, hyperactivation of macrophages, polarization of helper T-cells, and activation B-cells may have resulted in autoimmunization 19. Such helper T-cell polarization and its cascade of effects have been previously implicated in acute ITP 20. To our knowledge, ITP has not been described in the setting of severe burn injury. Because it is a common cause of thrombocytopenia in a well-appearing child, ITP was considered in our patient since he was clinically improving from his burns at the time he developed severe thrombocytopenia. The American Society of Hematology practice guidelines recommend withholding platelet-increasing therapies in patients with skin manifestations (bruising or petechiae) only 21. Assessment of the risks and benefits of IVIG and corticosteroids in burn wound healing compared to the bleeding risk associated with wound care in the setting of severe thrombocytopenia can be challenging. Therefore, the decision whether to initiate IVIG or corticosteroids should be individualized after a multidisciplinary discussion involving hematology and the burn and reconstructive surgery teams. JK drafted the initial manuscript, revised subsequent versions of the manuscript, and approved the final manuscript as submitted. CHH, KEL, WLG and RYC revised subsequent versions of the manuscript and approved the final manuscript as submitted. Additional Supporting Information may be found in the online version of this article. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.