INTRODUCTION

Advanced Trauma Life Support has set standard guidelines for treating polytrauma injuries [1]. However, certain complex presentations necessitate intensive evaluation and multifaceted management. Treating patients with both burns and musculoskeletal injuries presents a notable challenge. The two most common injury mechanisms are motor vehicle collisions and falls associated with electrical injuries [2]. Key factors for early recovery include adequate fluid resuscitation, infection prevention, and fracture stabilization. Wound contamination and an immunocompromised state can adversely impact prognosis.

Wound infection frequently complicates the management of burns due to their impact on the skin’s protective barrier—the body’s first line of defense—and the oxidative stress associated with a high catabolic rate [3]. The incidence of sepsis in patients with burns covering more than 20% of their total body surface area can range from 3% to 30%, with septic shock and multiorgan dysfunction syndrome accounting for approximately 54% of burn-related deaths [4]. When burn injuries present with compound fractures, the patient’s susceptibility to infection increases, with adverse impacts on other organ systems. For the associated blood dyscrasia, the differential diagnosis includes numerous conditions, such as hemorrhage (both internal and external), dilutional coagulopathy, systemic inflammatory response syndrome, sepsis-induced disseminated intravascular coagulation (DIC), fat embolism, third compartment fluid shift, thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, thrombotic microangiopathy (TMA), drug toxicity, and others.

Prophylactic antimicrobial therapy, which targets gram-positive, gram-negative, and anaerobic bacteria, is routinely administered during the first 48 hours following grossly contaminated injury. This is done to prevent the colonization of the wound by pathogenic bacteria. Consequently, the diagnosis of antimicrobial drug toxicity or reaction that may be causing hematological disturbances is not typically prioritized.

Sepsis-associated DIC is characterized by consumptive coagulopathy and TMA, which are induced by endotoxins. In contrast, drug toxicity or reactions trigger a dose-dependent reversible immune or nonimmune response against blood cells. This leads to multiple organ dysfunction and transient bone marrow suppression [5]. Severe hematological manifestations are rare in cases involving ceftriaxone [6] and metronidazole [7] but are more common with gentamycin [8]. Typically, removal of the causative drugs results in recovery within 7 to 10 days. For cases that do not respond to discontinuation, plasmapheresis, intravenous immunoglobulin, and steroid therapy may be necessary to eliminate the immune or nonimmune complexes from the body [9].

CASE REPORT

A 32-year-old man presented to the emergency room 4 hours after being involved in an accident, which resulted in burns to his right leg and a fracture with an open wound on his left leg. He had no significant medical, surgical, or family history. The patient occasionally consumed alcohol but had no history of other substance use. He worked as an electrician and was electrocuted while servicing a high-voltage transformer. Following the electrocution, he fell from the electric pole, his clothes were charred, and he lost consciousness for 15 minutes, after which he had no recollection of the event (Figs. 1, 2).

The patient’s Glasgow Coma Scale score was 15 of 15, accompanied by a rapid, thready pulse and mild tachypnea. Two large-bore intravenous cannulas were used to initiate a saline infusion. Following 20 minutes of fluid therapy, the patient’s vital signs normalized. During the primary survey, the wounds were thoroughly irrigated, and a splint was applied to immobilize the fracture. No entry or exit wounds were observed, indicating electrical flash burns. Noncontrast computed tomography of the brain and abdomen, as well as focused assessment with sonography for trauma evaluation, were normal.

After skin-sensitivity testing, empirical antibiotics—ceftriaxone, gentamicin, and metronidazole—were administered. Vital signs were monitored hourly. On the second day of admission, repeated blood tests revealed a substantial decrease in platelet count (<30×10³/mm³) and elevation of hepatic enzymes (more than threefold), total serum bilirubin (10.2 mg/dL), and serum creatinine (1.8 mg/dL), accompanied by an electrolyte imbalance. The patient exhibited tachycardia (pulse rate between 100 and 108 beats/min), a mean arterial pressure of 75 mmHg, and continuous mild pyrexia (<37.8 °C). An extensive evaluation was conducted to rule out any secondary or occult thoracic or abdominal bleeding, fulminant wound infection, or fat embolism. Sonography revealed no signs of internal organ injury. The patient received supportive care. However, by the following morning, several parameters had deteriorated further. At this point, the patient had a decreased platelet count (<12×10³/mm³), increased serum creatinine level (2.5 mg/dL), and elevated lactate dehydrogenase (LDH) level (1,070 U/L), and his total bilirubin remained high (6.4 mg/dL). Urine output was maintained at 30 to 45 mL/hr. Icterus was present, but he exhibited no other signs of mucosal bleeding, ecchymosis, or punctate bleeding.

The patient’s medication chart was reviewed, and the suspected drugs—ceftriaxone, gentamycin, metronidazole, and diclofenac—were discontinued. The patient was then transferred to the intensive care unit (ICU). Upon admission, the ICU protocol was initiated, which included a single injectable broad-spectrum antibiotic, meropenem. Repeat abdominal sonography revealed mild splenomegaly. The coagulation profile showed minimal changes, with a prothrombin time (PT) of 16.8 seconds and an international normalized ratio (INR) of 1.4. No conclusive diagnosis was established. Supportive care was provided, and the patient’s vital signs remained stable without further decline. The patient continued to experience a persistent mild fever with intermittent spikes not exceeding 38.3 °C.

By 48 hours after ICU admission and revision of the medication regimen, the patient’s hepatorenal functions had improved. Specifically, hepatic enzymes transitioned from over threefold elevation to comparatively mild elevation, total bilirubin decreased from 6.4 to 3.7 mg/dL, and serum creatinine improved from 2.5 to 1.9 mg/dL. However, hematological parameters deteriorated, as evidenced by marked decreases in hemoglobin level (from 9.6 to 7.4 g/dL), white blood cell (WBC) count (from 11.9×10³/µL to 7.4×10³/µL), and platelet count (12×10³/mm³). To prevent any spontaneous bleeding, 3 units of platelet concentrate were transfused. The patient developed a new symptom of respiratory distress, necessitating oxygen support at a flow rate of 5 L/min via a mask. Radiological evaluation revealed bilateral lower lobe infiltrates on chest x-ray. Vancomycin injection was added to the treatment regimen to provide coverage against gram-positive bacteria. Blood and sputum cultures were collected and sent to the laboratory to identify the causative pathogen and to guide the selection of definitive antimicrobial therapy. The burn wound was managed with regular aseptic dressings.

The patient experienced a further decrease in serum hemoglobin (to 5.7 g/dL) and a reduced WBC count (2,920/µL). To exclude the possibility of sepsis-induced DIC, we conducted a series of tests: serum haptoglobin (0.08 mg/dL), serum fibrinogen (508 mg/dL), fibrinogen degradation product (FDP) (≥5–<20 µg/mL), repeat coagulation profile (PT, 14 seconds; activated partial thromboplastin time, 24 seconds; INR, 1.2), and reticulocyte count (0.50%). The combination of pancytopenia, normal coagulation profile, and low reticulocyte count suggested peripheral intravascular blood cell destruction and suppressed hematopoietic cell proliferation in the bone marrow. The peripheral blood smear revealed an intermediate schistocyte count (1%–2%). The patient’s respiratory symptoms worsened, necessitating a transition to continuous positive airway pressure mechanical ventilation with a noninvasive mask. Despite empirical antibiotic treatment, the patient continued to exhibit a low-grade fever with intermittent spikes. As the patient was still under investigation, the fever was managed with cold sponging. Given the stress of the injury and compromised immune response, opportunistic fungal bronchopneumonia was suspected. A serum galactomannan test was ordered, and fluconazole (200 mg, once daily) was added to the treatment regimen. Additionally, the patient received a supportive transfusion of 1 unit of packed red blood cells and 3 units of fresh frozen plasma (Fig. 3).

The patient’s symptoms improved over the next 2 days as he was weaned from noninvasive mechanical ventilation to nasal prong support at a flow rate of 4 L/min. The patient received transfusions of 1 unit of packed red blood cells and 3 units of fresh frozen plasma daily for 2 consecutive days. Following these interventions, hematological parameters improved, with the hemoglobin level rising to 7.3 g/dL, the WBC count reaching 8,290/µL, and the platelet count increasing to 73×10³/mm³. By the seventh day of ICU admission, the supportive therapy had led to the normalization of the complete blood count, with hemoglobin at 10.6 g/dL, WBC at 9,300/µL, and platelets at 464×10³/mm³. The injectable antibiotics were discontinued on day 10 of ICU admission. The patient was then given oral linezolid 600 mg twice daily for 5 days and fluconazole 200 mg daily for 10 days.

The blood culture report, which arrived late, revealed an opportunistic infection with Ochrobactrum anthropi after 41 hours of incubation. Additionally, an elevated serum galactomannan level (optical density index, 1.13) confirmed the suspected diagnosis of fungal bronchopneumonia. By day 10 of hospitalization, the bilateral chest infiltrates had resolved. Subsequently, the patient underwent surgery for the left leg fracture, during which an external fixator was placed. The patient was then discharged and scheduled for follow-up in the outpatient department.

Ethics statement

Written informed consent for publication of the research details and clinical images was obtained from the patient.

DISCUSSION

Thrombocytopenia can be either inherited or acquired, with its etiology broadly classified into four categories: pseudothrombocytopenia, platelet underproduction, peripheral destruction, and splenic sequestration. Peripheral destruction of platelets can be caused by conditions such as TMA, DIC, TTP, immune thrombocytopenia (ITP), drug-induced thrombocytopenia (DITP), and heparin-induced thrombocytopenia. DITP is a rare entity and is generally a diagnosis of exclusion. Common causes of platelet underproduction should also be considered, including nutritional deficiencies (such as those of vitamin B12, folate, and copper), recent radiotherapy and chemotherapy, and various bone marrow disorders. Pseudothrombocytopenia is a dilutional effect that is commonly observed after the third day of initial fluid resuscitation in patients with major burns.

Differential investigations include a peripheral blood smear (to obtain a schistocyte count, assess megakaryocytes, and identify immature cells), a reticulocyte count to evaluate bone marrow response, and a coagulation profile, which encompasses PT, activated partial thromboplastin time, INR, serum haptoglobin, fibrinogen, fibrin degradation products, serum LDH, D-dimer, serum ADAMTS13 levels, and blood culture. Assessing drug-specific antibodies necessitates specialized testing, such as flow cytometry analysis, immunoblot analysis, and immunoprecipitation, which are not widely available.

A high schistocyte count (greater than 2%) with reticulocytosis is observed in cases of peripheral blood cell lysis, whereas a low reticulocyte count indicates hypoproliferation of progenitor cells and suppressed bone marrow activity. Laboratory investigations must be interpreted in conjunction with clinical findings, as coexisting disorders can complicate the diagnostic process. Liver disorders, such as hepatitis, can disrupt the production of coagulation factors, leading to elevated PT and INR and decreased serum haptoglobin levels, often accompanied by thrombocytopenia. Elevated serum LDH levels, indicative of cell damage, may be present in conditions such as trauma, malignancy, hepatitis, renal disorders, and hematological diseases. Serum fibrinogen, an acute-phase reactant synthesized by the liver, can have fluctuating levels due to the use of oral contraceptives, acute infections, neoplasms, and other states of physical stress. Serum FDP, which increases with the activation of the coagulation system, is considerably elevated (at 10 to less than 25 µg/mL) in DIC and is used as a diagnostic criterion alongside other markers [10]. An ADAMTS13 level below 10% is the most reliable indicator for distinguishing TTP from other conditions [11]. While this parameter is also known to decrease in sepsis, it typically remains above 30%.

Sepsis-induced DIC—the most common result of the differential diagnostic process in patients with burns—typically manifests 5 to 10 days after severe trauma or burn injuries. It is characterized by multiorgan dysfunction, abdominal distension, tachypnea, vasomotor signs of hypotension, and neurological decline. The infectious agents proliferate beneath necrotic debris and eschars, circumvent the host’s defense mechanisms through biofilm formation, invade local tissues, and release endotoxins into the bloodstream, triggering inflammatory responses. The temporal association of altered hepatic, renal, and hematological values within 24 hours of initiating drug therapy excluded the possibility of sepsis in this case. The rapid improvement in blood parameters following the discontinuation of antibiotics supported the diagnosis of drug-induced toxicity. The compound fracture wound on the left leg and the burn wound on the right leg were both clinically healthy, with sterile cultures showing no evidence of local infectious inflammation.

Procalcitonin (PCT), C-reactive protein (CRP), and interleukin-6/8 (IL-6/8) are reliable biomarkers for screening patients with suspected ongoing sepsis. PCT, a pro-peptide of calcitonin, increases 2 to 4 hours following the release of endotoxins and pro-inflammatory mediators, peaking at 24 hours after injury. In contrast, CRP levels rise more slowly, beginning 12 hours after the initial stimulus and remaining elevated for an extended period. A PCT level exceeding 1.5 ng/mL is highly sensitive in predicting the development of sepsis; however, like other acute-phase reactants, its utility is limited in the acute phase following major burn injury and polytrauma. IL-6 is a superior marker for sepsis, effectively distinguishing between inflammation and bacteremia. Patients with positive blood cultures exhibit significantly higher IL-6 levels. Overall, no single validated diagnostic test for sepsis is available at present, and its identification depends on a combination of clinical and laboratory criteria, including the burn Sequential Organ Failure Assessment (SOFA) score. Moreover, diagnosing sepsis in patients with severe burns (greater than 20% total body surface area) is further complicated by the overlap of clinical signs between the postburn hypermetabolic response and sepsis [12].

The index case represents a notable adverse reaction to ceftriaxone, gentamycin, and/or metronidazole, which are commonly used as prophylactic antibiotics. These drugs may also induce hepatorenal dysfunction and pancytopenia. The concurrent use of multiple drugs complicated our ability to attribute the diagnosis to a single drug or to additive side effects. According to the Naranjo adverse reaction probability scale, a probable association exists between the use of gentamycin and/or ceftriaxone and the development of pancytopenia. The Naranjo scale categorizes adverse drug reactions as doubtful, possible, probable, or definite [13]. In this case, the low reticulocyte count—indicative of pancytopenia—suggests a bone marrow origin, while elevated levels of LDH and FDP suggest an active hemolytic process, such as sepsis-induced DIC or ITP. However, the presence of polytrauma injury and hepatitis complicates the clinical picture. Additionally, the peripheral smear showed 1% to 2% schistocytes with megakaryocytes, which is neither sensitive nor specific for DIC. Therefore, in this case, the pancytopenia was inferred to be a result of single or additive drug toxicity due to gentamycin, ceftriaxone, or both.

We present a rare case of probable ceftriaxone/gentamycin-induced ITP with bone marrow suppression following the initiation of empiric prophylactic antibiotic therapy for grossly contaminated polytrauma injury. The administration and subsequent withdrawal of these sentinel drugs closely paralleled changes in hepatorenal function and complete blood cell count. This case underscores the importance of maintaining high clinical suspicion of DITP when encountering unexplained thrombocytopenia. Pancytopenia in the context of polytrauma injuries presents a diagnostic challenge and may require extensive evaluation with vigilant monitoring. Identifying the responsible medication can be difficult in patients who are acutely ill and were started on multiple new medications upon admission. The defined biomarkers (PCT, CRP, IL-6/8/10, and presepsin) provide only adjunctive support to the conclusions drawn from continuous, close clinical observation (via the burn SOFA score) in critically injured patients.

ARTICLE INFORMATION

Author contributions

Conceptualization: all authors; Methodology: PSS, TS; Project administration: PSS, TS; Visualization: PSS, TS; Writing–original draft: all authors; Writing–review & editing: all authors. All authors read and approved the final manuscript.

Conflicts of interest

The authors have no conflicts of interest to declare.

Funding

The authors received no financial support for this study.

Data availability

Data sharing is not applicable as no new data were created or analyzed in this study.

Fig. 1.

Right leg burns.

Fig. 2.

Left leg x-ray. (A) Anteroposterior view. (B) Lateral view.

Fig. 3.

Trends of blood investigation. (A) Hemoglobin drops to minimum at sixth day of hospitalization with normalization after 3 units of packed red blood cells transfer. (B) White blood cell (WBC) count was lowest on sixth day with gradual normalization at 2 weeks. (C) Hepatic enzymes start to improve dramatically at third day of admission. (D) Serum creatinine level normalized after 3 days of stopping the sentinel drugs. (E) Platelet count dips to lowest on second day, with increasing trend after sixth day of admission. AST, aspartate aminotransferase; ALT, alanine aminotransferase.

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