UNDIAGNOSED SYSTEMIC MASTOCYTOSIS PRESENTING AS POSTOPERATIVE DISTRIBUTIVE SHOCK: A CASE REPORT

Abstract

Systemic mastocytosis (SM) is a rare clinical condition resulting from a clonal proliferation of abnormal mast cells. The clinical presentation may vary from mild cutaneous manifestations to aggressive systemic symptoms including intermittent episodes of anaphylaxis. We present a case of a 69-year-old male with abrupt and recurrent episodes of anaphylaxis with refractory distributive shock following cardiac surgery with cardiopulmonary bypass. Following a complex postoperative course, a bone marrow biopsy ultimately confirmed the diagnosis. Although rare, SM should be considered in the differential diagnosis of postoperative patients with unexplained and recurrent episodes of distributive shock.

INTRODUCTION

Systemic mastocytosis (SM) is a rare clinical condition characterized by abnormal clonal proliferation of mast cells that accumulate in one or more organs.¹ The clinical manifestations of SM may overlap with other systemic diseases, thus posing a diagnostic dilemma.^2,3 We present the case of a 69-year-old male with unexplained episodes of refractory distributive shock following intramyocardial left anterior descending artery (LAD) unroofing with cardiopulmonary bypass (CPB), which was ultimately diagnosed as SM. Written informed consent was obtained from the patient for this report.

CASE DESCRIPTION

A 69-year-old male with a past medical history of hyperlipidemia was transferred to our institution for evaluation of recurrent episodes of chest pain, dyspnea and syncope. After an extensive work-up, he was found to have symptomatic and hemodynamically significant mid-LAD myocardial bridging. The symptoms persisted despite maximal medical therapy, and the decision was made to proceed with unroofing of the intra-myocardial LAD. Following separation from CPB and administration of protamine, the patient became profoundly hypotensive requiring re-initiation of CPB. Vasopressor therapy was rapidly instituted, the patient was re-heparinized, and CPB was promptly reinitiated given refractory hypotension. There were no perceived changes in airway pressures, ventilation adequacy, or arterial oxygenation. Hemodynamic stability was achieved after administration of high dose epinephrine therapy and initiation of a norepinephrine infusion. He was then separated from CPB successfully. Given concern for anaphylaxis, the patient was given dexamethasone and diphenhydramine, followed by a reduced dose of intra-aortic protamine. His activated clotting time (ACT) normalized to 104 seconds (reference 84–139) and hemostasis appeared to be adequate. His chest was subsequently closed, and he was transferred to the cardiac surgery intensive care unit (ICU).

During the first 3 hours of ICU admission, the patient had substantial sanguineous chest tube output (>500 ml/hr). He received multiple blood products in an attempt to optimize his coagulation status, but despite a normal thromboelastogram (TEG) and relatively unremarkable International Normalized Ratio (INR=1.5), activated partial thromboplastin time (aPTT=33 s), fibrinogen level (181 mg/dL), and platelet count (125 ×10⁹/L), the bleeding persisted. The patient was urgently transferred back to the operating room for mediastinal exploration. Although no obvious source of ongoing hemorrhage was visualized from the surgical sites, a large amount of bleeding was emanating from the soft tissues below the sternum and above the pericardium. After bleeding was controlled, the chest was closed and the patient was transferred back to the ICU. By postoperative day (POD) 1, chest tube output decreased (<100 ml/hr), hemodynamics improved, vasopressor therapy was discontinued, and the patient was successfully extubated.

On POD 2, the patient experienced an episode of acute hypotension characterized by an almost instantaneous fall in systolic blood pressure (140s mmHg to 50s mmHg), followed by respiratory distress and hypoxemia. Large boluses of intravenous (IV) vasopressors including epinephrine, phenylephrine, and calcium were given with minimal effect. Crystalloid boluses were rapidly administered simultaneously along with ventilatory assistance by bag mask and, ultimately, endotracheal re-intubation. Point-of-care transthoracic echocardiography revealed a hyperdynamic, and underfilled left ventricular cavity with minimal pericardial fluid. Distal pulses were lost and chest compressions were initiated. Emergent sternotomy was performed at the bedside, which was notable for diffuse microvascular bleeding from all soft tissues and no evidence of tamponade. He was transferred to the operating room for formal surgical exploration, which demonstrated diffuse microvascular bleeding. The overall impression was that his extreme clinical deterioration was not solely due to hemorrhagic shock. Coagulation tests were significant for prolonged INR (1.8), decreased fibrinogen (139 mg/dL), and prolonged aPTT (>300s) in the absence of heparin administration. Additionally, the ACT was greatly prolonged (412s), but a heparin concentration level was only mildly elevated at 0.3 IU/mL (reference<0.1 IU/ml; HepCon HMS Plus, Medtronic). After multiple blood product transfusions and vasopressor titration, the bleeding subsided and his hemodynamics stabilized. Given his prolonged aPTT and ACT, he was given a small dose of intra-aortic protamine following pretreatment with IV steroids and antihistamines. A repeat ACT showed normalization (119s), and the heparin concentration was now undetectable (<0.1 IU/mL). He was transferred back to the ICU on low dose epinephrine and norepinephrine infusions.

The patient was weaned of vasopressors and extubated the next day completely neurologically intact. On POD 4, the patient again experienced an episode of acute profound hypotension associated with respiratory distress and generalized flushing. Point-of-care transthoracic echocardiography revealed adequate left ventricular end-diastolic volume, hyperdynamic biventricular function, and normal inferior vena cava size without significant respiratory variation. During this episode, the patient was noted to be warm and well-perfused on exam despite the systemic hypotension, consistent with a distributive shock. The patient was started on high doses IV vasopressors, steroids, antihistamines, and continuous positive airway pressure support. The patient stabilized and vasopressors were weaned completely within minutes. A tryptase level was checked and returned elevated (143 ng/mL; normal<11.5 ng/mL). Over the course of the next 48 hours, the tryptase levels remained elevated (24 hours=100 ng/mL; 48 hours=95 ng/mL) ultimately prompting a bone marrow biopsy due to concern of SM (Figure 1). The biopsy revealed 5% burden of mastocytes with positive KIT Asp816Val mutation confirming the diagnosis. Antihistamine medications were initiated, and hemodynamics and coagulation derangements improved. The patient was discharged home on POD 9.

Figure 1.

Histopathology of bone marrow core biopsy. (A) Hematoxylin and eosin stain shows normal trilineage hematopoiesis. No abnormalities or dysplastic forms are identified. Tryptase (B) and CD117 (c-KIT) (C) stains highlight spindle shaped mast cells infiltrating the bone marrow. CD25 immunostain (D) highlights neoplastic mast cells supporting the diagnosis of systemic mastocytosis.

DISCUSSION

SM is a rare disorder of proliferation and activation of clonal mast cells.⁴ Here we describe an unusual case presenting as repeated episodes of refractory distributive shock following cardiac surgery. SM is characterized by mast cell hyperactivity resulting in allergic or anaphylactic reactions, gastrointestinal manifestations, neuropsychiatric conditions (e.g. depression), and musculoskeletal involvement (e.g. osteoporosis).⁴ Common signs and symptoms include nausea, diarrhea, urticarial rash, itching, flushing, pruritus, and anaphylaxis.⁴ Bone marrow involvement may lead to cytopenias, thus increasing the susceptibility to infections and bleeding diatheses. Moreover, advanced forms of the disease may present with hepatic, splenic and renal dysfunction.¹

Due to the wide range of clinical manifestations, the diagnosis of SM requires a high index of clinical suspicion. In the present case, the prompt recognition of SM was limited by multiple factors. First, the patient’s preoperative clinical presentation was atypical, as isolated chest pain and syncope are infrequent manifestations of the disease.⁴ Also, the patient did not report any additional systemic conditions consistent with SM. Furthermore, the patient had angiographic evidence of severe intramyocardial LAD bridging, which would certainly explain his clinical symptoms. During the initial operation, the severe hypotensive reaction to protamine, while severe, would not be uncommon in cardiac surgery. Protamine is known to be a trigger for histamine release by mast cells.⁵ To our knowledge, protamine reactions have not been described as being more frequent or more pronounced in patients with SM. Thus, the isolated occurrence of a protamine reaction did not automatically trigger thought of an underlying mast cell degranulation disorder. Postoperatively, the patient had both ongoing blood loss and vasoplegia, both of which are possible complications of cardiac surgery.⁶ The constellation of these perioperative findings undoubtedly contributed to difficulty in diagnosing underlying SM. Outside of the perioperative setting, other systemic diseases often share signs and symptoms with SM. The differential diagnosis is broad and includes gastrointestinal diseases (e.g. celiac disease), autoimmune processes (e.g. vasculitis), and endocrinological disorders (e.g. carcinoid syndrome).⁴ Following a comprehensive clinical evaluation with consultation from hematology and allergy, the aforementioned conditions were excluded in our patient. Elevated tryptase levels and a bone marrow biopsy revealing a clonal population of mastocytes confirmed the diagnosis.

The release of mast cell mediators among patients with SM is triggered by a variety of stimuli.^1,4 Precipitating factors include medications commonly used in anesthesia such as muscle relaxants, narcotics, and antibiotics.⁷ The physiologic stress associated with surgery and anesthesia is also considered a common trigger of mast cell release.^1,4 Our patient was exposed to multiple precipitating factors during the perioperative period, which likely contributed to the severity of his clinical presentation.

Though less recognized, patients with SM are at increased risk of coagulation abnormalities.⁸ Fatal bleeding in the setting of elevated heparin-like anticoagulant in SM has been previously reported.⁹ Mast cell degranulation leads to release of heparin and heparin-like anticoagulant mediators that result in aPTT prolongation.^8,10 This is consistent with the patient in our case, who displayed a significantly prolonged aPTT and ACT on POD 1 despite no recent heparin administration. However, our patient also experienced persistent microvascular bleeding in the immediate postoperative period despite perceived normalization of his coagulation status as evidenced by a normal TEG and normal aPTT. This could potentially be explained by the fibrinogenolytic and anticoagulant properties of massive tryptase release, which have not previously been correlated with TEG findings.¹⁰ Alternatively, the nature of the surgical procedure itself could have been the primary driver of this early postoperative coagulopathy, as postoperative bleeding is among the most frequent complications of cardiac surgery, particularly in those performed with CPB.¹¹ Further study to understand coagulation abnormalities and their potential impact on common laboratory coagulation tests is warranted in patients with SM.

Although a rare disorder, SM should be considered in the differential diagnosis of patients who present with recurrent episodes of anaphylactic shock during the perioperative period. The acute treatment consists largely of supportive measures commonly used for anaphylaxis, including epinephrine, steroids and antihistamines. Proper diagnosis and consultation with a hematologist is essential, given the significant long-term implications.

GLOSSARY OF TERMS

SM

systemic mastocytosis

LAD

left anterior descending artery

CPB

cardiopulmonary bypass

ACT

activated clotting time

ICU

intensive care unit

TEG

thromboelastogram

INR

International Normalized Ratio

aPTT

activated partial thromboplastin time

POD

postoperative day

IV

intravenous