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Marantic Endocarditis and Disseminated Intravascular Coagulation With Systemic Emboli in Presentation of Pancreatic Cancer

Division of Cardiovascular Medicine, Saint Elizabeth's Medical Center, Brighton, MA

Maria Ansari

Division of Hematology and Oncology, Saint Elizabeth's Medical Center, Brighton, MA

Hicham Skali

Division of Cardiovascular Medicine, Saint Elizabeth's Medical Center, Brighton, MA

Thein H. Oo

Division of Hematology and Oncology, Saint Elizabeth's Medical Center, Brighton, MA

Michael Maysky

Division of Cardiovascular Medicine, Saint Elizabeth's Medical Center, Brighton, MA

A 43-year-old woman with no significant past medical history was admitted to a community hospital with complaints of dull, epigastric pain radiating to her back, malaise, and loss of appetite. Throughout the previous months, she had undergone an extensive work-up for chronic cough that included blood work, endoscopy, an upper GI series, and a computed tomography (CT) abdomen/pelvis. These studies were notable only for gastroesophageal reflux, with the remainder being within normal limits. She was treated with a proton pump inhibitor with improvement of her symptoms. She had no history of tobacco use, consumed an occasional alcoholic beverage, and did not have any recent nonsteroidal anti-inflammatory drug use. Physical examination on presentation was significant for a well-appearing, middle-aged woman without icteris or jaundice. Cardiovascular examination revealed intact carotid and distal pulses without any bruits, regular rhythm with no cardiac murmurs. The abdomen was notable for mild epigastric tenderness and hypoactive bowel sounds, with no palpable masses. The integument revealed no lesions, rashes, or discoloration. Neurological exam was grossly intact. Initial laboratory data were notable for a complete blood count, basic metabolic panel, liver function test, coagulation studies, amylase, lipase, cardiac enzymes, triglycerides, and erythrocyte sedimentation rate (all within normal limits). ECG showed normal sinus rhythm with no ischemic changes. Chest x-ray was normal. CT abdomen/pelvis revealed diffuse enlargement of the body of the pancreas with a low density mass, none of which were present 3 weeks earlier. Although a malignancy was considered, given the significant change since the previous CT abdomen/pelvis 3 weeks earlier, it was felt to be more consistent with acute pancreatitis. She was treated with bowel rest, analgesics, and hydration.

During the ensuing 4 days, her clinical status changed significantly. She developed left-sided chest pain associated with left hand numbness and tingling. On physical examination, she was found to have a new systolic and diastolic murmur, diffuse subungual splinter hemorrhages in the fingernails and toenails (Fig 1A), and a blanching, mottled-appearing, reddish blue discoloration on the hands and feet (Figs 1B, 1C) that was consistent with livedo reticularis. She was subsequently transferred to a university-affiliated medical center for further work-up and management.

View larger version (67K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1.

Transesophageal echocardiography (Fig 2) was significant for multiple vegetations on a bileaflet aortic valve associated with moderate aortic regurgitation. Figure 2A depicts a short axis view at the level of the aortic valve. There is fusion of the left (L) and noncoronary (NC) cusp. Aseptic vegetations (arrows) can be seen along coaptation lines. A long axis view of the aortic valve in Figure 2B shows vegetations on both the left ventricular outflow tract (LVOT) and the aortic (Ao) sides of the valve.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2.

Repeat CT and magnetic resonance imaging (MRI) of the abdomen/pelvis (Fig 3) showed rapid development of a 3.5 x 4.3 cm mass in the body of the pancreas with encasement of the splenic artery and involvement of the surrounding vasculature. There were also multiple liver lesions noted consistent with metastases, as well as multifocal splenic and renal infarcts. Figure 3A shows a T1-weighted fat saturation postgadolinium MRI of the abdomen demonstrating a pancreatic mass (white arrow), hepatic metastases (yellow arrow), and splenic infarct (blue arrow). Figure 3B and 3C are from a contrast enhanced abdominal CT scan demonstrating a pancreatic mass encasing vasculature (white arrow), additional splenic infarcts (blue arrow) and left renal infarct (yellow arrow).

View larger version (40K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3.

The patient underwent CT-guided fine needle aspiration and core biopsy of the pancreatic mass for definitive diagnosis. The pathology specimen revealed poorly differentiated malignant cells that stained positive for markers of pancreatic adenocarcinoma. During a 2-week hospital course, she improved clinically on a regimen that included cardiac medications, unfractionated heparin, analgesia, blood products, and supportive care. The mild transaminitis and coagulopathy also improved. Per the patient's request, she was discharged home on low-molecular weight heparin and will consider enrollment onto an experimental clinical trial for advanced pancreatic cancer.

This case demonstrates a rare presentation of advanced pancreatic adenocarcinoma. Numerous reports have identified an association between nonbacterial thrombotic endocarditis (NBTE) and a variety of malignancies,^1-5 as well as part of the syndrome of DIC.⁶ To our knowledge, this is the first case report in the literature that definitively illustrates the antemortem diagnosis of marantic endocarditis and DIC as the initial presentation preceding the diagnosis of an underlying pancreatic adenocarcinoma.

NBTE is characterized by the presence of an amorphous mixture of platelets and fibrin on a valve leaflet in the absence of inflammation or micro-organisms, or destruction of the underlying cardiac valve.⁷ It is most often diagnosed only at postmortem examination because the small, friable vegetations frequently embolize, leaving remnants too small to be identified by echocardiography.⁸ Vegetations caused by NBTE are found in approximately 1.2% of patients during autopsy.⁸ Although the reported incidence of systemic emboli varies widely, on average 42% of patients embolize.⁸ Arterial embolization most frequently involves the spleen, kidney, brain, and heart, respectively.⁹ It is also the major cause of morbidity and mortality in these patients. The most common sites of vegetations are on the mitral and aortic valves along the coaptation line.¹⁰ However, the tricuspid and pulmonary valves as well as bivalvular involvement have been identified. The great majority of underlying neoplasms associated with NBTE are adenocarcinomas of the pancreas, colon, lung, and prostate, in descending order.¹⁰

The pathophysiologic mechanisms of NBTE have not been fully elucidated. The current hypothesis is that monocytes or macrophages interact with malignant cells thus releasing tumor necrosis factor, interleukin-1, and interleukin-6, causing endothelial damage.¹¹ This generates a thrombogenic surface on the vascular lining. In addition, the interaction between these cells activates the coagulation cascade leading to the generation of thrombin and thrombosis.¹¹ Hemodynamic circumstances such as turbulent flow along the closure margins of valves or antecedent valvular lesions have also been well established as predisposing factors in the development of NBTE.⁹ The presence of a congenital bicuspid aortic valve in our patient likely contributed to the development of NBTE. It is becoming increasingly evident in the literature that DIC plays an important pathogenic role as a hypercoaguable substrate in the development of valvular lesions in NBTE. The association of DIC and solid tumors has been known for decades. As many as 10% to 15% of patients with metastatic cancer have evidence of DIC.¹² Although the exact mechanism remains unclear, many studies indicate that tissue factor expressed on the surface of tumor cells is involved.¹³ Recent animal studies have demonstrated that the systemic formation of fibrin results from increased generation of thrombin, the simultaneous suppression of the physiologic anticoagulation cascade, and the delayed removal of fibrin. This derangement of coagulation and fibrinolysis in DIC is mediated by proinflammatory cytokines.¹² These cytokines likely represent the link between malignancies, NBTE, and DIC.

Although no established treatment strategies exist for tumor related NBTE and DIC, there are limited data supporting the use of anticoagulation in these patients. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy currently recommends that patients with disseminated cancer and NBTE be treated with full-dose unfractionated heparin.⁶ They also conclude that no benefit is observed with warfarin therapy. Recently, a multicenter, randomized trial by Lee et al¹⁴ demonstrated low-molecular weight heparin was more effective than warfarin in reducing the risk of recurrent thromboembolism in patients with cancer without increasing the risk of bleeding. Although no trial has compared unfractionated heparin with low-molecular weight heparin in patients with tumor associated NBTE, a multicenter double-blind trial published by Sakuragawa et al¹⁵ demonstrated that low-molecular weight heparin can be used as an alternative to unfractionated heparin in patients with DIC. Based on the limited data that exists, the use of low-molecular weight heparin in our patient enabled her to be discharged home, thus providing her an improved quality of life and autonomy as she sought additional therapies for her malignancy.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

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