jh
Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access
Article copyright, the authors; Journal compilation copyright, the J Hematol and Elmer Press Inc
Journal website http://www.thejh.org
 
Case Report
Volume 3, Number 1, March 2014, pages 19-21
                                                                                
Systemic Capillary Leak Syndrome Presenting as Apparent Polycythemia Vera: A Critical Diagnostic Dilemma

Yichao Wua, Ish Guptaa, Robert Weinsteina, b, c

aDepartment of Medicine, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, MA, USA
b
Division of Transfusion Medicine, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, MA, USA
c
Corresponding author: Robert Weinstein, Department of Medicine, University of Massachusetts Medical School, UMass Memorial Medical Center, 55 Lake Avenue North, Worcester, MA 01655-0002, USA
 

Manuscript accepted for publication December 4, 2013
Short title: Systemic Capillary Leak Syndrome
doi: http://dx.doi.org/10.14740/jh116w


Abstract
 

Polycythemia vera presents with true erythrocytosis (elevated red cell mass) and an expanded plasma volume, while apparent erythrocytosis presents with plasma volume contraction and a normal red cell mass. Here we report a case with recurrent episodes of severe apparent erythrocytosis, closely mimicking polycythemia vera, due to a rare condition known as systemic capillary leak syndrome (SCLS). This syndrome typically presents with the triad of hypotension, hemocencentration and hypoalbuminemia, combined with a monoclonal serum M-protein. Empirical treatment with intravenous immune globulin (IVIG) has successfully led to resolution of symptoms and correction of hemoconcentration in several reported cases as well as in our patient’s case. It is important for clinicians to differentiate true erythrocytosis from apparent erythrocytosis, and to be aware of this rare syndrome causing the latter, as aggressive phlebotomy and overtreatment with crystalloid fluids could result in serious adverse events and should be avoided. 

Keywords: Hemoconcentration; Pseudoerythrocytosis; Monoclonal gammopathy; Intravenous immune globulin
 

Introduction 

Polycythemia vera presents with true erythrocytosis (elevated red cell mass) and an expanded plasma volume [1, 2]. Apparent erythrocytosis in young men, which presents with plasma volume contraction and a normal red cell mass, may be associated with diuretic therapy, heavy smoking, hypertension (namely, Gaisbock’s syndrome), obesity or alcohol consumption [3, 4]. At the time of initial presentation, the distinction between true and apparent erythrocytosis may be difficult. Whereas polycythemia vera is appropriately treated with phlebotomy to avoid complications of thrombosis and hyperviscosity, phlebotomy may result in volume depletion and anemia in patients with apparent erythrocytosis [5]. The distinction can be difficult when the presentation of apparent erythrocytosis mimics multiple clinical aspects of polycythemia vera. We report herein a case that illustrates the importance of carefully distinguishing true from apparent erythrocytosis in the acute setting. 
 

Case Report 

First admission 

A 23-year-old man without significant past medical history presented after 12 h of nausea, vomiting, abdominal pain and repeated syncope. On admission, he was hypotensive and tachycardic with systolic blood pressure 60 - 70 mmHg and a heart rate of over 140/min. He had bilateral lower extremity edema, numbness and pain. His hemoglobin and hematocrit were markedly elevated at 25.8 g/dL and 75.4% respectively, and his white blood cell (WBC) count was 54 × 109/L. His peripheral blood film revealed a shift to the left with metamyelocytes, myelocytes and promyelocytes. His creatinine was 3.9 mg/dL. 

Because of hypotension and evidence of lower extremity vascular compromise, he received aggressive fluid resuscitation with 10 L of normal saline over 12 h. His hemoglobin and hematocrit fell to 14.3 g/dL and 42.8% respectively and his WBC count was 47.8 × 109/L. His serum albumin was 2.4 g/dL. He was provisionally diagnosed with polycythemia vera based on persistent erythrocytosis despite fluid resuscitation, marked left-shifted leukocytosis, and a clinical picture suggestive of bilateral lower extremity thrombosis. An attempt at therapeutic phlebotomy was unsuccessful because of whole blood hyperviscosity. 

He had progressive pain and dusky cyanosis of the distal lower extremities with poor capillary refill. Popliteal and dorsalis pedis pulses were difficult to appreciate via doppler ultrasound. His creatine phosphokinase was elevated and peaked at 21,000 units/L. An emergent vascular surgery consult found him to have painful lower extremities that were cool, insensate and paralyzed. Emergent bilateral femoral exploration, including direct palpation and bilateral angiography, demonstrated good femoral and popliteal pulses and patent femoral, popliteal and tibial arteries. He thus underwent bilateral four-compartment fasciotomies for symptom relief. The following morning his CBC revealed WBC 17.7 × 109/L, hemoglobin 10.1 g/dL, HCT 29.3% and platelet count 155 × 109/L. 

The results of a workup for polycythemia vera and other myeloproliferative neoplasms revealed a normocellular bone marrow with maturing trilineage hematopoiesis, absence of JAK2 or BCR-ABL mutations, a serum erythropoietin level of 20.2 mIU/mL (reference range 3.7-31.5), and a normal size spleen on abdominal ultrasound. After 3 weeks in hospital, he was transferred to a rehabilitation facility. 

Second admission

The patient was readmitted after 3 months with complaints of nausea, vomiting, hematemesis and bilateral lower extremity edema. His CBC revealed WBC 28.6 × 109/L, hemoglobin 22 g/dL and hematocrit 68.3%. Serum albumin was 3.1 g/dL. The patient again received aggressive IV fluid resuscitation. By hospital day 4, his CBC WBC was 5.2 × 109/L, hemoglobin 11.9 g/dL and hematocrit 36.5%. 

With polycythemia vera ruled out by bone marrow biopsy and genetic studies, and with repeated episodes of apparent erythrocytosis characterized by hypotension, hemoconcentration and hypoalbuminemia, a diagnosis of systemic capillary leak syndrome (SCLS) was considered [6-9]. Serum protein electrophoresis revealed an abnormal band of 0.4 g/dL in the gamma region. Serum immunofixation electrophoresis confirmed it to be an IgG lambda monoclonal band. 

The patient was treated with terbutaline and theophylline [10] which were discontinued because of symptomatic tachycardia. He was then treated with intravenous immune globulin (IVIG) 1 g/kg/day for 2 days [11-13] with significant improvement in lower extremity edema and tenderness. His blood counts normalized and remained in the normal range with a stable hematocrit of 36-42%. As of this report, the patient has been hospitalized on five more occasions with marked recurrent hemoconcentration, hypotension and lower extremity edema, all treated with IVIG with resolution of symptoms and correction of hemoconcentration. 
 

Discussion 

SCLS is a rare disorder characterized by unexplained recurrent episodes of severe hypotension, hemoconcentration and hypoalbuminemia, likely due to a derangement of the vascular endothelium that results in capillary hyperpermeability and leakage of plasma and proteins into the interstitial space [6-9]. Several studies describe a monoclonal gammopathy of uncertain significance (MGUS) in the majority of patients [14]. The specific role of paraproteins in the pathogenesis of SCLS has not been defined. Elevated levels of vascular endothelial growth factor and angiopoietin 2, contraction of endothelial cells due to apoptosis during SCLS attacks, and involvement of IL-2 and other inflammatory mediators, including leukotrienes and tumor necrosis factor alpha, have been implicated in the pathophysiology of SCLS [15-19]. 

The initial presentation of our patient with severe erythrocytosis, a leukemoid reaction and lower extremity vascular compromise was suggestive of polycythemia vera. However, the presentation with hypotension and hypoalbuminemia, and the rapid correction of his erythrocytosis and leukocytosis with fluid resuscitation was not consistent with this diagnosis. The absence of a JAK2 kinase or BCR-ABL mutation and the normal bone marrow morphology and erythropoietin level were also at odds with a diagnosis of a myeloproliferative neoplasm. 

The recurrent episodes of nausea and vomiting, and the triad of hypotension, hypoalbuminemia and hemoconcentration, were suggestive of SCLS. The identification of MGUS and the responsiveness to IVIG further supported this diagnosis. A prodromal phase with flu-like symptoms including respiratory or GI involvement is typical. This is followed by an extravasation phase where capillary leakage leads to the triad of hypotension, hemoconcentration and hypoalbuminemia [6-9]. Aggressive fluid resuscitation may lead to a compartment syndrome during the extravasation phase, and rhabdomyolysis may occur, as in this case [20, 21]. Acute tubular necrosis, ischemic brain injury or ischemic hepatitis have been reported. After several days, the extravasation phase is followed by a recovery phase during which extravasated fluids are recruited back into the intravascular space. SCLS patients may be at high risk for intravascular volume overload and pulmonary edema during this period, depending on the extent of fluid resuscitation during the extravasation phase [22]. 

In summary, here we report a case who presented with recurrent episodes of severe apparent erythrocytosis that turned out to be SCLS masquerading as polycythemia vera. The presenting triad of hypotension, hemocencentration and hypoalbuminemia, with a negative workup for myeloproliferative disorder, in combination with a monoclonal gammopathy, can be considered diagnostic for SCLS. This case illustrates the sometimes critical importance of differentiating true from apparent erythrocytosis: aggressive phlebotomy combined with volume expansion with crystalloid fluids in the latter can result in serious adverse events including anemia, pulmonary edema and further intravascular volume depletion. When common external factors causing apparent erythrocytosis, such as diuretic therapy or dehydration, are ruled out, an intrinsic process such as SCLS should be considered. Clinicians should be aware of this syndrome and the role of IVIG in its treatment. 
 

Funding 

None. 
 

Conflicts of Interest 

All authors have no financial or other conflicts of interest. 
 

Author Contributions 

All authors had access to the data and a role in writing the manuscript.
 

 
 
References
 

1.

Gilbert HS. Definition, clinical features and diagnosis of polycythaemia vera. Clin Haematol. 1975;4(2):263-290.
pubmed

2.

Golde DW, Hocking WG, Koeffler HP, Adamson JW. Polycythemia: mechanisms and management. Ann Intern Med. 1981;95(1):71-87.
doi
pubmed

3.

Fairbanks VF, Tefferi A. Normal ranges for packed cell volume and hemoglobin concentration in adults: relevance to 'apparent polycythemia'. Eur J Haematol. 2000;65(5):285-296.
doi

4.

Messinezy M, Pearson TC. The classification and diagnostic criteria of the erythrocytoses (polycythaemias). Clin Lab Haematol. 1999;21(5):309-316.
doi

5.

Barbui T, Finazzi MC, Finazzi G. Front-line therapy in polycythemia vera and essential thrombocythemia. Blood Rev. 2012;26(5):205-211.
doi
pubmed

6.

Druey KM, Greipp PR. Narrative review: the systemic capillary leak syndrome. Ann Intern Med. 2010;153(2):90-98.
doi
pubmed

7.

Kawabe S, Saeki T, Yamazaki H, Nagai M, Aoyagi R, Miyamura S. Systemic capillary leak syndrome. Intern Med. 2002;41(3):211-215.
doi
pubmed

8.

Clarkson B, Thompson D, Horwith M, Luckey EH. Cyclical edema and shock due to increased capillary permeability. Am J Med. 1960;29:193-216.
doi

9.

Gousseff M, Arnaud L, Lambert M, Hot A, Hamidou M, Duhaut P, Papo T, et al. The systemic capillary leak syndrome: a case series of 28 patients from a European registry. Ann Intern Med. 2011;154(7):464-471.
doi
pubmed

10.

Tahirkheli NK, Greipp PR. Treatment of the systemic capillary leak syndrome with terbutaline and theophylline. A case series. Ann Intern Med. 1999;130(11):905-909.
doi
pubmed

11.

Lambert M, Launay D, Hachulla E, Morell-Dubois S, Soland V, Queyrel V, Fourrier F, et al. High-dose intravenous immunoglobulins dramatically reverse systemic capillary leak syndrome. Crit Care Med. 2008;36(7):2184-2187.
doi
pubmed

12.

Kapoor P, Greipp PT, Schaefer EW, Mandrekar SJ, Kamal AH, Gonzalez-Paz NC, Kumar S, et al. Idiopathic systemic capillary leak syndrome (Clarkson's disease): the Mayo clinic experience. Mayo Clin Proc. 2010;85(10):905-912.
doi
pubmed

13.

Amoura Z, Papo T, Ninet J, Hatron PY, Guillaumie J, Piette AM, Bletry O, et al. Systemic capillary leak syndrome: report on 13 patients with special focus on course and treatment. Am J Med. 1997;103(6):514-519.
doi

14.

Zhang W, Ewan PW, Lachmann PJ. The paraproteins in systemic capillary leak syndrome. Clin Exp Immunol. 1993;93(3):424-429.
doi
pubmed

15.

Xie Z, Ghosh CC, Patel R, Iwaki S, Gaskins D, Nelson C, Jones N, et al. Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome). Blood. 2012;119(18):4321-4332.
doi
pubmed

16.

Lesterhuis WJ, Rennings AJ, Leenders WP, Nooteboom A, Punt CJ, Sweep FC, Pickkers P, et al. Vascular endothelial growth factor in systemic capillary leak syndrome. Am J Med. 2009;122(6):e5-7.
doi
pubmed

17.

Nagao Y, Harada H, Yamanaka H, Fukuda K. Possible mediators for systemic capillary leak syndrome. Am J Med. 2011;124(1):e7-9.
doi
pubmed

18.

Assaly R, Olson D, Hammersley J, Fan PS, Liu J, Shapiro JI, Kahaleh MB. Initial evidence of endothelial cell apoptosis as a mechanism of systemic capillary leak syndrome. Chest. 2001;120(4):1301-1308.
doi
pubmed

19.

Cicardi M, Gardinali M, Bisiani G, Rosti A, Allavena P, Agostoni A. The systemic capillary leak syndrome: appearance of interleukin-2-receptor-positive cells during attacks. Ann Intern Med. 1990;113(6):475-477.
doi
pubmed

20.

Sanghavi R, Aneman A, Parr M, Dunlop L, Champion D. Systemic capillary leak syndrome associated with compartment syndrome and rhabdomyolysis. Anaesth Intensive Care. 2006;34(3):388-391.
pubmed

21.

Matsumura M, Kakuchi Y, Hamano R, Kitajima S, Ueda A, Kawano M, Yamagishi M. Systemic capillary leak syndrome associated with compartment syndrome. Intern Med. 2007;46(18):1585-1587.
doi
pubmed

22.

Chihara R, Nakamoto H, Arima H, Moriwaki K, Kanno Y, Sugahara S, Okada H, et al. Systemic capillary leak syndrome. Intern Med. 2002;41(11):953-956.
doi
pubmed

 


This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Digital Object Identifier (DOI): http://dx.doi.org/10.14740/jh116w
About DOI and CrossRef
Journal of Hematology is published by Elmer Press Inc.

 
Home     |     Log In     |      About     |      Search     |      Current     |      Archives     |      Submit      |     Subscribe


 

     

Aims and Scope

Current Issues

Conflict of Interest

About Publisher

Editorial Board

Archives

Copyright

Company Profile

Editorial Office

Misconduct and Retraction

Permissions

Company Registration

Contact Us

Abstracting and Indexing

ICMJE

Ownership

Instructions to Authors

Access

Declaration of Helsinki

Contact Publisher

Submission Checklist

Reprints

Terms of Use

Company Address

Submit a Manuscript

Open Access Policy

Privacy Policy

Browse Journals

Publishing Fee

Publishing Policy

Disclaimer

Recent Highlights

Peer-Review Process

Publishing Quality

Code of Ethics

Advertising Policy

Manuscript Tracking

Advanced Search

For Librarians

Careers

Publishing Process

Publication Frequency

For Reviewers

Propose a New Journal

       
       

Journal of Hematology, quarterly, ISSN 1927-1212 (print), 1927-1220 (online), published by Elmer Press Inc.            
The content of this site is intended for health care professionals.
This is an open-access journal distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which permits unrestricted
non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Creative Commons Attribution license (Attribution-NonCommercial 4.0 International CC BY-NC 4.0)



This journal follows the International Committee of Medical Journal Editors (ICMJE) recommendations for manuscripts submitted to biomedical journals,
the Committee on Publication Ethics (COPE) guidelines, and the Principles of Transparency and Best Practice in Scholarly Publishing.

website: www.thejh.org    editorial contact: editor@thejh.org
Address: 9225 Leslie Street, Suite 201, Richmond Hill, Ontario, L4B 3H6, Canada
 

© Elmer Press Inc. All Rights Reserved.

IMPORTANT: THIS JOURNAL SITE OUTLOOK IS DESIGNED BY THE PUBLISHER AND COPYRIGHT PROTECTED. DO NOT COPY!