alexa IgG Monoclonal Immunoglobulin (M-protein) as Factor V Inhibitor in Multiple Myeloma Patient: Case Report and Discussion | OMICS International
ISSN: 2155-9899
Journal of Clinical & Cellular Immunology

Like us on:

Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
Meet Inspiring Speakers and Experts at our 3000+ Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on
Medical, Pharma, Engineering, Science, Technology and Business

IgG Monoclonal Immunoglobulin (M-protein) as Factor V Inhibitor in Multiple Myeloma Patient: Case Report and Discussion

Lewandowski Krzysztof1*#, Szczepaniak Tomasz1#, Dytfeld Dominik1, Wojtasińska Ewelina1, Dziatkiewicz Paulina1, Przysiecka Łucja2, Borowczyk Martyna1, Popławski Dariusz3 and Komarnicki Mieczysław1
1Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Szamarzewskiego 82/84, Poznan, Poland
2Nanobiomedical Centre, Adam Mickiewicz University, Umultowska 85, Poznan, Poland
3Department of Radiology, University Lord's Transfiguration Hospital, Szamarzewskiego 82/82, Poznan, Poland
#Authors are equally contributed to this study
*Corresponding Author : Lewandowski Krzysztof
Department of Hematology and Bone Marrow Transplantation
Poznan University of Medical Sciences
Szamarzewskiego 82/84, Poznan, Poland
Tel: +48618549356
E-mail: [email protected]
Received date: February 11, 2016; Accepted date: April 18, 2016; Published date: April 25, 2016
Citation: Krzysztof L, Tomasz S, Dominik D, Ewelina w, Paulina D, et al. (2016) IgG Monoclonal Immunoglobulin (M-protein) as Factor V Inhibitor in Multiple Myeloma Patient: Case Report and Discussion. J Clin Cell Immunol 7:410. doi:10.4172/2155-9899.1000410
Copyright: © 2016 Krzysztof L, et al. 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 author and source are credited.

Visit for more related articles at Journal of Clinical & Cellular Immunology

Abstract

We present a case of a 53-year-old male with a symptomatic relapse of IgGλ multiple myeloma who was readmitted to the hospital with clinical symptoms of retroperitoneal hematoma. Laboratory tests revealed high concentration of monoclonal immunoglobulin G (32 g/l, 91.6% of total IgG) in the serum, prolongation of activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT), significantly decreased factor V procoagulant activity and the presence of factor V inhibitor. After successful retreatment with the use of six cycles of bortezomib, adriamycin and dexamethasone, the monoclonal IgG concentration in the patient’s serum significantly decreased (up to 1.3 g/l). At that time, also the normalization of the results of aPTT, PT and TT was stated. Therefore, the presence of factor V inhibitor in monoclonal immunoglobulin fraction was suspected. To confirm this, the monoclonal immunoglobulin G from the patient's initial blood sample was isolated, a series of dilutions of it in standard human plasma was prepared and the activity of factor II, factor V and aPTT, PT and TT in the prepared plasma samples were measured. The results of ex vivo studies matched those obtained in vivo, proving that the monoclonal immunoglobulin G produced by multiple myeloma cells acted as a factor V inhibitor.

Keywords
Multiple myeloma; Factor V deficiency; Factor V inhibitor; M protein; Bleeding complications
Introduction
Multiple myeloma (MM) is a genetically heterogeneous tumour of transformed plasma cells, terminally differentiated effectors of the B cell lineage, specialized in producing large amounts of monoclonal immunoglobulins (M-protein) [1]. Irrespectively of typical symptoms, MM patients present a broad spectrum of uncommon disease signs, among which coagulation abnormalities constitute an important clinical problem [2]. Unlike venous thromboembolism, which is relatively frequent, major bleeding remains uncommon, ranging from 0-7% in patients newly diagnosed with MM [3,4]. Due to its infrequency, the management of bleeding complications is often symptomatic and based on standard recommendations. Due to complex pathogenesis of the bleeding predisposition in MM, the lack of access to experienced hemostasis laboratory differential diagnosis remains challenging [5]. Until today, only a few cases of bleeding manifestation of relapsed MM have been reported [6,7].
Case
Herein, we present a case of 53-years-old Caucasian male patient with symptomatic IgGλ multiple myeloma, stage IIIA according to Durie-Salmon classification. The initial treatment with thalidomide and dexamethasone (TD) resulted in a very good partial response (VGPR). At the time of autologous hematopoietic stem cell transplantation (autoHSCT), routine coagulation tests were normal. After autoHSCT he did not receive any maintenance therapy. The patient was readmitted to our department with malaise and abdominal pain of moderate intensity two years after autoHSCT. During hospitalization the pain deteriorated, peritoneal pressure symptoms became positive and nasal bleeding appeared. The abdominal ultrasonography (USG) showed a little amount of fluid in the right lower part of the peritoneal cavity and thickening of the intestinal wall. Computed tomography image showed enlargement of the right iliopsoas muscle. At the time of the admission, the laboratory tests revealed high concentration of monoclonal immunoglobulin G (32 g/l, 91.6% of total IgG) in the serum. The coagulation tests results showed prolongation of activated partial thromboplastin time (aPTT), prothrombin time (PT) and thrombin time (TT). The PT and the aPTT were not corrected with an equal volume plasma mixing test, which is indicative for circulating anticoagulant. Additionally performed coagulation tests confirmed significantly decreased factor V procoagulant activity and the presence of factor V inhibitor (5 Bethesda Units/ml). Screening tests for lupus-like inhibitor (LA) performed according to the manufacturer’s instruction (Lupus anticoagulant testing, Siemens) were negative (LA1/LA2-1.01; aPTT with Actin-32.7 sec.). Based on both the clinical signs of appendicitis, a decision to perform an appendectomy was made. During the procedure, a retroperitoneal hematoma was found and evacuated. There were no signs of appendicitis. After treatment with tranexamic acid and fresh frozen plasma the bleeding subsided. Thereafter, due to disease progression, six cycles of bortezomib, doxorubicin, and dexamethasone (PAD) were given. During the PAD treatment, the monoclonal IgG concentration in patient’s serum significantly decreased (up to 1.3 g/l). Finally, also normalization of the results of aPTT, PT and TT was stated. Therefore, the presence of factor V inhibitor in monoclonal immunoglobulin fraction was suspected. To confirm this, the retrospective, more detailed coagulation system analysis was undertaken. Activity of factor II, V, VIII and X was determined with the help of coagulometric methods and Helena BioSciences reagents. Coagulation system ex vivo studies were performed in normal human plasma after addition of lyophilized monoclonal IgG, isolated with the help of thiophilic adsorption method from 20 ml of the patient’s blood collected at the time admission [8-10]. Thereafter, the activity of factor II, factor V and aPTT, PT and TT in the prepared plasma samples (a series of dilutions of monoclonal IgG in standard human plasma at final concentration of 0, 0.468, 0.937, 1.875, 3.75, 7.5, 15 and 30 g/l, respectively) were measured. Results of the coagulation system evaluation before and during the treatment with PAD are presented in Table 1. The results of the performed ex vivo studies showed close relationship between the monoclonal immunoglobulin G plasma content and the degree of prolongation of PT and aPTT (Figure 1).
Interestingly, it matched those obtained in vivo . This may prove the concept that the monoclonal immunoglobulin G produced by multiple myeloma cells may act as a factor V inhibitor.
The impact of isolated M protein on factor II procoagulant activity was also studied in the ex vivo assay. The decrease of factor II activity was only observed at very high concentration of M protein in the plasma sample. In our opinion, this phenomenon is the effect of inhibition of factor V by M protein, which is a very important player in the prothrombinase complex. To support this hypothesis, additional ex vivo studies were performed, examining the inhibitory effect of M protein on thrombin time. They confirmed only a slight prolongation of thrombin time at high concentration of M protein in the plasma sample (Supplementary Figure 1). Also 2D crossed electrophoresis studies did not confirm M protein and thrombin (bovine) cross reactivity (data not shown).
Discussion
Patients with MM are a high-risk group as far as the emergence of unexpected events is concerned, and therefore there very frequently arises the need for immediate medical intervention [3]. In the presented case, USG imaging was not able to identify the bleeding episode, in contrast to angio-CT. However, it should be remembered that the diagnostic algorithm of hemoglobin and hematocrit drop in a patient with abdominal pain requires a customized procedure, including detailed laboratory evaluation of hemostasis
The pathogenesis of the observed clotting abnormalities in the presented patient is probably complex [11,12]. The increased fibrinogen concentration at the disease relapse is the result of disease activity and/or the coexistence of damaged muscle tissue. The high blood concentration of the M protein, with its impact on fibrin polymerization process, may be the cause of the prolongation of not only aPTT and PT, but also TT [13]. Interestingly, the results of equal volume plasma mixing test, before and during PAD treatment, showed no significant correction of the TT value in the beginning. However, later rapid normalization of abnormal test value was observed. The instant shortening of the TT right after the dilution of the M protein plasma content with fresh frozen plasma, supports the thesis that high concentration of monoclonal protein nonspecifically inhibits the fibrinogen polymerization. The value of PT and the aPTT was normalized when the factor V activity reached the level of 35%. The time for normalization of the PT and the aPTT was longer than in the case of TT. There was, however, close association between PT and aPTT values and the concentration of monoclonal immunoglobulin in the patient’s serum. Also, the results of periodically performed equal volume mix tests in case of PT and aPTT documented the normalization of abnormal coagulation tests results when chemotherapy related reduction of the monoclonal IgG serum content was noted. These facts, along with the result of the inhibitor titer measurement (Bethesda assay), suggested the presence of cross reacting factor V inhibitor in monoclonal immunoglobulin fraction. This was confirmed by our ex vivo studies.
Conclusion
To the best of our knowledge, the literature provides for only one reported case of factor V inhibitor in a MM patient with inherited factor V deficiency. Interestingly, the inhibitor completely disappeared after successful treatment with thalidomide [14]. This supports our thesis that protein M may act as a clotting factor inhibitor. Therefore, in our opinion it seems to be reasonable to recommend a detailed coagulation evaluation in MM patients with bleeding complications and prolongation of screening coagulation tests.
Disclosure of Conflict of Interests
Szczepaniak Tomasz: SC in Clinical Trials ran by Janssen-Cilag, Amgen, Onyx; received a fee for hematological workshop in September 2015 from Celgene; Dytfeld Dominik: Co-Investigator in Clinical Trials ran by Janssen-Cilag, Amgen, Onyx; received a grant from Janssen, Advisory Board Member: Celgene, Amgen, Janssen, Novartis; Komarnicki Mieczysław: Principal Investigator in Clinical Trials ran by Janssen-Cilag, Amgen, Onyx
The other authors declare that they have no competing interests.
Ethics Statement
This study was performed in agreement with the Declaration of Helsinki and approved by the local Ethical Committee (Poznan University of Medical Sciences).
References

Tables and Figures at a glance

Table icon
Table 1

 

Figures at a glance

Figure
Figure 1
Select your language of interest to view the total content in your interested language
Post your comment

Share This Article

Relevant Topics

Recommended Conferences

Article Usage

  • Total views: 8583
  • [From(publication date):
    April-2016 - May 27, 2018]
  • Breakdown by view type
  • HTML page views : 8492
  • PDF downloads : 91

Review summary

  1. Suzzane
    Posted on Jul 13 2016 at 6:51 pm
    This is a well described case study that relates multiple myeloma associated bleeding complications with monoclonal antibody behaving as a factor V inhibitor. This conclusion is mainly based on ex vivo analysis showing that the purified immunoglobulin increased activated partial thromboplastin time (aPTT), and prothrombin time (PT), and significantly decreased factor V procoagulant activity, which was consistent with the in vivo observations. The results are generally supportive of the hypothesis, but the manuscript would be strengthened by more conclusive evidence of direct factor V binding by the purified antibody, which was tested only in indirect assays.
 

Post your comment

captcha   Reload  Can't read the image? click here to refresh

Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2018-19
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

Agri & Aquaculture Journals

Dr. Krish

[email protected]

1-702-714-7001Extn: 9040

Biochemistry Journals

Datta A

[email protected]

1-702-714-7001Extn: 9037

Business & Management Journals

Ronald

[email protected]

1-702-714-7001Extn: 9042

Chemistry Journals

Gabriel Shaw

[email protected]

1-702-714-7001Extn: 9040

Clinical Journals

Datta A

[email protected]

1-702-714-7001Extn: 9037

Engineering Journals

James Franklin

[email protected]

1-702-714-7001Extn: 9042

Food & Nutrition Journals

Katie Wilson

[email protected]

1-702-714-7001Extn: 9042

General Science

Andrea Jason

[email protected]

1-702-714-7001Extn: 9043

Genetics & Molecular Biology Journals

Anna Melissa

[email protected]

1-702-714-7001Extn: 9006

Immunology & Microbiology Journals

David Gorantl

[email protected]

1-702-714-7001Extn: 9014

Materials Science Journals

Rachle Green

[email protected]

1-702-714-7001Extn: 9039

Nursing & Health Care Journals

Stephanie Skinner

[email protected]

1-702-714-7001Extn: 9039

Medical Journals

Nimmi Anna

[email protected]

1-702-714-7001Extn: 9038

Neuroscience & Psychology Journals

Nathan T

[email protected]

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

Ann Jose

[email protected]

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

[email protected]

1-702-714-7001Extn: 9042

 
© 2008- 2018 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version
Leave Your Message 24x7