International Seminars in Surgical
Oncology
BioMed Central
Open Access
Research
Incidence and risk factors of venous thromboembolism (VTD) in
patients with amyloidosis
Gordan Srkalovic*†1, Marte G Cameron†2, Steven R Deitcher†3,
Kandice Kattke-Marchant†4 and Mohamad A Hussein†5
Address: 1Sparrow Regional Cancer Center, Lansing, Michigan, USA, 2Helgelandssykehuset, Avdeling Sandnessjøen, Sandnessjøen, Norway,
3Nuvelo Inc, Sunnyvale, California, USA, 4Department of Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, USA and 5Cleveland Clinic
Myeloma Research Program, Cleveland Clinic Foundation, Cleveland, Ohio, USA
Email: Gordan Srkalovic* - gordan.srkalovic@sparrow.org; Marte G Cameron - marteandlans@hotmail.com;
Steven R Deitcher - sdeitcher@nuvelo.com; Kandice Kattke-Marchant - marchak@ccf.org; Mohamad A Hussein - mahhussein@runbox.us
* Corresponding author †Equal contributors
Published: 02 September 2005
International Seminars in Surgical Oncology 2005, 2:17
2-17
doi:10.1186/1477-7800-
Received: 01 August 2005
Accepted: 02 September 2005
This article is available from: http://www.issoonline.com/content/2/1/17
© 2005 Srkalovic et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background: Coagulation problems in amyloidosis are historically associated with bleeding
tendencies (mostly Factor X abnormalities). Increased clotting was observed in isolated cases
diagnosed with low-grade disseminated intravascular coagulation (DIC). Problem of venous
thromboembolic disaease (VTD) in amyloidosis was not systematically investigated.
Methods: We evaluated frequency of VTD and risk factors for VTD in 56 consecutive amyloidosis
patients with a documented disease evaluated and followed up at our Center from 1991–2001.
Data was collected in 5 categories: (a) demographics, (b) disease and treatment, (c) thrombosis
case information, (d) major risk factors for thrombosis and (e) baseline laboratory data. Univariable
correlates of VTD were assessed using Kaplan-Meier analysis and Cox proportional hazards
analysis.
Results: Mean age of the patients was 67 (years range 21 – 83). Male/female percentage ratio was
70/30. 29 % of the patients had high creatinine level (> 1.4 mg/dl). Personal or family history of VTD
was recorded in 2 and 0 % of patients, respectively. Known hypercoagulable state was present in
1 patient (2%). 8 % of patients were smokers. Of 56 patients, 6 developed VTD (11%). Median time
from diagnosis of amyloidosis to VTD was 12.5 month (range 1–107). Treatment was given within
a median of 1 month (range 0–4) from the development of thrombosis. Only sites of VTD were
lower extremities. No cases were associated with I.V. line. 1 case (17 %) was identified
postoperatively. We identified several univariable correlates of VTD in amyloid patients, including
greater age at diagnosis (HR-2.99, P = .041), personal history of DVT (HR-47.7, P = .006) and
immobility (HR-11.78, P = .006). Presence of circulating serum M-protein had protective role in
our analysis (HR-.08, P = .031). There was no correlation with the type of treatment patients were
receiving.
Conclusion: Risk for thromboembolic diseases in patients with amyloidosis is similar to one
previously described for multiple myeloma. Additional studies with higher number of
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thromboembolic events could help to further elucidate risk factors for VTD in this population of
patients.
Background
amyloidosis is characterized by organ deposition of fibrillar substances of different types that have a homogeneous
eosinophilic appearance on light microscopy [1,2]. The
diagnosis is confirmed by demonstration of an applegreen birefringence under polarized light of specimens
stained with Congo red. Primary amyloidosis (AL) should
be considered in any patient who has a monoclonal protein in the serum or urine and refractory congestive heart
failure, nephrotic syndrome, sensorimotor peripheral
neuropathy, carpal tunnel syndrome, orthostatic hypotension, or steatorrhea. At diagnosis, approximately onethird have nephrotic syndrome, one-fifth have carpal tunnel syndrome, one-fourth have congestive heart failure,
and about 15% have peripheral neuropathy [1,2].
Bleeding problems due to vascular deposition of amyloid
resulting in vascular fragility, deficiencies of clotting factors (particularly Factor X) or enhanced fibrinolytic activity often complicate this disease [3]. Acquired deficiency
of Factor X is the most common coagulation factor deficiency identified in patients with amyloidosis [4]. Thrombosis, although less common, also can occur. Some case
reports described thromboembolic complications of amyloidosis [5,6]. Association of nephrotic syndrome, welldocumented complication of systemic amyloidosis, and
renal vein thrombosis are well documented [7,8]. Cardiac
amyloidosis produces cases of atrial electromechanical
dissociation with resulting atrial arrhythmias and formation of atrial clots [9]. Various pathogenic factors have
been proposed to explain abnormal hemostasis in
patients with amyloidosis. Recently, impairment of the
thrombin-antithrombin pathway, in association with the
low antithrombin biological activity was recognized to
have possible pathogenic role in hypercoagulability of
amyloidosis patients [10].
However, the problem of venous thromboembolic disease (VTD) in this disease was not systematically investigated. We evaluated the frequency of VTD and risk factors
for VTD in 56 consecutive amyloidosis patients with a
documented disease evaluated and followed up at our
Center from 1991–2001.
Methods
We reviewed complete medical records of all patients with
amyloidosis who were prospectively entered in the database. Fifty-six patients were identified. They were evaluated and followed up by staff oncologists in the
Department of Hematology and Oncology, Myeloma
Research Program at the Cleveland Clinic Foundation in
the period 1991–2001.
The Cleveland Clinic Foundation (CCF) is an urban tertiary referral center and a teaching hospital. Our proposal
was submitted to the CCF Institutional Review Board, and
we were granted approval, based on an expedited review.
The requirement for obtaining informed consent was
waived based on the study designs (standard medical
record based review) and patient anonymity. The study
did not require any third party funding.
The patients' computerized inpatient and outpatient medical records were initially reviewed by one of the co-investigators (CMG). Additional review was done
independently by a second co-investigator (SG). If electronic data were incomplete, the hard copies of charts
were also reviewed. When necessary, missing information
was sought from referring providers. However, in a
number of cases, this was unavailable.
All cases of VTD of extremities were diagnosed by Duplex
ultrasound. Term immobility was used for patients who
were hospitalized or bed bound for more than 7 days at
the time of VTD diagnosis.
Personal history of VTD was defined as a history of documented thromboembolism prior to the diagnosis of PCD.
Patients were screened for a hypercoagulable state only
when they developed what appeared to be a vascular event
that needed further investigation.
Data was collected in 5 categories: (a) demographics, (b)
disease and treatment, (c) thrombosis case information,
(d) major risk factors for thrombosis and (e) baseline laboratory data. Data were manually recorded onto
researcher-developed data collection forms and subsequently entered into a computerized database.
Statistical analysis
Categorical variables are summarized as frequencies and
percentages and continuous variables as the mean, standard deviation, median, and range. Time until development of a VTD was estimated using the Kaplan-Meier
method. Follow-up was calculated from the date of diagnosis to the date of either the first VTD or the date of final
follow-up visit. Cox proportional hazards analysis was
used to identify univariable correlates of thromboembolic
event. If Cox analysis could not be done due to lack of variability, then the log-rank test was performed instead.
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Male/Female
39/17
There were 8 possible risk factors for VTD: personal and
family history of VTD, known hypercoagulable state, nonplasma cells related concomitant neoplasm's, immobility,
estrogen treatment, smoking, and use of indwelling catheters at any time from initial diagnosis.
Age (years)
Median
Range
67
(21–83)
All statistical analyses were two-sided; P < 0.05 was used
to indicate statistical significance. Analyses were performed using SAS® software, version 6.12.
Serum M-Protein (g/L)1
Mean
Median
Range
(N = 18)
0.5
0.2
(0–4.0)
24-hour Urine Protein (g)1
Mean
Median
Range
(N = 47)
3.2
0.4
(0–26.9)
BMPC* (%)2
Mean
Median
Range
(N = 53)
8
5
(0–50)
B2 Microglobulin (mg/dl)1
Mean
Median
Range
(N = 47)
3.4
2.7
(0.3–18.4)
Serum albumin (g/L)1
Mean
Median
Range
(N = 53)
3.4
3.6
(1.0–5.4)
Immunoglobulin type Heavy Chain
IgA (%)
IgG (%)
IgM (%)
Unknown
Light Chain
λ
κ
(N = 12)
2 (17)
9 (75)
1 (8)
0
(N = 25)
18 (72)
7 (28)
History of VTD Personal
Yes (%)
No (%)
Unknown (%)
1 (2)
53 (94)
2 (4)
Family
No (%)
Unknown (%)
52 (93)
4 (7)
Table 1: Clinical characteristics of amyloidosis patients at
presentation (N = 56)
Characteristics
1 CCF
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Laboratory reference range, normal values:
Serum M-protein: 0 g/dl
Urine Protein: 0–0.15 g/24°
β2 Macroglobulin: 0.3–1.9 mg/dl
Serum Albumin: 3.5–5.0 g/L
2 Bone Marrow Plasma Cells
Results
Patients' characteristics
Data was available on 56 patients (Table 1.). 50 (89%)
had primary amyloidosis (AL), 1 (2%) had kappa light
chain disease, and in 5 (9%) patients type could not be
identified. One patient had both AL and familial amyloidosis. 37 (66%) had confirmed cardiac involvement by
biopsy or alternatively, typical findings on Echocardiogram. Confirmed (biopsy) renal involvement was found
in 18 (32%) of patients. Localized amyloidosis was identified in 6 (11%) of patients. Two cases were pulmonary,
2 gastrointestinal, and one case was localized to skin and
genitourinary tract, respectively. 39 (70%) were men and
17 (30%) were women. Average age was 67 years (range
21 – 83). Of the heavy chain types found in patients, 75%
were IgG, 17% IgA, 1% IgM. 44/56 (78.5%) of patients
did not have heavy chain M-protein in the serum.
The light chain was lambda (λ) in 18 (32% of all patients)
and kappa (κ) in 7 patients (13%). The remainder did not
have identifiable light chain (31, 55%). All patients had
amyloid deposits by Congo Red stain. The bone marrow
biopsy results were available in 53 patients (95%) at the
time of diagnosis. The median percentage of bone marrow
occupied by plasma cells was 5% (range 0.0 – 50%).
Serum creatinine level was elevated in 29% of all patients.
Albumin was low (< 3.5 gm/dl) in 45% patients overall.
Beta-2-microglobulin was high (>1.9) in the majority of
patients (70%). Bone survey was negative for lytic lesions
in all cases.
Out of 56 patients with amyloidosis, 1 (2%) patients had
personal and no one had family history of thromboembolism. 1/56 were diagnosed with hypercoagulable state
(antithrombin deficiency). Patients were treated with
multiple regimens that included: steroids (36%), α-interferon (23%), vincristine (16%), liposomal doxorubicin
(16%), melphalan (9%), thalidomide (2%) and rituximab (2%).
The five different drug combinations used in the treatment of amyloid patients are presented in Table 2. No
patients were treated with high-dose chemotherapy with
peripheral stem cell support (HDC-PSC).
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Table 2: Combination chemotherapies used in the treatment of
amyloidosis
Table 3: Clinical characteristics of amyloidosis (N = 6) patients
with VTD
Type of Treatment
N
%
Characteristics
HD steroids1
DVd2
MP3
CP4
TD5
20
9
5
1
1
36
16
8
2
2
Male/Female
N – Number of patients
% – Percentage of patients treated with particular regimen
1 High-dose Dexamethasone
2 Doxil®, Vincristine, Dexamethasone
3 Melphalan, Prednisone
4 Cytoxan, Prednisone
5 Thalidomide, Dexamethasone
Patients with VTD
Cases of thromboembolism were diagnosed by Duplex
ultrasound. There was no evidence of pulmonary embolism or atrial clots in this group of patients. Of 56 patients
reported in this paper 6 (11%) had one or more episodes
of symptomatic, objectively documented VTD after the
diagnosis of amyloidosis (Table 3). All cases were of lower
extremities. The time from diagnosis to development of
VTD was 12.5 months (range 1–107). Median time from
last treatment to VTD event was 1 month (0–4). Out of 6
patients with VTD 17% (1 case) had a personal history of
thromboembolism. No patients with VTD had a history of
hypercoagulable state, smoking, or oral estrogen use. Four
(67%) patients with VTD had prolonged immobility and
1 (17%) had indwelling catheter at some point during the
disease. One patient (17%) developed VTD within 6
weeks from surgery.
Univariable correlates of VTD in amyloidosis patients are
presented in Table 4. A large number of factors were
entered into the model including the following: gender,
age at diagnosis, immunoglobulin type, personal history
of VTD, hypercoagulable state, non-plasma cell related
concomitant neoplasms, smoking, immobility, indwelling catheters, estrogen treatment, percentage of plasma
cells in the bone marrow biopsy, creatinine level, corrected serum calcium level, serum albumin, white blood
cells and platelet count, hemoglobin level, β 2-microglobulin, serum M protein level, 24 hour urine protein level,
as well as individual agents and combination of chemotherapeutic agents.
Among these, personal history of VTD (HR-47.7; P = .006,
CI-2.98–766), immobility (HR-11.78; P = .006, CI-2.02–
68.8), absence of measurable M-protein (HR-12.5; P =
.031, CI-1.25–100), and age at diagnosis (HR-2.99, P =
.041, CI-1.05–8.56) were identified as univariable corre-
4/2
History of VTD
Personal
Yes
No
Family
No
Serum M-Protein1
None
Yes
Unknown
3
2
1
24-hour Urine Protein1
<0.15 gr
>0.15 gr
Unknown
3
2
1
BMPC2
≤ 5%
> 5%
Unknown
3
1
2
B2 Microglobulin1
< 1.9 mg/L
> 1.9 mg/L
Unknown
1
4
1
Serum albumin1
< 3.5 g/L
3.5 – 5.0 g/L
3
3
Immunoglobulin type
None
IgG
IgM
4
1
1
1
5
6
None
κ
4
2
WBC count
4 – 11 × 106/L
6
Platelet count
150 – 400 × 106/L
6
1CCF Laboratory reference range, normal values:
Serum M-protein: 0 g/dl
Urine Protein: 0–0.15 g/24°
β2 Macroglobulin: 0.3–1.9 g/dl
Serum Albumin: 3.5–5.0 g/L
2 Bone Marrow Plasma Cells
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Table 4: Identifying univariable correlates of VTD in amyloidosis
(N-56)
Variable (Reference)
Age at Diagnosis (per 10 year increase)
Personal History of VTD (Yes/No)
Immobile (Yes/No)
Serum M-protein
Per 1 mg/dl increase
Normal/Abnormal
HR2
95% CI2
P1
2.99
47.7
11.78
1.05–8.56
2.98–766
2.02–68.8
0.0411
0.0061
0.0061
0.43
12.5
0.05–3.70
1.25–100
0.45
0.0311
1 significant
2 HR
(P < 0.05)
– Hazard Ratio; CI – Confidence Interval
lates of VTD in amyloidosis patients (Table 4.) Multivariable analysis could not be done due to low number of
events.
inadequate. From available records it seems that none of
the 56 patients had a family history of VTD. Although this
could be due to the low number of patients a more probable explanation is poor history taking. Therefore; family
history was not included in univariable analysis. Types of
treatment (individual drugs or chemotherapy combinations) do not correlate with VTD. It is important to mention that none of the patients included in this study had
treatment with high dose chemotherapy and stem cell
support.
One of the univariable correlates of VTD identified in our
group of amyloidosis patients is increased age. Risk of
VTD in these patients is increasing 3 times with every 10year increase in age. A number of studies support an association between increasing age and a higher incidence of
venous thromboembolism [14-16]. Patients over age 40
are at a significantly increased risk compared with
younger patients [17]. Risk continues to increase with
increasing age, approximately doubling with each decade
after age of 40 [18].
Discussion
This study shows increased incidence of VTD (11% at 10
years review) in amyloidosis patients as compared to the
general population (0.1% per person/per year) [11]. This
is similar to frequency of VTD found in multiple myeloma
(MM) (10%) [12], and slightly higher than in patients
with monoclonal gammopathy with undetermined significance (MGUS) (7.5%) [12]. Previously, only case reports
of thromboembolism in patients with amyloidosis were
presented in the literature [5,6,9,13].
Studies presented herein have significant limitations. It is
highly dependent on the quality of historical data.
Absence of a potential risk factor or patient characteristics
in the medical records is assumed to mean that the factor
is absent. The statistical analysis is limited by the fact that
several of the variables that were considered as correlates
of VTD were not baseline characteristics. Ideally, these variables would be analyzed as time-dependent covariates.
However, timing of these variables was not known. It is
only known that they occurred before development of the
event in patients with VTD or before the last follow-up
among patients who did not develop VTD yet.
Results of the study presented herein point to strong correlation between some of the established risk factors for
VTD (personal history and immobility) and thromboembolic events in patients with amyloidosis. Other wellknown VTD risk factors (estrogen use, concomitant solid
malignancies, and use of indwelling catheters) did not
seem to be of importance in our patients.
Data about family history of VTD is missing in more than
10% of patients. Additionally, existing data seem to be
It seems that in our amyloidosis patients, VTD age risk is
in excess of that seen in general population. It does not
seem that this increased risk correlates with more aggressive disease, since age was not found to be an important
prognostic factor for survival in primary systemic amyloidosis in multiple studies [19-21]. However, other types,
such as senile with normal transthyretin (ATTR), amyloidosis associated with Alzheimer's disease (Aβ), and
islet amyloid polypeptide deposits (AIAPP) are very
strongly associated with both old age and the aging
process.
Another significant risk factor of VTD in our patients was
absence of circulating monoclonal protein. This is a characteristic for types of disease other than primary amyloidosis (AL) including secondary (AA), familial with
genetically variant transthyretin (ATTR), amyloidosis
associated with dialysis (Aβ2M), as well as Aβ and AIAPP
forms. Again, these results point to possible increase incidence of VTD in the forms other than primary.
Human serum amyloid A (SAA) is a precursor protein in
inflammation-associated secondary amyloidosis (AA). It
could interfere with the coagulation process through
interaction with heparin/heparan sulfate at the specific
binding site (C-terminal residue 78 to 104) [22]. SAA also
seems to play a role in atherogenesis, as well as in thrombus formation at the vascular injury site [23,24]. Secondary amyloidosis (AA) is manifested in patients with
underlying chronic inflammation (rheumatoid arthritis,
ankylosing spondylitis, inflammatory bowel disease,
tuberculosis, osteomyelitis, Familial Mediterranean
Fever) [25-27]. It is driven by different cytokines, includ-
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International Seminars in Surgical Oncology 2005, 2:17
ing tumor necrosis factor (TNF-α), interleukin-6 (IL-6),
and interleukin-1 (IL-1) [28]. IL-6 was found to promote
coagulation without affecting fibrinolysis [29]. It activates
coagulation cascade through tissue factor stimulation and
increased transcription of factor VIII, up regulates transcription of fibrinogen, increases von Willebrand's factor,
and decreases protein S [29]. Is there any correlation
between SAA or any other circulating non-monoclonal
protein precursors of amyloid and VTD will have to be
elucidated in future studies. It is still uncertain if proposed
increased incidence of thromboembolism is the result of
the very process of deposition of the abnormally folded
protein outside cells, consequential organ damage, or
alternatively, underlying processes leading to amyloid
deposits. However, it does not seem to be related to the
type of treatment used in this disease. This is in accordance with our own findings in the patients with multiple
myeloma and MGUS [12].
Conclusion
Our analysis confirmed that well-known risk factors for
thromboembolism including personal history of VTD and
immobilization could represent confounding factors in
amyloidosis patients, too. However, additional correlates
have to be considered, including type of disease and
patients' age.
http://www.issoonline.com/content/2/1/17
MAH have made significant contribution to concept and
design of the study, revision of the manuscript and have
given final approval of the version to be published.
All authors read and approved manuscript
Acknowledgements
Authors would like to thank Miss Marion McElhaney for valuable technical
assistance.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
In our opinion, these patients need to be closely monitored for development of VTD. Standard thromboembolic
prophylaxis should be used with extreme caution, considering bleeding tendency in the patients with amyloidosis.
10.
11.
In our opinion development of prospective studies dealing with venous thromboembolism in amyloidosis
patients is of utmost importance. We will need to define
pathophysiological mechanisms responsible in order to
employ the most effective prophylactic measures.
Competing interests
The author(s) declare they have no competing interest.
Authors' contributions
GS have made significant contribution to conception and
design of the study, analysis and interpretation of the data
and drafting the manuscript
MGC have been involved in collection, analysis, interpretation of the data and critical revision of the manuscript
SRD have been involved in drafting and revising the
manuscript
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KKM have been involved in revising manuscript for
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