Acquired Factor X Deficiency and Amyloidosis
JOHN R. KRAUSE, M.D.
Krause, John R.: Acquired factor X deficiency and amyloidosis. Am J Clin Pathol 67: 170-173, 1977. A selective
acquired Factor X deficiency is an unusual occurrence.
Six cases of an acquired Factor X deficiency in association
with amyloidosis have been reported. This paper describes
two additional cases, suggesting that this relationship may be
more than coincidental. The mechanism by which amyloid
may affect Factor X levels remains unknown, but suggestions include consumption, inactivation or decreased synthesis
of Factor X. Factor II, VII, IX, and X concentrate
transiently increased the Factor X level to normal in one of the
patients. In an adult patient who has an isolated Factor
X deficiency, amyloidosis should be actively sought. (Key
words: Factor X deficiency; Amyloidosis; Coagulation factor
defects.)
A SELECTIVE ACQUIRED factor X deficiency
leading to a coagulation defect is unusual. Ten cases
have been located in the literature.2~4'8'11,12,14'16'18'21
Interestingly, six of these cases have been associated
with amyloidosis. 2 ' 4 ' 1112 - 14,18 Within the past two years,
the author has encountered two additional cases of an
acquired factor X deficiency associated with amyloidosis through consultations and diagnostic work performed in the clinical pathology laboratory.
Report of Two Cases
Case I: A 60-year-old woman, well all her life,
noticed the onset of pronounced shortness of breath
on exertion three months prior to admission, but did
not seek medical care at that time. About two weeks
prior to admission, she noticed red spots on her skin,
which prompted her to see a physician, and she
was subsequently admitted to the hospital. There was
no prior history of easy bruising, and the patient
had not bled excessively following a hysterectomy
two years earlier.
Significant physical findings included petechiae on
Received February 19, 1976; received revised manuscript March
25, 1976; accepted for publication March 25, 1976.
Address reprint requests to Dr. Krause: Central Hematology
Laboratory, Presbyterian-University Hospital, Pittsburgh, Pennsylvania 15213.
Department of Pathology,
University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania
the forehead, neck, back and chest. A 5 x 5 cm,
bluish-black bruise was present on the right forearm,
as well as several 3 x 4 cm bruises on the left thigh.
Examination of the heart revealed a left parasternal
heave and a Grade II/VI holosystolic murmur at the
left sternal border. The liver was palpable 3 fingerbreadths below the right costal margin. There was no
splenomegaly. The rest of the physical examination
was within normal limits.
The EKG showed small QRS waves. Chest x-ray
revealed interstitial congestion with bilateral pleural
effusions. Cardiomegaly was also found. Stool
guaiac was 2 + . On admission the laboratory data
were: hemoglobin 9.5 gm/dl (1.47 mmol/1), hematocrit 29.8% (.298); leukocyte count 15,500/mm:! (15.5
x 109/1)—neutrophils 70%, bands 7%, lymphocytes
15%, monocytes 6%, eosinophils 2%. The erythrocytes appeared hypochromic, and a few fragmented
forms were seen. Platelet count was 66,000/mm:t (.066
x 1012/1). Urinalysis contained trace protein with a
specific gravity of 1.020. The sediment was unremarkable. Blood chemistry values included glucose 105 mg/
dl (5.77 mmol/1), blood urea nitrogen 10 mg/dl (3.57
mmol/1), creatinine 0.9 mg/dl (68.7 jumol/l), calcium
9.0 mg/dl (2.25 mmol/1), phosphorus 3.8 mg/dl (1.23
mmol/1), sodium 140 mEq/1 (140 mmol/1), potassium
4.6 mEq/1 (4.6 mmol/1), chloride 108 mEq/1 (108 mmol/
1), and bicarbonate 24 mEq/1 (24 mmol/1). Enzyme
values were within normal limits. Serum protein values
included total protein 6.2 g/dl (62 g/1) with 3.5 g/dl
(0.54 mmol/1) albumin, 0.3 (g/dl (3.0g/1) alpha,-globulin,
0.9 g/dl (9.0 g/1) alpha 2 -globulin, 0.9 g/dl (9.0 g/1) betaglobulin and 0.6 g/dl (6.0 g/1) gamma-globulin.
Serum immunoelectrophoresis revealed slight decreases in concentrations of IgG, IgA, IgM, kappa
and lambda chains, but no qualitative abnormality.
170
171
AMYLOIDOSIS AND FACTOR X DEFICIENCY
vol. 67. No. 2
Table 2. Coagulation Data, Case 2
Table I. Coagulation Data, Case 1
Test
Normal
Patient
Test
Normal
Patient
Bleeding time
4 min
1-6 min
Bleeding time
4'/i min
1-6 min
Clotting time (glass)
6'/i min
6-12 min
Clotting time (glass)
8 min
6-12 min
Clot retraction
4+
3-4+
Clot retraction
4+
3-4+
Prothrombin time/control
29 sec/12 sec
11-14 sec
Prothrombin time/control
27 sec/12.5 sec
11-14 sec
Activated partial thromboplastin time/control
70 sec/32 sec
25-35 sec
Activated partial thromboplastin time/control
68 sec/30 sec
25-35 sec
Fibrinogen
210mg/dl
(6.09 ju.mol/1)
150-400 mg/dl
(4.4-11.6 ju.mol/1)
Fibrinogen
175 mg/dl
(5.1 /*mol/l)
150-400 mg/dl
(4.4-11.6/nmol/l)
Prothrombin (Factor II)
95%
50-150%
Prothrombin (Factor II)
90%
50-150 mg%
Factor V
90%
50-150%
Factor V
85%
50-150 mg%
75%
50-150 mg%
Factor VII
80%
50-150%
Factor VII
Factor VIII
90%
50-150%
Factor VIII
100%
40-150 mg%
Factor IX
100%
50-150%
Factor IX
90%
50-150 mg%
Factor X
9%, 10%, 10%
50-150%
Factor X
15%
50-150 mg%
Fibrin split products
0
<\2 fig/ml
Fibrin split products
2 /Ltg/ml
<12 jug/ml
Subsequent immunoelectrophoresis showed that the
urine contained an increased concentration of a
homogeneous lambda protein.
The initial clinical impression was low-grade chronic
disseminated intravascular coagulation, possibly due
to an occult malignancy. A coagulation work-up
(Table 1) was ordered, as well as a bone marrow
aspirate and biopsy for iron stores/tumor. The coagulation studies were performed according to the following
methods: bleeding time (modified Ivy),15 whole-blood
clotting time-glass (modified Lee-White),6 clot retraction,23 prothrombin time,20 activated partial thromboplastin time,19 fibrinogen,7 prothrombin,17 Factors
V, VII, and X using prothrombin time assays utilizing mixtures of patient's and specific factor-deficient
plasmas, Factors VIII, IX, XI, and XII using activated partial thromboplastin time assays utilizing
mixtures of patient's and specific factor-deficient
plasmas and fibrin split products.9
Factor X levels were determined on several occasions and were always low (Table 1). The coagulation studies were corrected in vitro by the addition
of normal plasma in a 1:1 ratio, which was evidence
of the absence of an inhibitor of any potency.
About this time the bone marrow biopsy was reported
to have amyloid deposits in several vessel walls.
Subsequent rectal and gingival biopsies also contained
amyloid, and the patient was considered to have
primary systemic amyloidosis. There were 3% plasma
cells in the marrow.
Before further coagulation studies could be performed the patient suffered a cardiac arrest. She did
not recover from this episode, and died about a week
later. Permission for autopsy was refused.
Case 2: A 54-year-old woman bled excessively
following a tooth extraction and was referred for
evaluation of a possible coagulation disorder. The patient had had several teeth extracted five years previously without complication. She stated that she had
never bruised easily, and there had been no bleeding
complication associated with the delivery of three
children. Other pertinent past medical history included
repair of a carpal-tunnel syndrome two years previously.
Physical examination revealed slight oozing of blood
from the packing in the extracted molar socket.
Pertinent findings included a grade II/VI murmur
heard along the left sternal border and a liver palpable 5 cm below the right costal margin.
Chest X-ray revealed slight enlargement of the cardiac
silhouette, and EKG showed reduction in voltage
across the precordium. The laboratory data included:
hemoglobin 10.1 g/dl (1.56 mmol/l), hematocrit 31%
(0.31), leukocyte count 11,500/mm3 (11.5 x 1071), with
65% polys, 7% bands, 20% lymphocytes, 6% monocytes
and 2% eosinophils. Platelet count was 175,000/mm3 (0.175
x 1012/1). Urinalysis showed 1+ protein with a specific
gravity of 1.020. Examination of the sediment revealed 3 leukocytes per high-power field. Stool guaiac
was negative. Blood chemistry values included glucose
100 mg/dl, (5.50 mmol/l), BUN 20 mg/dl (7.1 mmol/l)
and creatinine 0.9 mg/dl (79.5 ^mol/I). Electrolytes
were within normal limits. Alkaline phosphatase was
65 IU (normal 10-40); other enzymes were within
KRAUSE
172
Table 3. Factor X Levels Following Infusion of Factor
II, VII, IX, and X Concentrate
Time
Factor X Level
(%)
0
5 minutes
1 hour
4 hours
24 hours
48 hours
72 hours
5 days
20
95
70
52
34
22
18
15
normal limits. Serum electrophoresis revealed a normal pattern with a total protein of 6.8 g/dl (68 g/1);
albumin was 3.8 g/dl (0.58 mmol/1), alpha,-globulin
0.3 g/dl (3.0 g/i), alpha2-globiilin 0.8 g/dl (8.0 g/1),
beta-globulin 0.7 g/dl (7.0 g/1), and gamma-globulin
1.2 g/dl (12.0 g/1).
The coagulation data, obtained utilizing the same
procedures described above, are presented in Table 2.
The important findings were prolonged prothrombin
and activated partial thromboplastin times and a
selective Factor X deficiency. These studies were
corrected in vitro by the addition of normal plasma
in a 1:1 ratio, again evidencing the absence of an
inhibitor of any potency. At this time the patient was given two vials or Proplex* (600 U Factor
IX-vial). The potency is adjusted in terms of Factor
IX, and the other factors (II, VII, X) are stated
to be present in approximately the same amount.
One vial of concentrate is considered equivalent
in activity to two units of fresh frozen plasma.
Factor X levels were determined at selected times,
and the results are shown in Table 3. The halflife (Ti) of Factor X is 24-42 hours.1 Because of the
awareness of selected Factor X deficiency and
amyloidosis, a rectal biopsy was done; the specimen
stained positively for amyloid with Congo red and
crystal violet stains.
The bleeding from the extracted tooth stopped and
the patient was discharged,, to be followed on an
outpatient basis regarding her factor deficiency and
amyloidosis. However, the patient failed to keep her
initial appointment and has been lost to follow-up.
Discussion
Factor X deficiency was originally described as a
congenital coagulation defect associated with mild
hemorrhagic diatheses.10-22 The first acquired case was
associated with fungicide poisoning, with apparent
complete spontaneous recovery.8 All succeeding cases
* Proplex (Factor II, VII, IX, X Concentrate), Hyland Laboratories, Costa Mesa. California.
A.J.C.I'. • I chruury 1977
of acquired Factor X deficiency in adults have been
associated with amyloidosis. This paper describes
two additional cases of an acquired Factor X deficiency
also found to be associated with amyloidosis and reinforces the presumption that there may be more than
a casual relationship between the two entities.
Hemorrhage may occur in amyloid disease, and in
one large series was due to amyloid infiltration of blood
vessel walls.5 None of these patients had coagulation
defects or thrombocytopenia. Hemorrhagic manifestations are also known to occur with diffuse amyloidosis
of the liver.13 In these cases, the coagulation abnormality has been attributed to multiple clotting factor defects, such as may be encountered in any diffuse hepatic disease.
The patients described in this paper had isolated
Factor X deficiencies with hemorrhagic manifestations
occurring late in life. Both patients had borne children
and had had surgical and dental procedures without
reported bleeding abnormalities. Although the parents
or siblings of the patients could not be studied,
the daughter of the patient of Case 1 had normal
Factor X levels. Family histories failed to support
any evidence of bleeding diatheses.
t h e coagulation defects in both patients were corrected in vitro by normal plasma, up to and including
a 60-minute incubation period. Although in-vitro
testing may be corrected by normal plasma and seems
to negate a circulating anticoagulant, in vivo correction has not been realized by infusion of normal
plasma into patients.2-3-8'11-12-14,1" This may be due, in
part, to a dosage effect, in triat insufficient fresh
plasma was given. In our Case 2, 2 units of Proplex
(Factor II, VII, IX, X concentrate) were given and
Factor X levels determined at intervals (Table 3).
Immediately following infusion, Factor X reached a
normal level, 95%. (The theoretical level was calculated to be 65%). The half-life for factor X is 24-42
hours, and thus there was a rapid decline to preinfusion levels by 48 hours (22%). Factor X concentrations are being studied in Proplex since a greater
response than expected was obtained.
The mechanisms by which amyloid may affect
Factor X levels are not known. Various postulates
include decreased synthesis, consumption, and inactivation. Diffuse amyloid infiltration of the liver could
decrease synthesis of Factor X, as well as other coagulation factors produced by the liver, but in the cases
in the literature, including the two reported here,
there was no evidence of extensive hepatic disease
or multiple factor deficiencies. Andre and associates2
were unable to remove Factor X activity from normal
plasma with a specimen of bone marrow from a patient
with amyloidosis. Similarly, Bernhardt and associates4
AMYLOIDOSIS A N D FACTOR X DEFICIENCY
V o l . <>7 . N o . :
mixed
normal
plasma
with
specimens
of
soluble
amyloid with inconclusive results. These failures do
not conclusively
rule out the possibility of
in-vivo
adsorption of Factor X. Unfortunately the death of one
of the patients and the loss of the other to follow-up
has prevented further work of this nature. A
third
mechanism might be the presence of a circulating
anticoagulant or Factor X neutralize! - , although studies
//; vitro
failed to demonstrate this. Perhaps amyloid
disease
acts
as a marker
for
the
presence
of a
yet unidentifiable substance that removes Factor X
from the circulation. Further work on this interesting
association is necessary.
Summary
T w o cases of acquired Factor X deficiency associated with amyloidosis are described. The mechanism of this association is not known. In any adult
patient who has an isolated Factor X deficiency,
amyloidosis should be actively sought.
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