SANDLER ET AL. A.J.C.P.
June 1985
764
induced thromboctyopenia, thrombosis and hemorrhage. Surgery
1979;86:148-155
8. Mueller-Eckhardt C, Mersch-Baumert K: The problem of platelet
autoantibodies. I. Evaluation of platelet factor 3 availability
test for their detection. Vox Sang 1977; 33:221-233
9. Nelson JC, Lerner RG, Goldstein R, Cagin NA: Heparin-induced
thrombocytopenia. Arch Intern Med 1978; 138:548-552
10. Rhodes GR, Dixon RH, Silver D: Heparin-induced thrombocy-
topenia with thrombotic and hemorrhagic complications. Surg
Gynecol Obstet 1973; 136:409-416
11. Rhodes GR, Dixon RH, Silver D: Heparin-induced thrombocy-
Heparm-Like Anticoagulant Associated with
Plasma Cell Myeloma
GEOFFREY S. CHAPMAN, M.D., CHRISTOPHER B. GEORGE, M.D., AND DAVID L. DANLEY, PH.D.
A 54-year-old man with plasma cell myeloma had sustained
bleeding develop after prophylactic hip hemiarthroplasty. Rou-
tine coagulation studies revealed significant prolongation of the
prothrombin time, activated partial thromboplastin time, and
thrombin time. Further evaluation showed failure of the acti-
vated partial thromboplastin time to correct in a 1:1 mixture
with pooled normal plasma, correction of the prolonged thrombin
time by addition of protamine, and a normal reptilase time. A
purified preparation of the immunoglobulin component of patient
plasma produced the same pattern of coagulation abnormalities,
suggesting the paraprotein possessed heparin-like anticoagulant
activity. This appears to be a rare mechanism of bleeding
diathesis in plasma cell myeloma. (Key words: Multiple my-
eloma; Blood coagulation disorders) Am J Clin Pathol 1985;
83: 764-766
THE MALIGNANT DYSPROTEINEMIAS are fre-
quently associated with a bleeding diathesis. Thrombo-
cytopenia, qualitative platelet dysfunction, inhibition of
fibrin monomer aggregation, and decreased coagulation
factor activity have all been described in these diseases.810
We report a patient with plasma cell myeloma who had
sustained postoperative bleeding develop, associated with
a heparin-like inhibitor that resided in the immunoglob-
ulin fraction of his plasma.
Materials and Methods
Coagulation times were measured using a dual-channel
photooptical instrument and commercially available re-
Received August 6, 1984; received revised manuscript and accepted
for publication October 9, 1984.
The opinions or assertions contained herein are the private views of
the authors and are not to be construed as official or as reflecting the
views of the Department of the Army or the Department of Defense.
Address reprint requests to Technical Publications Editor, Letterman
Army Medical Center, Presidio of San Francisco, California 94129-
6700.
topenia: Eight cases with thrombotic-hemorrhagic complications.
Ann Surg 1977; 186:752-758
12. Stevenson MM: Letter. N Engl J Med 1976; 295:1200-1201
13. Towne JB, Bernhard VM, Hursey C, Garancis JC: White clot
syndrome. Arch Surg 1979; 114:372-377
14. Trowbridge AA, Caraveo J, Green JB, Amaral B, Asone MJ:
Heparin-related immune thrombocytopenia. Studies of antibody-
heparin specificity. Am J Med 1978; 64:277-283
15. Wahl TO, Lipschitz DA, Stechschulte DJ: Thrombocytopenia
associated with anti-heparin antibody. JAMA 1978; 240:2560-
2562
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Hematology-Oncology Service, Department of Medicine,
and Department of Clinical Investigation, Letterman Army
Medical Center, Presidio of San Francisco, California
agents (General Diagnostics, Sigma Chemical Company,
St. Louis, MO). Thrombin times were performed in a
fibrometer at a final thrombin concentration of 1.5 to 2
units/mL. Protamine mixed thrombin times contained
a final concentration of 10 mg/dL protamine. Coagulant
factor assays were performed using an aPTT-based one
stage assay.3
The immunoglobulin fraction of the patient's plasma
was separated by precipitation in saturated ammonium
sulfate and then purified by column chromatography
according to the method of Garvey and associates.6
Total protein was then determined spectrophotometri-
cally,2 followed by lyophilization. To verify that the
lyophilized preparation contained the paraprotein, a
sample was reconstituted in physiologic saline. Cellulose
acetate electrophoresis showed a monoclonal protein
with mobility identical to that in the patient's original
serum. Agarose gel immunoelectrophoresis using goat
antisera (Beckman Instruments, Inc., Brea, CA) dem-
onstrated IgG kappa immunoglobulin.
Report of a Case
A 54-year-old black male retiree of the U.S. Armed Forces had a
diagnosis of plasma cell myeloma based uponfindingsof hypoprolifer-
ative anemia, serum protein electrophoresis showing monoclonal IgG
kappa at a concentration of 2.87 g/dL, and bone marrow aspirate and
biopsy showing 50% overall cellularity with 50% of the nucleated cells
being plasmacytes. He had been treated intermittently with pulse
melphalan, prednisone, and vincristine. This therapy was complicated
Vol. 83 No. 6 CASE REPORTS 765
Table 1. Coagulation Studies Using Patient Plasma Table 2. Activated PTT Mixture Study
Using Patient Plasma
Test Result (seconds) Normal Range
aPTT Result
PT 13.5 10-12 (seconds)
aPTT 59 25-36
Thrombin time 38 16-22 Study Immediate One Hour
Protamine corrected thrombin
time 16.1 16-22 Control plasma 34 34
Reptilase time 17.6 18-22 Patient plasma 59 62
Patient plasma + control plasma
(1:1 mixture) 45 47

by sustained thrombocytopenia, which necessitated discontinuation of

melphalan four months prior to admission. In June 1983 he was
hospitalized elsewhere because of a large, painful, lytic bone lesion in polymerization by the FAB portion of the paraprotein
the subtrochanteric region of the left femur. Prophylactic hemiarthro-
plasty was complicated by sustained postoperative bleeding refractory
molecule. In all of these patients, inhibition occurred at
to intensive blood product support. At that time he was transferred to the terminal stage of the coagulation cascade, i.e., fibrin
our institution, where laboratory evaluation revealed hemoglobin of aggregation and polymerization. This was manifested as
9.6 g/dL, white blood cell count of 5,200/mm3, platelet count of prolongation of the thrombin time and reptilase time
80,000/mm3, and BUN of 22 mg/dL. The template bleeding time was

Downloaded from http://ajcp.oxfordjournals.org/ by guest on April 10, 2016

11.5 minutes, correcting to 8 minutes after administration of random
donor platelet transfusions. The prothrombin time (PT) was 13.5
seconds (normal range 10-12 seconds), the activated partial thrombo-
plastin time (aPTT) ranged from 36-60 seconds on several determi-
nations (normal 25-36 seconds), the thrombin time ranged from 25
to 38 seconds (normal range 16-22 seconds), and the quantitative
fibrinogen was 300 mg/dL.
To further investigate the coagulopathy, we performed coagulant
factor assays, reptilase time, and mixture studies using pooled normal
plasma (PNP) and protamine. The results suggested inhibitor activity
directed against thrombin (Tables 1-3). The patient was not receiving
heparin at this time.
In an effort to demonstrate that paraprotein was responsible for the
observed heparin-like anticoagulant activity, we prepared a purified
immunoglobulin fraction from the patient's plasma. Addition of this
material to PNP yielded the same pattern of coagulation test abnor-
malities as observed in the patient's plasma; furthermore, protamine
corrected the prolonged thrombin time observed in the mix-
ture (Table 4).
Studies attempting to demonstrate antigenic specificity of the para-
protein were inconclusive. Using Laurel rocket crossed Immunoelec-
trophoresis we were unable to demonstrate precipitin lines between
the purified immunoglobulin fraction of patient plasma and human
fibrinogen, thrombin, and antithrombin III.
Discussion
Patients with malignant paraproteinemias may have
bleeding develop as a result of a variety of mechanisms.
Although qualitative platelet dysfunction is probably the
most common mechanism, inhibitors with activity at
various other stages in the coagulation scheme have also
been described. 810 One such phenomenon is direct in-
hibition of fibrin monomer aggregation, resulting in a
gelatinous friable clot, poor clot retraction, prolongation
of the thrombin time, and prolongation of the reptilase
time. Augmentation of the calcium concentration in the
reaction mixture partially corrects the thrombin time.
Coleman and co-workers4 described seven such patients
and demonstrated direct inhibition of fibrin monomer
with failure to correct the former by addition of prot-
amine.
Heparin-like inhibitors are rarely associated with the
paraproteinemias. Perkins and colleagues,10 in a review
of 62 patients with dysproteinemia associated with var-
ious diseases, failed to detect a case with "circulating
heparinoid material." This particular phenomenon is
not mentioned in a review by Lackner.8 There are two
case reports in the European literature1,5 of plasma cell
myeloma with a coagulopathy characterized by prolon-
gation of the thrombin time, which was corrected by
protamine. In one case1 the anticoagulant activity resided
in the immunoglobulin fraction of the serum protein
electrophoresis. Palmer and colleagues9 reported a patient
with plasma cell leukemia who died with visceral hem-
orrhage in the presence of a heparin-like anticoagulant
that prolonged the thrombin time (reversible with ad-
dition of toluidine blue) and failed to prolong the
reptilase time. In 1980 the Mayo Clinic group7 reported
a patient with multiple myeloma who had a circulating
anticoagulant that prolonged the aPTT and the thrombin
time and was correctible with the addition of protamine.
The reptilase time was normal. Biochemical character-
ization revealed that the inhibitor material was a heparan
sulfate proteoglycan, which was indistinguishable from
commercial heparin in its ability to inhibit thrombin
action by potentiating antithrombin III activity. However,
Table 3. Coagulant Factor Assays Performed
on Patient Plasma
Factor Result (%) Normal Range
VIII 300 50-150
IX 80 50-150
XI 110 50-150
XII 70 50-150
766 CHAPMAN, GEORGE, AND DANLEY
Table 4. Coagulation Studies Using Lyophiiized Immunoglobulin Fraction (LIF) from the Patient's Plasma
Reaction Mixture PT
Pooled normal plasma (PNP) 10.3
PNP + LIF 12.7
PNP + LIF + protamine
PNP + protamine
(Normal range values) (10.5-13.0)
the anticoagulant was not associated with the immuno-
globulin fraction of the patient's plasma, nor could it
be extracted from the patient's plasmacytes.
Our patient had sustained clinical bleeding, which we
attributed to a heparin-like anticoagulant found within
the immunoglobulin portion of the patient's plasma.
Like heparin, the inhibitor produced prolongation of
the aPTT and protamine-correctible prolongation of the
thrombin time. The reptilase time was normal. Although
a few similar cases have been reported previously, this
type of paraprotein-associated coagulopathy appears to
be quite rare.
Acknowledgments. The authors thank Harlene Palkuti for performing
the coagulation studies and Dee Villaflor and John Rukkila for assisting
in preparation of the manuscript.
References
1. Benda L, Deutsch E, Mammen E: Ueber eine Gerinnungsstorung
bei einem Patienten mit multiplem Myelom. Wien Klin Woch-
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Isoimmune Neonatal Thrombocytopenia:
A Case Report and Review
DONALD CHANDLER, M.D. AND SARA JO DANIEL, M.D.
Isoimmune neonatal thrombocytopenia is an unusual problem
with significant morbidity and mortality. Though it is often
self-limited, it is potentially fatal due to hemorrhage. Specific
therapy with compatible platelets is indicated. In previously
unrecognized cases, platelet antigen and antibody studies delay
therapy unacceptably. Therefore, maternal platelets are used,
which also aid in establishing a therapeutic diagnosis. A case
of isoimmune neonatal thrombocytopenia is reported, and the
Received August 14, 1984; accepted for publication October 29,
1984.
Address reprint requests to Dr. Chandler: P.O. Box 1369, Selma,
Alabama 36702-1369.
The author has requested enhancement of the downloaded file. All in-text references underlined in blue are linked to publications on ResearchGate.
AJ.C.R.June 1985
Result (seconds)
aPTT Thrombin Reptilase
26 20.0 16.9
74 34.0 21.4
18.5
14.0
(23-25) (16-22) (16-22)
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University of South Alabama Medical Center,
Mobile, Alabama
etiology, clinical and laboratory implications, and methods of
management are discussed. (Key words: Thrombocytopenia;
Isoimmune; Neonatal) Am J Clin Pathol 1985; 83: 766-768
A 27-YEAR-OLD white female vaginally delivered a 4-pound neonate
at 34 weeks gestation. The infant's platelet count was 21,000/mm3,
and the skin was covered with petechiae. The pregnancy had been
uncomplicated except for slight vaginal bleeding at 4 months gestation
and aflu-likesyndrome two weeks antepartum.