Heparin-Induced Thrombocytopenia,
Thrombosis, and Hemorrhage
DONALD SILVER, M.D., DONALD N. KAPSCH, M.D., EDMUND K. M. TSOI, M.D.
Sixty-two patients with a heparin-induced thrombocytopenia are
reported. Clinical manifestations of this disorder include hem-
orrhage or, more frequently, thromboembolic events in patients
receiving heparin. Laboratory testing has revealed a falling
platelet count, increased resistance to heparin, and aggregation
of platelets by the patient's plasma when heparin is added.
Immunologic testing has demonstrated the presence of a heparin-
dependent platelet membrane antibody. The 20 deaths, 52 hem-
orrhagic and thromboembolic complications, and 21 surgical
procedures to manage the complications confirm the seriousness
of the disorder. Specific risk factors have not been identified;
therefore, all patients receiving heparin should be monitored.
If the platelet count falls to less than 100,000/mm3, while the
patient is receiving heparin, platelet aggregation testing, using
the patient's plasma, is indicated. Management consists of ces-
sation of heparin, platelet anti-aggregating agents, and alternate
forms of anticoagulation when indicated.
EPARIN WAS DISCOVERED in 1916, introduced clin-
ically in 1935, and became firmly established as
an excellent agent for managing thromboembolic events
by 1960.`'- The utilization of heparin for managing and
preventing thromboembolism has become so widely ac-
cepted that approximately one trillion units of heparin
are utilized in this country each year. Despite the large
amounts of heparin administered, complications remain
low, with the two most common complications being
hemorrhage in 7% to 10% and sensitivity reactions in
2% to 5% of patients receiving heparin.4
Heparin administration may cause a temporary re-
duction of the number of circulating platelets in patients
and animals. This temporary thrombocytopenia has lit-
tle, if any, clinical significance. Weismann and Tobin5
and Roberts et al.6 reported patients with additional
thromboembolic events while receiving heparin and
speculated that the heparin may have contributed to the
Presented at the Annual Meeting of the American Surgical Asso-
ciation, May 12-14, 1983, Boca Raton, Florida.
Reprint requests: Donald Silver, M.D., Department of Surgery,
University of Missouri-Columbia Health Sciences Center, One Hos-
pital Drive, Columbia, Missouri 65212.
Submitted for publication: May 16, 1983.
0003-4932/83/0900/0301 $01.10 K) J. B. Lippincott Company
301
From the Department of Surgery, University of Missouri-
Columbia Health Sciences Center, Columbia, Missouri
thromboembolism. It was suggested in 19697 and con-
firmed in 19738 that thromboembolic events could be
caused by a heparin-induced thrombocytopenia.
This report reviews our experiences with 62 patients
with heparin-induced thrombocytopenia and throm-
bohemorrhagic complications.
Materials and Methods
During the past 12 years, the possibility of a heparin-
induced thrombocytopenia has been evaluated in pa-
tients receiving heparin who developed thrombocyto-
penia (platelets less than 100,000 mm3), new throm-
bohemorrhagic events, and/or an increased resistance
to heparin.
Duplicate platelet counts were performed by phase
microscopy or with the Coulter counter. Coagulation
testing, done more extensively on the earlier patients,
has included the activated partial thromboplastin time,
prothrombin time, clotting time, thromboplastin gen-
eration time, fibrinogen concentration, euglobin and
rapid clot lysis times, and fibrin degradation product
concentrations.
Platelet-rich and platelet-poor plasmas were prepared
by differential centrifugation from blood collected in
3.8% citrate (1 ml of anticoagulant/9 ml of blood) or a
mixture of prostaglandin E, (0.1 ml, 1 gg/ml), theo-
phyline (0.1 ml, 30 mmole/ml), and EDTA (0.1 ml of
10% EDTA) per 3 ml of blood. Type-specific, fresh, nor-
mal donor platelets were utilized for aggregation studies.
The patient's platelet-poor plasma was stored at -70 C.
Complement fixation and platelet surface-bound im-
munoglobulins were assayed in the first eight patients.9
Sera from six patients were analyzed with an agarose
countercurrent electrophoresis system, while Ouchter-
lony diffusion techniques were used to analyze the sera
of 13 patients.'0
302 SILVER, KAPSCH, AND TSOI
Aggregation studies were performed on the plasma
from 61 patients with the Chronolog aggregometer.'0
All patients, with the exception of the first, who re- Mortality: 20 patients; 14 deaths directly related to heparin.
ceived both bovine and porcine heparin, were antico-
agulated with bovine heparin.
Results
Twenty-eight women and 34 men with a heparin-in-
duced thrombocytopenia have been studied during the
past 12 years. The patients ranged in age from 19 to 93
years, with 59 of the patients being over 40 years of age.
Thirty-eight of the 62 patients received heparin as part
of the management of their arterial and/or venous
thromboembolism, while 24 of the patients received
heparin as prophylaxis against deep venous thrombosis,
arterial or small graft thrombosis. Forty-two patients
received, intravenously, 15,000 to 75,000 U of heparin
daily, while the other 20 patients received, subcutane-
ously, 9000 to 15,000 U of heparin daily.
The first patients were recognized and treated only
when they developed thrombohemorrhagic complica-
tions while receiving heparin or because they became
"resistant" to heparin.9 Later, patients have been de-
tected earlier as they develop thrombocytopenia, in-
creased heparin resistance, and/or thromboembolism.
Despite our awareness of this disorder, 20 of the 62
patients died, with 14 of the deaths being attributed to
complications of the heparin-induced thrombocyto-
penia.
Fifty-two thromboembolic complications occurred in
38 of the 62 patients (Table 1). Twenty-one of the first
31 patients and 17 of the last 31 patients developed
complications. Those patients not having complications
were detected early, by platelet counts and/or coagula-
tion testing, and the heparin was stopped prior to the
occurrence of complications. The interval of heparin
administration prior to the onset of complications and/
or thrombocytopenia and increased heparin resistance
was 4 to 15 days (mean, 8.8 days) in those patients re-
ceiving heparin for the first time and 2 to 9 days (mean,
5 days) in those patients who had received heparin pre-
viously.
Twenty-two surgical procedures were required to
manage the complications. One of the early patients
developed thrombocytopenia, heparin resistance, and a
right temporal hematoma while receiving heparin pro-
phylaxis (9000-12,000 U heparin subcutaneously each
day) after a lumbar fusion. The hematoma required sur-
gical evacuation. Another of the early patients had two
unsuccessful brachial thrombectomies-heparin was
not discontinued. Three patients had femoral throm-
bectomies: two were successful in patients who did not
receive additional heparin; one failed in a patient who
Ann. Surg. * September 1983
TABLE 1. Mortality and Morbidity ofHeparin-Induced
Thrombocytopenia
Hospitalization: 7 to 87 days with 0 to 50 days secondary to
complications from heparin.
Morbidity: 56 complications in 62 patients.
Pulmonary embolism 12 Aortic thrombosis 8
Myocardial infarction 5 AFB graft thrombosis I
CVA*-thrombosis 3 Arterial thrombosis 9
CVA*-hemorrhage 1 Deep venous thrombosis 5
Bowel infarct 1 Skin slough 2
Wound hematomas 9
* Cerebrovascular accident.
continued to receive heparin. Seven patients required
ten aortoiliac thrombectomies: five thrombectomies, in
two patients who continued to receive heparin, failed;
five thrombectomies were successful in the five patients
who did not receive heparin after operation. One patient
required a thrombectomy of his aortofemoral graft. His
platelet count was 69,000/mm3 the day of the graft
thrombosis. Heparin was stopped and a successful
thrombectomy was accomplished during the first post-
operative day. The inability to restore flow resulted in
five lower extremity amputations. Nine patients devel-
oped hematomas in their wounds during the time of the
thrombocytopenia.
The patients had "normal" platelets by smear or platelet
counts that ranged from 130,000 to 920,000/mm3 at ad-
mission (Table 2). The nadir of the platelet count varied
from 5000 to 83,000/mm3 and occurred between the 4th
and 15th day (following initiation of heparin therapy) for
patients receiving heparin for the first time and between
the 2nd and 9th day for those receiving subsequent courses
of heparin. The platelet count responded to cessation of
heparin, becoming greater than 100,000/mm3 in all sur-
viving patients by 7 days. Bone marrow examination, in
five patients, demonstrated normal or an increased num-
ber of megakaryocytes. Fifty-seven patients had positive
aggregation studies. The platelets of four patients did not
aggregate in response to heparin, and one patient did not
have aggregation studies. The five patients not having
positive aggregation tests had an immediate rise in their
platelet count and a remission of their thromboembolic
complications with cessation of heparin therapy.
TABLE 2. Heparin-Induced Thrombocytopenia Platelet Studies
Admission 130,000 to 920,000/mm3
Nadir 5,000 to 83,000/mm3
Recovery to > 100,000/mm3: 1 to 7 days
>200,000/mm3: 2 to 6 days
Bone marrow 5 patients, all T megakaryocytes
Aggregation 57 positive, 4 negative
Vol. 198 No. 3
- HEPARIN-INDUCED THROMBOCYTOPENIA, THROMBOSIS, AND HEMORRHAGE
Currently, patients with a suspected heparin-induced
thrombocytopenia and a negative aggregation test have
aggregation testing for 2 to 3 days after cessation of hep-
arin. The plasma from three patients that did not ag-
gregate platelets while the patient was receiving heparin,
did aggregate platelets within three days after heparin
was discontinued. The four negative aggregation tests
in the early patients may have become positive if they
had been repeated after cessation of heparin.
The thrombocytopenia was not related to an intra-
vascular coagulation. The activated partial thrombo-
plastin time was prolonged in patients receiving heparin
and was normal or only minimally prolonged after the
heparin in the specimen was neutralized with protamine.
The fibrinogen remained more than 170 mg/ 100 ml in
the 35 patients in whom it was measured. Fibrin deg-
radation products were greater than 40 gg/ml in only
five patients-two patients had pulmonary emboli, one
had carcinomatosis, one had gram-negative sepsis, and
the other had recurrent arterial thrombosis. The eug-
lobulin and rapid clot lysis times were normal in the six
patients studied with these tests.
Immunologic studies have been reported in de-
tail.8-'0 The complement lysis inhibition, complement
fixation, countercurrent electrophoresis, Ouchterlony
diffusion, and aggregation testing confirmed the occur-
rence of a heparin-dependent platelet membrane anti-
body in the patients who developed this disorder.
The early patients were recognized after their throm-
bohemorrhagic complications had occurred. Currently,
the disorder is suspected when the platelet count be-
comes less than 100,000 mm3 and/or thrombohemor-
rhagic complications occur in patients receiving heparin.
A positive aggregation test and/or increase in platelet
count and decrease in thrombohemorrhagic complica-
tions in response to cessation of heparin confirm the
diagnosis. Management consists of stopping the admin-
istration of heparin, providing aspirin (300 mg twice a
day) and dipyridamole (50 mg four times a day) as plate-
let inhibiting drugs, and using alternate anticoagulants
when anticoagulation is needed.
Twelve patients with known heparin-induced throm-
bocytopenia have received additional heparin 8 days to
12 months after their initial exposure to heparin. Three
early patients were challenged with heparin 12 days to
2 months after platelet recovery and had recurrent
thrombocytopenia, with a mean reduction of 197,000
platelets/mm3.9 The platelet counts rose promptly after
the brief challenges. Seven patients received heparin 8,
11, 14, 23, and 24 days and 4 and 12 months after the
initial heparin infusion and developed recurrent throm-
bocytopenia and a positive platelet aggregation test. Two
patients with the disorder had no response to heparin
303
23 days and 4 months after the initial infusion of hep-
arin.
Besides the high mortality and morbidity associated
with a heparin-induced thrombocytopenia, the disorder
is quite costly in consumption of medical resources. The
length of hospitalization for the 62 patients varied from
7 to 87 days, with up to 50 days (usually 10-14 days)
being directly related to the management of the com-
plications of the heparin-induced thrombocytopenia.
Discussion
The administration of heparin to man or animals is
frequently associated with a temporary thrombocyto-
penia which usually has no clinical consequence.'2"3
The thrombocytopenia is thought to result from revers-
ible platelet aggregation, margination, and peripheral
sequestration. The mechanism of this process is not un-
derstood but seems to be related to a heparin-induced
release of ADP. 14
In 1958, Weismann and Tobin5 reported ten cases of
frequently multiple, arterial embolism in patients re-
ceiving heparin. They noted that their patients had "fri-
able aortic thrombi" and that the arterial embolism was
"a possible complication of vigorous heparin therapy in
those persons with pre-existing aortic thrombi." In 1964,
Roberts et al.6 reported 11 patients with "unexplained
arterial embolization" during heparin therapy. They
suggested that the heparin might be associated with the
"formation of thrombi by platelet deposition"' as a "re-
sult of an antigen-antibody mechanism." Natelson et
al.7 reported, in 1969, a heparin-induced thrombocy-
topenia in one patient-treated with heparin for a con-
sumption coagulopathy. Although heparin diminished
the consumption of the clotting factors, the thrombo-
cytopenia (nadir of 5000 platelets/mm3) continued until
cessation of heparin.
Rhodes et al.8 reported, in 1973, the first two patients
of the present report and, using complement fixation
studies and agglutination and aggregation absorption
studies, confirmed "a heparin dependent antibody as
being the cause for the thrombocytopenia." The throm-
bocytopenia was associated with thrombotic and hem-
orrhagic complications in both patients.
During the past 10 years, there have been several re-
ports of a heparin-induced thrombocytopenia that has
been associated with a high mortality and risk of throm-
boembolic or hemorrhagic complications. The throm-
bocytopenia in these reports, like that in the present
series, was not related to age, sex, blood type, underlying
disease process, type of heparin administered, route of
heparin administration, or amount of heparin admin-
istered.'5-'8 These reports confirm the findings of the
304 SILVER, KAPSCH, AND TSOI
present study that the nadir of the platelet count, which
may be as low as 5000 platelets/mm3, occurs around the
eight day after heparin therapy is begun, and on the fifth
(second to ninth day) of heparin therapy in patients who
have received heparin previously.
The 20% mortality rate and very high morbidity of
this series, as well as the 18% to 36% mortality rate and
high morbidity reported by others'5"6 attest to the se-
riousness of the disorder. The mortality and morbidity
seem to be directly related to the consequences, and
management, of arterial thromboembolism, pulmonary
embolism, myocardial infarction, and/or significant
hemorrhage. All of our patients had a platelet count of
less than 100,000/mm3, and several patients required
increasing amounts of heparin to maintain a stable level
of anticoagulation at the time of complication and/or
diagnosis. These findings have prompted us to suspect
a heparin-induced thrombocytopenia in any patient
with increased heparin resistance and/or a platelet count
that falls below 100,000/mm3 while the patient is re-
ceiving heparin (and the coagulation screen does not
indicate the presence of an intravascular coagulation).
An immunologic basis for drug-induced thrombo-
cytopenia has been documented for a wide range of com-
pounds.'9'20 Although heparin is generally considered a
weak antigen, it may combine with a component of the
platelet membrane to form a hapten that stimulates the
production of platelet membrane antibodies. Tritium-
labeled heparin has been demonstrated to bind to the
platelet membrane fractions.2' Platelets from patients
with heparin-induced thrombocytopenia have been
found to have increased levels of platelet surface im-
munoglobulins after incubation of platelet-rich plasma
with heparin.9"' 22 Complement fixation studies, aggire-
gation studies, agarose countercurrent immunoelectro-
phoretic studies, Ouchterlony diffusion studies, and hep-
arin-platelet absorption studies all support the thesis of
a heparin-dependent platelet membrane antibody in
some patients receiving heparin.8'02223
A review of all patients receiving heparin, during a
6-month period, in the University ofMissouri-Columbia
Hospital revealed that 0.6% of those patients developed
a heparin-induced thrombocytopenia. The high mor-
tality and morbidity associated with the disorder, espe-
cially if it is not recognized until the onset of compli-
cations or death, have prompted us, and others,23 to
monitor the platelet counts on all of our patients who
are receiving heparin. The platelet count is repeated ev-
ery 2 to 3 days for the first 15 days of heparin therapy.
Any patient developing a thrombocytopenia and/or in-
creased heparin resistance has aggregation testing of his
serum. A positive aggregation test confirms the diagnosis
and mandates that the heparin be discontinued. A neg-
Ann. Surg. * September 1983
ative aggregation test may occur while the patient is
receiving heparin and may become positive only after
the heparin has been discontinued for 1 to 3 days. We
frequently stop heparin and initiate treatment for the
disorder while continuing daily aggregation testing. If
the aggregation test remains negative for 3 days after the
heparin has been discontinued, the patient is considered
not to have had the disorder.
Management of a heparin-induced thrombocytopenia
includes cessation of heparin therapy and, when indi-
cated, the use of alternate forms of anticoagulation.
Continued administration of heparin is associated in-
variably with a progressive thrombocytopenia and com-
plications. If anticoagulation is to be continued, the au-
thors utilize warfarin, orally or intravenously, in 10 to
15 mg doses daily until the prothrombin time becomes
twice that of the control prothrombin time. Subsequent
doses are determined by the prothrombin times. In ad-
dition to stopping heparin, agents that interfere with
platelet aggregation should be administered. Dextran
was given to some of the early patients. We now use
aspirin, by mouth or per rectum, and dipyridamole.
Cessation of heparin therapy has been associated with
a prompt increase in the platelet count in all surviving
patients.
We have been unable to identify any factors that place
a patient at risk for developing a heparin-induced throm-
bocytopenia and, therefore, consider all patients receiv-
ing heparin to be at risk. Previous heparin exposure ap-
pears to hasten the occurrence of the thrombocytopenia
and the thrombohemorrhagic complications. The per-
sistence of the platelet membrane antibody varies con-
siderably, with two patients having no response to repeat
administration of heparin 23 days and 4 months after
the initial infusion, and seven patients responding to
heparin with thrombocytopenia 8, 11, 14, 23, and 24
days and 4 and 12 months after the initial infusion of
heparin. It is not known how long the sensitivity to hep-
arin persists. However, quinine-induced thrombocyto-
penia may persist for years.24 Therefore, all patients with
previous heparin-induced thrombocytopenia are consid-
ered to be at increased risk for the redevelopment of
thrombocytopenia with recurrent heparin administra-
tion. Heparin is avoided or used cautiously with frequent
platelet monitoring in those patients who require a sec-
ond course of heparin.
The pathophysiology of the heparin-induced throm-
bocytopenia and its sequelae is outlined in figure 1. A
few patients, while receiving heparin, develop heparin-
dependent platelet membrane antibodies. These anti-
bodies, in the presence of heparin, cause platelet aggre-
gation. With platelet aggregation, there is a release of
platelet factor IV, which has heparin neutralizing activ-
Vol. 198 * No. 3 HEPARIN-INDUCED THROMBOCYTOPENIA, THROMBOSIS, AND HEMORRHAGE
Heparin-ln&iced lrombocytopenia
Hrin most pktients antittromnbosis
reversible platelet aregation
OA%
patients
Heparin depp_dit platelet membrane atibody
* heparin
+ platelets
Patelet Aggregation
pPF3 *
1 Coagulation Platelet-fibrin thr
He + Colation
* Heparin rvestnce
FIG. 1. Scheme of the pathophysiology of the heparin-induced throm-
bocytopenia.
ity and may contribute to the increasing heparin resis-
tance that occurs in some of these patients. If sufficient
platelets aggregate, marked thrombocytopenia and
bleeding may occur. The platelet aggregates are probably
responsible for the arterial and venous thromboses, with
these thromboses also contributing to the increased hep-
arin resistance. The mechanism outlined is consistent
with the hypothesis that the platelet membrane antibody
induces platelet aggregation in the presence of heparin
and that the aggregation contributes to thrombocyto-
penia and thrombohemorrhagic complications.
The absence of reliable, identifiable risk factors and
the serious consequences of the heparin-induced throm-
bocytopenia, with its insidious onset, make the moni-
toring of platelet counts and close observation of the
patients receiving heparin for more than a few days es-
sential. The development of a decreasing platelet count,
increasing heparin resistance, or new or recurrent
thrombohemorrhagic events strongly suggests the pres-
ence of this disorder. Discontinuation of the heparin is
necessary if these patients are to be managed success-
fully.
References
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DISCUSSION
DR. WILLARD JOHNSON (Boston, Massachusetts): On the Surgical
Service of the Boston V.A. Medical Center, we see about two patients
a year with this disorder. I can attest to the existence of the syndrome,
and the catastrophic nature of the cardiovascular events that occur in
these patients.
305
2. Best CH. Preparation of heparin and its use in the first clinical
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21. Shanberge JN, Kambayashi J, Nakagawa M. The interaction of
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I'd like to address my remarks to therapy; and relate our experience
in two recent cases. One was a patient who had acute thrombosis of
a 5-year-old aortic prosthetic graft while on heparin therapy. We chose
to administer streptokinase to this patient with low-dose intra-arterial
therapy. After 2 days there was successful lysis of the entire graft.
The second patient was on chronic dialysis, and unexpectedly one
day, clotted his dialysis machine, as well as his AV fistula. With the aid