Research Article
Prevalence of Heparin-Induced Thrombocytopenia Type II among Cardiac Surgery Patients
Abdulrazaq S1, Reem Bahmaid2*, Nathem S3, Edward B4, Elias J Saad5 and Tarek M Owaidah6
1Department of Medical/Critical Care Pharmacy, King Faisal Specialist Hospital and Research Centre, Riyadh,
Saudi Arabia
2Department of Cardiovascular Pharmacotherapy, King Fahad Medical City, Riyadh, Saudi Arabia
3Department of Cardiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
4Department of Epidemiology &Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh,
Saudi Arabia
5Department of Intensivist Consultant, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
6Department of Hematology Consultant, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi
Arabia
*Corresponding author: Reem Bahmaid, Department of Cardiovascular Pharmacotherapy, King Fahad Medical City, Riyadh, Saudi Arabia
Published: 06 Jul 2017
Cite this article as: Abdulrazaq S, Reem Bahmaid, Nathem
S, Edward B, Elias J Saad, Tarek M
Owaidah. Prevalence of Heparin-
Induced Thrombocytopenia Type II
among Cardiac Surgery Patients. Clin
Surg. 2017; 2: 1538.
Abstract
Objective: To assess the prevalence of heparin - induced thrombocytopenia type II (HIT) among
suspected patients who received heparin in cardiac surgery intensive care unit at a single tertiary
care hospital.
Method: This is a retrospective cohort study conducted to calculate the prevalence of HIT type II
among all patients who underwent cardiac surgery and tested for HIT over one decade, from 1st of
January 2004 to 31st of December 2014. Patients who were suspected to have HIT were stratified
according to the results of HIT assay result, using Diamed PaGIA and\or ELISA screening test, into
two groups; HIT positive group and HIT negative group.
Result: During the study period, 5,104 patients had cardiac surgery, 264 patients were suspected
clinically to have HIT with a prevalence of 5.17% (95% CI, 4.59% to 5.81%). Out of these patients
only 35 patients had positive test result, with a prevalence of 13.25% (95% CI, 9.11% to 17.28%).
This makes the prevalence among the whole population to be 0.68% (95% CI, 0.45% to 0.91%).
In the 264 cases of suspected HIT, the retrospectively calculated 4T’s probability score were high
among 30 patients (11.4%), intermediate in 197 (74.6%) and low in 37 patients (14%). Among HIT
negative patients there was a significant difference between risk of developing thrombocytopenia
and selected pre-defined confounding variables; particularly sepsis and the use of cardiac devices
(P value < 0.001).
Conclusion: The prevalence of true HIT type II among cardiac patients is rare, although it's not
uncommon among clinically suspected cases.
Keywords: Heparin-induced thrombocytopenia; Low molecular weight heparin; CSICU
Abbreviations
CSICU: Cardiac Surgery Intensive Care Unit; CT: Computed Tomography; ECMO: Extracorporeal Membrane Oxygenation; ELISA: Enzyme Immune Assay Test; IABP: Intra-Aortic Balloon Pump; HIT: Heparin-Induced Thrombocytopenia Type II; Hg: Hemoglobin; KFSH&RC: King Faisal Specialist Hospital and Research Centre; LMWH: Low Molecular Weight Heparin; MR: Magnetic Resonance; SRA: Serotonin Release Assay; UFH: Unfractionated Heparin; VAD: Venticular Assit Devise
Background
There are two types of heparin-induced thrombocytopenia (HIT). Heparin-induced
thrombocytopenia type I that occurs in 10% to 20% of patients receiving heparin [1], and HIT type
II that occurs between the fifth and fourteenth day of heparin therapy unless there was a previous
heparin exposure. Type II HIT is one of the serious side-effects associated with heparin therapy [2].
The incidence of HIT type II has been reported to range from 1% to 5% among patients using heparin [1], and is more commonly seen in orthopedic surgery patients receiving UHF [3]. Early diagnosis of HIT type II is crucial to prevent
thrombosis complications. Despite the relatively high prevalence of
anti-PF4/heparin antibodies in patients undergoing cardiac surgery,
the incidence of HIT in this patient population is about 2.4% [3].
Laboratory analysis should be done to confirm the diagnosis
of suspected HIT for all cases associated with intermediate or high
probability of HIT type II as defined by the 4T's probability score
which consist of thrombocytopenia, time of thrombocytopenia,
thrombosis, and absence of other causes of thrombocytopenia
[2,4]. However, there are some inconsistencies when it comes to the
definition of suspected HIT and HIT type II [5-10]. Regardless, HIT
type II is defined as unexplained thrombocytopenia, with a 30% to
50% reduction of the platelet from baseline occurring within 5-14
days after initiating heparin with or without thrombosis in addition
to the positive gold standard assay; serotonin release assay "SRA" [11].
Others defined diagnosis of HIT type II depends on screening tests
(Diamd gel or ELISA) and functional assay (SRT). The sensitivity
and specificity of these tests are different and affect the rate of HIT
diagnosis.
For patients who are receiving UFH, there are various factors
that can lead to thrombocytopenia other than UFH itself, which may
complicate the diagnosis and management. Incorrect diagnosis or
high suspicious of HIT may lead many practitioners to initiate HIT
management. In cardiac surgery intensive care unit (CSICU), several
other factors including drug-induced thrombocytopenia, surgery
and sepsis [12,13], can further complicate the diagnosis. Therefore,
we hypothesize that the prevalence of HIT type II is overestimated
among suspected cases who received UFH or Low Molecular Weight
Heparin (LMWH) which may lead to inappropriate management
squeal. This study aims to assess the prevalence of HIT type II among
suspected patients who received UHF or LMWH in post-cardiac
surgery patients. Additionally, the study will assess the performance
of 4T’s probability scoring in retrospective manor whenever it is
possible in the same setting.
Methods
Study design
This is a retrospective cohort study that aims to assess the
prevalence of HIT type II among all cases of suspected HIT in CSICU
and its step down units. All patients who were admitted to CSICU
in our institution and transferred to one of its step down units over
one decade, from 1st of January 2004 to 31st of December 2014 were
included in the study. Patients who were clinically suspected for HIT
were stratified according to the result of the HIT assay into group
A "patients who had positive HIT test" and group B "patients who
had negative for HIT test", and then were compared with regard to
clinical presentation and management consequences. Suspected HIT
was defined as all cases who had HIT assay test positive for enzyme
immune assay test "ELISA" and/or "Diamed PaGIA" test during the
study period. Where, HIT type II was defined as all cases that had a
positive HIT assay result.
Study population
All patients who were suspected to have HIT during the defined
study period, at CSICU and its step down units at King Faisal
Specialist Hospital and Research Centre (KFSH & RC), Riyadh, Saudi
Arabia, were included.
Inclusion criteria
All adult and pediatric patients who were admitted to CSICU and
its step down units with suspected HIT were included in the study.
The study was approved by the Research Advisory Council (RAC:
2151029).
Data collection
The medical charts of all suspected patients as defined previously,
from 2004 through 2014, were reviewed, and the following data
were collected: demographic data, drug data (history of using
UFH\LMWH, within the last three months, type of non-heparin
anticoagulant used for suspected HIT, including lepirudin,
bivalirudin, argatroban or fondaparinux), laboratory data (baseline
platelet count, nadir platelet count, follow up platelet count for
14 days [14] after sending HIT assay, baseline hemoglobin (Hg),
fibrinogen, and D - dimer level), 4T’s score at time of suspected HIT,
result of HIT assay, chart documentation of confirmed HIT, and
other clinical outcomes including documentation of radiologically
confirmed venous/arterial thromboembolism, and major bleeding
that is defined as clinical evidence of bleeding documented in
patients’ chart with therapeutic intervention including blood product
and/or pharmacological agents administration, ICU mortality, and
hospital length of stay. Also we assessed the presence or absence of
other confounding factors defined as sepsis, cardiac surgery; type of
cardiac surgery; drug-induced thrombocytopenia including GP II(b)/
III(a) inhibitor, amiodarone, carbamazepine, milirinone, valproic
acid, phenytoin and cardiac devices used such as intra-aortic balloon
pump (IABP), extracorporeal membrane oxygenation (ECMO) and
ventricular assist devices (VADs).
Outcome measures
The primary outcome of our study was to assess the prevalence
of HIT type II among cardiac surgery patients with suspected HIT.
Several secondary outcomes were measured including; the 4T’s
probability scoring which consist of thrombocytopenia, time of
thrombocytopenia, thrombosis, and absence of other causes of
thrombocytopenia at the time of suspecting HIT, the correlation
between high, moderate, and low clinical probability using 4T’s
scoring and the presence of HIT type II, impact of overall use of nonheparin
anticoagulants and the suspicion of HIT in terms of presence
of thrombosis and length of hospitalization among all suspected cases
comparing group A (positive HIT test) to group B (negative HIT
test). Impact of overall use of non-heparin anticoagulants in terms of
major bleeding during and after their use among all suspected cases
and comparing group A with group B for the rate of discontinuation
of non-heparin anticoagulants and re-initiation of heparin among
patients who had negative HIT assay results, electronic chart
documentation and time of platelet recovery among all suspected
cases and comparing group A and group B. The correlation between
thrombocytopenia and the presence of one of the confounding factors;
drug-induced thrombocytopenia, sepsis, type of cardiac surgery, and
the use of cardiac devices were assessed. The predictive value of using
4T's among cardiac surgery patients, and the correlation between
age and risk of developing thrombocytopenia, as well as correlation
between age and results of negative HIT assay were also investigated.
Statistical analysis
Taking into account the data previously reported [15], we
hypothesized that the incidence of HIT among suspected cases will
be around 0.47% among surgical ICU patients and 27% among suspected cases admitted to cardiac surgery ICU. From a brief review
of charts, it was projected that approximately 350 patients will qualify
as HIT type II suspected cases. If the incidence of true HIT type II is as
high as 27%, then the true incidence should be estimated to be within
five percentage points. Continuous variables were expressed as the
mean + SD and categorical variables as percentages. For categorical
variables, comparisons were made using the χ2 test or Fisher exact
test and continuous variables was made using the student t-test. We
compared the two groups by using a student t-test. For those variables
which showed non-normality on the distribution, the non-parametric
Wilcox on test was used instead. Multivariable analysis was used in
the situation where more than one independent factor was analyzed for one outcome at the same time. SAS version 9.4 software was used
to analyze the data.
Figure 1
Figure 2
Table 1
Table 1
Baseline characteristics of all patients with suspected Heparin-induced
Thrombocytopenia (HIT) type II.
Results
During the study period, 5104 patients had cardiac surgery, from
those 264 patients were clinically suspected to have HIT. Details of
baseline characteristics of all 264 subjects, with comparison for both
groups, are presented in (Table 1) and Table II. The prevalence of
suspected HIT type II was 5.17% (95% CI, 4.59% - 5.81%), (Figure
1). Based on the results of Diamed PaGIA and or ELISA screening
test we found that only 35 patients tested positive for one or more of
the HIT tests, with a prevalence of 13.25% (95% CI, 9.11% - 17.28%)
among the suspected HIT, and 0.68% (95% CI, 0.45% - 0.91%) among
the whole study population. Among the 264 cases of suspected HIT,
the calculated 4T’s probability score were high among 30 patients
(11.4%), intermediate in 197 (74.6%) and low in 37 patients (14%).
Moreover, among those who had a positive HIT assay the "high"
4T’s probability score encountered in one patient only (2.8%),
"intermediate" encountered in 29 (82.86%), and "low" encountered in
5 patients (14.3%). The "intermediate" and "high" 4T's scores have a
sensitivity of 85.7% (95% CI, 0.49% - 1.23%) and a specificity of 14%
(95% CI, 0.095% – 0.185%) in predicting true HIT among cardiac
surgery patients with suspected HIT. The positive predictive value
of 4T’s scoring was 13.2% (95% CI, 0.088% - 0.176%), and negative
predictive value 86.5% (95% CI, 0.753% – 0.974%).
We found that there were no differences in the baseline
hematological values and other label parameters between the positive
HIT patients compared to negative HIT patients, (Table 2). Also, we
found no difference between HIT positive patients and HIT negative
patients in regard to the distribution of confounding factors, that
might influenced the development of HIT type II, (Table 3).
Among the 264 patients of suspected HIT, thrombosis developed
in 16 patients (6.1%); 15 (6.55%) of them had negative HIT and
one patient (2.87%) had positive HIT; p-value=0.44. Among the 264 patients with suspected HIT, non-heparin anticoagulants were
used in only 13 patients (4.92%), and there was no difference in the
development of thrombosis among patients who used non-heparin
anticoagulant compared to those who were kept on heparin. On the
other hand, among the suspected HIT patients bleeding developed in
100 patients (37.9%), 20 patients (20%) had positive HIT test. Where
all of them received blood product, but platelet transfusion was given
for 18 patients (18%), while surgical interventions were done for 13 of
them (13%), and 24 patients (24%) received pharmacological agents
to reverse bleeding. From those 100 patients who developed bleeding,
20 patients (20%) had positive HIT test and all of them received
blood transfusions, and 3 (15%) of them received platelet transfusion.
Moreover, there was no significant difference in the hospital stay, and
mortality among non-heparin anticoagulant users in those with HIT
positive (3 patients) and HIT negative patients (10 patients) who did
not use non-heparin anticoagulants. Also there was no difference in
the hospital stay and mortality between those with HIT positive and
HIT negative in general despite using non-heparin anticoagulant,
which can be hard to interpret because of the small sample size.
Electronic chart documentation for the result of positive HIT was
done only for 21 (60%) patients out of 35 patients.
One-way analysis revealed that among HIT negative patients
there was a significant difference between risk of developing
thrombocytopenia and the pre-defined confounding variables; sepsis
and the use of cardiac devices; with P value < 0.001. Moreover, the
mean reduction in platelet count was higher among negative HIT
patients who had ECMO -87.816 + 3.72, and patients who had IABP
-82.780 + 4.31 compared to negative HIT who had not have cardiac
device not -76.286 + 1.33, and -77.099 + 1.33, P value < 0.05. The type
of surgery did not influence the risk of thrombocytopenia (Table 4).
In patients who had on-pump surgery, there was a positive
correlation between thrombocytopenia and the prolonged time
of cardiopulmonary bypass, while no influence on the risk of
thrombocytopenia and the cross-clamping of the aorta time, Figure 2.
Young patients, who have mean age under 30.7 + 19.8 years, were
more susceptible to develop thrombocytopenia than patients whose
age was more than 45.3 + 31 years, with P value 0.0001. Reversibly,
we found that the risk of getting HIT positive is significantly higher
among older patients; median age for positive HIT was 52.32 years
(IQR, 35.4 - 60) versus 37.2 years (IQR, 0.88 - 56.9), P value 0.0096.
Table 2
Table 2
Baseline characteristics among suspected Heparin-induced Thrombocytopenia (HIT) stratified based on HIT test results.
Table 3
Table 3
Laboratory variables for all patients of suspected Heparin-induced Thrombocytopenia (HIT); comparing HIT positive to HIT negative patients.
Table 4
Table 4
Distribution of confounding factors among all patients with suspected HIT; comparing HIT positive to HIT negative patients.
Discussion
In our study we found that the prevalence of HIT type II to be
low, 0.68%, among cardiac surgery patients. This prevalence falls in
the range of previously published studies that ranged between 0.2%
- 1.4%. However, we had a great interest to know the prevalence of
HIT type II among the suspected cases, and we found it to be 13.2%,
which means one patient of every eight suspected cases will have true
HIT type II. This consistent finding will help in understanding that
there are many factors that could contribute to the development of
thrombocytopenia among patients post-cardiac surgery. Also these factors could affect the decision of using non-heparin anticoagulant
among suspected cases [16].
As it is known, 4T’s scoring system is validated to identify
patients with low, intermediate or high probability of HIT type II, as a
screening tool before sending the confirmatory test. Moreover, it is well
established that 4T’s probability scoring system have high sensitivity
with inconsistent specificity for HIT type II. In general, patients with
intermediate or high 4T’s probability have a sensitivity range between
89% and 100% and specificity range between 39% and 76%. Our
study showed a sensitivity of 85.7% and specificity of 14%, only. This
can be explained by the multi-factorial causes of thrombocytopenia
in this setting. Therefore, 4T’s probability scoring system has a high
negative predictive value for HIT type II, and negligible positive
predictive value among cardiac surgery patients suspected to have
HIT type II. It’s very well known that some confounding factors
may contribute to the development of thrombocytopenia in cardiac
surgery patients apart from heparin; some of these factors have
valuable size on the impact of 4 T's probability. In our study we found
that the risk of thrombocytopenia higher among patients who have
these confounding factors. Moreover, there was no difference in the
development of thrombosis and bleeding among HIT positive and HIT
negative patients. Using non-heparin anticoagulant did not influence
the duration of hospital stay, this can be attributed to its use in small
percentage of suspected cases of HIT type II. Additionally, we detected
a significant risk of developing thrombocytopenia in patients with
sepsis and patients who had ECMO or IABP [17]. Furthermore, there
is positive correlation between the development of thrombocytopenia
and the cardiopulmonary bypass time. The present findings of the
positive association between thrombocytopenia and mechanical
cardiac assist devices reaffirm that they should be considered while
diagnosing HIT type II among cardiac surgery patients who were
placed on these devices. Furthermore, it flags the importance of revalidating
and revising the 4T’s probability score f it will be used
in cardiac surgery setting. Providing the predictive value for the
clinical probability score and highlighting the effect of confounding
factors on the development of thrombocytopenia in cardiac surgery
setting; a prospective clinical study using specific clinical probability
score for cardiac surgery patients is warranted. Our study has some
limitations, including the retrospective design. There was incomplete
information about the total amount of platelet transfusion received
and the amount of platelets used among thrombocytopenic patients.
Discussion
The prevalence of true HIT type II among cardiac patients is rare, although it's not uncommon among suspected cases. The use of 4T portability scoring in this setting demonstrated high sensitivity, but low specificity may be due to the multi-factorial cause of thrombocytopenia.
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