Cases & Commentaries

Hidden Heparins: HIT Happens

Spotlight Case
Commentary By Patrick F. Fogarty, MD

Case Objectives

  • Review the presentation of
    heparin-induced thrombocytopenia (HIT) and its primary
    complication, thrombosis.
  • Discuss the management of HIT, including
    use of direct thrombin inhibitors and extended anticoagulation with
    a coumarin derivative.
  • Identify safeguards that medical
    institutions can undertake to avoid exposure to heparin in
    individuals who have received the diagnosis of HIT.

Case & Commentary: Part 1

A patient with a history of end-stage renal
disease requiring hemodialysis was admitted for evaluation of
non-healing ulcers and leukocytosis. She had been admitted 1 month
prior for evaluation of peripheral artery disease. During that
hospitalization, the patient underwent angioplasty of the right
femoral artery, complicated by postoperative gangrene of the right
foot requiring above-the-knee amputation. She also developed
axillary vein thrombosis, and ultimately a diagnosis of
heparin-induced thrombocytopenia (HIT) was made. She was treated
with argatroban, and it was noted on the chart that the patient
should receive no further heparin.

Heparin-induced thrombocytopenia (HIT) occurs
when heparin molecules stimulate formation of a pathogenic IgG
antibody (HIT antibody) that leads to platelet activation
(promoting thrombosis) and clearance (leading to thrombocytopenia).
The typical presentation of HIT involves a hospitalized patient who
develops thrombocytopenia within 5–10 days of receiving
heparin; decreases in the platelet count to 9/L or by greater than or equal to 50%
below the baseline value are generally considered to be
significant.(1) Up
to half of patients with HIT will experience thrombosis, in either
the arterial or venous circulation.(3)
This patient appears to have experienced thrombosis (axillary vein
thrombosis, and possibly a lower extremity arterial event leading
to limb ischemia and amputation) as her primary manifestation of
HIT.

In a hospitalized patient, the diagnosis of HIT
may be confounded by the presence of other potential causes of
thrombocytopenia. Still, a pretest scoring system, such as the 4
Ts—which takes into account the degree of
Thrombocytopenia, Timing of the platelet count
decline in relation to heparin use, presence of any
Thrombosis, and any oTher potential causes for
thrombocytopenia (Figure
1
)—may facilitate assignment of a diagnosis.(4)
Laboratory studies such as the HIT antibody enzyme-linked
immunoassay (ELISA) and the serotonin-release assay can later
confirm the diagnosis, but initiation of treatment for HIT should
not be delayed pending results of these specialized studies.

Unfractionated heparin (UFH) is associated with
HIT more frequently than low-molecular-weight heparin (LMWH). A
recent meta-analysis including 7000 medical and surgical patients
who received UFH or LMWH as thromboprophylaxis showed a rate of HIT
of 2.6% and 0.6%, respectively.(2) As
the patient in this case had undergone angioplasty of the right
femoral artery for treatment of peripheral arterial disease, it is
likely that she received heparin at some point during that hospital
stay.

Due to the high risk of thrombosis associated
with HIT, the appropriate initial management of the condition
includes discontinuation of all forms of heparin (including
flushes) and initiation of an alternative anticoagulant, such as a
direct thrombin inhibitor (DTI). Argatroban, lepirudin
(Refludan®), and bivalirudin (Angiomax®) are DTIs that are
commercially available in the United States (Table). The DTI should be continued until the platelet
count has recovered and the patient is adequately
anticoagulated with a coumarin derivative (warfarin). Because of
the risk of venous limb gangrene that can result from transient
hypercoagulability associated with early warfarin therapy in HIT
patients, warfarin therapy should not be started until the platelet
count recovers and then only with overlapping DTI therapy. In
patients with HIT and thrombosis, as in this case, anticoagulation,
usually with a coumarin derivative, should be continued for a
minimum of 3–6 months following detection of the
thrombosis.(5,6)
Even in patients with HIT who present without thrombosis, the risk
of thrombosis persists for at least 30 days, with up to 50% of
patients developing venous or arterial events.(3) Therefore, patients with confirmed HIT without
thrombosis should be anticoagulated (typically with a coumarin
derivative) for at least 4 weeks after HIT is detected.(6)

Case & Commentary: Part 2

On this admission, the patient was found to be
tachycardic and hypotensive, with excoriations of the skin over the
breast, abdomen, right thigh, and gluteal region. Her labs were
significant for leukocytosis of 17.1 x
109/L and hypoalbuminemia of 2.4 gm/dl.
The patient was started on antibiotics (amikacin and vancomycin).
Blood cultures eventually grew candida, and amphotericin was added
to her regimen. She appeared to be improving with a decrease in
white blood cell count (WBC) to 10 x
109/L. Over the next few days, however,
she developed ischemia in her right hand, which eventually became
cold and pulseless. It was also noted at this time that her
platelet count had dropped since admission. On hospital day 8, the
leukocyte count increased again, her respiratory status worsened,
and she died, presumably from overwhelming sepsis.

In light of the high risk of thrombosis that
accompanies the diagnosis of HIT, it is possible that the
patient’s presenting signs of tachycardia and hypotension
stemmed from an HIT-related central venous or arterial thrombotic
event, such as myocardial infarction or pulmonary embolism.
Leukocytosis does not complicate HIT per se, but
inflammation or infection from ischemia could lead to an elevated
white cell count.

Shortly after admission, this patient did develop
signs of arterial insufficiency with right hand ischemia that
progressed to pulselessness. Although HIT is complicated by
symptomatic venous thrombosis more often than arterial thrombosis
(7),
arterial thrombosis may occur more frequently in certain patients
with HIT, such as individuals with cardiovascular
disease.(8)

Interestingly, this patient presented with
“excoriations” of the skin. Up to 10%–20% of
patients receiving subcutaneous UFH or LMWH who develop HIT will
first have erythematous, nodular, plaque-like, or necrotic lesions
(Figure
2
) at the injection site.(7)
Although HIT antibodies are detectable in most of these patients,
thrombocytopenia is present in only a minority.(9) We are not told that heparin was ever injected
subcutaneously in this case, and the location of some of the
lesions (e.g., breast) makes an injection-related phenomenon less
likely, although skin lesions that occur at sites that are distant
from the location of subcutaneous injection have been
reported.(10)
Dermal necrosis also has been reported following use of intravenous
heparin.(11)

In contrast, coumarin-induced skin necrosis
(CISN) rarely occurs when warfarin is introduced in a patient with
HIT and typically begins within days of starting the oral
anticoagulant. A proposed mechanism for the condition involves
worsening of HIT-induced hypercoagulability due to an acute
reduction in levels of protein C or S. Localized, progressive,
microvascular thrombosis ensues that typically leads to necrosis of
the dermis overlying the breast, abdomen, thigh, or leg.(7) We
are not told that this patient ever received warfarin, but the
dermatologic “excoriation” may well have been a skin
manifestation of HIT.

Case & Commentary: Part 3

Autopsy revealed thrombi in the vessels of the
skin of breast and abdomen. A thorough review of the chart and
hemodialysis records revealed that, during this second
hospitalization, the patient had been repeatedly exposed to heparin
during dialysis sessions, despite her recent history of HIT and the
chart notes to avoid heparins.

The histologic finding at autopsy of microthrombi
in dermal vessels strongly suggests that the skin lesions that were
initially observed over the breast, abdomen, and thigh represented
sequelae of ongoing HIT, which probably had developed following
exposure to heparin during the first admission to the hospital.
Although HIT had been documented and treated during that
hospitalization, the patient continued to receive heparin in the
hemodialysis suite.

A diagnosis of HIT does not necessarily obviate
any future use of heparin, but several factors must be carefully
considered before heparin is given. Although certain patients may
experience no recurrence of thrombocytopenia upon re-challenge with
heparin as soon as 1.5 months after an episode of HIT (1),
most patients with HIT continue to test positive for HIT antibodies
well after the thrombocytopenia has resolved. When measured by
ELISA, the median duration of HIT antibody positivity is 85
days.(1)
This observation has led to the usual practice of waiting at least
100 days before considering use of heparin in patients with a prior
history of HIT and documenting negativity for the HIT antibody
before re-exposing to heparin. If re-exposure is absolutely
necessary (i.e., for vascular surgery), short-term use of the
heparin may be considered with frequent monitoring of the platelet
count. Patients with persistent HIT antibodies, as our patient most
likely had, who are re-challenged with heparin can develop
rapid-onset HIT, in which thrombocytopenia and thrombosis
develop with alarming speed, sometimes as soon as a day after
re-exposure to heparin.(7)

This case underscores the need for safeguards for
patients who are diagnosed with HIT to prevent
“accidental” exposure to heparin. In our hospital (UCSF
Medical Center), the electronic pharmacy profile (WORx, Mediware
Information Systems, Lexena, Kansas) of any patient in whom HIT is
diagnosed is updated to indicate the diagnosis. If a heparin (UFH
or LMWH) subsequently is ordered by a care provider, an alert is
generated (Figure
3
) that is visible to the hospital pharmacist, who contacts the
ordering provider to advise of the prior history. In this regard,
patients with a prior history of HIT are “protected”
from orders for UFH or LMWH that are written without a knowledge of
the patient’s history of HIT, and the protection extends to
future admissions. As an additional precaution, a placard
indicating “Heparin-Induced Thrombocytopenia: No
Heparin” is placed above the bedside in rooms of inpatients
who receive the diagnosis, and an allergy is recorded in the
medical record.

Unfortunately, in most hospitals, heparins
(typically UFH) are stocked in more locations than simply the
clinical pharmacy, and patients can be exposed to the drug, usually
as part of a “routine” maneuver such as flushing a
venous access device. Administration of heparin in quantities as
small as those routinely used to flush central venous catheters and
other vascular access devices can lead to HIT antibody formation or
HIT itself (12–14), and minor exposure via this route in a
patient with persistently circulating HIT antibodies can promote
re-emergence or worsening of thrombocytopenia or
thrombosis.(15) To
reduce the risk of promoting or exacerbating HIT through use of
heparin flushes of invasive catheters, some institutions have
adopted a policy of routinely using normal saline for their
flushes. Such an approach is supported by several studies,
including a randomized controlled trial of UFH versus saline
flushes for invasive catheters used in the operating suite and a
meta-analysis of patency rates of peripheral venous catheters
flushed with UFH or normal saline, which found no benefit to UFH
for this purpose.(12,16)
Heparin is still used routinely to prevent thrombosis of the
hemodialysis circuit, however. Because heparin usually is stocked
in the dialysis unit, the pharmacy and aforementioned system of
alerts can be bypassed.

The significant risk of HIT and its devastating
sequelae has prompted consideration of policies that aim to remove
heparin from all patient care areas. When such policies are
implemented, ordering heparin requires an MD order to the pharmacy,
even when the heparin is for flushing of catheters. Implementation
of computerized electronic alerts, especially if linked to
physician ordering screens, may provide the best method of risk
notification, as has been demonstrated in other
applications.(18)

Take-Home Points

  • HIT can occur in medical or surgical
    patients after exposure to UFH or LMWH in any form (subcutaneous
    injection, intravenous, flushes).
  • The clinical presentation of HIT can
    include isolated thrombocytopenia, isolated arterial or venous
    thrombosis, or both conditions. Skin lesions occur in a minority of
    patients with HIT but increase the probability of the diagnosis in
    a thrombocytopenic patient who has been exposed to heparin.
  • Patients with a history of HIT should
    generally not be re-exposed to heparin (either UFH or LMWH), but
    when clinically indicated, heparin may be used for a short period
    of time provided HIT antibodies are no longer detectable.
  • All patients with a prior history of HIT
    should have the medical and pharmacy record permanently amended to
    indicate the diagnosis.
  • Identifying uses of heparins that
    circumvent provider orders can lower the risk that a patient with
    HIT (or at risk for HIT) will be exposed to heparin.

Patrick F. Fogarty, MD
Director, Hemostasis and Thrombosis Clinic
Department of Medicine, Division of Hematology/Oncology
University of California, San Francisco

Faculty Disclosure: Dr. Fogarty has
declared that neither he, nor any immediate member of his family,
has a financial arrangement or other relationship with the
manufacturers of any commercial products discussed in this
continuing medical education activity. The commentary does include
information regarding off-label use of bivalirudin for treatment of
HIT. All conflicts of interest have been resolved in accordance
with the ACCME Updated Standards for Commercial Support.

References

1. Warkentin TE, Kelton JG. Temporal aspects of
heparin-induced thrombocytopenia. N Eng J Med.
2001;344:1286–1292.
[go to PubMed]

2. Martel N, Lee J, Wells PS. Risk for
heparin-induced thrombocytopenia with unfractionated and
low-molecular-weight heparin thromboprophylaxis: a meta-analysis.
Blood. 2005;106:2710–2715.
[go to PubMed]

3. Warkentin TE, Kelton JG. A 14-year study of
heparin-induced thrombocytopenia. Am J Med. 1996;101:502–507.

[go to PubMed]

4. Lo GK, Juhl D, Warkentin TE, Sigouin CS,
Eichler P, Greinacher A. Evaluation of pretest clinical score (4
T’s) for the diagnosis of heparin-induced thrombocytopenia in
two clinical settings. J Thromb Haemost. 2006;4:759–765.

[go to PubMed]

5. Fogarty PF, Dunbar CE. Thrombocytopenia. In:
Rodgers GP, Young NS, eds. Bethesda Handbook of Hematology.
Philadelphia, PA: Lippincott, Williams and Wilkins;
2005:256–257.

6. Alving BM. How I treat heparin-induced
thrombocytopenia and thrombosis. Blood. 2003;101:31–37.
[go to PubMed]

7. Warkentin TE. Clinical picture of
heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A,
eds. Heparin-Induced Thrombocytopenia. 3rd ed New York, NY: Marcel
Dekker; 2004:53-106.

8. Boshkov LK, Warkentin TE, Hayward CP, Andrew
M, Kelton JG. Heparin-induced thrombocytopenia and thrombosis:
clinical and laboratory studies. Br J Haematol.
1993;84:322–328.
[go to PubMed]

9. Warkentin TE, Roberts RS, Hirsh J, Kelton JG.
Heparin-induced skin lesions and other unusual sequelae of the
heparin-induced thrombocytopenia syndrome: a nested cohort study.
Chest 2005;127:1857–1861.
[go to PubMed]

10. Balestra B, Quadri P, Dermarmels Biasiutti F,
Furlan M, Lämmle B. Low molecular weight heparin-induced
thrombocytopenia and skin necrosis distant from injection sites.
Eur J Haematol. 1994;53:61–63.
[go to PubMed]

11. Hartman AR, Hood RM, Anagnostopoulos CE.
Phenomenon of heparin-induced thrombocytopenia associated with skin
necrosis. J Vasc Surg. 1988;7:781–784.
[go to PubMed]

12. Warkentin TE, Ling E, Ho A, Sheppard JI.
“Incidental” unfractionated heparin (UFH) vs normal
saline (NS) flushes for intraoperative invasive catheters and the
frequency of formation of heparin-induced thrombocytopenia IgG
antibodies (HIT-IgG): a randomized, controlled trial. Blood.
1998;92(suppl 1):91b.

13. Brushwood DB. Hospital liable for allergic
reaction to heparin used in injection flush. Am J Hosp Pharm.
1992;49:1491–1492.
[go to PubMed]

14. Heeger PS, Backstrom JY. Heparin flushes and
thrombocytopenia. Ann Intern Med. 1986;105:143.
[go to PubMed]

15. Rice L, Jackson D. Can heparin cause
clotting? Heart Lung. 1981;10:331–335.
[go to PubMed]

16. Randolph AG, Cook DJ, Gonzalez CA, Andrew M.
Benefit of heparin in peripheral venous and arterial catheters:
systematic review and meta-analysis of randomised controlled
trials. BMJ. 1998;316:969–975.
[go to PubMed]

17. Vanholder RC, Camez AA, Veys MM, et al.
Recombinant hirudin: a specific thrombin inhibiting anticoagulant
for hemodialysis. Kidney Int. 1994;45:1754–1759.
[go to PubMed]

18. Kucher N, Koo S, Quiroz R, et al. Electronic
alerts to prevent venous thromboembolism among hospitalized
patients. N Engl J Med. 2005;352:969–977.
[go to PubMed]

Table

Direct thrombin inhibitors.

Agent Description Indication Dosing Comment
Argatroban Synthetic direct thrombin inhibitor Prophylaxis or treatment of HIT, including
post–percutaneous coronary intervention
Obtain baseline PTT. Start continuous infusion at
2
m
/kg/min. Titrate to achieve PTT of 1.5–3 times the
baseline value. Do not allow PTT to exceed 100 seconds, nor the
infusion rate to exceed 10
m
g/kg/min.
•  Patients with hepatic insufficiency: initial
infusion rate = 0.5
m
g/kg/min.
•  Increases the INR in warfarin-treated patients;
interpret INR accordingly.
Lepirudin (Refludan®) Recombinant hirudin; direct thrombin
inhibitor
Treatment of HIT with associated thrombosis Obtain baseline PTT. Give slow bolus of 0.4 mg/kg
then continuous infusion of 0.15 mg/kg/hr. Titrate to achieve PTT
of 1.5–2.5 times baseline value. PTTs should be obtained 4
hours after starting the infusion and at least daily during
treatment.
•  Patients with renal insufficiency: initial bolus =
0.2 mg/kg.
•  50% of patients develop anti-drug antibodies that
increase half-life; may necessitate a decrease in dose.
Bivalirudin (Angiomax®) Semi-synthetic derivative of hirudin; direct
thrombin inhibitor
Unstable angina in patients undergoing
percutaneous transluminal coronary angioplasty
1.0 mg/kg IV bolus followed by 2.5 mg/kg/hr
infusion for 4 hours; may continue infusion at 0.2 mg/kg/hr for up
to 20 hours.
•  FDA-approved for concomitant use with
aspirin.
•  Not approved for use in patients with HIT.

Figures

Figure 1. A Clinical Pretest Approach to the
Diagnosis of HIT (Adapted from Lo et al.[4]).

Characteristic of Heparin-Induced
Thrombocytopenia (HIT)
Score (Fill in
0–2)
Pretest Probability
Score
2 1 0
Thrombocytopenia (x
109/L)
____ Nadir 20–100, or >50% platelet fall from
baseline
Nadir 10–19, or 30–50% platelet fall
from baseline
Nadir
Timing of onset of platelet fall after starting
heparin
____ Day 5–10, or less than or equal to day 1 if
recent heparin*
>Day 10, or timing uncertain but compatible with
HIT
Less than or equal to Day 1 (no recent
heparin)
Thrombosis/additional manifestations ____ Proven thrombosis, skin necrosis, or
ASR†
Progression or recurrence of established
thrombosis; silent thrombosis; erythematous skin lesions
None
Other potential causes of platelet decline ____ None evident Possible Definite
Total Pretest Probability Score ____ See “Total PreTest Probability
Score,” below
Total Pretest
Probability Score
High Moderate Low
8 7 6 5 4 3 2 1 0
Stop heparin‡, give alternative
non-heparin anticoagulant Argatroban or lepirudin (or
bivalirudin)
Avoid warfarin**
(Individualize management) Continue
(LMW) heparin

*Recent heparin = exposure within the past 30 days (2 points) or
past 30–100 days (1 point).
†ASR = acute systemic reaction, including hypertension,
tachypnea, fever, following intravenous heparin bolus.
‡Discontinue all forms of heparin, including vascular
catheter heparin flushes and heparin-coated catheters.
**Warfarin should not be started until platelet count has recovered
(plt >100K); starting dose should be low, and therapy should be
overlapped with a direct thrombin inhibitor for a minimum of 5
days.

Figure 2. Heparin-Induced Skin Necrosis.
(Picture reprinted with permission from International Journal of
Dermatology.)


Figure 3. Example of an Electronic Alert upon
Attempting to Order Heparin in a Patient with a Heparin Allergy:
WORx® Software.


Click on thumbnail for larger view.