Keywords
thrombocytopenia - heparin - antibody
Autoimmune heparin-induced thrombocytopenia (aHIT) is a subset of HIT in which patients
have high levels of antiplatelet factor 4 (PF4)/heparin antibodies that are able to
activate platelets even in the absence of heparin.[1]
[2]
[3]
[4] Due to the autoimmune nature of aHIT, discontinuation of heparin alone is not adequate
and patients should be promptly treated with therapeutic doses of a nonheparin anticoagulant.
Normalization of platelet counts upon start of alternative anticoagulation in aHIT,
however, delays for several days and thrombocytopenia may persist.[1]
[5] In certain situations, a rapid recovery in platelet count is needed such as in patients
who require antiplatelet treatment (APT). In this article, we report on the use of
intravenous immunoglobulin (IVIG) as successful adjunctive treatment of aHIT after
transcatheter aortic valve implantation (TAVI).
A 68-year-old male patient (96 kg, 160 cm) with a 12-year history of diabetes mellitus,
arterial hypertension, and chronic renal insufficiency was admitted to our hospital
with cardiac decompensation and cardiogenic shock due to aortic valve stenosis. The
patient underwent coronary angiography which revealed severe calcification of the
valve that caused reduced left ventricular (LV) function with an ejection fraction
of 30%. An emergency percutaneous transluminal balloon valvuloplasty (PTV) was performed
after giving one dose of low-molecular-weight heparin (LMWH; enoxaparin, 4,000 anti-Xa
units, s.c.). Cardiogenic shock persists despite PTV, and progressive worsening of
LV function with increasing catecholamine requirement was observed. Therefore, a transcatheter
aortic valve was implemented via a transfemoral approach. For the TAVI procedure,
another 4,000 anti-Xa units of LMWH (enoxaparin) was given. Additionally, patient
received dual-antiplatelet treatment (DAPT) consisting of aspirin (ASA 100 mg/day)
and clopidogrel (Plavix 75 mg/day). The TAVI procedure was uneventful and patient
was successfully weaned and extubated 48 hours after intervention.
On day 7, platelet count dropped to 98 × 109/L ([Fig. 1]) and thrombocytopenia was initially thought to be due to platelet consumption. The
next day, a further drop in platelet count to below 30 × 109/L was documented and DAPT was discontinued to avoid potential bleeding. The pretest
probability for HIT was estimated using the 4Ts score revealing a score of 5. Strong
anti-PF4/heparin immunoglobulin G antibodies were detected in patient's serum using
enzyme-linked immunosorbent assay (optical density: 3.825, cutoff: 0.300). Platelet
activation was investigated using the functional assay HIPA. Patient's serum induced
rapid activation of platelets from four donors in the presence of 0.2 IU/mL LMWH (reviparin)
as well as in the absence of heparin, but not after addition of high concentration
of heparin (100 IU/mL). Duplex ultrasound imaging of the lower-limb veins confirmed
subclinical deep-vein thrombosis (left superficial femoral vein).
Fig. 1 (A) Recovery in platelet count in an autoimmune HIT after transcatheter aortic valve.
(B) The impact of IVIG on platelet activation by autoimmune HIT antibodies. Patient's
serum was incubated with platelets from four healthy donors in the presence of 0.2
IU/mL LMWH (reviparin) and different concentrations of IVIG. Platelet activation was
determined by measurement of time until platelet aggregation in the HIPA assay. DAPT,
dual antiplatelet therapy; DOAC, direct oral anticoagulant; HIT, heparin-induced thrombocytopenia;
IVIG, intravenous immunoglobulin; LMWH, low-molecular-weight heparin; MAb IV.3, Fc
gamma receptor IIa blocking monoclonal antibody.
Owing to the recent TAVI, rapid correction of platelet count to values higher than
50 × 109/L was required to enable prompt start of DAPT in addition to the anticoagulation
(HIT-associated thrombosis). Recent studies showed that high-dose IVIG can inhibit
platelet activation in HIT indicating an additional treatment option in patients with
aHIT.[6]
[7]
[8] To verify the inhibitory effect of IVIG, the HIPA was performed in the presence
of patient's serum, 0.2 IU/mL LMWH and IVIG. A strong inhibition of platelet activation
was observed at a final concentration of 30 mg/mL IVIG ([Fig. 1]). Our patient was then treated with a combination of argatroban (2 µg/kg body weight
per minute, Argatra) and IVIG (100 g/day for 2 consecutive days, Gamunex 10%). Platelet
count increased within 2 days to reach values higher than 50 × 109/L, where we felt comfortable to restart DAPT ([Fig. 1]). The patient was switched to rivaroxaban as platelet count recovered and discharged
on day 16. After 3 months, a follow-up testing revealed normal platelet count and
no new thrombotic events under rivaroxaban.
To our knowledge, this is the first case of an aHIT after TAVI. This severe form of
HIT was caused by anti-PF4 antibodies that are able to activate platelets even in
the absence of heparin. As in our patient, recent case reports indicated that high-dose
IVIG can inhibit platelet activation by HIT antibodies and accelerate platelet count
recovery in aHIT patients.[7]
[8] However, it should be emphasized that due to the known thrombotic risk of high-dose
IVIG treatment, this therapeutic option should be used with caution in the prothrombotic
disease aHIT. In fact, it was recently suggested that patients with aHIT who are treated
with high-dose IVIG should undergo serial measurements of hemostatic markers, including
D-dimer, to exclude thrombotic side effects.[8]
Current guidelines recommend the use of aspirin plus ADP receptor blocker for the
initial 1 to 6 months following the TAVI procedure.[9]
[10] In addition, recent data showed that anticoagulation decreases the risk of bioprosthetic
valve dysfunction after TAVI.[11] However, in thrombocytopenic patients, triple antithrombotic treatment is associated
with increased risk of bleeding.[12] Therefore, we believed it was important to raise the platelet count quickly so as
to be able to administer triple antithrombotic therapy in this high-risk post-TAVI
patient. In addition, taking into consideration the HIT-associated thrombosis, we
decided to combine argatroban treatment with high-dose IVIG which successfully increased
platelet count to above 50 × 109/L enabling a safe restart of APT.
For long-term antithrombotic treatment, emerging evidence suggests that direct oral
anticoagulants (DOACs) can be used in HIT.[6] However, published experience with these drugs in aHIT patients is still limited
and does not allow final conclusion on their safety and efficacy to treat this severe
form of HIT. Of a particular importance appears to be the observed low trough levels
of the DOAC, which might cause inadequate protection against new thrombosis in aHIT
patients. In our case, we started the rivaroxaban treatment as platelet count recovered
to stabile values indicating normal hemostasis. A follow-up testing after 3 months
revealed no new thrombotic events. Consistent with previous report,[13] our finding suggests that rivaroxaban may be safely used to prevent new thrombosis
in aHIT patients.
Taken together, our case shows that the management of HIT after TAVI is challenging
as patients need immediate DAPT treatment to avoid cardiovascular complications.[12] A combined administration of nonheparin anticoagulation and IVIG was effective to
achieve safe platelet count that enabled rapid restart of DAPT. Our observation supports
the emerging concept that high-dose IVIG is effective for treating aHIT disorders
including delay onset of HIT syndrome.
