
==== Front
Intern Med
Intern Med
Internal Medicine
0918-2918
1349-7235
The Japanese Society of Internal Medicine

38072405
10.2169/internalmedicine.2859-23
Case Report
Heparin-induced Thrombocytopenia with Anaphylactoid Reaction during Hemodialysis
Murakami Yoichi 1
Tomoda Atsuya 1
Fujita Suzu 1
Hayashi Saki 1
Hattori Soken 1
Sugiura Takeshi 1
Matsushima Hideki 1
1 Department of Nephrology, Seirei Mikatahara General Hospital, Japan
Correspondence to Dr.　Yoichi Murakami, ymurakami-ryk@umin.org

11 12 2023
15 8 2024
63 16 23212324
3 9 2023
29 10 2023
Copyright © 2024 by The Japanese Society of Internal Medicine
https://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).
We herein report a 64-year-old man with heparin-induced thrombocytopenia accompanied by anaphylactoid reaction during hemodialysis. The patient was admitted to our hospital with acute myocardial infarction and developed acute kidney injury after percutaneous coronary intervention. When maintenance hemodialysis with heparin was initiated, the patient developed an anaphylactoid reaction with dyspnea, hypotension, nausea, and vomiting. Laboratory tests revealed thrombocytopenia. Immunoglobulin G antibodies to heparin-platelet factor 4 complexes were positive, and a functional assay showed heparin-independent platelet activation. These results provide a definitive diagnosis of heparin-induced thrombocytopenia. The onset timing supported a diagnosis of ‘rapid-onset’ heparin-induced thrombocytopenia.

heparin-induced thrombocytopenia
hemodialysis
anaphylactoid reaction
acute systemic reaction
anaphylaxis
==== Body
pmcIntroduction

Heparin-induced thrombocytopenia (HIT) is a complication triggered by heparin exposure. IgG-HIT, an IgG antibody that recognizes platelet factor 4 (PF4) in complex with heparin, is the etiology (1). Most patients undergoing hemodialysis are repeatedly exposed to heparin and thus are at a high risk for developing HIT. Reportedly, 3.9% of hemodialysis patients are clinically diagnosed with HIT within 59 days of starting hemodialysis and heparin administration (2). HIT is suspected based on the scoring of clinical manifestations, known as the 4Ts score, which consists of four categories: “thrombocytopenia”; “timing of decreased platelet count”; “thrombosis or other sequelae” and “other causes of thrombocytopenia” (3). Notably, for hemodialysis patients, circuit clotting can count for 0-2 points in the category of “thrombosis or other sequelae,” depending on the onset timing after initial heparin administration (4). For a definitive diagnosis, laboratory tests, detection of IgG-HIT, and functional assays are necessary.

We herein report a patient with HIT who developed an anaphylactoid reaction characterized by hypotension, nausea, and vomiting during hemodialysis.

Case Report

A 64-year-old man with diabetic nephropathy was transported to our hospital with nausea, vomiting, and an altered mental status. He smoked 20 cigarettes per day and had a history of hypertension treated with valsartan 80 mg and cilnidipine 10 mg. Based on a diagnosis of acute myocardial infarction (AMI), percutaneous coronary intervention (PCI) was performed, and 20,000 U of heparin per day was infused 2 days after admission (Figure). A temporary pacemaker was necessary to treat atrioventricular block. As renal replacement therapy (RRT) for acute kidney injury after PCI, continuous hemodiafiltration (CHDF) with nafamostat mesylate anticoagulant was initiated. The dialyzer was polysulfone (PS) sterilized by gamma radiation. Three days after admission, the patient's platelet count decreased to 115×103/μL (from 183×103/μL on admission) without any sign of thrombosis, and spontaneously recovered to 145×103/μL within 2 days (Figure). RRT was changed to intermittent hemodialysis five days after admission, still with nafamostat mesylate and a PS dialyzer. A flush solution containing 3,000 U heparin was used to maintain the patency of the dialysis catheter. Fifteen days after admission, an arteriovenous fistula shunt was created between the left radial artery and cephalic vein, and 3,000 U of heparin was infused at the end of the surgical procedure (Figure). The other medications administered included oral aspirin (100 mg, prasugrel 3.75 mg, cilnidipine (10 mg), lansoprazole (15 mg), and rosuvastatin (2.5 mg). Insulin was administered using the sliding-scale method, where the dose was based on the patient's blood sugar level immediately before a meal.

Figure. Platelet counts after admission and heparin administration. ＊: heparin administration 20,000 U during and after PCI. ◆: heparin administration 3,000 U after A-V fistula shunt formation. ⬇: heparin administration 1,000 U bolus and continuous 500 U/hr infusion during hemodialysis. ☆: anaphylactoid reaction during hemodialysis. ⇋: a flush solution containing 3,000 U of heparin was used to maintain patency of the dialysis catheter.

Twenty days after admission, the hemodialysis anticoagulant was changed from nafamostat mesylate to heparin. Within 30 min after the initiation of hemodialysis with heparin as the anticoagulant, the patient's systolic blood pressure dropped to 80 mmHg, and he experienced nausea, vomiting, and dyspnea (Figure). Therefore, the treatment was finished within one and a half hours. His systolic blood pressure had recovered to 147 mmHg by the end of hemodialysis. His vital signs were as follows: blood pressure, 128/54 mmHg; pulse rate, 78 beats/min; respiratory rate, 18 breaths/min; and temperature, 36.9°C.

Twenty-three days after admission and 30 min after the initiation of hemodialysis treatment, the patient developed hypotension, nausea, and vomiting. His blood pressure gradually decreased during treatment. His blood tests showed the following: red blood cell count, 348×104/μL; hemoglobin, 10.1 g/dL; hematocrit, 32.0%; leukocyte count, 6.82×103/μL (neutrophils, 3,500 /μL; eosinophils, 800 /μL; lymphocytes, 1,880 /μL); and platelet count, 83×103/μL. The patient's C-reactive protein level was 0.2 mg/dL. These results indicated the presence of mild thrombocytopenia, but no anemia, infection, or eosinophilia was detected.

Twenty-five days after admission, we changed the dialyzer from PS to a polymethylmethacrylate (PMMA) membrane, but his symptoms during hemodialysis did not improve. Furthermore, clotting was also observed in the dialyzer. His blood tests revealed a platelet count of 78×103/μL. Mildly decreased platelet counts and clotting on the dialyzer suggested the possibility of HIT. Therefore, we sent the samples to an external company (SRL, Akasaka, Tokyo, Japan) to test for HIT antibodies using latex turbidimetry. This assay was positive (≥5.0 U/mL, reference range: ＜1.0 U/mL).

Twenty-seven days after admission, we changed the hemodialysis anticoagulant from heparin to nafamostat mesylate, and the patient remained stable, without any systemic symptoms, during a 4-hour hemodialysis treatment. Thirty days after admission, his platelet count had recovered to 152×103/μL (Figure). Echocardiography performed 34 days after admission revealed mild hypokinesis in the inferior part of the left ventricle, with an ejection fraction of 68%.

Overall, heparin administration, thrombocytopenia, anaphylactoid reaction, circuit clotting, and the presence of HIT antibody (identified by latex turbidimetry) suggested a likely diagnosis of HIT. The patient's 4Ts score was 7 (thrombocytopenia, 1 point; timing of platelet count decrease, 2 points; thrombosis or other sequelae, 2 points; and other causes of thrombocytopenia, 2 points), and he was categorized as having a “high probability” of HIT (3). Based on the tentative diagnosis of HIT, we sent the samples to the National Cerebral and Cardiovascular Center in Japan for further study. An enzyme immunoassay for IgG-HIT (PF4-IgG; Genetic Testing Institute, Waukesha, USA) performed on a sample collected 30 days after admission showed a high optical density (OD) of 2.648 (Table), which can be regarded as a strong positive result. An OD ≥2.00 units indicates that the probability of detecting platelet activation with functional assays is approximately 90% (4). The functional assay, which detects platelet-derived microparticles using flow cytometry (5), showed heparin-independent platelet activation in the serum of our patient (Table). This indicates that normal platelets were activated by the patient's serum without the addition of heparin. These results provide a definitive diagnosis of HIT.

Table. The Results of IgG-HIT and Functional Assay.

Days after admission	IgG-HIT (optical density)	Functional assay	
30	2.648	Strong positive*	
40	2.373	Strong positive	
101	1.651	Strong positive	
157	1.336	Strong positive	
255	0.584	Weak positive	
360	0.784	Negative	
458	0.706	Negative	
540	0.491	Negative	
Strong positive*: heparin-independent platelet activation.

After replacement of heparin with nafamostat mesylate as a hemodialytic anticoagulant, the platelet count recovered, and the patient did not develop any symptoms related to HIT. The patient recovered well enough to walk by himself and was discharged 36 days after admission, without thrombotic sequelae. Subsequently, he started visiting a clinic three days a week for maintenance hemodialysis. At the clinic, the hemodialytic anticoagulant was changed to argatroban. Repeated tests showed that the ability of the patient's serum to activate normal platelets, as measured by the functional assay, gradually decreased and became negative within approximately one year. However, the IgG-HIT level was 0.491 (normal range, ＜0.4) on day 540 after the initiation of heparin administration (Table). Therefore, in this case, the IgG-HIT level remained persistently high for longer than in previously reported cases (6).

Discussion

Patients on hemodialysis who develop HIT might have other possible risk factors for anaphylactoid reactions, such as drug-induced anaphylaxis, dialyzer-related allergy, or hemodialysis-related hypotension. Therefore, distinguishing whether the symptoms are derived from HIT or other causes and making a prompt diagnosis of the condition are sometimes difficult. In our case, it was important to distinguish the cause of hypotension because the patient might have experienced cardiac failure complicated by AMI, leading to hypotension. In such cases, laboratory tests to confirm HIT, as well as re-assessing the dry weight and evaluating the patient's cardiovascular function, are necessary. Echocardiography performed 34 days after admission showed that the patient's ejection fraction was preserved, indicating that his hypotension was not caused by cardiac failure. Echocardiography should be performed earlier, and while we waited for laboratory test results to confirm HIT, we should have started argatroban (or danaparoid, if available) anticoagulant therapy, as this is recommended to prevent thrombosis in patients with HIT who require RRT (7).

We assume that the onset of HIT occurred 20 days after admission when the patient had an anaphylactoid reaction. This can be categorized as ‘rapid-onset’ HIT because the patient had a history of exposure to heparin within the previous 90 days before the onset, and HIT appeared abruptly on re-exposure to heparin (8). This means that the HIT antibody was formed by heparin exposure after admission, the heparin infusion on day 15 caused slight thrombocytopenia, and the heparin infusion on day 20 when starting hemodialysis caused ‘rapid-onset’ HIT.

Remarkably, our patient showed a high IgG-HIT titer, heparin-independent platelet activation, and prolonged elevated IgG-HIT levels in his serum (Table). Matsuo et al. reported that among 13 patients who were diagnosed with HIT, eight patients with a high IgG-HIT titer (n=8, median IgG-HIT =1,530 μg/mL) presented with an acute systemic reaction, while five patients with a low titer (n=5, median IgG-HIT =339 μg/mL) did not show signs of a systemic reaction (p＞0.05) (9). Although the result was not statistically significant, it was consistent with our case.

In contrast, an association between heparin-independent platelet activation in a functional assay and anaphylactoid reactions has not been reported. The presence of heparin-independent platelet activation supported categorizing the case as autoimmune HIT. In such cases, one reasonable explanation is that HIT antibody recognizes a slight structural change in PF4 bound to chondroitin sulfate on the platelet surface and eventually induces heparin-independent platelet activation (10). Heparin-independent platelet activation has been associated with “delayed platelet recovery,” defined in cases where more than 1 week is required for the platelet count to recover to more than 150×103/μL (11). However, our patient's platelet count recovered to 152×103/μL within 3 days after the replacement of heparin with nafamostat mesylate as a hemodialytic anticoagulant (27 days after admission). Likewise, we could not find any reports showing an association between the prolonged presence of IgG-HIT and anaphylactoid reactions. Because this case occurred before the COVID-19 pandemic, the formation of IgG-HIT had no relationship with COVID-19 or vaccination against it. Hartman et al. reported that IgG-HIT antibodies remained positive for an average of 165 (range, 53-333) days in 4 patients with HIT and acute systemic reactions (6). Although Birschmann et al. reported a case in which serum IgG-HIT remained high for more than 4 years, IgG-HIT generally tends to disappear within 40-100 days. To our knowledge, while this case showed the most protracted presence of serum IgG-HIT, the patient showed only mild transient ischemic attack without any systemic symptoms (12). These reports indicate that there is no obvious association between prolonged serum IgG-HIT and anaphylactoid reactions.

The mechanism underlying HIT with anaphylactoid reaction remains elusive. A previous patient with an anaphylactoid reaction due to HIT did not show an increased tryptase level, which is a marker of mast cell activation and anaphylaxis, indicating that the underlying mechanism is not the same as the typical anaphylaxis associated with mast cell activation (13). Furthermore, heparin-PF4-antibody complexes activate platelets, endothelial cells, and monocytes (8), some of which may be associated with an anaphylactoid reaction.

We assume that a brief course of heparin reexposure when necessary, such as for cardiac surgery, was appropriate in our case, as the functional assay result became negative and only weak positivity was noted for IgG-HIT (14). After reexposure, we should carefully monitor platelet counts and thrombin production using assays such as TAT, and we should also confirm the lack of IgG-HIT re-elevation. We also assume that long-term heparin reexposure, such as that for maintenance hemodialysis, should be avoided as in usual cases of HIT. HIT had critical effects on our patient, so lifelong avoidance is preferable.

In conclusion, we report a patient with ‘rapid-onset’ HIT who presented with an anaphylactoid reaction, high serum IgG-HIT titers, and the prolonged presence of serum IgG-HIT. The patient's serum showed heparin-independent platelet activation in the functional assay, which generally means that the patient had autoimmune HIT. In patients who present with anaphylactoid reactions during hemodialysis. High IgG-HIT titers may have contributed to the anaphylactoid reaction; however, this hypothesis remains speculative. The association between anaphylactoid reaction and heparin-independent platelet activation with the prolonged presence of IgG-HIT has not been previously reported.

Informed consent was obtained from the individual participant included in the study.

The authors state that they have no Conflict of Interest (COI).

Acknowledgement

We thank Shigeki Miyata and Takuma Maeda for providing the IgG-HIT, functional assay data, and helpful comments.
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