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Acute aortic intraluminal thrombus with embolisation and lower-limb ischaemia following intravenous iron sucrose infusion reaction
  1. Iva Okaj1,
  2. Menaka Pai1,2,3,4,
  3. John Harlock5 and
  4. Theodore Earl Warkentin1,2,3,4
  1. 1Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  2. 2Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
  3. 3Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada
  4. 4Service of Benign Hematology, Hamilton Health Sciences, Hamilton, Ontario, Canada
  5. 5Division of Vascular Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
  1. Correspondence to Theodore Earl Warkentin; twarken{at}mcmaster.ca

Abstract

A woman in her 50s developed iron deficiency anaemia. Her medical history included hypertension, asthma and remote postpartum pulmonary embolism. There was a strong family history of atherosclerosis. After receiving intravenous iron sucrose (500 mg), she developed vomiting and large-volume diarrhoea, followed by diaphoresis, back pain, haemoconcentration (haematocrit increase, 0.242 to 0.326), leucocytosis and platelet count decline. Myocardial infarction was ruled out and the truncal pain subsided. However, 2 days postdischarge, she was diagnosed with aortic intraluminal thrombus (ILT) with embolisation into the lower extremities. The limbs were salvaged by emergency embolectomies and fasciotomies. Acute aortic ILT is a rare disorder that has not been previously reported as a complication of parenteral iron therapy. We postulate that acute intravascular volume losses (vomiting and diarrhoea) with resulting haemoconcentration and catecholamine-associated platelet activation and consumption, in a patient with subclinical aortic atherosclerosis, triggered acute aortic ILT presenting as lower-limb ischaemia.

  • Haematology (drugs and medicines)
  • Drugs: gastrointestinal system
  • Unwanted effects / adverse reactions
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Background

Hypersensitivity reactions to intravenous (IV) iron infusions are rare (estimated prevalence<0.1%). Associated clinical features range from chest and abdominal pain, nausea, vomiting and diarrhoea to life-threatening anaphylaxis.1 2 In theory, volume losses and dehydration from iron-induced gastrointestinal (GI) losses can be harmful. Several studies have reported ischaemic events, including venous thromboembolism and stroke, that were attributable to volume contraction.3–5 Dehydration increases blood viscosity and is also thought to affect coagulation factors such as von Willebrand factor.6 In this report, we describe an unusual case of acute limb ischaemia secondary to acute aortic intraluminal thrombus (ILT) and embolisation which followed a severe GI reaction to IV iron sucrose.

Case presentation

A woman in her 50s presented with microcytic anaemia and iron deficiency (haemoglobin, 76 g/L (reference range (RR), 115–165); mean corpuscular volume 68.9 fL (RR, 82–99); serum ferritin, 2 µg/L (RR, <23 indicating iron deficiency)). She could not tolerate oral iron due to constipation. Upper and lower endoscopy and small bowel follow-through studies were negative. Screening tests for coeliac disease were negative. The iron deficiency anaemia was attributed to low nutritional iron intake and menstrual blood losses. Medical history included hypertension (treated with felodipine and cilazapril), asthma (treated with inhalers and montelukast) and postpartum pulmonary embolism 21 years earlier treated with heparin followed by 3 months of warfarin, without ongoing anticoagulation or thrombosis recurrence. She had smoked for 20 years but stopped a decade earlier. There was a strong family history of coronary artery disease.

She received her first dose of IV iron sucrose (Venofer), 500 mg, administered over 4 hours. She received premedication with IV dimenhydrinate (Gravol; 25 mg) and oral dexamethasone (Decadron; 10 mg). Towards the end of the infusion, she developed nausea and six episodes of bilious vomiting, as well as large volume diarrhoea with several episodes of faecal incontinence. She also complained of retrosternal chest pressure, diaphoresis and dramatic pain across her lower back. Physical examination revealed blood pressure 101/67 (reduced from 134/76 earlier in the treatment session), heart rate 110/min (increased from 73/min) and respiratory rate 14/min, without wheezes. She was transferred to the emergency room, where serial ECGs and cardiac enzymes ruled out acute myocardial ischaemia. Three hours later, her truncal pain had subsided, but she developed bilateral lower extremity pain, especially in the right-lower limb. She was monitored overnight, and her vital signs returned to normal. Although the lower-limb pain had not completely resolved by the next morning, she was discharged to home at noon.

Over the next 30 hours, she continued to have fluctuating lower extremity pain, especially in the right leg, with worsening difficulties with walking. She therefore attended a local emergency room, where she was found to have absent right foot pulses, lower extremity pallor and inability to dorsiflex or plantarflex her toes. She was urgently transferred to the nearest vascular surgery centre (the same institution as the clinic where she had received her iron sucrose infusion).

Investigations

Immediately after the IV iron infusion, there was an increase in haemoglobin from 76 to 100 g/L, with a corresponding increase in haematocrit from 0.242 to 0.326, and leucocyte count increase from 5.5 to 10.0×109/L (RR, 4.0–11.0). The abrupt increase in haemoglobin was believed to be consistent with haemoconcentration, given the marked vomiting, diarrhoea and diaphoresis. Notably, there was a further rise in her leucocyte count to 22.3×109/L. In contrast, platelets decreased from 354 to 217×109/L (RR, 150–400) postinfusion. Figure 1 depicts the serial laboratory results—platelet counts, haematocrits and white blood counts—in relation to key clinical events.

Figure 1

Acute aortic intraluminal thrombus (ILT) following intravenous (IV) iron sucrose infusion: timeline of clinical events and laboratory test results until postinfusion day 10. Based on the observed change in haematocrit, the estimated platelet count fall was approximately 47% (ie, from 352×109/L to approximately 186×109/L), adjusted for change in haematocrit, based on assumption of an initial intravascular blood volume of 3.5 L (per patient’s sex, height and weight), with initial estimated loss of intravascular blood volume of approximately 900 mL (consistent with initial increase in haematocrit from 0.242 to 0.326), with calculation of the adjusted platelet count measurement. Original figure prepared by TEW (coauthor). ELISA, enzyme-linked immunosorbent assay; h, hours; HIT, heparin-induced thrombocytopenia; IV, intravenous; PF4, platelet factor 4; PO, per os; WBC, white blood count.

CT angiography demonstrated ILT within the distal aorta and bilateral common iliac arteries. Thrombus was also noted in branches of the right profunda femoris artery, with thrombotic occlusion of the distal right popliteal artery and tibioperoneal trunk, and no contiguous runoff to the ankle. She was treated with embolectomies and fasciotomies for her acute limb ischaemia. During revascularisation surgery, an unusual mix of white clots with erythematous components was extracted. The pathologist identified platelet-rich thrombus with prominent acute inflammatory infiltrates.

Postoperatively, when the haematologist informed the vascular surgery service about the severe back pain that had accompanied the initial post-IV iron reaction, imaging was repeated to include the thoracic and abdominal aorta. The follow-up CT angiogram of chest and runoff showed atherosclerotic disease of the thoracic and abdominal aorta, with non-occlusive thrombi in the descending thoracic aorta and near-occlusive thrombi in the distal abdominal aorta.

Creatine kinase peaked at 8912 U/L (RR, <168), consistent with ischaemic muscle injury. A consulting neurologist diagnosed right foot drop secondary to ischaemic injury to the common peroneal nerve, and opined that eventual good recovery was possible over the next months.

Differential diagnosis

Given the acute postiron infusion nausea, vomiting, diaphoresis and truncal pain, and the strong family history of coronary-artery disease, concern for acute coronary syndrome was high. However, serial ECGs and troponins were unremarkable, and the patient was discharged with a diagnosis of acute GI reaction caused by IV iron sucrose infusion. Following readmission for lower-limb ischaemia and the ensuing diagnosis of acute aortic ILT, further laboratory investigations for a chronic hypercoagulability disorder all returned normal or negative (see figure 1).

Treatment

Unfractionated heparin, administered intraoperatively, was continued postoperatively in therapeutic doses with monitoring by activated partial thromboplastin time, with subsequent transition to warfarin (continued postdischarge). Surgical revascularisation consisted of right popliteal embolectomy, right anterior tibial embolectomy, and right tibial peroneal trunk embolectomy with four-compartment fasciotomies. She completed combined warfarin and antiplatelet therapy (aspirin) for 1 year, followed by dual antiplatelet therapy (aspirin and clopidogrel) for another year, followed by long-term aspirin monotherapy. She also received intermittent transfusion with red cell concentrates (seven units transfused over the subsequent 5 years), under the supervision of a haematologist, to manage her chronic iron deficiency anaemia.

Outcome and follow-up

Following surgery, lower-limb ultrasound demonstrated good flow and excellent ankle and toe pressures bilaterally. Her right limb motor function gradually improved over the next year. At 5 year follow-up with the vascular surgeon, she had improved neuropathic pain, and excellent perfusion, shown by repeat ultrasonography, to her lower extremities. At 7 year follow-up, she reported intermittent neuropathic pain but had healthy flow patterns by ultrasonography and normal ankle-brachial indices bilaterally.

Discussion

We describe a rare complication of bilateral lower-limb ischaemia secondary to acute aortic ILT that began after a severe GI reaction (vomiting and diarrhoea) to high-dose (500 mg) iron sucrose infusion in a patient with underlying subclinical aortic atherosclerosis. Our report is novel, as—to the best of our knowledge—occurrence of aortic ILT with resulting acute lower-limb ischaemia postiron infusion has not been reported previously. Parenteral iron sucrose is an effective and increasingly common treatment for iron deficiency, and has a favourable safety profile; for this reason, we feel it is important to highlight this rare and unusual clinical outcome.

Studies of IV iron infusion indicate that serious or severe adverse reactions are relatively uncommon.7–12 The majority of such adverse reactions occur during or immediately after the first IV iron infusion.13 GI complications of parenteral iron are associated with higher doses, and the high initial iron sucrose dose (500 mg) was likely contributory.14 Consistent with the literature, our patient developed the adverse reaction towards the end of the 4 hour infusion, suggesting a dose-dependent GI reaction. In response to this serious adverse event, we (MP and TEW) have altered our haematology practice to start with lower initial doses of iron sucrose (generally, 200 mg), and if well tolerated, to increase the dose in 100 mg increments on subsequent administrations, to a maximum of 400 mg per dose. This practice is supported by literature,14 indicating a high frequency of acute reactions with 500 mg iron sucrose dosing. Also, in the absence of a history of previous postiron infusion reactions, and in light of literature indicating a higher frequency of adverse reactions in patients given premedications,15 we now omit routine administration of dimenhydrinate and corticosteroid preiron infusion.

Two randomised trials found that iron sucrose infusion was associated with a higher frequency of usually minor GI reactions compared with alternative formulations.8 16 Iron sucrose formulations have higher proportions of labile iron content, which may carry more potential for toxicity from oxidative stress, especially with higher doses.16 17

We note that iron deficiency anaemia per se is associated with increased risk of thrombosis, particularly in the setting of thrombocytosis.18 19 Iron deficiency is a well-known explanation for reactive thrombocytosis due to diminished inhibition of thrombopoiesis. Our patient’s preinfusion platelet count was 352×109/L, an upper normal value, which was higher than subsequent platelet counts measured during long-term follow-up when her iron deficiency anaemia had resolved (the mean platelet count of eight serial measurements, obtained 3 to 8 years later, was approximately 250×109/L). However, many patients (like ours) who develop thrombosis in the setting of iron deficiency anaemia do not necessarily have overt thrombocytosis.18 19 As pointed out by Al-Samkari and colleagues,19 ‘intravenous iron replenishment may have additional advantages in mitigating the thrombogenic potential of iron deficiency’. Moreover, Nashashibi and coworkers20 have provided laboratory evidence that IV iron therapy lowers coagulability. These investigators evaluated thrombin generation using calibrated automated thrombogram parameters, assessed before and approximately 3 weeks postiron repletion, underscoring the irony of our patient developing a dramatic thrombotic event shortly after receiving parenteral iron replacement.

Available literature on acute ILT and complete aortic thrombosis provides insights into potential mechanisms explaining our patient’s aortic thrombosis and associated embolisation to the distal lower-limb vasculature. A review of acute aortic thrombosis21 listed two main underlying cardiovascular disorders, namely large-saddle embolus (eg, from a cardiac chamber) to the aortic bifurcation (not seen in our patient) or acute thrombosis within an atherosclerotic aorta (seen in our patient), with or without associated aortic aneurysmal changes (not seen in our patient). In the minority of patients with aortic thrombosis who do not evince cardiovascular disease, an acute or chronic hypercoagulability disorder (not seen in our patient) is typically found.21–23

Regarding potential proximate triggers of aortic thrombosis in patients with atherosclerosis, a classic 1995 study23 of 48 patients who presented with acute aortic thrombosis to a single vascular centre over a 19 year period identified in-situ thrombosis in 44 (92%) patients and underlying aortic atherosclerosis in 36 (75%) patients. Of particular significance, several patients with underlying aortic atherosclerosis had aortic thrombosis and acute limb ischaemia attributable to ‘low-flow state caused by … severe volume depletion’.23 In our patient, we suggest that the severe vomiting and diarrheal illness precipitated by the iron sucrose infusion, with resulting intravascular volume contraction, helped to trigger acute platelet activation and thrombosis in the presence of endothelial disruption from pre-existing atherosclerotic disease. Our patient clearly developed marked volume depletion, corroborated by the significant haemoconcentration, as reflected by the abrupt increase in her haemoglobin (76 to 100 g/L) and haematocrit (0.242 to 0.326) values. Moreover, her platelet counts decreased abruptly following the iron infusion (352 to 217×109/L), a phenomenon that appears to have been even more marked (ie, from 352 to approximately 185×109/L) if one adjusts the platelet counts for the marked changes in haematocrit (as a lower plasma volume secondary to GI fluid losses would help mask true platelet count declines). Indeed, the estimated abrupt 47% drop in platelet count (see figure 1 legend for further discussion) is consistent with platelet consumption related to platelet deposition on the atherosclerotic aorta. Acute diaphoresis associated with volume contraction and an associated catecholamine response could have contributed to acute platelet activation.24 Dexamethasone (premedication) administration and ensuing leucocytosis could also have contributed to the inflammatory thromboses extracted. Another potential contributing factor could have been endothelial injury, with associated adhesion of monocytes, resulting from iron sucrose infusion, as shown in an experimental model.25

In summary, we report a patient with moderately severe iron deficiency anaemia who developed acute GI fluid losses (vomiting and diarrhoea) following a relatively high first-dose IV iron sucrose therapy (500 mg), with laboratory evidence of acute haemoconcentration, consumptive thrombocytopenia and leucocytosis. Progressive lower-limb ischaemia over the ensuing hours to a few days led to diagnosis of distal aortic ILT with peripheral embolisation in a patient with subclinical aortic atherosclerosis. Fortunately, emergency embolectomies and fasciotomies salvaged the lower limbs.

Patient’s perspective

I entered the hospital for a routine iron infusion, my first. Just as the second and final bag was finishing up, I began to feel nauseated, and started to vomit. I also had a lot of diarrhoea. Not long after, I felt a pain in my back. The nurse acted quickly and called for a doctor. I was taken to the emergency department where I stayed overnight. It was in emergency that I kept telling the staff that I believed there could be blood clotting. The pain in my back was better, but I now had some pains in my legs, especially my right one, which at times was so severe that pain medication was not alleviating the pain entirely. The doctors ruled out a heart attack, and I was discharged the next day, even though the pain had not completely gone away. I even had some difficulty walking. Over the subsequent 24 hours, I was unable to sleep, eat or walk. So, that evening, I was brought to the local emergency department. It was frustrating that it took so much time to figure out that there was clotting happening in my legs. I am extremely grateful that the doctor at emergency determined that I had no pulses in my right leg and quickly called a vascular surgeon. I was provided with pain medication and was transported to the emergency room at the same hospital where I had received the iron infusion. I was admitted back into hospital and had surgery at 5 am. I learnt that I would likely lose a toe, a foot or even my leg. My family and I feel very blessed that we had a surgeon that made every effort to save my limbs, and he did. We appreciate how hard the hospital team worked to diagnose my illness and to take care of me. I spent 3 weeks in the hospital and during this time, had many tests and two surgeries. I was surprised to find out how unusual this complication is. It turns out that no one has been able to find a similar case in the medical literature of ‘aortic intraluminal thrombus’ following iron infusion, so this must be a rare side effect indeed.

Learning points

  • Intravenous iron sucrose, especially in larger doses, can result in acute gastrointestinal toxicity, including large-volume emesis and diarrhoea, due to labile iron content.

  • Rarely, acute intravascular volume depletion can precipitate acute aortic intraluminal thrombus, perhaps as a consequence of acute haemoconcentration and catecholamine release, with acute platelet activation and consumption.

  • Acute limb pain requires careful and repeated clinical assessment, as progressive embolisation may not result in loss of pedal pulses until later in the clinical course.

Ethics statements

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References

Footnotes

  • Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: IO, MP, JAH and TEW. The following authors were responsible for drafting of the text, investigation results and critical revision for important intellectual content: IO, MP, JAH and TEW. The following author was responsible for drawing an original diagram: TEW. The following authors gave final approval of the manuscript: IO, MP, JAH and TEW.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests Competing interests: IO, MP and JAH have no conflicts to declare. TEW has received lecture honoraria from Alexion and Instrumentation Laboratory, and royalties from Informa (Taylor & Francis) and UptoDate (Wolters Kluwer); has provided consulting services to Aspen Canada, Aspen Global, CSL Behring, Ergomed, Instrumentation Laboratory (Werfen), Paradigm Pharmaceuticals, Octapharma and Veralox Therapeutics; has received research funding from Instrumentation Laboratory (Werfen); and has provided expert witness testimony relating to heparin-induced thrombocytopenia (HIT) and non‐HIT thrombocytopenic and coagulopathic disorders. Lead clinician ensured the veracity of all author declarations of conflict of interest and author disclosures.

  • Provenance and peer review Not commissioned; externally peer reviewed.