A 35-Year-Old Woman With Progressively Worsening Abdominal Pain and Shortness of Breath

AUTHOR:
Ronald N. Rubin, MD^1,2 —Series Editor

AFFILIATIONS:
¹Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
²Department of Medicine, Temple University Hospital, Philadelphia, Pennsylvania

CITATION:
Rubin RN. A 35-year-old woman with progressively worsening abdominal pain and shortness of breath. Consultant. 2021;61(10):e21-e23. doi:10.25270/con.2021.10.00005

DISCLOSURES:
The author reports no relevant financial relationships.

CORRESPONDENCE:
Ronald N. Rubin, MD, Temple University Hospital, 3401 N Broad Street, Philadelphia, PA 19140 (blooddocrnr@yahoo.com)

A 35-year-old woman called her primary care provider about a week’s duration of upper abdominal pain and ongoing shortness of breath, most noticeable with exertion. The abdominal pain had started by awakening her from sleep 5 days ago and has been essentially constant since. It is characterized as sharp and most marked in the upper abdomen below her ribs bilaterally. This pain is not relieved by bowel movements, eating, or antacids. There is some nausea and vomiting associated with the pain. The shortness of breath had onset at essentially the same time and is most noticed when the patient exerts herself, such as when she performs her usual fitness routine or walks quickly. There is no cough, purulent sputum, or hemoptysis.

The patient is a previously healthy woman who is an office manager and does not smoke or consume excess alcohol. She takes vitamins, but her only other medicine exposure is a low-estrogen oral contraceptive. She received a COVID-19 vaccination 2 weeks prior to presentation and did not have any adverse effects.

Results of a physical examination revealed a normal temperature, a high pulse rate of 100 beats/min, a low blood pressure of 115/70 mm Hg, and high respiration rate of 16 breaths/min. An examination of her head, eyes, ears, nose, and throat showed unremarkable results. Results of a chest examination showed decreased breath sounds and fine rales of the left base. Her heart had regular rhythm without obvious murmur or rub. Her abdomen was tender in the upper quadrants. Bowel sounds were present but diminished, and there was no rebound. There was the impression that the most tender area was the left upper quadrant.

A plain-film chest radiography scan did not show infiltrates, and an office portable Doppler did not reveal lung infiltrates, effusion, or pneumothorax.

Results from initial laboratory studies showed a completely normal basic metabolic and comprehensive metabolic panel. Results of a complete blood cell count showed a normal hemoglobin level of 13.2 g/dL, an elevated white blood cell count of 14.1/μL with a slight left shift and platelets of 68 × 10³/μL. Her arterial oxygen saturation was 93 mm Hg, but there was a gradient of 14 mm.

Answer and discussion on next page.

Correct answer: C. Administer intravenous immunoglobulin, 1 g/kg, for 2 days

I am sure that many of you quickly recognized that the patient was manifesting a life-threatening and fortunately rare complication of COVID-19 vaccination with certain of the vaccines in use, namely thrombotic thrombocytopenia syndrome. It would be an oversight by me to not address in some way the COVID-19 pandemic in our “What’s the Take Home?” column, given its importance these last 2 years. I will not get into diagnosis/therapeutics of actual COVID-19 infection, as one cannot open a newspaper or medical journal without encountering information overload about the entity. Instead, we will deal with a complication related to the spectacularly successful vaccine program, which happily seems quite rare. Of note is that it is primary care providers who may see this first. And let us complement our profession for its very prompt recognition, accurate response and good science that has addressed the problem.

Months into vaccination programs in early 2021, sporadic cases of significant and extremely morbid thrombotic events were noted in patients receiving the ChAdOx1 nCOV-19 vaccine.^1,2 A thrombotic thrombocytopenia syndrome characterized by thrombotic events at unusual sites—overrepresented by the central nervous system and abdominal organs—was encountered roughly 5 to 15 days after receiving the vaccine. The initial cases provided a demographic pattern of middle age (32-54 years), marked premenopausal female predominance with exposure to contraceptives.^1,2 Red flag symptoms were headache and/or abdominal pain. Should routine laboratory studies be conducted in the office or urgent care setting, the finding of thrombocytopenia was the alarm-ringing item. Early on, it seemed that some form of catastrophic hypercoagulability had been triggered (which indeed is/was true), yet routine or aggressive use of anticoagulants or platelet transfusions was not at all effective. In fact, it made the situation worse to an intensive care physician or hematologist. In retrospect, this very much resembled another morbid situation we have become too familiar with (but are now able to handle rather routinely), namely heparin-induced thrombocytopenia/thrombosis syndrome (HITT).³ The problem was that there had been no exposure to heparin in any of these patients.

These facts require a brief discussion of the pathophysiology and therapeutics of HITT, which leads to a hypothesis regarding how a vaccination might mimic this and how to reverse the process. In HITT, heparin compounds, polyanions, are complexed onto plasma proteins with the complex creating a neoantigen, which is absorbed onto the platelet surface, specifically the PF4 site. This neoantigen elicits an antibody in 1% to 3% of heparin-exposed patients, which is not inert but is rather biologically active and triggers widespread intense platelet activation and aggregation, resulting in widespread thrombosis throughout the body. Paradoxically, in the setting of obvious, overt clinical thrombosis, when more heparin is given and/or the more platelets are transfused to address a thrombocytopenia on laboratory tests, the worse the situation becomes.⁴ In recent decades, we have learned to avoid both heparins, even the low-molecular-weight form and platelet transfusions, to apply alternative anticoagulants such as the direct thrombin inhibitor, argatroban^4,5 to blunt the described pathophysiology. The vaccine syndrome seems to have followed an identical playbook to HITT in behavior.

But how can such a syndrome be initiated in the absence of heparin? It turns out that there exists other “clinical scenarios with apparent nonpharmacologic triggers [that] have been classified under the terms ‘autoimmune HITT’ or ‘spontaneous’ HITT,” as has been described and studied by Warkentin and colleagues.^2,5 And this seems to be the case with COVID-19-vaccine-induced thrombocytopenia thrombosis. Because of the striking clinical resemblance of these adverse events to classical HITT, detailed testing using HITT methods has revealed that there are indeed autoantibodies against platelets, specifically PF4, in high titers among these patients. Why there is the interesting demographic of premenopausal female predominance and whether the actual “triggering event” is intense immune reaction related to immunization or the formation of cross-reacting antibody to the vaccine itself remain unknown and topics for further study. For now, what seems to be a secure fact is that the finding of high-titer heparin-PF4 antibodies, defined as an Elisa antibody optical density of more than 3.0, in suspect patients who have not received heparin is a strong “rule-in” laboratory finding suggesting the presence of vaccine-related thrombocytopenia thrombosis syndrome.² And the HITT Elisa test is relatively easily performed and readily available, which should be an early laboratory test ordered whenever there is suspicion in a post-vaccination scenario.

What has also been helpful therapeutically, as well as diagnostically, in studying patients with post-vaccination thrombosis syndrome is that invitro addition of intravenous immunoglobulin completely blocks the activity of the heparin-PF4 autoantibody (or cross-reactive antibody) most likely by occupying the platelet FCY (activation) receptor. And when this observation has been translated into clinical use of treating patients with high doses of intravenous immunoglobulin, the process has been halted with salutary clinical benefit and recovery, such that intravenous immunoglobulin, 1 g/kg, for 2 days, Answer C, is the therapy of choice based upon excellent science and clinical findings in case studies to date.^1,2

And what may be most effective and lifesaving of all is likely the administration of high doses (eg, 1 g/kg for 2 days) of intravenous immunoglobulin, which bind and negate the platelet-activating sites of the vaccine-induced platelet-activating anti-PF4 antibodies, which will thus raise the platelet counts and ameliorate the profound hypercoagulable state.^1,2 Thus, Answer C is the correct choice here. Answer E (steroids) is a therapy for acute idiopathic thrombocytopenic purpura, which is not the diagnosis here. The remaining answers, as discussed above, will in fact feed the pathophysiologic process and are strongly contraindicated/incorrect options.

Patient Follow-Up

The timing of the clinical events in relation to the patient’s COVID-19 vaccination, which was confirmed to be ChAdOx1, was recognized by her physicians who responded quickly and accurately. The association of new, unexpected thrombocytopenia suggested the possible presence of the thrombocytopenia thrombosis syndrome caused by COVID-19 vaccination. More-detailed coagulation testing showed a partial thromboplastin time of 41 sec and international normalized ratio of 1.4 (both slightly prolonged), a decreased level of fibrinogen of 150 mg/dL, markedly elevated d-dimer levels, and an extremely high PF4 heparin Elisa of 3.9 optical density.

Angiographic studies revealed the presence of a pulmonary embolism in the left lower lobar artery and the presence of splanchnic thrombosis in the distal portal vein and splenic arteries with an evolving splenic infarction.

Therapy was immediately initiated in the form of intravenous immunoglobulin, 1 g/kg, for the following 2 days and oral apixaban, 5 mg, twice daily. Her condition clinically stabilized with improved pulmonary findings. By day 4, her platelet count was 152,000 × 10³/μL, and her overall status continued to improve.

What’s the Take Home?

A dangerous and life-threatening condition, termed thrombocytopenic thrombocytopenia, has been found to rarely complicate the use of the ChAdOx1 nCOV-19 vaccine. Current estimates suggest an incidence rate of 1 in 1 million vaccinations.⁶ The clinical behavior and laboratory findings are very similar to heparin-induced thrombocytopenia thrombosis (HITT) syndrome, as is the pathophysiology involving the formation of an antibody that is biologically active at the FCY platelet activation receptor. Clinical clues will be the presence of thromboses, often at unusual sites (splanchnic central nervous system) and new thrombocytopenia with onset roughly 5 to 20 days post vaccination. A key set of early laboratory findings include a depressed platelet count and an elevated d-dimer level. An essentially confirmatory, readily available test is a high titer PF4 heparin Elisa, which simply should not be present in the absence of heparin.

Appropriate recognition of the condition and administration of therapeutics are critical, as use of heparin in all forms—even in a patient with documented thrombosis or platelet administration, even if the computed tomography scan shows central nervous system thrombosis with bleeding—is absolutely contraindicated and can worsen the pathophysiology to catastrophic levels. Experience is accruing with successful outcomes using high doses of intravenous immunoglobulin to bind and block the binding sites of the abnormal antibody and platelet receptors and the use of non-heparin direct-acting oral anticoagulants (ie, apixaban, rivaroxaban) to address the hypercoagulability.

References

1. Schultz NH, Sørvoll IH, Michelsen AE, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021;384(22):2124-2130. https://doi.org/10.1056/nejmoa2104882

2. Greinacher A, Selleng K, Warkentin TE. Autoimmune heparin-induced thrombocytopenia. J Thromb Haemost. 2017;15(11):2099-2114. https://doi.org/10.1111/jth.13813

3. Greinacher A. Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med. 2015;373(3):252-261. https://doi.org/10.1056/nejmcp1411910

4. Warkentin TE. High-dose intravenous immunoglobulin for the treatment and prevention of heparin-induced thrombocytopenia: a review. Expert Rev Hematol. 2019;12(8):685-698. https://doi.org/10.1080/17474086.2019.1636645

5. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med. 2021;384(22):2092-2101. https://doi.org/10.1056/nejmoa2104840

6. Sadoff J, Davis K, Douoguih M. Thrombotic thrombocytopenia after Ad26.COV2.S vaccination - response from the manufacturer. N Engl J Med. 2021;384(20):1965-1966. https://doi.org/10.1056/nejmc2106075