Ophthalmic Manifestations of Heparin-Induced Thrombocytopenia
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Disease Entity
Heparin-Induced Thrombocytopenia (HIT) is an immune-mediated reaction to heparin that results in thrombocytopenia and hypercoagulability. Paradoxically, although platelet counts are decreased in patients with HIT, thrombosis occurs due to IgG mediated activation of platelets via concurrent attachment of IgG to platelet factor 4 (PF4)-heparin complexes and the Fc receptor of platelets.[1] Thrombocytopenia occurs in 95% of HIT patients, while thrombosis occurs in up to 50% of patients.[2]
Disease
Epidemiology
The incidence of HIT is approximately tenfold higher in patients who receive unfractionated heparin than in patients who receive low-molecular weight heparin.[2] and is decreased in patients receiving shorter durations of treatment with heparin. Furthermore, female and elderly patients are reported to be at increased risk.[1] Lastly, following major surgeries, there is increase in the likelihood of HIT due to increased exposure to heparin in the postoperative period and platelet hyperaggregability. [3]
Pathophysiology
Multiple steps are involved in the pathogenesis of HIT:
- The generation of IgG antibodies against Platelet Factor 4 (PF4) and polyanion complexes. These complexes can be either:
- PF4-heparan sulfate complexes[2]
- Heparan sulfate is a negatively-charged glycosaminoglycan that is found on the surface of endothelial cells. PF4 is a positively-charged chemokine that is synthesized by megakaryocytes and stored in the alpha granules of platelets. When PF4 is released from platelets, it can bind to heparan sulfate.
- Oddly, in this case the body will create IgG antibodies against a complex that is made of endogenous components that are found in circulation
- PF4-lipopolysaccharide complexes[4]
- In addition to binding GAGs, PF4 can also bind the lipopolysaccharides that make up the outer membranes of gram-negative bacteria.
- These complexes serve as a “danger signal” to the body and allow for the rapid generation of IgG antibodies. This in turn allows for a rapid opsonization and phagocytosis of the bacteria that bind PF4.
- PF4-heparan sulfate complexes[2]
- Administration of heparin and formation of PF4-heparin complexes
- IgG binds to PF4-heparin complex
- IgG-PF4-heparin complex binds to FcgRII receptor on platelets, thus activating them and initiating the intrinsic pathway of the coagulation cascade.
- This results in (potentially widespread) thrombosis and subsequent thrombocytopenia.
Diagnosis
Currently, HIT is a diagnosis of exclusion. Physicians should use clinical and laboratory diagnostic techniques to verify that a given patient:
- Developed thrombosis/thrombocytopenia 5-14 after heparin administration, and
- Has no other cause of their thrombocytopenia (i.e. infections, medications, etc.).
Additionally, should a patient present with ocular symptoms presumed secondary to systemic diseases such as HIT, it is recommended that physicians perform a thorough history and physical exam to ensure that no other systemic symptoms are present.
Clinical Diagnosis
The clinical diagnostic features of HIT can be organized into an algorithm called the “4 T’s”. Each “T” stands for the name of a specific diagnostic criterion: thrombocytopenia, timing, thrombosis, and other causes of thrombocytopenia. Each criterion is scored from 0-2, and a score is assigned after adding the values from each criterion. The scores indicate the probability that a patient is suffering from HIT, with scores between 6-8 signifying a high probability, between 4-5 signifying an intermediate probability, and between 0-3 indicating a low probability.[2]
Laboratory Diagnosis
A diagnosis of HIT can be confirmed by ordering a PF4-heparin immunoassay and functional platelet activation assay (e.g., serotonin release assay). If either of these tests is positive, it makes the diagnosis of HIT much more likely.[4]
Ophthalmic Signs
Ophthalmic manifestations of HIT may be challenging to definitively identify, as hemorrhagic or thrombotic events in the eye may be related to etiologies independent of HIT, such as pre-existing or concurrent vascular disease.
Reported ophthalmic manifestations of HIT include:
- Spontaneous orbital hemorrhage[7]
- Homonymous hemianopia secondary to occipital lobe infarction[8]
- Ptosis, diplopia, and retro-orbital pain[9]
- Vascular occlusions
HIT should be considered in patients with thrombocytopenia and ophthalmic symptoms. However, there may be a diagnostic challenge in patients with comorbid vascular risk factors that could explain signs and symptoms.
Management
There are two components to managing patients with HIT. First all heparin must be stopped immediately. Second, patients should be placed on a non-heparin anticoagulant (e.g. argatroban, lepirudin, etc.)
The risk of thrombosis remains high even after heparin cessation. Thus, careful monitoring and alternative anticoagulant therapy are important.[2]
High-dose intravenous immunoglobulin (IVIG) may inhibit HIT antibody-induced platelet activation and can be considered for patients with severe or refractory symptoms.[12]
Prognosis
Patients with a history of HIT should avoid all heparin-containing products indefinitely. Despite medical advancements, serious thrombotic events may occur in 20 to 50% of HIT cases, resulting in myocardial infarction, stroke, deep vein thrombosis, limb ischemia and amputation, or death, which is estimated to occur in up to 30% of cases.[2] Early detection and treatment significantly improve the prognosis of HIT.
References
- ↑ 1.0 1.1 Nicolas D, Nicolas S, Hodgens A, Reed M. Heparin-Induced Thrombocytopenia. In: StatPearls. StatPearls Publishing; 2024. Accessed September 9, 2024. http://www.ncbi.nlm.nih.gov/books/NBK482330/
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Arepally, G. M. & Ortel, T. L. Heparin-Induced Thrombocytopenia. Annu. Rev. Med. 61, 77–90 (2010).
- ↑ May, J.; Westbrook, B.; Cuker, A. Heparin-Induced Thrombocytopenia: An Illustrated Review. Res. Pract. Thromb. Haemost. 2023, 7 (5), 100283. https://doi.org/10.1016/j.rpth.2023.100283.
- ↑ 4.0 4.1 Greinacher, A. Heparin-Induced Thrombocytopenia. N Engl J Med 373, 252–261 (2015).
- ↑ Krauel, K. et al. Platelet factor 4 binds to bacteria, inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia. Blood 117, 1370–1378 (2011).
- ↑ Gallagher, J. T. & Walker, A. Molecular distinctions between heparan sulphate and heparin. Analysis of sulphation patterns indicates that heparan sulphate and heparin are separate families of N-sulphated polysaccharides. Biochemical Journal 230, 665–674 (1985).
- ↑ Scholl, H. P. N.; Thiel, H. J.; Schlote, T. Orbitablutung als folge einer heparininduzierten thrombozytopenie. Klin. Monatsbl. Augenheilkd. 1999, 215 (3), 197–200. https://doi.org/10.1055/s-2008-1034698.
- ↑ Mizrachi, I. B.-B.; Schmaier, A. H.; Trobe, J. D. Homonymous Hemianopia Caused by Occipital Lobe Infarction in Heparin-Induced Thrombocytopenia and Thrombosis Syndrome. J. Neuroophthalmol. 2005, 25 (3), 193. https://doi.org/10.1097/01.wno.0000179357.20858.22.
- ↑ Tsai, H. C.; Yen, H. C.; Hsu, J. C.; Lin, C. L. Heparin-Induced Thrombocytopenia Associated with Intra-Tumour Haemorrhage in Cavernous Sinus after Cardiac Myxoma Surgery. Br. J. Neurosurg. 2009, 23 (1), 95–96. https://doi.org/10.1080/02688690802272164.
- ↑ Nguyen QD, Do DV, Feke GT, Demirjian ZN, Lashkari K. Heparin-induced antiheparin-platelet antibody associated with retinal venous thrombosis. Ophthalmology. 2003;110(3):600-603. doi:10.1016/S0161-6420(02)01766-9
- ↑ Meyer T, Robles-carrillo L, Robson T, et al. Bevacizumab immune complexes activate platelets and induce thrombosis in FCGR2A transgenic mice. J Thromb Haemost. 2009;7(1):171-181. doi:10.1111/j.1538-7836.2008.03212.x
- ↑ Warkentin, T. E. 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.
