Ocular Signs of Heparin-Induced Thrombocytopenia

Key Points at a Glance

Key Points of This Disease

• HIT (heparin-induced thrombocytopenia) is an immune-mediated reaction to heparin administration, resulting in thrombocytopenia and a paradoxical hypercoagulable state.
• Despite a decrease in platelet count, thrombosis occurs in up to 50% of patients.
• Ophthalmic complications include retinal vascular occlusion, orbital hemorrhage, homonymous hemianopia, ptosis, and diplopia.
• Diagnosis combines clinical assessment using the 4T score with anti-PF4 ELISA and SRA testing.
• The principle of treatment is immediate discontinuation of all heparins and switching to non-heparin anticoagulants.
• Since thrombotic risk persists after heparin cessation, continuation of alternative anticoagulation is essential.
• Unfractionated heparin (UFH) carries approximately 10 times higher risk than low molecular weight heparin (LMWH).

1. What are the ophthalmic signs of heparin-induced thrombocytopenia?

Heparin-Induced Thrombocytopenia (HIT) is an immune-mediated reaction to heparin administration. IgG antibodies are produced against the complex of platelet factor 4 (PF4) and heparin, leading to platelet activation. This paradoxically results in a decrease in platelet count while the blood becomes hypercoagulable.

HIT is classified into type I and type II. HIT type I is a transient thrombocytopenia that resolves spontaneously. HIT type II is antibody-mediated and a severe condition with thromboembolic complications. ¹⁾

Epidemiology

• Thrombocytopenia is observed in 95% of HIT patients.
• Thrombosis occurs in up to 50% of patients.
• The incidence in patients receiving UFH is about 10 times higher than in those receiving LMWH.
• The incidence in all UFH-treated patients is up to 5%, and the mortality rate reaches up to 10%. ²⁾
• The incidence after cardiac surgery is 0.1–3%, which is higher than in the general population (0.1–0.3%). ¹⁾
• Thromboembolic events occur in 29.1% of HIT cases after cardiac surgery, and the postoperative mortality rate reaches 21.8%. ³⁾
• Risk is higher in women, the elderly, and after major surgery.

Ocular complications occur when HIT-related thrombosis or hemorrhage affects the ocular vasculature. Ophthalmic management is required in parallel with systemic management of HIT.

Q How often does HIT occur?

A

In patients receiving UFH, the incidence is up to 5%, and in those receiving LMWH, it is about one-tenth of that. After cardiac surgery, the incidence is 0.1–3%, higher than in the general population, and the mortality rate can reach up to 10%. ²⁾

2. Main Symptoms and Clinical Findings

heparin induced thrombocytopenia cherry red spot oct

Central retinal artery occlusion following COVID-19 vaccine administration. Am J Ophthalmol Case Rep. 2022 Feb 18; 26:101430. Figure 1. PMCID: PMC8855623. License: CC BY.

Clinical and optical coherence tomography findings: (A) Dilated fundus ophthalmoscopy showed the presence of arterial narrowing with cherry red spot (white arrow). (B) Optical coherence tomography showed severe macular swelling of the inner retina layers (red arrows). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Subjective Symptoms

Ocular symptoms vary depending on the location of thrombosis or hemorrhage.

• Acute vision loss: Caused by retinal vascular occlusion. Often sudden onset.
• Visual field defect: Appears as homonymous hemianopia secondary to occipital lobe infarction.
• Ptosis and diplopia: Occur as compression symptoms due to orbital thrombosis or hemorrhage.
• Retro-orbital pain (pain behind the eye): Appears with orbital lesions.

Clinical Findings (Findings Confirmed by Physician Examination)

• Spontaneous orbital hemorrhage: Occurs due to a combination of thrombocytopenia and anticoagulation.
• Homonymous hemianopia: Occurs secondary to occipital lobe infarction. It is a finding where the same side of the visual field is missing in both eyes.
• Ptosis and ocular movement disorder (diplopia): Caused by orbital compression or intraorbital hematoma.
• Retinal venous occlusion: A venous thrombus occludes the retinal vein.
• Branch retinal artery occlusion: An arterial thrombus affects the retinal artery.

Diagnostic Note

Ocular hemorrhagic or thrombotic events can also occur due to other causes such as pre-existing vascular diseases. It may be difficult to establish a causal relationship with HIT. In patients with concurrent thrombocytopenia and ocular symptoms, HIT should be considered regardless of the presence of vascular risk factors.

3. Causes and Risk Factors

The cause of HIT is an immune-mediated reaction to heparin administration. The main risk factors are as follows.

• Unfractionated heparin (UFH): Approximately 10 times higher risk compared to LMWH.
• Duration of administration: Risk increases with long-term use.
• Cardiac surgery (with cardiopulmonary bypass): High-dose UFH administration, tissue factor release, and inflammation during CPB promote HIT antibody production. ³⁾ After CPB, seroconversion of PF4/H antibodies occurs in up to 50% of patients, but only 1–2% develop clinical HIT. ¹⁾
• Women: Higher risk than men.
• Advanced age: Recognized as a risk factor.

For patients using heparin

While receiving heparin, have your platelet count monitored regularly. If you notice any eye abnormalities such as changes in vision, visual field defects, or eye pain, inform your doctor immediately.

Q Can HIT occur with low molecular weight heparin?

A

HIT can also occur with LMWH, but the incidence is about 1/10 that of UFH. Even though the risk is lower, platelet monitoring cannot be omitted.

4. Diagnosis and testing methods

HIT is a diagnosis of exclusion. It is suspected when thrombosis and thrombocytopenia occur 5–14 days after heparin administration and other causes are ruled out.

4T Score (Clinical Probability Assessment)

The 4T score is a clinical probability score consisting of four criteria: Thrombocytopenia, Timing, Thrombosis, and oTher causes. Each criterion is scored 0–2 points, and the total score classifies the probability.

Total Score	Probability Classification
6–8 points	High probability
4–5 points	Moderate
0–3 points	Low probability

The positive predictive value of the 4T score is approximately 10% for a moderate score of 4 points and approximately 80% for a high probability score of 8 points. ⁴⁾

In cardiac surgery patients, platelet count typically decreases by 30–50% after CPB, and if a biphasic pattern of thrombocytopenia is observed, it is considered a characteristic finding of HIT. ³⁾¹⁾

Laboratory Diagnosis

The main diagnostic tests are the anti-PF4/heparin antibody test (anti-PF4 ELISA) and the serotonin release assay (SRA).

• Anti-PF4 ELISA: Sensitivity >99% is high, but specificity is low at about 50%. NPV 98–99%, vitrectomy 10–50%. Useful for screening. ²⁾
• Serotonin Release Assay (SRA): Specificity >95%, vitrectomy 89–100%. Sensitivity varies from 56–100%. Used as a confirmatory test. ²⁾

The ASH guidelines recommend anti-PF4 ELISA for patients with a moderate or higher 4T score, and if positive, confirm with SRA. ²⁾

Rare discordant cases of anti-PF4 ELISA negative and SRA positive (16 of 8,546 cases, 0.2%) have been reported; caution is needed when HIT is strongly suspected clinically. ²⁾

Phase classification of HIT

The management strategy for HIT differs depending on the phase. ³⁾

Acute HIT

Platelet count: Decreased

Functional assay (SRA): Positive

Immunoassay (ELISA): Positive

The highest risk period. Discontinue all heparin immediately and switch to a non-heparin anticoagulant.

Subacute HIT A

Platelet count: Normalized

Functional assay (SRA): Positive

Immunoassay (ELISA): Positive

Platelet count has recovered but functional assay is positive. Cardiac surgery should be postponed if possible.

Subacute HIT B

Platelet count: Normal

Functional assay (SRA): Negative (median 50 days to seroconversion)

Immunoassay (ELISA): Positive

Intraoperative short heparin exposure is low risk. Continue heparin avoidance postoperatively.

Remote HIT

Platelet count: Normal

Functional assay (SRA): Negative

Immunoassay (ELISA): Negative (PF4/H antibodies disappear at a median of 85 days)

Short-term heparin administration upon re-exposure is possible.

In patients with ocular symptoms secondary to HIT, a thorough history and physical examination should be performed to check for other systemic symptoms.

Q What is the 4T score?

A

This score evaluates the clinical probability of HIT based on four criteria: degree of thrombocytopenia, timing of onset, presence of thrombosis, and exclusion of other causes. The total score ranges from 0 to 8, with a score of 6 or higher indicating high probability.

5. Standard Treatment

Principles of Treatment

When HIT is diagnosed or strongly suspected, the following should be implemented immediately.

1. Immediate discontinuation of all heparins: including heparinized saline for flushes and heparin-coated catheters.
2. Initiation of a non-heparin anticoagulant: because the risk of thrombosis persists after heparin cessation, an alternative agent must be used.

Alternative Anticoagulants

Argatroban

Classification: Direct thrombin inhibitor

Half-life: 39–51 minutes (normal liver function), up to 181 minutes with liver impairment

Metabolism: Hepatobiliary excretion. Advantageous in patients with renal impairment.

Bivalirudin

Classification: Direct thrombin inhibitor

Half-life: 25 minutes (normal to mild renal impairment)

PCI dose: 0.75 mg/kg bolus + 1.75 mg/kg/h

CPB dose: 1 mg/kg bolus + 2.5 mg/kg/h (add 50 mg to priming solution)³⁾

The ASH 2018 guidelines recommend bivalirudin for PCI. In 52 cases of PCI use, a procedure success rate of 98% and major bleeding of 1.9% have been reported.³⁾

Management of Refractory HIT

For refractory HIT in which thrombosis progresses despite appropriate non-heparin anticoagulation, consider the following. ⁵⁾

• High-dose IVIG: Administer at a dose of 2.0–2.5 g/kg over an average of 3 days. It may suppress platelet activation by HIT antibodies. A small case series of 3 patients reported platelet improvement within 3 days.
• TPE (therapeutic plasma exchange): Consider if there is no response to IVIG. No established protocol exists; a systematic review (30 cases) reported an average of 4 sessions with a plasma exchange volume of 1.3 PV. ⁵⁾
• Rituximab: Positioned as a salvage therapy.

Management during cardiac surgery

If a patient with acute HIT/subacute HIT A requires cardiac surgery, consider the following three options. ³⁾

1. Postpone surgery until functional tests become negative (if possible)
2. Intraoperative anticoagulation with bivalirudin
3. Re-administration of heparin after TPE, or re-administration of heparin with potent antiplatelet agents (iloprost, cangrelor, tirofiban)

Management of Ophthalmic Complications

Retinal vascular occlusion and orbital hemorrhage are managed ophthalmologically in parallel with systemic management of HIT.

Important Notes on Treatment

• Warfarin bridging contraindicated: Administering warfarin alone during the acute phase of HIT carries a risk of skin necrosis. Continue non-heparin anticoagulants until platelet count recovers.
• Platelet transfusion generally avoided: Platelet transfusion may increase the risk of arterial thrombosis (OR 3.4). ⁵⁾
• Thrombotic risk persists after heparin cessation: Appropriate continued management with alternative anticoagulants is essential.

Q If HIT is diagnosed, what is used instead of heparin?

A

Switch to a direct thrombin inhibitor such as argatroban or bivalirudin. Both directly inhibit thrombin through a mechanism different from heparin and are not affected by HIT antibodies. The choice of agent depends on liver function, kidney function, and clinical situation.

6. Pathophysiology and Detailed Mechanism of Onset

The onset of HIT progresses through the following stages.

Step 1: Complex formation and antibody production

PF4 (platelet factor 4) is a positively charged chemokine derived from megakaryocytes and stored in platelet alpha granules. PF4 forms complexes with negatively charged heparan sulfate (GAG on vascular endothelial surface) or LPS (gram-negative bacterial outer membrane). These complexes act as “danger signals” and enable rapid production of IgG antibodies.

Step 2: Formation of PF4-heparin complexes

Heparin administration leads to the formation of PF4-heparin complexes. Because heparin has a molecular structure similar to LPS and heparan sulfate, pre-existing IgG binds to it.

Step 3: Platelet activation and hypercoagulability

The IgG-PF4-heparin complex binds to FcγRII receptors (FcγRIIa) on platelets, activating them. The intrinsic pathway of the coagulation cascade is initiated, leading to widespread thrombosis and thrombocytopenia due to platelet consumption. This is the essence of the “paradoxical” pathophysiology of HIT.

Special antigens and refractory HIT

In addition to normal PF4, antibodies targeting IL-8, protamine, and NAP-2 are detected in less than 1% of HIT workup cases. ²⁾ Furthermore, anti-PF4 antibodies that activate platelets even in the absence of heparin (heparin-independent HIT antibodies) may be involved in the pathophysiology of refractory HIT and autoimmune HIT. ⁵⁾

Antibody dynamics after cardiac surgery

After CPB, seroconversion of PF4/H antibodies occurs in up to 50% of patients, but only 1–2% develop clinical HIT. ¹⁾ High-dose UFH administration during CPB, release of tissue factor, and inflammation are thought to promote HIT antibody production. ³⁾

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7. Latest Research and Future Prospects (Research Stage Reports)

For patients: Please be sure to read

The following content is currently at the research stage or in clinical trials and is not a standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Fc-Modified Antibodies (Fc-Modified KKO)

This is a deglycosylated formulation of the mouse monoclonal IgG2b anti-PF4/H antibody KKO. By blocking FcγRIIa-mediated binding, it suppresses platelet activation and complement activation.

In mouse models, it has been reported to improve thrombocytopenia and reduce thrombus size. ⁵⁾ This is a stage that requires evaluation in future clinical trials.

Heparin Re-administration Strategy Using Cangrelor

A strategy of re-administering heparin during CPB using the P2Y12 inhibitor cangrelor is being investigated.

In a case series of 10 patients, the dose was adjusted using VerifyNow P2Y12 PRU, and no thrombotic complications were reported. ⁵⁾ A standardized protocol has not yet been established.

Establishing an Optimal TPE Protocol

Although the efficacy of TPE is recognized, a unified protocol has not been established.

A systematic review (30 cases) reported an average of 4 TPE sessions and a plasma exchange volume of 1.3 PV, but the level of evidence is low, and future prospective studies are needed. ⁵⁾

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8. References

1. Tugulan C, Chang DD, Bates MJ. Heparin-Induced Thrombocytopenia After Mitral Valve Replacement. Ochsner J. 2021;21(1):100-104.

2. Attah A, Peterson C, Jacobs M, et al. Anti-PF4 ELISA-Negative, SRA-Positive Heparin-Induced Thrombocytopenia. Hematol Rep. 2024;16(1):90-97.

3. Pishko AM, Cuker A. Heparin-induced thrombocytopenia and cardiovascular surgery. Hematology Am Soc Hematol Educ Program. 2021;2021(1):478-485.

4. Mele M, Iacoviello M, Casavecchia G, et al. Coronary thrombosis due to heparin-induced thrombocytopenia after percutaneous coronary intervention. Clin Case Rep. 2021;9(6):e04291.

5. Adeoye O, Zheng G, Onwuemene OA. Approaches to management of HIT in complex scenarios, including cardiac surgery. Hematology Am Soc Hematol Educ Program. 2024;2024(1):267-278.