Ocular Signs of Thrombotic Thrombocytopenic Purpura (TTP)

Key points at a glance

Key Points at a Glance

• Thrombotic thrombocytopenic purpura (TTP) is a rare blood disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and neurological abnormalities.
• Ocular signs occur in 14–20% of cases, including retinal hemorrhage, vascular occlusion, serous retinal detachment, and papilledema.
• The underlying cause is the formation of platelet-rich microthrombi due to decreased ADAMTS13 activity.
• Untreated mortality reaches approximately 90%, but plasma exchange reduces it to 10–20%.
• Plasma exchange is the first-line treatment; platelet transfusion is contraindicated as it may worsen microthrombi.
• Risk stratification using the PLASMIC score is useful for diagnosis and treatment decisions.
• Photocoagulation may be considered for neovascularization secondary to retinal ischemia.

1. Ocular signs of thrombotic thrombocytopenic purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP), also known as Moschcowitz disease, is a rare blood disorder characterized by the pentad of microangiopathic hemolytic anemia (MAHA), thrombocytopenic purpura, acute kidney injury, neurological abnormalities (altered mental status), and fever.

Ocular signs are reported in 14–20% of cases, presenting various findings due to microthrombi formation in retinal and choroidal vessels.

Epidemiology

The incidence is reported to be 3.7 to 11 cases per million people per year. In the French adult population, it is reported as 1.5 cases per million per year⁵⁾. The annual prevalence is approximately 10 cases per million people⁷⁾, and it is known to occur more frequently in women.

• Sex difference: Women develop the disease 2 to 3 times more often than men⁶⁾.
• Predisposing background: More common in Afro-Caribbean and obese patients.
• Untreated mortality: Approximately 90%. With plasma exchange, it is reduced to 10–20%³⁾.

Classification of disease types

TTP is classified into congenital and acquired types.

• Congenital TTP (Upshaw-Schulman syndrome): Caused by ADAMTS13 gene mutations. Accounts for about 5% of all cases. Over 260 mutation sites have been identified in the NCBI ClinVar database, with approximately 60% being missense mutations and about 20% being small deletions or insertions⁶⁾.
• Acquired TTP: Caused by autoantibodies against ADAMTS13, accounting for about 95% of all cases³⁾.

Q How often do ocular signs of TTP occur?

A

Ocular signs have been reported in 14–20% of cases. These include retinal hemorrhages, vascular occlusion, serous retinal detachment, and papilledema. Since ocular symptoms may precede systemic symptoms, ophthalmologists may be the first to suspect TTP.

2. Main symptoms and clinical findings

ttp postoperative disc hemorrhage fundus

Bilateral proliferative retinopathy and ischemic optic neuropathy in a patient with atypical hemolytic-uremic syndrome: A case report. Medicine (Baltimore). 2019 Sep 27; 98(39):e17232. Figure 4. PMCID: PMC6775429. License: CC BY.

Fundus color photograph of the right eye after surgery. Although there is visible hemorrhage around the optic disc, the retina is well-attached.

Subjective Symptoms

The following ophthalmic subjective symptoms have been reported.

• Rapid vision loss: Due to retinal lesions.
• Blurred vision: Occurs secondary to papilledema.
• Diplopia: Associated with eye movement disorders due to cranial nerve palsy.
• Transient blurred vision and yellow vision: Reported in cases of pregnancy-associated TTP³⁾.

Systemic subjective symptoms of TTP include headache, altered consciousness, mental disorders, epilepsy, focal neurological deficits, fever, malaise, arthralgia, jaundice, nausea and vomiting¹⁾. Skin and mucosal bleeding (purpura, petechiae, gingival bleeding) also occurs secondary to thrombocytopenia³⁾.

Clinical Findings

Ophthalmic clinical findings are classified into retinal findings and neuro-ophthalmic findings.

Retinal and Choroidal Findings

Retinal hemorrhage: Observed in association with microvascular damage.

Retinal artery or vein occlusion: Caused by retinal ischemia due to thrombotic retinal vascular occlusion.

Serous retinal detachment: Develops secondary to choroidal circulatory disturbance.

Neovascularization: Forms secondary to retinal ischemia.

Retinopathy: More likely to develop when nephropathy is present, observed in about 10% of cases.

Neuro-ophthalmologic findings

Papilledema: Caused by increased intracranial pressure.

Anisocoria: Occurs with cranial nerve disorders.

Ocular misalignment: Occurs with cranial nerve disorders.

Hypertensive retinopathy/optic neuropathy: Secondary to malignant hypertension due to concurrent renal failure.

3. Causes and Risk Factors

The root cause of TTP is decreased ADAMTS13 activity. ADAMTS13 is a protease that cleaves von Willebrand factor (vWF) multimers. When its activity is reduced, large vWF multimers accumulate in the bloodstream, leading to the formation of platelet-rich microthrombi.

Congenital (hereditary) TTP

ADAMTS13 gene mutations are the cause, and they often become apparent when triggered by pregnancy. In congenital TTP, the risk of recurrence during pregnancy reaches 100%, while in acquired TTP it is reported to be 0–50%³⁾.

Triggers of Acquired TTP

• Infection: Sepsis, Salmonella infection, etc.⁸⁾
• Pregnancy: In the third trimester, vWF levels increase 1.5- to 3-fold, and ADAMTS13 decreases to 25-30% ³⁾.
• Autoimmune diseases: SLE, antiphospholipid syndrome (APS), Sjögren’s syndrome, etc.¹⁾⁷⁾.
• Drugs: Tyrosine kinase inhibitors, etc.
• Vaccines: Onset after COVID-19 vaccination has been reported, most frequently after BNT162b2 (7 out of 10 cases in the literature)⁵⁾.
• Surgery: Cases have been reported after cardiac surgery (valve replacement, TAVR)⁴⁾.
• HIV infection⁷⁾.

Q Is TTP inherited?

A

Congenital TTP (Upshaw-Schulman syndrome) is caused by mutations in the ADAMTS13 gene and is an inherited disorder. The NCBI ClinVar database lists over 260 mutation sites, often in the form of compound heterozygous mutations. However, about 95% of all TTP cases are acquired, caused by autoantibodies against ADAMTS13.

Lifestyle precautions

TTP can occur suddenly. If you experience rapid vision loss, double vision, blurred vision, along with systemic symptoms such as fever, jaundice, skin purpura, or decreased urine output, seek medical attention immediately.

4. Diagnosis and Testing Methods

The diagnosis of TTP is primarily based on confirming two findings: microangiopathic hemolytic anemia (MAHA) and thrombocytopenic purpura. Treatment should be initiated without waiting for the results of ADAMTS13 activity testing.

Blood Test Findings

• Platelet count: Usually <20×10⁹/L¹⁾.
• Hemoglobin: Usually <8 g/dL (80 g/L)¹⁾.
• LDH and bilirubin: Elevated, reflecting intravascular hemolysis¹⁾.
• Peripheral blood smear: Confirmation of schistocytes²⁾.
• Reticulocytes: Increased²⁾.
• Haptoglobin: Decreased⁵⁾.
• ADAMTS13 activity: <10% has diagnostic significance; cases with <5% have also been reported⁵⁾.
• ADAMTS13 antibody: Used to confirm acquired TTP²⁾.
• Troponin: Indicator of cardiac damage. Levels ≥0.25 μg/L are considered an independent predictor of mortality (OR 2.87)³⁾.

PLASMIC Score

The PLASMIC score is a scoring system used for risk stratification of TTP.

Item	Description
PLT <30×10⁹/L	1 point
Hemolysis findings	1 point
No active cancer	1 point
No history of organ transplant	1 point
MCV <90 fL	1 point
INR <1.5	1 point
Cr <2 mg/dL	1 point

• 0–4 points: low risk, 5 points: intermediate risk, 6–7 points: high risk⁴⁾.
• Even if ADAMTS13 activity is 10–30%, TTP cannot be ruled out (intermediate/high-risk patients)⁴⁾.

Differential Diagnosis

In pregnancy-related cases, differentiation from the following diseases is important.

• HELLP syndrome, hemolytic uremic syndrome (HUS), acute fatty liver of pregnancy, obstetric APS³⁾.

Other diseases that present with low ADAMTS13 activity, such as sepsis, DIC, liver disease, and falciparum malaria, also require differentiation.

If ocular findings are present, take a detailed history of other systemic symptoms and check for the classic pentad of TTP.

5. Standard Treatment

Plasma Exchange (PEx)

Plasma exchange is the first-line treatment. The following four effects are expected.

• Replenishment of ADAMTS13
• Removal of inhibitors (autoantibodies)
• Removal of ultra-large von Willebrand factor multimers (UL-vWFM)
• Replenishment of normal vWF

In pregnancy-associated TTP, 2,000 mL/session (40–60 mL/kg) is performed 1–2 times per day ³⁾. Plasma exchange reduces the untreated mortality rate from 90% to 10–20% ³⁾.

If severe acquired ADAMTS13 deficiency is absent, infusion of fresh frozen plasma is also an option.

Steroid therapy

• Glucocorticoids: Initiate immediately if moderate or higher clinical suspicion exists ⁴⁾.
• Steroid pulse therapy: High-dose intravenous methylprednisolone.

Rituximab

Used as an adjunctive therapy for refractory or recurrent cases.

• Standard dose: 375 mg/m² once weekly for 4 weeks⁵⁾.
• Low dose (100 mg/week × 4 doses) has also been reported to achieve complete remission²⁾. Complete remission rate is reported to be 83–100%²⁾.

Other treatments

• Refractory/recurrent cases: Immunosuppressive drugs such as vincristine sulfate and cyclophosphamide, and splenectomy may be considered.
• Ophthalmic treatment for retinal ischemia: Photocoagulation is performed. This is done to address neovascularization.

Precautions in treatment

• Platelet transfusion is contraindicated. It should not be administered because it worsens microthrombi.
• High-dose corticosteroids carry risks of hypertension and fluid overload, and are not recommended in cases complicated by posterior reversible encephalopathy syndrome (PRES)¹⁾.

Q Why is platelet transfusion contraindicated in TTP?

A

In TTP, platelet-rich microthrombi form in the microvasculature throughout the body. Platelet transfusion in this state may promote further microthrombus formation and worsen the condition. The first-line treatment is plasma exchange, and platelet transfusion should not be performed except in cases of life-threatening bleeding.

Q How is treatment for ophthalmic complications performed?

A

If retinal ischemia occurs, photocoagulation is performed. This is done to address neovascularization secondary to retinal ischemia. Papilledema may be due to increased intracranial pressure or malignant hypertension and must be managed in parallel with treatment of the underlying disease (TTP).

6. Pathophysiology and Detailed Mechanism

The mechanism of ophthalmic signs in TTP stems from a cascade of microthrombus formation triggered by ADAMTS13 deficiency.

vWF is a protein secreted by vascular endothelial cells and megakaryocytes, and is normally cleaved and degraded by ADAMTS13. In acquired TTP, autoantibodies against ADAMTS13 are formed, while in congenital TTP, mutations in the ADAMTS13 gene are the cause.

Deficiency or decreased activity of ADAMTS13 leads to accumulation of high-molecular-weight von Willebrand factor (ultra-large vWF multimers) resistant to cleavage in the plasma. These multimers bind to platelets, forming platelet-rich microthrombi that occlude small blood vessels throughout the body. Mechanical hemolysis causes anemia (microangiopathic hemolytic anemia).

Mechanisms of Ocular Manifestations

• Microthrombi in retinal and choroidal vessels → Impaired blood supply to the retina → Retinal hemorrhage, vascular occlusion, and serous retinal detachment.
• Secondary changes due to retinal ischemia → Formation of new blood vessels.
• Cranial nerve disorders secondary to thrombotic ischemia → Anisocoria and abnormal eye position.
• Concurrent renal failure → Hypertensive emergency (malignant hypertension) → Papilledema, hypertensive retinopathy, and optic neuropathy.

Association with Neurological Complications

The prevalence of stroke in TTP is reported to be 13.9%, which is higher than the 6.3–7.8% in the general elderly population ¹⁾. Posterior reversible encephalopathy syndrome (PRES) is a condition that can complicate TTP, and diffusion-weighted MRI (DWI) is useful for differentiating between vasogenic edema and cytotoxic edema ¹⁾.

7. Latest Research and Future Perspectives (Reports under Investigation)

For Patients: Please Read Carefully

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

Caplacizumab

Caplacizumab is a humanized nanobody (single-domain antibody) targeting the A1 domain of vWF. In the HERCULES trial, it was shown to accelerate platelet count normalization, reduce the number of plasma exchange sessions, and lower the relapse rate²⁾³⁾. Its efficacy in refractory TTP has also been reported⁵⁾.

Recombinant ADAMTS13

In a review of pregnancy-associated TTP cases by Xu et al (2024), recombinant ADAMTS13 was suggested to potentially overcome inhibitory antibodies and normalize vWF cleavage activity, making it a promising future treatment option³⁾.

Other Novel Therapeutic Agents

• N-acetylcysteine: Reduces the size and activity of vWF³⁾.
• Bortezomib: Being investigated for depletion of ADAMTS13 antibodies³⁾.
• Enzyme replacement therapy using gene expression proteins: Research is progressing as a potential treatment option in the near future.

Possibility of treatment without plasma exchange

Galindo-Calvillo et al (2021) reported a case of relapsed TTP that achieved complete hematologic remission with low-dose rituximab (100 mg/week × 4 doses) and prednisone (1 mg/kg) alone without plasma exchange during the COVID-19 pandemic²⁾. This suggests the possibility of a treatment strategy that does not require plasma exchange in a subset of stable relapsed TTP patients without organ damage.

COVID-19 vaccine-associated TTP

Reports of TTP onset after BNT162b2 vaccination are the most numerous in the literature (7 out of 10 cases), with most occurring after the second dose⁵⁾. Epitope mimicry is suspected as the mechanism, but further research is needed to establish causality.

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8. References

1. Zhu H, Liu J-Y. Thrombotic thrombocytopenic purpura with neurological impairment: A Review. Medicine. 2022;101(49):e31851.
2. Galindo-Calvillo CD, Torres-Villalobos G, Higuera-Calleja J, et al. Treating thrombotic thrombocytopenic purpura without plasma exchange during the COVID-19 pandemic. Transfus Apher Sci. 2021;60:103107.
3. Xu J, Cai H, Xu J, et al. Case report of thrombotic thrombocytopenic purpura during pregnancy with a review of the relevant research. Medicine. 2024;103(20):e38112.
4. Shao X, Hao P, Dong X, et al. Thrombotic Thrombocytopenia Purpura (TTP) following emergent aortic valve replacement after a complicated TAVR procedure. J Cardiothorac Surg. 2024;19:545.
5. Hammami E, Mdhaffar M, Jamoussi K, et al. Acquired Thrombotic Thrombocytopenic Purpura After BNT162b2 COVID-19 Vaccine: Case Report and Literature Review. Lab Med. 2022.
6. Li P, Lv T, Chen S, et al. An ADAMTS13 mutation that causes hereditary thrombotic thrombocytopenic purpura: a case report and literature review. BMC Med Genomics. 2021;14:252.
7. Lin HC, Chen PC, Chen YF, et al. Concurrence of immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura: a case report and review of the literature. J Med Case Rep. 2023;17:38.
8. Wang Z, Xu H, Peng B, et al. Flavorubredoxin, a Candidate Trigger Related to Thrombotic Thrombocytopenic Purpura. Front Cell Infect Microbiol. 2022;12:864087.