Understanding the Paradox: Why Does Bleeding Occur in Essential Thrombocythemia?

October 1, 2025 •

5 min read

Essential thrombocythemia (ET), a rare myeloproliferative neoplasm, can paradoxically increase the risk of both clotting and bleeding. This counterintuitive dual risk challenges the assumption that high platelet counts always lead to increased coagulation. The key to understanding why does bleeding occur in essential thrombocythemia lies in the dysfunctional nature of the overproduced platelets and secondary clotting factor deficiencies.

Quick Summary

Bleeding in essential thrombocythemia happens despite high platelet counts due to acquired von Willebrand syndrome, where excess platelets adsorb and degrade clotting factors, and from intrinsic defects in the abnormally produced platelets.

Key Points

Acquired von Willebrand Syndrome: Extreme thrombocytosis leads to an acquired clotting disorder by depleting the most active von Willebrand factor multimers from circulation.
Platelet Dysfunction: The platelets overproduced in ET are often structurally and functionally defective, contributing to an ineffective clotting process despite high numbers.
Genetic Influence: The JAK2 V617F mutation, common in ET, is associated with a higher likelihood of bleeding and may exacerbate acquired von Willebrand syndrome and platelet dysfunction.
Medication Risk: Antiplatelet drugs like aspirin, used to prevent clotting, can worsen bleeding risk in patients with underlying acquired von Willebrand syndrome.
Paradoxical Condition: Bleeding in ET is a paradoxical complication that can occur alongside a high risk of blood clots, complicating treatment strategies.
Reversible Effect: The acquired clotting defect is often reversible with cytoreductive therapy aimed at lowering the platelet count to a safer level.

The Paradox of High Platelet Counts

Essential thrombocythemia (ET) is a blood disorder where the bone marrow produces an excessive number of platelets, also known as thrombocytes. Platelets are blood cell fragments that play a crucial role in forming blood clots to stop bleeding. Given this function, one might assume that having too many platelets would only increase the risk of clotting. However, patients with ET face a paradoxical risk of both thrombosis (abnormal clotting) and hemorrhage (abnormal bleeding). This dual risk is a hallmark of the disease and requires careful management. The reasons for the bleeding tendency are complex and multifaceted, primarily involving an acquired deficiency in a key clotting protein and intrinsic abnormalities within the platelets themselves.

Acquired von Willebrand Syndrome (AVWS)

One of the most significant reasons why bleeding occurs in essential thrombocythemia is the development of acquired von Willebrand syndrome (AVWS), especially when platelet counts are extremely high (typically over 1,000,000/µL).

VWF Function: Von Willebrand factor (VWF) is a large, complex protein in the blood that acts as a crucial bridge for platelets, helping them adhere to the site of an injury and to each other to form a clot. It exists in various sizes, or multimers, with the largest multimers being the most hemostatically active and effective at promoting clotting.
The Adsorption Mechanism: In ET with extreme thrombocytosis, the sheer mass of platelets creates an enormous surface area. The excess platelets begin to adsorb and bind the large, functional VWF multimers from the blood.
Multimer Depletion: Once bound to the platelets, these large VWF multimers are more susceptible to being cleaved and broken down by a protease called ADAMTS13. This leads to a quantitative and qualitative defect in VWF, effectively mimicking an inherited bleeding disorder and impairing the body's ability to form a proper clot. The clinical symptoms of bleeding often resolve with treatment that reduces the platelet count, confirming that the AVWS is secondary to the high platelet count.

Intrinsic Platelet Dysfunction

In addition to the VWF deficiency, the platelets produced by the abnormal bone marrow stem cells in ET are not functionally normal. They are often large, irregularly shaped, and inherently defective, a state known as platelet dysfunction.

Abnormal Production: The neoplastic megakaryocytes in the bone marrow produce platelets that are structurally and functionally impaired.
Impaired Aggregation: In laboratory tests, these platelets often show inconsistent or impaired aggregation responses to certain stimuli. For example, some studies have noted a decreased or absent aggregation response to epinephrine.
Altered Biochemistry: Platelets in ET may also have altered internal components, including dense granules or alpha granules, which are essential for releasing factors that help platelets stick together and promote clotting. This can lead to an inefficient hemostatic plug despite the high number of circulating platelets.

Role of Genetic Variants (JAK2 V617F)

The specific genetic mutation present in an ET patient can influence their risk of bleeding. The JAK2 V617F mutation, found in approximately half of all ET cases, has been linked to an increased risk of both thrombotic and bleeding complications compared to other mutations like CALR. Research suggests that this specific mutation may alter platelet function and contribute to AVWS more significantly. For example, animal models with the JAK2 V617F mutation showed an acquired von Willebrand-like disorder characterized by a loss of large VWF multimers.

Iatrogenic Factors: Antiplatelet Medications

Patients with ET are at risk of thrombosis, so they are often prescribed antiplatelet medications like aspirin to reduce this risk. However, aspirin works by inhibiting platelet function. For patients with a very high platelet count and coexisting AVWS or intrinsic platelet dysfunction, adding aspirin can further tilt the balance towards an increased bleeding risk. A clinical dilemma arises, especially for patients with extreme thrombocytosis, where balancing the risks of bleeding and clotting is critical. For this reason, screening for AVWS is recommended for ET patients with extremely high platelet counts before starting or continuing antiplatelet therapy.

Common Symptoms of Bleeding in ET

Easy Bruising: Unexplained and frequent bruising, even from minor bumps.
Nosebleeds (Epistaxis): Repeated or prolonged nosebleeds are common.
Bleeding Gums: Noticed during brushing or flossing.
Gastrointestinal (GI) Bleeding: Major hemorrhages can occur, often involving the gastrointestinal tract, and may appear as blood in the stool.
Other Mucocutaneous Bleeding: Bleeding from the mouth or other mucous membranes.

Management and Considerations

Balancing the risk of bleeding versus thrombosis is a primary challenge in managing ET. Cytoreductive therapy, aimed at lowering the platelet count, is often employed in cases with extreme thrombocytosis to reverse AVWS and decrease the risk of bleeding. Careful monitoring of VWF activity is crucial for patients, especially those requiring invasive procedures or undergoing antiplatelet therapy. A personalized treatment approach, taking into account the patient's specific genetic profile and overall clinical picture, is essential for mitigating both bleeding and clotting risks. For more in-depth information, you can consult resources from the MPN Research Foundation.

Mechanisms of Bleeding in Essential Thrombocythemia


Feature	Acquired von Willebrand Syndrome (AVWS)	Intrinsic Platelet Dysfunction
Underlying Cause	High platelet mass adsorbs and clears large von Willebrand factor (VWF) multimers.	Neoplastic megakaryocytes produce qualitatively abnormal platelets.
Effect on VWF	Reduces levels of the most functional, high-molecular-weight VWF multimers.	Platelets show inconsistent function despite potentially normal VWF levels.
Effect on Platelets	Excessive, but functionally impaired due to external VWF deficiency.	Excessive and inherently dysfunctional due to internal defects.
Clinical Manifestation	Mucocutaneous bleeding, especially with extreme thrombocytosis.	Contributes to overall impaired clotting and bleeding risk.
Management Impact	Often requires cytoreductive therapy to lower platelet count and reverse VWF defect.	Difficult to predict or test for, requires balancing with other therapies.

Conclusion

Bleeding in essential thrombocythemia is a complex phenomenon arising from a combination of acquired von Willebrand syndrome and intrinsic platelet dysfunction, primarily triggered by extremely high and abnormal platelet counts. Rather than simply being an issue of too many platelets, the problem is a deficiency of key clotting factors and the poor quality of the platelets themselves. Effective management relies on careful assessment of the patient's bleeding and thrombotic risks, often involving cytoreductive therapy to normalize platelet counts and reverse the acquired clotting defect. This nuanced understanding is vital for guiding treatment and improving outcomes for individuals with ET.

Frequently Asked Questions

Yes, it is a paradoxical but recognized complication of essential thrombocythemia. Despite having a high number of platelets, defects in the quality of the platelets and the depletion of a crucial clotting protein, von Willebrand factor, can cause bleeding.

AVWS is a bleeding disorder that develops in some patients with essential thrombocythemia. When platelet counts are extremely high, the excess platelets can adsorb and clear the large, most effective von Willebrand factor multimers from the blood, impairing normal clotting.

The abnormal stem cells in the bone marrow produce platelets that are not functionally normal. They can have altered internal components and show impaired aggregation responses to certain signals, making them ineffective at forming proper clots.

Yes. While aspirin is often used to reduce the risk of clotting in ET, it inhibits platelet function. In patients with pre-existing AVWS or intrinsic platelet dysfunction, aspirin can further intensify the bleeding risk, especially if platelet counts are very high.

Patients with the JAK2 V617F mutation are at a higher risk of both bleeding and thrombosis. This mutation can produce functionally abnormal platelets and may also contribute to the development of acquired von Willebrand syndrome.

Common symptoms include easy bruising, nosebleeds, bleeding gums, and more rarely, major gastrointestinal bleeding. These are signs of the impaired clotting ability caused by the disease.

Management often involves cytoreductive therapy to lower the excessive platelet count. By reducing the platelet mass, this treatment can reverse the acquired von Willebrand syndrome and improve clotting function. Careful monitoring is also essential, especially when antiplatelet medications are used.