Erythrocytosis and ADAMTS13 Deficiency: A Complex Intersection of Thrombosis Risk and Hemostatic Imbalance

Abstract

Erythrocytosis, characterized by elevated red blood cell mass, and ADAMTS13 deficiency, a central factor in the pathogenesis of Thrombotic Thrombocytopenic Purpura (TTP), may interact in complex ways to influence thrombosis risk. This article explores the biochemical and clinical relationship between erythrocytosis, ADAMTS13 genetic markers, von Willebrand Factor (vWF) abnormalities, and the potential roles of supportive treatments like saline and anticoagulants such as heparin. It also reviews the current understanding of therapeutic strategies for managing patients with these overlapping hematologic abnormalities.

Introduction

ADAMTS13 (A Disintegrin and Metalloprotease with Thrombospondin type 1 motif, member 13) is a critical enzyme responsible for cleaving ultra-large multimers of von Willebrand Factor (vWF), thus regulating platelet adhesion and aggregation. Deficiency in ADAMTS13 activity, either congenital or acquired, leads to the accumulation of these ultra-large vWF multimers and the development of Thrombotic Thrombocytopenic Purpura (TTP).

Erythrocytosis, the increase in red blood cell mass (commonly seen in Polycythemia Vera or secondary to hypoxia), increases blood viscosity and can independently raise the risk of thrombosis. When coexisting with ADAMTS13 deficiency, this presents a unique and poorly understood interaction that may exacerbate microvascular thrombosis and organ damage.

1. ADAMTS13 and Its Clinical Significance
ADAMTS13 cleaves the A2 domain of vWF, particularly under high shear stress in arterioles and capillaries. If ADAMTS13 activity drops below 10%, patients are at risk for TTP, a life-threatening condition characterized by:

Microangiopathic hemolytic anemia

Severe thrombocytopenia

Renal dysfunction

Neurologic symptoms

Fever (in some cases)

Genetic Markers of ADAMTS13

Patients may carry multiple genetic variants or mutations in the ADAMTS13 gene. These may cause:

Congenital TTP (Upshaw-Schulman Syndrome) — autosomal recessive

Predisposition to acquired TTP — especially in autoimmune settings

2. von Willebrand Factor (vWF) and Its Role

vWF mediates platelet adhesion and aggregation at sites of vascular injury. Some patients with ADAMTS13-related disorders also show abnormalities in vWF type 2 or type 5, indicating qualitative defects in the protein’s function. This can result in either bleeding or clotting tendencies, depending on the vWF subtype and interplay with ADAMTS13.

3. Erythrocytosis: Amplifying the Hemostatic Imbalance

 Erythrocytosis can be:

Primary: as seen in Polycythemia Vera (PV) — often due to a JAK2 mutation

Secondary: due to hypoxia (e.g., lung disease, high altitude), tumors (e.g., RCC), or excess erythropoietin

Relative: due to dehydration

Hemorheological Impact:

 

Increased blood viscosity leads to higher shear stress in the vasculature.

 

Shear stress causes vWF unfolding, exposing cleavage sites that require ADAMTS13 to regulate.

 

In the presence of low or dysfunctional ADAMTS13, this stress amplifies thrombotic risk.

 

Combined Risk:

When erythrocytosis and ADAMTS13 deficiency coexist:

The risk of platelet-rich microthrombi increases.

Organs with high microvascular density (brain, heart, kidneys) are particularly vulnerable.

Clinical presentations may include stroke-like symptoms, renal dysfunction, or cardiac ischemia without overt atherosclerosis.

 

6. Supportive Therapies: Saline and Heparin

Saline — Helpful in:

            Hydration during plasma exchange

Managing dehydration-related hemoconcentration

Supporting renal perfusion in hemolysis

But: Saline does not address the underlying cause (enzyme deficiency or vWF abnormality).

Heparin — Not Helpful (and possibly harmful) in:

            TTP: Heparin does not reduce vWF or help ADAMTS13 function.

Active bleeding: Common in vWF disorders.

Heparin-Induced Thrombocytopenia (HIT): A concern in patients with immune activation or low platelets.

Heparin is only useful if there's another indication, such as confirmed DVT or PE, not as a treatment for ADAMTS13-related conditions.

Conclusion

The coexistence of erythrocytosis and ADAMTS13 deficiency creates a perfect storm for thrombotic complications, particularly in the microvasculature. While supportive measures like saline can help stabilize patients, and heparin may be indicated in select thrombotic contexts, the primary treatment must target the underlying pathophysiology — whether that’s replacing ADAMTS13, suppressing autoantibodies, or controlling red cell mass.

Proper diagnosis, frequent monitoring, and collaboration with hematology are essential to reduce morbidity and mortality in patients with this complex interplay of hemostatic disorders.

Next Steps for Patients and Clinicians

Consider genetic counseling for patients with inherited ADAMTS13 or vWF mutations.

Rule out JAK2-positive myeloproliferative neoplasms in erythrocytosis.

Do not initiate heparin or anticoagulants in microangiopathy without clear indication.

Develop individualized care plans with hematology input for overlapping syndromes.

References:

Pathophysiology of TTP; learn how ADAMTS13 deficiency leads to microvascular thrombosis.
https://www.thebloodproject.com/module/thrombotic-thrombocytopenic-purpura/pathophysiology/

Polycythemia, or erythrocytosis: https://www.ncbi.nlm.nih.gov/books/NBK526081/

What Is Erythrocytosis? https://www.webmd.com/a-to-z-guides/what-is-erythrocytosis

Inherited ADAMTS13 deficiency (Upshaw-Schulman syndrome): A short review
https://www.sciencedirect.com/science/article/abs/pii/S0049384814004691

Understanding Hematocrit: What Your HCT Levels Reveal About Your Health
https://www.youtube.com/watch?v=UEQcyeIVrgg

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© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9