The Phenomenon of Thrombotic Microangiopathy in Cancer Patients
Abstract
:1. Introduction
- Thrombotic thrombocytopenic purpura (TTP), characterized by reduced ADAMTS13 activity;
- Hemolytic–uremic syndrome (HUS);
- Hereditary deficiency of the metalloproteinase ADAMTS13, known as Upshaw–Schuman syndrome;
- Hereditary or acquired forms of atypical hemolytic-uremic syndrome (aHUS);
- Hemolytic–uremic syndrome associated with Shiga toxin-producing Escherichia coli (STEC-HUS);
- TMA induced by medications that exert a direct toxic effect upon the endothelium, such as certain chemotherapeutic agents and drug-induced immune-mediated endothelial injury, etc.
2. The Historical Trajectory of the Identification and Ensuing Exploration of TMA
3. Clinical Variations and the Epidemiological Characteristics of TMA
4. Pathogenetic Variants in TMA
4.1. Role of ADAMTS13 in the Pathogenesis of TMA
4.2. Features of Drug-Induced TMA
4.3. Cancer-Associated TMA
- Neoplastic microangiopathy: malignancies such as lymphomas, leukemias, metastatic carcinomas, and hemangiopericytomas have the capacity to incite microangiopathic changes, precipitating the coagulation of blood within diminutive vascular structures [41].Contributory neoplastic factors to the genesis of microangiopathy [42] are
- A.
- The direct invasion of adjacent tissues by the tumor potentially resulting in the obstruction of small blood vessels and the subsequent disturbance of vascular perfusion;
- B.
- The process of tumor neoangiogenesis;
- C.
- The necrosis and degradation of neoplastic tissue, which may actuate the activation of the coagulatory cascade.
- 2.
- Disruption of Vascular Endothelium Integrity: neoplastic proliferation and the associated tumor microenvironment are implicated in the impairment or outright disruption of the vascular endothelium. This pathology may subsequently facilitate thrombus formation [43];
- 3.
- Tumor-Induced Hypoxia and Necrosis: within the tumor matrix, hypoxic conditions often prevail, potentially correlating with microthrombi development and coagulatory system activation [44];
- 4.
- Hemostatic System Activation: malignant neoplasms, contingent upon their histological classification, can initiate various degrees of coagulation pathway activation, thereby promoting thrombogenesis. Oncogenic factors and molecules associated with tumor presence may have interactions with the coagulatory cascade, amplifying the propensity for TMA;
- 5.
- Paraneoplastic Syndromes: certain neoplasms may precipitate paraneoplastic syndromes that subsequently impact the vascular system and coagulation pathways.
- A.
- Disseminated Intravascular Coagulation (DIC) syndrome may manifest as a sequela of various malignancies, notably those originating from the stomach, pulmonary, prostatic, and additional organ systems. This syndrome is associated with compromised platelet functionality and the genesis of microthrombi within diminutive vessels, potentially culminating in the onset of TMA;
- B.
- Polycythemia Vera (PV) is distinguished by a hyperproliferation of erythrocytes within the bone marrow and may present concomitantly with thrombocytosis and amplified thrombotic risk. TMA may emerge as a clinical presentation within this disorder;
- C.
- Goodpasture’s Syndrome, an infrequent paraneoplastic condition frequently linked to colorectal cancer, is typified by a constellation of findings, including TMA, hyperproteinemia, and renal pathology [45].
5. The Diagnostic Criteria for TMA
- gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and altered bowel movements, including frequent watery stools, which may occasionally be blood-stained;
- fluid retention presenting as peripheral and cavity edema, oliguria or anuria, and discoloration of urine;
- respiratory distress evidenced by dyspnea;
- dermatological signs, including hemorrhagic rashes;
- neurological complaints like headaches and visual disturbances, which may range from slight blurring to complete loss of vision;
- general symptoms including malaise, fatigue, anorexia, vertigo;
- neurobehavioral changes such as psychomotor fluctuations or seizures and partial paralysis.
- Complete Blood Count: evaluation includes checking for anemia (specifically microangiopathic hemolytic anemia (MAHA) that is Coombs-negative), thrombocytopenia (platelet count under 150 × 109/L or a decline exceeding 25% from the baseline), and reticulocytosis (notably, MAHA can occasionally manifest in the absence of thrombocytopenia);
- Peripheral Blood Smear: investigation for schizocytes, where the criterion is an excess of 0.1% in a peripheral blood smear;
- Biochemical Blood Test: measurements include lactate dehydrogenase (LDH) levels, which should be elevated, and/or haptoglobin levels, which should be reduced. The manifestation of acute kidney injury is characterized by elevated concentrations of creatinine and urea, along with disturbances in electrolyte balance such as hyperkalemia, hyponatremia, hypocalcemia, and hyperphosphatemia. Concurrently, there is an increase in uric acid levels, indicative of hyperuricemia. In cases where nephrotic syndrome ensues, significant reductions in protein levels are observed, notably hypoproteinemia and hypoalbuminemia, accompanied by an increase in α2-globulin. Additionally, this condition is associated with heightened levels of cholesterol and triglycerides, denoting hypercholesterolemia and hypertriglyceridemia, respectively.
- General Urine Analysis: may reveal proteinuria, with the potential presence of either microhematuria or macrohematuria;
- Antiglobulin Test: should demonstrate a negative Coombs test;
- Complement System Components Assessment: a decline in C3 concentrations, occurring simultaneously with consistent C4 levels, can be observed in roughly 50% of patients with aHUS. It is important to note that standard C3 levels do not rule out aHUS. In patients with STEC-HUS, a decline in C3 levels might occur, akin to any other infection, yet C4 levels may stay within the normal range [38].
- the presentation of Coombs-negative MAHA, which is characterized by elevated serum LDH levels, serum haptoglobin concentrations that are undetectable or markedly diminished, and the presence of schistocytes in the peripheral blood smear—a condition that is not, however, a compulsory criterion;
- he occurrence of thrombocytopenia;
- the involvement of multiple organ systems, notably characterized by renal dysfunction, neurologic anomalies, and gastrointestinal symptoms; renal complications may present as acute renal injury, proteinuria, or hypertension;
- the maintenance of normal coagulation profiles.
6. The Significance of Assessing ADAMTS13 and VWF in Patients with Gynecological Cancers
7. Differential Diagnosis of TMA
8. Thrombo-Inflammation and TMA
9. COVID-19 Associated TMA
10. The Phenomenon of DITMA
11. Treatment Principles for TMA
- Determining the etiology of secondary TMA and mitigating or eradication of the inciting factor;
- Implementation of plasmapheresis, a process designed to extract immunologically active substances from the plasma, which may arrest the advancement of TMA and avert life-threatening sequelae. This modality is particularly efficacious in cases of TTP;
- Administration of immunosuppressive agents such as glucocorticoids, cyclophosphamide, or rituximab, with the intention of inhibiting the immune system to obviate further progression of TMA;
- Provision of adjunctive care: TMA can precipitate a multitude of complications, including but not limited to renal impairments, central nervous system disturbances, and anemia. Indispensable supportive therapies, potentially encompassing dialysis, antihypertensive agents, and transfusion of blood products, may be requisite.
12. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Vorobev, A.; Bitsadze, V.; Yagubova, F.; Khizroeva, J.; Solopova, A.; Tretyakova, M.; Gashimova, N.; Grigoreva, K.; Einullaeva, S.; Drozhzhina, M.; et al. The Phenomenon of Thrombotic Microangiopathy in Cancer Patients. Int. J. Mol. Sci. 2024, 25, 9055. https://doi.org/10.3390/ijms25169055
Vorobev A, Bitsadze V, Yagubova F, Khizroeva J, Solopova A, Tretyakova M, Gashimova N, Grigoreva K, Einullaeva S, Drozhzhina M, et al. The Phenomenon of Thrombotic Microangiopathy in Cancer Patients. International Journal of Molecular Sciences. 2024; 25(16):9055. https://doi.org/10.3390/ijms25169055
Chicago/Turabian StyleVorobev, Alexander, Victoria Bitsadze, Fidan Yagubova, Jamilya Khizroeva, Antonina Solopova, Maria Tretyakova, Nilufar Gashimova, Kristina Grigoreva, Sabina Einullaeva, Maria Drozhzhina, and et al. 2024. "The Phenomenon of Thrombotic Microangiopathy in Cancer Patients" International Journal of Molecular Sciences 25, no. 16: 9055. https://doi.org/10.3390/ijms25169055