Abortion: a modern approach to the diagnosis and treatment of hemostasis defects associated with obstetric pathology

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Relevance. Thrombocytopenic purpura (TTR) is a rare and very aggressive pathology that endangers the patient's life, characterized by thrombocytopenia and hemolytic anemia with clinical consequences of thrombosis. TTP is caused by a deficiency of ADAMTS13 metalloproteinase (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13), which cleaves von Willebrand factor (vWF). ADAMTS13 is a critically important enzyme that is synthesized in stellate liver cells (perisinusoidal Ito lipocytes) [1].
Upshaw-Shulman syndrome (USS) is a rarely reported congenital form of thrombotic thrombocytopenic purpura (TTP) resulting from mutations in the ADAMTS13 gene [2]. ADAMTS13 deficiency contributes to the development of microthrombosis caused by the retention of super-large vWF multimers in the blood circulation. According to a few studies involving pregnant women, the heterogeneity of manifestations made it difficult to diagnose this pathology. The disease occurs unexpectedly and is associated with an increased risk of death. The need for monthly monitoring of ADAMTS13 for relapses is emphasized, while prevention is of paramount importance to prevent maternal and intrauterine mortality [2, 3, 4].
The aim of the work is to analyze the relevance of diagnosing ADAMTS13 pathologies and identify morphological features of emerging obstetric complications associated with the pathogenesis of the disease.
Materials and methods of research. A computer literature search was conducted using the databases PubMed, EMBASE, Medline, Scopus, ScienceDirect, Google Scholar and Web of Science, attention is focused on the latest developments in the field of diagnostics and histological examination. Keywords used are thrombotic thrombocytopenic purpura; Upshaw-Shulman syndrome; von Willebrand factor; ADAMTS13; vascular microthrombosis; pregnancy; placenta. Studies that met the criteria and were prospective, multicenter, and randomized were systematically studied.
The results of the study. The pathophysiological mechanism of TTP is either a protease deficiency due to a mutation of the ADAMTS13 gene (Upshaw-Shulman syndrome), or the production of specific inhibitory autoantibodies. Acquired TTP with autoantibodies and severe ADAMTS13 deficiency (<10%) is a fairly common form of this disease: it has been shown that proteins found in placental circulation can serve as maternal triggers for the production of autoantibodies to ADAMTS13 and be associated with pregnancy complications [1]. The only known role of ADAMTS13 is in splitting vWF multimers [1].
The physiological role of multimeric vWF is to ensure platelet adhesion to the subendothelial matrix under conditions of vessel damage and hemodynamic stress [5]. Low molecular weight fragments of vWF circulating in the systemic circulation have a weak ability to bind to platelets and do not exhibit hemostatic activity. While the affinity of individual vWF subunits to platelets is extremely low, vWF multimers simultaneously provide many sites of binding to platelet Ib receptors, which significantly increases the strength of the vWF-platelet interaction [6]. vWF multimeric "tapes" can be fixed on the surface of endothelial cell membranes using P-selectin, which is secreted from Weibel-Palade bodies simultaneously with vWF. Thus, in conditions of absolute ADAMTS13 deficiency, vWF is in an "untreated" (super-large multimeric) form and microvessels are blocked by giant ultra-high molecular weight VWFS, on which an increasing number of platelets settle, forming platelet thrombi blocking the microvascular bed [7].
Thrombosis and microangiopathy lead to fragmentation of red blood cells and the formation of schizocytes. That is, the first clinical signs of USS are acute microangiopathy, characterized by microangiopathic hemolytic anemia, severe thrombocytopenia and vascular microthrombi. As a result, the resulting ischemic lesions can affect any organ, including the placenta [1, 2, 3, 8].
Physiological and immunological changes during pregnancy are associated with the unique manifestations of TTP during this period. In obstetric pathology, TTR is more common in nulliparous patients, whose estradiol levels are significantly higher than in multipartum patients. Pregnancy itself, as well as the postpartum period, represent a physiological state of procoagulation, which is also a risk factor for acute TTR. During pregnancy, changes in the hemostasis system predispose the patient to hypercoagulation, which gradually returns to normal about six weeks after delivery. The concentration of vWF increases significantly in the third trimester of pregnancy, whereas ADAMTS13 gradually decreases starting from the second trimester, returning to its normal values on the 21st day after delivery. In addition, estrogenic protease control also plays a special role [1, 2, 3, 8].
Maternal and fetal complications (fetal growth retardation, premature birth, fetal death, maternal stroke) are usually common and can be difficult for the patient, and the recurrence rate is 100% [8, 9].
Most hospitals are not technologically equipped to make a correct and complete diagnosis: there is no ADAMTS13 diagnostic kit. A timely diagnosis can save the patient's life. In addition, the diagnostic complex should include tests for troponin and D-dimer for proper assessment of ischemia in TTP, LDH determination and quantitative determination of schizocytes in a peripheral blood smear. A simple reference book with a quick differential diagnosis algorithm would be useful. But currently, a therapeutic decision may be delayed due to the ease of making mistakes in determining the pathology of ADAMTS13, which leads to delays with serious consequences for the pregnant woman [1, 2, 3, 9].
First-line therapy is based on clinical data and consists of plasmapheresis and administration of fresh or frozen plasma. Low molecular weight heparin (LMWH) therapy is required to prevent thrombosis. If there is a risk of bleeding, platelet transfusion should be used [9, 10].
Immunosuppression is the main treatment method and is achieved by administering steroids or targeting antibodies to ADAMTS13 with rituximab as an initial therapy [9, 10].
Kaplacizumab, a humanized monoclonal antibody derived from lam, has the effect of inhibiting the interaction of vWF with platelets – it was the first drug specifically approved for the treatment of TTP. There is sufficient evidence indicating that caplacizumab significantly accelerated the normalization of platelet count, reducing the risk of exacerbation [9].
N-acetylcysteine is an antimucolytic agent that destroys disulfide bonds in vWF, which helps to reduce the size of vWF multimers and their prothrombotic potential. N-acetylcysteine appears to inhibit vWF-dependent platelet aggregation, but has currently been studied only in animals [9].
As for surgical treatment, splenectomy has been considered, and it is a possible option for patients with chronic relapse. Although splenectomy previously had an increased risk of adverse events, improvements in surgical methods have significantly reduced the number of complications, especially when using laparoscopic techniques [9, 10].
Treatment should be adjusted according to ADAMTS13 levels, the patient's response to treatment and a thorough obstetric assessment, which will require an interdisciplinary approach as well as the integration of telemedicine. The role of a neonatologist is considered in the third trimester of pregnancy for further assessment of the newborn's condition [9-10].
Management of subsequent pregnancies and monthly monitoring of ADAMTS13 for signs of relapse is crucial [9-10].
Currently, we are faced with low or moderate certainty regarding the sequence of actions; there is insufficient data to determine the most effective therapeutic approach. Interdisciplinary recommendations are required, as well as innovative treatment methods, although there are limitations with regard to high-quality data on the latter [9-10].
Conclusion. Obstetricians and gynecologists should be aware of a rare and fatal disease – thrombotic thrombocytopenic purpura in Upshaw-Shulman syndrome. Establishing the correct diagnosis by determining ADAMTS13 and conducting additional tests is a key event to achieve a positive outcome. Interdisciplinary approaches are strongly recommended to reduce the risk of misdiagnosis.
Prevention is preferred. Monitoring of ADAMTS13 serum levels is carried out when planning a subsequent pregnancy.
Long-term complications of TTP in the form of stroke, hypertension, coronary heart disease, cognitive impairment, and decreased quality of life must be taken into account.
Pregnancy with Upshaw-Shulman syndrome will become one of the main areas of obstetric development in the coming years, further associative and high-quality research is needed to form the best therapeutic innovations and opportunities in the future.

About the authors

Aglaya Borisovna Kazumova

Sechenov First Moscow State Medical

Email: aglaya.kazumowa@yandex.ru
ORCID iD: 0009-0003-6481-6017
Russian Federation, 8-2 Trubetskaya str. Moscow, Russian Federation 119991

Natalya Victorovna Samburova

Sechenov First Moscow State Medical

Author for correspondence.
Email: nsamburova@bk.ru
ORCID iD: 0000-0002-4564-8439
SPIN-code: 9084-7676

PhD, Associate Professor

Russian Federation, 8-2 Trubetskaya str. Moscow, Russian Federation 119991

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