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Publicly Available Published by De Gruyter September 25, 2017

The acquired form of ADAMTS-13 deficiency as the cause of thrombotic microangiopathy in a pregnant woman with recurrent cerebral circulation disorders, venous thromboembolism, preeclampsia and fetal loss syndrome

Viktoriya O. Bitsadze, Jamilya Khizroeva and Alexandr D. Makatsariya

Abstract

Background

Thrombotic microangiopathy (TMA) is one of the most difficult thrombotic complications, characterized by damage of microvessels of various organs and accompanied by thrombocytopenia and hemolytic anemia. Today, TMA includes thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, heparin-induced thrombocytopenia and hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome. A key characteristic in the development of TMA is endothelial dysfunction. Recent discoveries suggest that this pathology is more widespread than it was previously. One of the most important triggers for TMA is pregnancy.

Methods

The clinical observation of a patient with an inhibitory form of a disintegrin and metalloproteinase with a thrombospondrin type 1 motif, member 13 (ADAMTS-13) deficiency, recurrent thrombotic and “typical obstetric” severe complications is presented.

Results

We diagnosed a reduction in the activity of ADAMTS-13, an increase in the level of antibodies to ADAMTS-13 and disturbances in functioning of the protein C system along with symptoms of disorders of blood flow in the mother-placenta-fetus system as a poor prognosis in regard to both thrombotic and placenta-mediated combinations.

Conclusions

An analysis of cases such as this patient immediately pushes the clinician to the idea of antiphospholipid syndrome (APS). It is questionable whether this patient could be regarded as an APS patient if her symptoms do not correspond with the classic diagnostic criteria for the syndrome. At the same time, the discovery of molecular mechanisms of TMA warrants a fresh look into the pathogenesis of thrombotic complications associated with pregnancy, as well as the pathogenesis of placental obstetric complications, including severe forms of preeclampsia, premature detachment of normally situated placenta and septic shock.

Clinical case report

Patient. A 20-year-old woman was seen for the first time in the women’s medical center in 2002 at the 12th week of her second pregnancy, with the upcoming delivery being her second.

Medical history: The patient suffered from rheumatic disease (remission stage from the age of 12 years) and chorea minor during her childhood. The first pregnancy was at the age of 19 years. An ischemic stroke in the basin of the left middle cerebral artery with hemiplegia and a speech disorder (dysarthria) occurred at 15–16 weeks of the first pregnancy. After therapy, the pregnancy was continued but severe preeclampsia developed against the background of intrauterine growth retardation (IUGR) and placental insufficiency at 36 weeks. The patient was subjected to an urgent operative delivery by cesarean section. A boy was born in a state of severe hypoxia, with a weight of 2250 g and a height of 47 cm. His Apgar score was 3–4 points. He died on the 38th day.

Pathological-anatomical diagnosis of the newborn. Basic disease: malformation of cerebral vessels and meninges with multiple foci of proliferation of arterial and venous vessels of different caliber and formation of multiple large and small aneurysms; macrofocal gray and red softening of the brain substance; multiple tissue dysplasia: angiomatosis of epicardial vessels, subendocardial fibrosis and simple renal dysplasia with glomerular cysts of subcapsular zone; and adrenal dysplasia.

Complications: 1. Generalized circulatory disorders in tissues and organs and focal hemorrhages in the parenchyma of the lung. 2. Intrauterine hypoxia.

Tanatogenesis was conditioned by severe necrotic changes in the brain substance.

Three weeks after the cesarean section, iliofemoral thrombosis on the right limb and thrombosis of the inferior vena cava coming from an occluded right common iliac vein developed in the patient. Angiography confirmed thromboembolism of small branches of the pulmonary artery. After intravenous infusion of heparin, the patient was treated with warfarin at a dose of 7.5 mg daily to achieve an international normalized ratio (INR) of 2.0–3.0, which she received for 2 years until the onset of the next pregnancy.

After learning about the second pregnancy, the patient herself canceled warfarin treatment at the 5th week of pregnancy and took aspirin at a dose of 75 mg per day. Against the background of this therapy, she appealed to our clinic.

Status praesens: Slight flattening of the right nasolabial fold was identified at the examination. The pupils were symmetrical. The patient was mobile. The skin was of normal color. Marked livedo reticularis was noticed on the hands, arms, thighs and legs. The patient’s blood pressures were 110/70 mm Hg and 100/65 mm Hg on the right and left hands, respectively. The body temperature was 36.7°C. Abdominal ultrasonography revealed no pathological changes. An echocardiogram revealed mitral valve prolapse with first-degree regurgitation. A rheumatologist excluded systemic lupus erythematosus and other systemic diseases.

Hemostasis examination: A detailed examination for the presence of acquired and genetic forms of thrombophilia and disorders of hemostasis was carried out in the pathology of hemostasis laboratory (Table 1).

Table 1:

Blood analysis.

Laboratory data Reference range On presentation
aPTT (s) 21–27 29
Prothrombin time (s) 11–16 31
Protein C, % 70–130 98
Protein S, % 60–140 65
Platelet aggregation with different inductors:
 ADP, % 50–75 87
 Ristomycin, % 50–75 95
 Adrenaline, % 50–75 75
 Collagen, % 50–75 54
 Arachidonic acid, % 50–75 55
Soluble fibrin monomer complexes Negative Positive
Protein C global assay [protein C activation time normalized ratio (PCAT-NR)] >0.7 0.69
Lupus anticoagulant (K = La1/LA2) K < 1.2 – negative 1.0
K = 1.2–1.5 – weakly positive
K = 1.51–1.80 – positive
K > 1.81 – strongly positive
Homocysteine, μmol/L 5–7 (pregnant women) 11.5
<11 (non-pregnant women)
Antiphospholipid antibody screen (includes antibodies to phosphatidylserine, phosphatidylcholine, sphingomyelin, phosphatidylethanolamine, phosphatidylinositol), ELISA, U/mL Ig G – 0.0–10.0 Ig G – 0.1
Ig M – 0.0–10.0 Ig M – 0.03
Antibodies to cardiolipin, U/mL Ig G – 0.0–10.0 Ig G – 22.0
Ig M – 0.0–7.0 Ig M – 15.0
Antibodies to b2-glycoprotein, U/mL Ig G – 0.0–5.0 Ig G – 0.01
Ig M – 0.0–5.0 Ig M – 0.5
Antibodies to annexin V, mL Ig G – 0.0–5.0 Ig G – 1.6
Ig M – 0.0–5.0 Ig M – 0.7
Antibodies to prothrombin, U/mL Ig G – 0.0–10.0 Ig G – 0.5
Ig M – 0.0–10.0 Ig M – 0.3
C-reactive protein, mg/L 0–5 3
Rheumatoid factor, IU/mL 0–14 1
Antistreptolysin O titer [AS(L)O], IU/mL >200 – positive 112
Antinuclear antibodies Negative Not found
Antibodies to DNA Negative Not found
Antibodies to SS-A/Ro Negative Not found
Antibodies to SS-B/La Negative Not found
Antibodies to Sm Negative Not found

A study on the presence of mutations and polymorphisms in the genes of the hemostatic system, predisposing to increased blood clotting: MTHFR(C677T), PAI-1 4G/4G and ACE I/D.

Despite considerable progress in the field of molecular medicine and genetics, some forms of thrombophilia remain unknown. Perhaps this is one of the reasons for the contradictory data about the role of genetic thrombophilia in the pathogenesis of obstetric complications (in addition to factors such as gene penetrance, study design, etc.). However, if we assume that thrombophilia is a general biological concept, which characterizes a high readiness of the organism to macro- and microthromboses, including microcirculation disorders, then it can be supposed that the role of both genetic and acquired thrombophilia (apart from APS) is much greater than it is considered to be. Our experience shows an undeniable role of thrombophilia in the pathogenesis of both thrombotic and common obstetric complications, which are now combined into a group of so-called placenta-mediated vascular complications.

The discovery of APS as well as the most common genetic forms of thrombophilia in the last 30 years has led to a major revision of existing concepts of the pathogenesis of various obstetric complications. While the role of thrombophilia in the occurrence of thrombotic complications of pregnancy is not in doubt, the pathogenetic role of genetic thrombophilia, in contrast to APS, in the development of severe forms of preeclampsia and hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome of early and late reproductive ages is still the subject of numerous studies, whose results are sometimes very contradictory [2], [12]. Thus, despite the existence of clear clinical criteria, the laboratory criteria for APS are absent. Nevertheless, we have diagnosed 12 weeks of pregnancy, seronegative APS, polymorphisms of genes of the hemostatic system and aggravated thrombotic and obstetrical histories in the patient.

Low-molecular-weight heparin therapy and low doses of aspirin were prescribed. The pregnancy proceeded without complications. At the 39th week, the patient was subjected to operative delivery by cesarean section. A girl was born with a weight of 3100 g and a height of 51 cm. Her Apgar score was 7–8. Eight hours after the operation, antithrombotic prophylaxis with nadroparin was continued at a dose of 2850 IU once a day for 3 months, with a further recommendation for transitioning to warfarin.

In 2004, the third unplanned pregnancy occurred, which was interrupted at the request of the patient at a gestational age of 5 weeks. In 2005, the fourth pregnancy ended in a miscarriage at a gestational age of 7 weeks.

In 2006, the patient, in the absence of pregnancy, had a transient ischemic attack against the background of emotional stress and hypertensive crisis with a blood pressure of 200/110 mm Hg (with walk infringement). At the time of the transient ischemic attack, the patient only took aspirin and not warfarin. After antihypertensive therapy and intravenous infusion of heparin, movement function fully recovered and the patient continued with aspirin therapy.

In 2007, the fifth pregnancy took place and the second stroke happened at a gestational age of 5 weeks. The patient was taken to the emergency department in a severe condition by ambulance, with symptoms of aphasia and right-sided hemiplegia. She was diagnosed with brain infarction (repeated) and left middle cerebral artery syndrome. Nadroparin therapy was initiated at a dose of 5700 IU per day subcutaneously, as well as therapy with the neuroprotective drug pentoxifylline. At a gestational age of 8 weeks, the pregnancy was artificially terminated (abortion was performed for medical reasons). For the following year, the patient had a rehabilitation course with good results, constantly receiving warfarin at a dose of 5 mg per day and aspirin at a dose of 100 mg per day.

She re-applied at our clinic in 2012 for advice on the preparation for pregnancy. We explained to her that the pregnancy would present a high risk of recurrent thrombotic events for her. However, the patient was in a second marriage and was eager to have a second child.

A new examination showed that reliable laboratory criteria for APS were still absent.

Final diagnosis

Given the history of recurrent strokes, livedo reticularis, venous thromboembolism, obstetric complications, the patient was diagnosed with Sneddon’s syndrome, seronegative APS, fetal loss syndrome, homozygous polymorphism of the PAI-1 4G/4G gene, heterozygous polymorphisms of the MTHFR (C677T) and ACE I/D genes, a complicated thrombotic history, varicose vein disease, post-thrombotic syndrome of the right lower limb and tibio-caval segment, rheumatism and chorea minor (remission stage).

Management

The patient was treated with enoxaparin at a dose of 40 mg per day and aspirin at a dose of 100 mg per day. Besides, folic acid was administered at a dose of 4 mg and vitamins B6 and B12. In the first trimester, in addition to the standard tests, we determined the activity and the level of antibodies to a disintegrin and metalloproteinase with a thrombospondrin type 1 motif, member 13 (ADAMTS-13). In the first trimester, ADAMTS-13 activity was 58% and the level of antibodies to ADAMTS-13 was 1.98 U/mL; both parameters were within the reference range.

At the 22nd week of the pregnancy, according to studies of the hemostatic system, negative dynamics appeared: disturbances in the protein C system (protein C global assay): PCAT-NR = 0.45 (>0.7 in a norm); antibodies to ADAMTS-13 (58.77 U/mL), but some parameters were within the reference range: ADAMTS-13 activity = 48.6%; D-dimer level = 2100 μg/mL; antithrombin III = 70%; and protein C = 95%. Platelet aggregation was also within the reference range. Anti-Xa was 0.1 U/mL. Clexane (enoxaparin) dosage was increased to 40 mg twice a day. After 10 days, anti-Xa was increased to 0.4 U/mL. Control of ADAMTS-13 activity, level of antibodies to ADAMTS-13 and natural anticoagulation (protein C, antithrombin III and protein C global assay) was carried out every 2 weeks after 22 weeks of pregnancy. Dynamic control of uteroplacental and fetoplacental blood flows (doplerometry) was also performed. From the 32nd week of the pregnancy, cardiotocography was carried out. Starting from the 31st week of the pregnancy, enoxaparin dosage was increased to 80 mg twice a day (anti-Xa was 0.5 U/mL).

At the 30th week of the pregnancy, the initial signs of IUGR and decrease of blood flow in the uterine arteries had appeared.

At the 35th week of the pregnancy, the level of antibodies to ADAMTS-13 dramatically increased to 140 U/mL and ADAMTS-13 activity decreased to 34%. A significant enhancement of resistance to activated protein C was also observed (Table 2).

Table 2:

ADAMTS-13, D-dimer, AT III and protein C activities.

Laboratory data Reference range On presentation before pregnancy 22 weeks of pregnancy 35 weeks of pregnancy 3 months after delivery
ADAMTS-13 activity, % 40–130 58.0 48.6 34 74
ADAMTS-13 antibodies, U/mL <12 1.98 58.77 140 15
ADAMTS-13 concentration, μg/mL 0.6–1.6 1.02 0.57 0.41 0.7
PCAT-NR >0.7 0.69 0.45 0.3 0.65
D-dimer, mg/mL 10–550 240 2100 4400 430
Protein C, % 70–130 98 95 75 92
Antithrombin III, % 75–125 81 70 68 84

  1. Bold values indicate that reduced ADAMTS-13 activity or appearance of ADAMTs-13 antibodies at the end of pregnancy are associated with thrombotic risk.

Discovery of the ADAMTS-13 enzyme became an important step not only in the understanding of thrombotic thrombocytopenic purpura (TTP) pathogenesis (Moschcowitz’ disease), but also in the pathogenesis of certain critical conditions in obstetrics, such as severe preeclampsia, HELLP syndrome and stroke. A special form of secondary thrombotic microangiopathy (TMA) is TMA associated with pregnancy. Often hidden, ADAMTS-13 deficit, as well as antiphospholipid antibodies, manifests the first time during pregnancy. This is connected with the pathological conversion of physiological changes inherent in pregnancy; in particular, in the second and third trimesters trimesters ADAMTS-13 activity decreases, the level of blood clotting factors increases and the activity of natural anticoagulant systems decreases, the activation of systemic inflammatory response syndrome and the complement system gradually increases and endotheliopathy increases [1]. The catastrophic form of antiphospholipid syndrome (CAPS) is a rare and the most severe form of APS, which occurs in approximately 1% of patients with APS [2]. It is manifested by multiple thromboses of vital organs with the development of multiple organ failure and TMA [3]. CAPS, as well as TTP, is a life-threatening condition and requires emergency treatment [4]. An undeniable fact is that the infection and a systemic inflammatory response are quite often associated with CAPS, and perhaps they are its most frequent triggers, but CAPS does not develop in all patients with APS and infection. Whether it is connected with the so-called profile of antiphospholipid antibodies, combinations thereof and/or willingness of the body (hidden congenital or acquired deficiency of natural anticoagulants, in particular, protein C, ADAMTS-13 deficiency, etc.) is an open question, which is extensively being studied. Second and third trimesters of pregnancy are accompanied by precisely those changes of the hemostatic system, and the development of CAPS is more characteristic for the end of pregnancy. Moreover, CAPS is not always recognized in obstetric practice, and severe preeclampsia or HELLP syndrome and multiple organ failure within disseminated intravascular coagulation (DIC) syndrome or sepsis, or, more rarely, hemolytic-uremic syndrome, is most often diagnosed [5], [6]. At the same time, in terms of current knowledge about the role of ADAMTS-13, we express the view that antibodies to ADAMTS-13 (acquired ADAMTS-13 deficiency) may be the trigger that leads to the development of severe microangiopathy with total thrombosis of the microcirculation and clinical manifestations of CAPS [7].

At the 36th week of pregnancy, the patient was subjected to operative delivery by cesarean section. A live girl was born with a weight of 2900 g and a height of 49 cm. Her Apgar score was 7–8. On the first day, she was on artificial pulmonary ventilation. Postoperatively, 8 h after the operation, the mother was treated with enoxaparin at a dose of 0.6 mL once per day for 3 months, with a further recommendation of transitioning to warfarin at a dose of 7.5 mg per day and aspirin at a dose of 100 mg per day. There was no recurrent stroke or venous thrombosis. After 3 months, the level of antibodies to ADAMTS-13 decreased to 15 U/mL and ADAMTS-13 activity increased and reached 74%.

The question arises as to whether ADAMTS-13 antibodies can be attributed to antiphospholipid compounds [7]. If so, then this requires a revision of laboratory criteria for APS and changes the strategy of diagnosis, prevention and treatment of pregnant women with so-called seronegative APS and circulating antibodies to ADAMTS-13, when the activity of ADAMTS-13 is not yet reduced, which can often be seen before pregnancy and in early pregnancy [8], [9]. We have regarded the reduction in the activity of ADAMTS-13, the increase in the level of antibodies to ADAMTS-13, disturbances in functioning of the protein C system along with the symptoms of disorders of blood flow in the mother-placenta-fetus system as a poor prognosis in regard to both thrombotic complications (recurrent stroke, venous thromboembolism) and placenta-mediated complications of pregnancy (IUGR, antenatal fetal death, preeclampsia and placental abruption).

TMA is one of the most difficult thrombotic complications characterized by damage of microvessels of various organs and includes TTP, hemolytic-uremic syndrome and heparin-induced thrombocytopenia. Deficiency of ADAMTS-13 is a specific feature of TTP, which makes it possible to differentiate this pathology from other TMAs. ADAMTS-13 is a plasma reprolysin-like metalloprotease that proteolyzes the multimeric molecule of von Willebrand factor (VWF). Insufficient proteolysis of von Willebrand multimers, having a high capacity to activate platelets, is associated with defects of the ADAMTS-13 enzyme. A significant decrease in the activity of ADAMTS-13 (<5%) ± the presence of antibodies confirms TTP (90% specificity). A level of <40% but >5–10% can be determined in a wide range of other diseases and pathological conditions that occur with the development of microangiopathy (strokes, heart attacks and thrombosis with rare localization) and poor response to standard antithrombotic therapy [10], [11].

To date, the role of the effects of ADAMTS-13 deficiency in the pathogenesis of “large” microangiopathy syndromes, such as HELLP syndrome, severe preeclampsia, CAPS, hemolytic-uremic syndrome, heparin-induced thrombocytopenia and direct TTP, is being studied [12]. A characteristic feature uniting these syndromes is the presence of thrombocytopenia and microangiopathy, as well as a high percentage of mortality in the absence of therapy. However, the etiology of these complications varies, although pathogenetic mechanisms may overlap, and thus the differential diagnosis of various forms of TMA is extremely important because it determines the strategy of treatment and prevention of these serious complications.

Gradually, clinical material is being accumulated, including our own data, about the role of ADAMTS-13 deficiency in the pathogenesis of critical conditions in obstetrics and thrombotic complications, including stroke and venous thromboembolism.

Commentary

Thus, patients with recurrent thrombotic complications, TMA (severe preeclampsia and HELLP syndrome) and recurrent brain strokes need a differential diagnosis of the thrombophilic conditions.

Determination of ADAMTS-13 and inhibitor activities may be a useful tool in the case of unexplained pregnancy-related thrombosis. Today, the possibility of diagnosing ADAMTS-13 deficiency already exists, so we can hope that the first synthetic ADAMTS-13 preparations will appear soon and allow carrying out timely diagnosis, pathogenetic prophylaxis and therapy of critical conditions, including those in obstetrics associated with TMA and ADAMTS-13 deficiency.

Author’s Statement

  1. Conflict of interest: Authors state no conflict of interest.

Material and Methods

  1. Informed consent: Informed consent has been obtained from all individuals included in this study.

  2. Ethical approval: The research related to human subject use has complied with all the relevant national regulations, and institutional policies, and is in accordance with the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee.

References

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Received: 2017-05-26
Accepted: 2017-07-11
Published Online: 2017-09-25

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