RESEARCH ARTICLES

Trombocitopenia la gravidele cu trombofilie tratate cu heparine cu greutate moleculară mică

 Thrombocytopenia in pregnant women with thrombophilia treated with low-molecular-weight heparin

Melinda-Ildiko Mitranovici, Smaranda Ilea, Mihai Morariu, Daniel Mureşan, Izabella Petre

First published: 18 aprilie 2019

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/ObsGin.67.1.2019.2295

Abstract

Thrombophilia is a pathology introduced into the clinical practice, with risk of venous thromboembolism (VTE) in pregnancy. Objectives. The potential risks for the mother and fetus should be considered when using anticoagulants in pregnancy. Materials and method. In this study, we followed-up the evolution under prophylaxis with Fraxiparine® of 81 pregnant patients with inherited thrombophilia, of which 63 gave birth until the end of the study. Laboratory and adjacent tests were performed to determine the occurrence of complications related to thrombophilia, but also the adverse effects of the anticoagulant treatment. Results. Fraxiparine® was found not to be associated with dangerous adverse effects. Discussion. Procoagulant and fibrinolytic factors are involved in hemostasis. In addition, besides the coagulation cascade, the complement cascade, vascular factors, and quinine also play a role. Platelet aggregation can be diminished, being involved in pregnancy bleeding, especially at birth. The retractability of the clot may also be diminished by the occurrence of thrombasthenia, which should be monitored especially under anticoagulant treatment when a paradoxical thrombocytopenia syndrome might occur. Conclusions. We did not find any dangerous side effects, not even HIT syndrome (heparin-induced thrombocytopenia), which is common in other anticoagulant treatments.

Keywords
thrombocytopenia, pregnant women, thrombophilia, LMWH

Rezumat

Trombofilia este o patologie asociată cu risc de tromboembolism venos (TEV) în sarcină. Scopul lucrării. Utilizarea anticoa­gulantelor în sarcină necesită luarea în considerare a potenţialelor riscuri pentru mamă şi făt. Materiale şi metodă. În acest studiu am urmărit evoluţia profilaxiei în cazul a 81 de paciente gravide cu trombofilie moştenită tratate profilactic cu Fraxiparine®, din care 63 au născut până la finalul studiului. S-au efectuat teste paraclinice pentru a putea determina apariţia unor complicaţii legate de trombofilie, dar şi efectele adverse ale anticoagulantului. Rezultate. Nu s-au constatat efecte adverse în cazul utilizării Fraxiparinei®, nici măcar trombocitopenia asociată altor heparine cu greutate moleculară mică (LMWH). Discuţie. În hemostază sunt implicaţi factori procoagulanţi şi fibrinolitici. În plus, pe lângă cascada coagulării, joacă un rol şi cascada complementului, factorii vasculari şi chininele. Agregarea trombocitară poate fi diminuată, având un rol important în sângerările din sarcină şi implicit la naştere. Retractilitatea cheagului poate fi, de asemenea, diminuată prin apariţia trombasteniei, proces care ar trebui urmărit în special sub tratamentul anticoagulant, când poate apărea un sindrom paradoxal de trombocitopenie, fenomen studiat în cazul prezentat de noi. Concluzii. Acest sindrom paradoxal – denumit sindrom TIH (trombocitopenia indusă de heparină) – nu a apărut, potrivit studiului nostru.

Introduction

Thrombophilia is an important and highly debated medical issue, and the disease is often undiagnosed, with a series of severe comorbidities, including death(1-3). The management of thrombophilia involves anticoagulant therapy, but the use of these agents is not very well known anyway. The fact that there are a few studies in pregnancy and the recommendations are based mostly on investigations carried out on non-pregnant women(4-6).

Thrombophilia is associated with increased venous thromboembolism and placental damage, up to fetal loss and thrombocytopenic purpura in the newborn(1-5, 7-10).

The coagulation and fibrinolysis systems are two separate but linked enzyme cascades that regulate the formation and segmentation of the fibrinogen. The blood coagulation system, or the coagulation pathway, is a proteolytic cascade. Thrombophilia is a pathology recently introduced into the clinical practice.

The thrombophilias are classified as inherited and acquired. The inherited ones are those with inherited defects of the factors involved in the coagulation cas­cade. The acquired one is caused by the antiphospholipid antibodies developed in various pathologies. APLAs are antibodies directed towards phospholipid-binding proteins. These are lupus anticoagulant and anticardiolipin antibodies associated with autoimmune diseases(6,11).

Pregnancy is physiologically a state of hypercoagulability. Thus, when thrombophilia overlaps it, we must carefully evaluate the balance of haemostasis(6,12-21).

Heparin-induced thrombocytopenia (HIT) represents the decrease in platelet count due to the anticoagulant treatment(20).

Recently, HIT is considered a paradoxical syndrome induced by the antithrombotic treatment, an important side effect for pregnant women.

Materials and method

In this study, the data was collected using Microsoft Excel. The statistical analysis was performed with SPSS v17. The use of these programs was possible due to the collaboration with the “Victor Babeş” University of Medicine and Pharmacy from Timişoara.

The study included 81 patients from Hunedoara county with various gestational ages, of whom 63 gave birth until its completion. It was a prospective study which took place in the Department of Obstetrics and Gynecology of the “Dr. A Simionescu” Municipal Hospital, Hunedoara. All of the pregnancies were correctly supervised over a six-year period.

The patients underwent various paraclinical tests to determine the severity of their condition and the adverse effects of the medication to which they had been subjected to.

We used the following exclusion criteria: infections, chronic HTA or renal disease, drug abuse, karyotype or congenital abnormalities, placental or umbilical abnormalities, diabetes, low progesterone.

The numerical variables were compared with the nonparametric Mann-Whitney test (we compared here 63 pregnant women with thrombophilia under Fraxiparine® treatment with 63 healthy pregnant women). The statistical significance was considered for p<0.05.

Results

In this study, we had a group of Caucasian women, aged 26 to 41 years old, in which we observed their responses to the use of Fraxiparine® during pregnancy. We calculated the central trend parameters and plotted the histogram of this variable (Table 1 and Figure 1). The volume of the sample in this case was 63, because only 63 of the 81 women reached the delivery date by the end of the study.
 

Table 1. Descriptive statistics on the number of platelets the women had before birth
Table 1. Descriptive statistics on the number of platelets the women had before birth
Figure 1. The histogram for the number of platelets
Figure 1. The histogram for the number of platelets

Fraxiparine® was found not to be accompanied by this dangerous adverse effect, as outlined in Table 1.

Only one patient developed thrombocytopenia during pregnancy (under 100,000 platelet/mm3), and this occurred in the third trimester of pregnancy. The treatment used was Fraxiparine® 0.4 IU/day in all cases.

We used a Mann-Whitney test, and we obtained a significantly lower p-value (p<0.001).

Heparin treatment has also side effects which we present in Table 2. We noticed that they were a few, rarely causing bleeding, osteoporosis, and allergic reactions such as hives or skin rash. In newborns – in which the physiology of the hemostasis has some particularities – the thrombocytopenic purpura described in the literature was not encountered.
 

Table 2. The occurrence frequency of possible side effects
Table 2. The occurrence frequency of possible side effects

There is no specific adverse reaction for most low-molecular-weight heparin (LMWH) treatments, except for HIT syndrome. All pregnant women with thrombophilia used Fraxiparine® until delivery and six weeks after that, and all of them signed an informed consent regarding the study.

Discussion

The risk of thromboembolism is six times higher in pregnant women than in non-pregnant women, according to literature data. Also, the women with a history of venous thromboembolism (VTE) have a 3-4 times higher risk of recurrence. Studies up until now suggest that the pharmacological thromboprophylaxis is underused in at least 30% of patients at high and very high risk of VTE and in over 50% of those at medium risk. The causes are multiple. However, associating thrombophilia with pregnancy complications presents methodological limitations which make it difficult to obtain accurate data. A significant proportion of the population has a detectable abnormalities, but most of them develop thrombosis in the presence of an additional risk factor(8-10).

Conclusions

The platelet count is very important for the pregnant woman, especially near the date of delivery, as giving birth is a process associated with an important loss of blood. This is why we considered it necessary to do also a descriptive statistic on the numeric variable platelet count.

Until now, low-molecular-weight heparin has been found to be able to induce long-term thrombocytopenia, and should be monitored in pregnancy. But in our study we obtained good results with Fraxiparine®, which is the only LMWH not accompanied by thrombocytopenia and bleeding risk at delivery.

However, the treatment in pregnancy should be judiciously evaluated, taking also into account the physiological changes in pregnancy, especially when approaching the delivery date, which is a process accompanied by major bleeding risk(21,22).  

Conflict of interests: The authors declare no conflict of interests.

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