Thrombosis In Young Women Research Articles

Thrombosis in Young Women on Ocps Likely Is Caused By an Unmasking Effect of Estrogens on Underlying Thrombophilias

Background: Estrogen-containing oral contraceptives (OCPs) increase the risk for thrombosis 3-4 fold in otherwise healthy young women, although the absolute thrombosis rate in young OCP users is only 0.05% per year (Trenor CC, Pediatrics. 2011;127: 347). In our prospective cohort database 70% of lower extremity venous thromboembolism in adolescent girls were associated with OCP use, usually of recent onset (<6months). OCPs are associated with acquired resistance to activated protein C (APC), an important thrombin regulatory pathway, with an increase in fibrinolysis (Douxfils J, Contraception, 2020;102:396). A causative role for estrogens in thrombus formation in young women is not completely understood. Aims: This study evaluated thrombin generation, thrombin reduction by APC (activated protein C resistance, APCR), fibrinolysis and thrombophilia in healthy young males, healthy young females who were using or not using estrogen hormone therapy (i.e. oral contraceptive pills/OCPs) and young females with thrombosis who were using or not using OCPs at the time of thrombus presentation. The goal of this study was to measure the effects of OCPs on laboratory assays of coagulation and fibrinolysis to reveal potential mechanisms in increased thrombosis risk. Methods: This was an analysis of a consented, prospective cohort study (Thrombo-PICS). Healthy controls included men and women with no personal or family history of bleeding or clotting who were using or not using OCPs and on no other relevant medications. Study groups included females who presented with thrombosis with no OCP use, or OCP use for less than six months versus six or more months. All participants with a history of thrombosis were studied three or more months following the onset of thrombosis and no longer on OCPs. Laboratory assays performed included calibrated automated thrombography (CAT) with and without thrombomodulin (CAT TM) to determine thrombin generation (endogenous thrombin potential, ETP) and thrombin reduction with APC (% ETP reduction, APCR) respectively, and the euglobulin clot lysis time (ELT) to model fibrinolysis. Factors known to cause APCR and to be associated with thrombosis were also assayed, including factor V Leiden (FVL), the prothrombin gene mutation (PTM), protein C, protein S, lipoprotein(a), and the lupus anticoagulant (LA). Overall results were presented using descriptive statistics. Chi-Squared tests and paired t-tests were used to make paired comparisons. Parametric and non-parametric paired comparisons were used to evaluate group differences in ETP, % ETP reduction, ELT and presence thrombophilic traits relative to estrogen use and history of thrombosis. Results: Table 1 and Figure 1 display results. All groups of females with a history of thrombosis had decreased mean %ETP reduction compared to healthy females not on OCPs (p=0.02), with the lowest values occurring in females with thrombosis following less than six months of OCP use. There was also a lower prevalence of abnormal CAT TM values amongst healthy controls not on OCPs as compared to thrombosis patients not on OCPs (19 vs 51%, p=0.005).Healthy females on OCPs showed an increased ETP (p=0.002) and a marked reduction in ELT (p<0.001) as compared to all other groups. Females with a history of thrombosis, whether associated with OCPs or not, were similar to healthy females not using OCPs in regard to ETP and ELT. Furthermore, females who developed thrombosis on OCPs were more likely to have a thrombophilic trait than healthy controls on OCPs (48 vs 4%, p<0.001). Healthy men were found to have a greater %ETP reduction than healthy women (p=0.04), while having a lower ETP than healthy women (p=0.007). There were no differences in ELTs between healthy male and female controls (p=0.39). Discussion: OCPs were associated with increased thrombin generation, increased APCR and accelerated fibrinolysis in healthy female controls. The lower ELT in healthy controls using OCPs suggests that increased fibrinolysis may partially balance acquired APCR from estrogen use. We were unable to test fibrinolysis in females on OCPs prior to the onset of thrombosis. Females with thrombosis onset within six months of starting OCPs showed the highest prevalence of thrombophilic traits known to cause APCR. These data suggest that the APCR effect of OCPs potentially augments the prothrombotic effect of underlying thrombophilias in the promotion of clinical thrombosis.

Risk factors venous and arterial thrombosis in young women out of pregnancy

Introduction : to assess the influence of factors independently associated with arterial and venous thrombosis in women aged 18-44 years outside pregnancy. Material and methods . The case-control study included 319 women: the cases group included 134 patients with verified arterial and venous thrombosis, the control group included 185 patients without thrombosis. inclusion criteria: age 18-44 years; the presence of the first episode of instrumental^ verified arterial or venous thrombosis; consent to participate in the study. Exclusion criteria: pregnancy; the postpartum period up to 6 weeks at the time of thrombosis; mental disorders and mental illness. All women underwent clinical examination, collection of somatic and obstetric history, testing for biochemical parameters, hereditary and acquired thrombophilia. To quantify the independent relationships of risk factors with thrombotic events, the multiple logistic regression method was used. Results. In the group of cases, venous thrombosis was in 75% women, arterial thrombosis - in 25%. Ischemic strokes prevailed in the structure of arterial thrombosis. The most common trigger was the use of estrogen-progestin containing contraceptives in combination with other risk factors. In 23 cases (17.2%) the thrombosis were unprovoked. The proportion of women ≥ 40 years old, smoking intensity; family history of VTE in relatives up to 50 years of age, dyslipidemia, hyperfibrinogenemia, comorbidity, and the presence of thrombophilia met with a higher frequency in the group of cases. Independent factors associated with the development of arterial and venous thrombosis in young women were: the presence of diseases of the gallbladder (OR = 12,1 95% CI 2.5-67.5), cardiovascular diseases (OR = 10.2; 95% CI 3.6-29.1); total cholesterol level (OR = 7.7; 95% CI 4.4-13.5); respiratory diseases (OR = 3.7; 95% CI 1.0-11.5); the use of combined hormonal contraceptives (OR = 3.4; 95% CI 1.7-6.8); varicose veins of the lower extremities (OR = 2.5; 95% CI 1.0-4.9). Conclusion. The identification of the most important risk factors for arterial and venous thrombosis will expand the understanding of the common pathogenetic way of thrombosis in a population of women of childbearing age and improve their personalized prognosis and early prevention.

Pregnancy loss and risk of ischaemic stroke and myocardial infarction.

We investigated whether pregnancy loss increases the risk of arterial thrombosis in young women. Women (age 18-50years) with ischaemic stroke (IS) or myocardial infarction (MI) and at least one pregnancy were compared for pregnancy loss in a control group. Odds ratios (OR) with 95% confidence intervals (CI), adjusted for matching variables, cardiovascular risk factors, cardiovascular family history and the presence of antiphospholipid antibodies, were calculated for the number of pregnancy losses as well as the type of unsuccessful pregnancy (early miscarriage, late miscarriage and stillbirth). 165 IS cases, 218 MI cases and 743 controls were included. Women with multiple (≥3) pregnancy loss had a doubled risk of arterial thrombosis (OR 2·37, 95%CI 0·99-5·70) compared with women without pregnancy loss, similarly to women who experienced stillbirth (OR 1·68, 95%CI 0·79-3·55). Both relative risks were higher for IS (OR 3·51, 95%CI 1·08-11·35 and 2·06, 95%CI 0·81-5·23, respectively) than for MI (OR 2·04, 95%CI 0·71-5·86 and 1·04, 95%CI 0·39-2·79). Adjustment for antiphospholipid antibodies did not affect the estimates. Multiple pregnancy loss and stillbirth increases the risk of IS and, to a lesser extent, of MI, even when other cardiovascular risk factors and antiphospholipid antibodies are accounted for.

Analyse de la distribution anatomique de 172 thromboses veineuses des membres inférieurs chez 996 jeunes femmes en contexte hormonal. Impact sur l’exploration écho-Doppler

To analyze localizations of duplex ultrasonography-diagnosed lower-limb venous thrombosis in young women in hormonal periods in order to optimize the ultrasound exploration. From 42,018 standardized ultrasonography report forms, incremented in a database (January 2001 - July 2013), those performed for a first diagnosis of venous thrombosis in women ≤ 45 years were selected (n = 996). Among those, diagnosed venous thrombosis (n = 172) were classified into three groups: oral contraception (n = 74), pregnancy (n = 39) and post-partum period (n = 59). Clinical symptoms and thrombosis distribution were analyzed. In the contraception group, pulmonary symptoms at presentation were much more frequent than in the obstetrical group: 69% vs 20% (P < 0.001). The thrombosis was limited to the iliac veins in 31% (23/74) and to the left internal iliac vein in six patients. During pregnancy, the thrombosis was limited to the iliac veins in 28% (11/39), and to the left internal iliac vein in two patients. In the post-partum period, superficial venous thromboses were found more frequently (37/59). Among the 22 deep venous thromboses, nine were limited to the proximal segment, including four in the vena cava coming from a right ovarian vein thrombosis. Duplex ultrasonography in young women taking oral contraception, as during pregnancy, must target iliac venous segments, especially on the left side, otherwise one thrombosis out of three may be missed; in the post-partum period, the inferior vena cava and superficial veins are to be explored too.

C0408 Case report: Oral contraceptives, thrombophilias and deep vein thrombosis in young women after tonsillectomy

C0408 Case report: Oral contraceptives, thrombophilias and deep vein thrombosis in young women after tonsillectomy

Acute Budd Chiari and Underlying JAK 2 Mutation Requiring TIPS Placement

Purpose: The JAK2V617F mutation is strongly implicated in the pathogenesis of myeloproliferative disorders (MPD) which account for at least 50% of cases of Budd-Chiari Syndrome (BCS). MPD is a common cause of splanchnic vein thrombosis in young women. Patients with BCS and underlying JAK2 mutation have severe hepatic outflow obstruction with worse Child-Pugh scores, and often require decompressive procedures such as transjugular intrahepatic portosystemic shunts (TIPS) placement or liver transplantation compared to those without the mutation. A 19 year old Caucasian woman with chronic abdominal pain, nausea and vomiting was found to have splenic vein thrombus on ultrasound. An initial hypercoagulable workup was negative. She was instructed to discontinue her oral contraceptives and started on anticoagulation with warfarin. Imaging studies two months later showed resolution of the thrombus. She was noncompliant with her anticoagulation and presented six months later with similar symptoms. A repeat ultrasound of the abdomen showed thrombosis of two of her hepatic veins, right portal vein and splenic vein. She was immediately restarted on anticoagulation. She was noted to have a mildly elevated ALT in the 50-60 range but her other liver function tests remained normal. She also had a normal CBC except for mild anemia and a normal INR. Further workup revealed a positive JAK2 mutation. She was admitted one month later with worsening abdominal pain, new large ascites and occlusion of all three hepatic veins despite anticoagulation. She was diagnosed with acute BCS. Hepatic venography demonstrated “spider web” collaterals of the right and left hepatic veins consistent with BCS. She underwent a large volume paracentesis and successful TIPS placement with decrease in her hepatic venous pressure gradient from 27 to 5 mm Hg. Liver biopsy showed evidence of moderate to severe sinusoidal dilation in zone 3 consistent with BCS. She recovered well with resolution of her ascites and abdominal pain. She was discharged home with the anticipation of lifelong anticoagulation. Patients with newly diagnosed BCS should be routinely screened for JAK2 mutations. Unlike the majority of patients with MPD, this subgroup of patients have normal hemoglobin levels, platelet counts and erythropoietin levels making diagnosis difficult with laboratory values alone. These patients present with severe hepatic outflow obstruction which portends a worse clinical outcome, and thus should be aggressively intervened upon at time of presentation to ensure long-term survival.

Intrinsic Coagulation Activation and the Risk of Arterial Thrombosis in Young Women

Background— Classically, intrinsic coagulation proteins are thought to have a minor role in hemostasis. Recently, these proteins, especially FXII, were implicated as possible key players in the pathogenesis of arterial thrombosis. This study aims to determine the risks of arterial thrombosis conferred by increased activation of intrinsic coagulation proteins in young women and the effect of oral contraceptive use on this association. Methods and Results— The Risk of Arterial Thrombosis In relation to Oral contraceptives (RATIO) study is a population-based case-control study including young women (age 18 to 50 years) with myocardial infarction (n=205) and ischemic stroke (n=175) and 638 healthy controls. Intrinsic coagulation protein activation was determined by measuring activated protein-inhibitor complexes. This complex is with C1 esterase inhibitor (FXIIa-C1-INH, FXIa-C1-INH, Kallikrein-C1-INH) or antitrypsin inhibitor (FXIa-AT-INH). Odds ratios (ORs) and corresponding confidence intervals (95% CIs) were calculated with logistic regression. High levels of protein activation (&gt;90th percentile of controls) showed an increased risk of ischemic stroke: FXIIa-C1-INH (OR, 2.1; 95% CI, 1.3 to 3.5), FXIa-C1-INH (OR, 2.8; 95% CI, 1.6 to 4.7), FXIa-AT-INH (OR, 2.3; 95% CI, 1.4 to 4.0), and Kallikrein-C1 (OR, 4.3; 95% CI, 2.6 to 7.2). If anything, myocardial infarction risk was only increased by Kallikrein-C1-INH (OR, 1.5; 95% CI, 0.9 to 2.5). Oral contraceptive use further increased the risks. Conclusions— High levels of activated proteins of the intrinsic coagulation system are associated with arterial thrombosis, whereas the strength of these associations differs for myocardial infarction and ischemic stroke. This contradicts similar analyses among men in the Northwick Park Heart Study. Together with the finding that oral contraceptive use further increases the risks, the question of whether the role of intrinsic coagulation proteins in the pathogenesis of arterial thrombosis is sex-specific is raised.

Aortic thrombosis in young women with Crohnʼs disease receiving adalimumab: Report of two cases

Aortic thrombosis in young women with Crohnʼs disease receiving adalimumab: Report of two cases

Inherited thrombophilia in infertile women: implication in unexplained infertility

Many studies evaluating a possible relationship between inherited thrombophilia and the etiology of unexplained infertility have been performed recently. No significant difference in the prevalence of three genetic mutations associated with the increased risk of thrombophilia (Factor V Leiden G1691A, prothrombin G20210A, and methylenetetrahydrofolate reductase [MTHFR] C677 T) was found in 100 infertile women with unexplained infertility when compared with 200 control fertile women without an infertility history.

Cerebral venous sinus thrombosis associated with oral contraceptives: the case for neurosurgery

The goal of this study was to provide data about neurosurgical management of cerebral venous sinus thrombosis in young women after use of oral contraceptives. Between 1990 and 2007, the authors treated 15 women (age range 23-45 years) in whom neurosurgical management was used for overt thrombosis of cerebral sinus. All were healthy, with a history of use of oral contraceptives. Severe headache was the most common symptom, followed by motor focal deficits and comatose state. Deep infarcts were located in the thalamic and basal ganglia region in 11 cases. Seven women had associated intracerebral hemorrhage, and 3 had ventricular dilation. Angiographic MR imaging was done in 10 patients, and conventional angiography was done in 7. Genetic analysis of chromosomal abnormalities associated with stroke was done in 5 cases. The intracranial pressure (ICP) was monitored in all cases. Three patients underwent external ventricular drainage, and 1 had a decompressive craniotomy. All had absence of signal in the cerebral sinus rectus, with associated thrombosis of the transverse sinus in 7 cases. Angiograms were negative for additional vascular malformation. Medical treatment included sodium heparin and mannitol in 9 cases, and enoxaparin in the other 6 patients. Genetic analysis was positive for prothrombin mutation G20210A (factor II variant) in 2 cases. The mean follow-up duration of 53 months demonstrated no neurological deficit in 10 patients, hemiparesis in 3, and severe hemiparesis with aphasia in 1 case. One woman died 5 days after a decompressive craniotomy. Cerebral venous sinus thrombosis secondary to oral contraception in young women, including lesions in critical and deep regions, can be treated medically with acceptable morbidity. In spite of this, a subgroup of patients needed basic neurosurgical management of the lesions, including surgical measures for controlling raised ICP.

Infarctus du myocarde et contraceptifs oraux

Shortly after the introduction of oral contraceptives in 1960, myocardial infarction (MI) started to emerge as a major adverse effect. Its mechanism and pathophysiology have remained elusive. Many epidemiological studies identified smoking, hypertension, diabetes and hypercholesterolemia as risk factors for coronary thrombosis in young women using oral contraceptives. The pathogenesis of MI involves two phases: atherosclerotic plaque formation, and thrombotic arterial occlusion. The use of very low doses of estrogen (less than 50 microg of ethinyl estradiol) and new progestagens have minimized the vascular risks. However, the risk remains in women who smoke or have other atherosclerotic risks factors. We report 12 cases of MI in women aged 35 +/- 5 years who were using different types of oral contraceptive. All the women had several risks factors, such as smoking, hypertension, hypercholesterolemia, obesity, and type II diabetes. Coronarography during the acute phase showed either occlusions on severe atherosclerotic stenoses or thrombosis of arteries with non significant atherosclerotic plaque. In two cases coronarography was normal after thrombolysis. Ten women recovered without sequelae, but reversible left ventricular dysfunction occurred in the other two women, who did not have acute-phase revascularization. Recent case-control studies show that the cardiovascular risk is very low with new, third-generation combined contraceptives. But the risk of MI increases with age, smoking, hypertension, dyslipidemia and diabetes. The absolute risks associated with oral contraceptives and smoking are higher in women over 35, because of the steeply rising incidence of atherosclerosis. It is mandatory to respect the classical contraindications of oral contraception.

Arterial thrombosis in young women after ovarian stimulation: case report and review of the literature

Both venous and arterial thrombosis have been described in women after ovarian stimulation and/or hyperstimulation for infertility management. The ratio between venous and arterial thrombosis in this condition is about 2 or 3 to 1, contrary to what seen during pregnancy or oral contraception where it is 5 or 10 to 1. An accurate perusal of the literature and of personal files has yielded 34 cases of arterial thrombosis after assisted reproductive technologies (ART) which entailed ovarian stimulation. There were 15 cases of ischemic strokes; 7 cases of carotid and/or vertebral artery occlusion; 6 of aorta and peripheral vessel thrombosis, 2 of mesenteric artery occlusion, 3 with myocardial infarction and 2 with intracardiac thrombosis. Associated risk factors were as follow: smoking in 4 women; antiphospholipid antibodies in 2; decrease in protein S in 1. Furthermore, polycystic ovaries were present in two women. Ovarian hyperstimulation was obtained with several protocols which included human chorionic gonadotropin (HCG) in all but a few instances. Age of women varied between 22 and 41 with an average of 32. Nineteen women were pregnant at the time of thrombosis. Only seven of these 19 pregnancies were brought to term with fetal survival. Abortion was spontaneous in 5 cases and therapeutic in the additional 7. There were two maternal fatalities.

Heterogeneous ethnic distribution of the factor v leiden mutation

Inherited resistance to activated protein C caused by the factor V Leiden (FVL) mutation is the most common genetic cause of venous thrombosis yet described, being found in 20-60% of patients with venous thrombophilia. A relationship between the FVL mutation and an increased predisposition to arterial thrombosis in young women was recently reported. We assessed the prevalence of the FVL mutation in 440 individuals (880 chromosomes) belonging to four different ethnic groups: Caucasians, African Blacks, Asians and Amerindians. PCR amplification followed by MnlI digestion was employed to define the genotype. The FVL mutation was found in a heterozygous state in four out of 152 Whites (2.6%), one out of 151 Amerindians (0.6%), and was absent among 97 African Blacks and 40 Asians. Our results confirm that FVL has a heterogeneous distribution in different human populations, a fact that may contribute to geographic and ethnic differences in the prevalence of thrombotic diseases. In addition, these data may be helpful in decisions regarding the usefulness of screening for the FVL mutation in subjects at risk for thrombosis.

Increased Risk of Venous Thrombosis in Oral-Contraceptive Users Who Are Carriers of Factor V Leiden Mutation

We investigated whether the occurrence of venous thrombosis in young women who use oral contraceptives might be explained by the factor V Leiden mutation, which leads to resistance to activated protein C and enhances susceptibility to thrombosis. We compared 155 consecutive premenopausal women, aged 15 to 49, who had developed deep venous thrombosis in the absence of other underlying diseases, with 169 population controls. The risk of thrombosis among users of oral contraceptives was increased 4-fold (relative risk 3.8 [95% CI 2.4-6.0]). The risk of thrombosis among carriers of the mutation compared with non-carriers was increased 8-fold (7.9 [3.2-19.4]). Compared with women who did not use oral contraceptives and were not carriers of the mutation, the risk of thrombosis among those with both risk factors was increased more than 30-fold (34.7 [7.8-154]). Recalculation of population incidences from these relative risks shows that the absolute risk of venous thrombosis in young women who use oral contraceptives is much larger when they carry the factor V Leiden mutation. When a young woman develops thrombosis, her factor V Leiden status should be considered in counselling about her future method of contraception.

Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation

SummaryWe investigated whether the occurrence of venous thrombosis in young women who use oral contraceptives might be explained by the factor V Leiden mutation, which leads to resistance to activated protein C and enhances susceptibility to thrombosis.We compared 155 consecutive premenopausal women, aged 15 to 49, who had developed deep venous thrombosis in the absence of other underlying diseases, with 169 population controls. The risk of thrombosis among users of oral contraceptives was increased 4-fold (relative risk 3·8 [95% Cl 2·4-6·0]). The risk of thrombosis among carriers of the mutation compared with non-carriers was increased 8-fold (7·9 [3·2-19·4]). Compared with women who did not use oral contraceptives and were not carriers of the mutation, the risk of thrombosis among those with both risk factors was increased more than 30-fold (34·7 [7·8-154]).Recalculation of population incidences from these relative risks shows that the absolute risk of venous thrombosis in young women who use oral contraceptives is much larger when they carry the factor V Leiden mutation. When a young woman develops thrombosis, her factor V Leiden status should be considered in counselling about her future method of contraception.

Primary myeloproliferative disorder and hepatic vein thrombosis. A prospective study of erythroid colony formation in vitro in 20 patients with Budd-Chiari syndrome.

We assessed the prevalence of overt and latent primary myeloproliferative disorders in hepatic vein thrombosis. Cultures of bone marrow or peripheral blood mononuclear cells were done in 20 patients with Budd-Chiari syndrome. Erythroid colony formation in the absence of erythropoietin, which is a reliable indicator for a primary myeloproliferative disorder, was seen in 16 patients in whom Budd-Chiari syndrome was due to hepatic vein thrombosis, including 13 women aged 18 to 45 years. Among these 16 patients, the conventional criteria for the diagnosis of a primary myeloproliferative disorder were met in only 2. Primary myeloproliferative disorder, often without peripheral blood changes, is a major cause of hepatic vein thrombosis in young women.

Intracranial venous thrombosis in young women.

Twenty women of child-bearing age with intracranial venous thrombosis are reported. Thirteen developed thrombosis post-partum; 6 while on oral contraceptives. In one patient no cause was found. All diagnoses were confirmed by carotid angiography and in 10 out of 14 patients laboratory data indicated a hypercoagulable state. Coagulation studies were performed in 14 normal puerperal women, matched by age, who served as controls. No statistical differences was found between thrombotic and control groups. Radiologic signs of sino-venous occlusion are reviewed. Conservative treatment with anti-edematous agents, anticonvulsants and antiplatelet aggregants is advocated.

Coronary thrombosis in young women on oral contraceptives: Report of two cases and review of the literature

Two young, menstruating women—aged 29 and 38—with acute myocardial infarctions are presented. Case No. 1 (M. Z.) had an abnormal glucose tolerance test; however, Case No. 2 (L. J.) was free of any of the major risk factors. Both patients were taking oral contraceptives at the time of their acute myocardial infarctions. In one case (M. Z.), selective coronary angiography revealed segmental occlusion of the left anterior descending artery. In the second case (L. J.), there was minimal irregularity at the proximal left anterior descending artery. The literature has been reviewed and mechanisms by which oral contraceptives might precipitate thrombosis have been discussed. Although such occurrences are rare, there is a high index of suspicion that synthetic estrogen therapy and coronary thrombosis are related. It is suggested that in young females presenting with chest pain who are on oral contraceptives, coronary artery disease should be suspected even though these women are still menstruating and are free of major risk factors.