Prevention and management of venous thromboembolism in pregnancy: cutting through the practice variation

There is clinical practice variation in the area of prevention and management of venous thromboembolism (VTE) in pregnancy. There are limited data and differing recommendations across major clinical practice guidelines, especially relating to the role of postpartum low-molecular-weight heparin (LMWH) for patients with mild inherited thrombophilia and those with pregnancy-related VTE risk factors. This chapter explores the issues of practice variation and related data for postpartum VTE prevention. Controversial topics of VTE management in pregnancy are also reviewed and include LMWH dosing and the role of anti-Xa level monitoring, as well as peripartum anticoagulation management around labor and delivery.

Acquired and Inherited Thrombophilia Testing in Patients with Chronic Thromboembolic Pulmonary Hypertension: Value of Testing in an Academic Health Center

Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is classed as group 4 in the present classification of pulmonary hypertension. The pathophysiology of CTEPH is complex, mainly is a consequence of prior acute pulmonary embolism with failure of thrombi to resolve and the recent recognition of added small vessel changes which impacts long-term outcomes even after surgical management. The role of thrombophilia testing in this condition has been debated. Hence, we here analyzed the utility of thrombophilia testing in CTEPH from a center in a developing country. Methods This is a single institution (Narayana Health City, Bangalore); retrospective study including patients ≥ 18 years of age who underwent thrombophilia workup in a diagnosis of CTEPH from January 2019 till July 2021. Tests done to evaluate thrombophilia included factor V Leiden; prothrombin F20210A mutation; MTHFR gene mutation; Protein C, S, and antithrombin deficiency; lupus anticoagulant, anti-beta2 glycoprotein I (IgM and IgG) and anticardiolipin antibody (IgM and IgG); hyperhomocysteinemia and anti-nuclear antibody testing (ANA-IF). The study was approved by the ethics committee of the institute and was carried out in accordance with the principles of the declaration of Helsinki. Results and discussion The study included 56 patients with a median age of 37 years (range 23-50), and 36 (64%) were males. Patients with recurrent venous thrombosis included 37 (66%), with the majority having thrombosis at 2 sites (53%; 22 patients with associated deep vein thrombosis). A family history of thrombosis was present in 4 patients. The majority of patients received vitamin K antagonists (76%), with the rest receiving direct oral anticoagulants (DOAC). Among the tests sent for acquired thrombophilia, ANA-IF and antiphospholipid antibody (APLA) were most frequently evaluated (94%). ANA-IF and APLA tests were positive in 5.6% and 30.1%, respectively. Among the APLA tests, Anti-beta2 glycoprotein I (IgM or IgG) was the most commonly detected antibody (13/46), followed by anticardiolipin antibody (IgG or IgM) (9/43) and lupus anticoagulant (7/40). Double and triple positive APLA were present in 3 and 4 patients, respectively. Homocysteine levels were high in 93.7% though only 16 patients were tested in this cohort. Among the tests for inherited thrombophilia, genetic tests (factor V Leiden, prothrombin F20210A mutation, and MTHFR gene mutation) were tested in only ~50%. Twenty-three percent were positive for heterozygous MTHFR followed by MTHFR compound heterozygous (10%) and heterozygous factor V Leiden heterozygous (10%). Antithrombin III, protein C, and S were tested in ~30% of patients. Antithrombin III was low in only 1 patient, with protein C and S assays being normal in all the patients. The cost analysis was calculated, showed a median of $364 (₹ 27,055) was spent per person on thrombophilia workup. The median cost incurred per patient for inherited thrombophilia workup was $232 (₹ 17,300) and for acquired thrombophilia was $132 (₹ 9814), respectively. Conclusion This single-institution study on thrombophilia workup in CTEPH patients reveals that APLA was the most commonly performed test with high positivity rates of 30.1%. Among the inherited thrombophilia, the positivity rate of MTHFR mutation was highest (33.3%), with other tests having a low positivity rate (0-10%). Hence, we would recommend APLA testing in all patients with CTEPH considering its high positivity and clinical utility. Testing for other thrombophilias should be pursued judiciously especially in economically restrictive settings. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

High Mortality and Risk of Severe Sepsis in in-Hospital Cardiac Arrest Patients with Antithrombin Deficiency: Analysis of National Inpatient Sample Database

Background: Previous studies found the association between hereditary thrombophilia (HT) and increased risk of inpatient arterial thromboembolism, such as myocardial infarction and ischemic stroke. Nevertheless, the outcomes of hospitalized HT patients with cardiac arrest remains unclear. We aim to investigate the outcomes of inherited thrombophilia after in-hospital cardiac arrest (IHCA). Methods: This is a retrospective analysis of National Inpatient Sample database with 2016-2018 data years. We included adult (age above 18 years old) who had IHCA. IHCA, various types of HT (Factor V Leiden/activated protein C resistance, prothrombin mutation, deficiencies of antithrombin [AT] III, protein C or S deficiencies, other inherited thrombophilia), and other comorbidities were identified with International Classification of Diseases, 10th Revision, Clinical Modification Procedure Codes and Diagnosis Codes. Charlson Comorbidity Index (CCI) was used to adjust for comorbidities. Age distribution was analyzed with unpaired two-samples t-test. Gender and racial group distribution were compared with Chi-square test. Primary outcome was mortality. All independent factors associated with IHCA in inherited thrombophilia were determined by weighted multivariable logistic regression. SAS and R were used for statistical analysis. Results: Among 67,351 adult patients with IHCA, 620 patients had at least one diagnosis of HT (Factor V Leiden: 86; antithrombin III deficiency: 235; protein C/S deficiencies: 301; prothrombin gene mutation: 6; 5 cases have both factor V Leiden and protein C/S deficiencies; 3 cases have both antithrombin III and protein C/S deficiencies). Patients with HT were significant younger (mean age: 60.6 vs 65.9, p value < 0.0001) with fewer comorbidities (mean CCI: 5.32 vs 5.81, p value <0.0005). There was no significant difference in gender and racial groups distribution. HT was not associated with risk of mortality after IHCA (adjusted odds ratio (aOR): 0.98, Confidence interval (CI): 0.82 - 1.16, p value = 0.75). Nevertheless, subgroup analysis with different types of HT revealed increased mortality in AT III deficiency group (aOR: 1.40, CI: 1.02 - 1.91 p value < 0.05). On the contrary, factor V Leiden and protein C/S deficiencies had a weak association of lower mortality (aOR: 0.70, p value < 0.1; aOR: 0.80, p value = 0.06). AT III deficiency was also associated with higher risk of developing severe sepsis (aOR: 1.56, p < 0.005). Myocardial infarction, ischemic stroke, pulmonary embolism, and deep venous thrombosis were not significantly associated with HT after adjusted for other potential confounders. Conclusion: HT patients who developed IHCA were younger with fewer underlying comorbidities. Only AT III deficiency subgroup was associated with higher odds of mortality and severe sepsis. Factor V Leiden and protein C/S deficiencies had a tendency of favorable outcomes. The unfavorable outcome of AT III deficiency subgroup couldn't be attributed to either arterial or venous thromboembolism. Disclosures No relevant conflicts of interest to declare.

Heritable Thrombophilia in Venous Thromboembolism in Northern Pakistan: A Cross-Sectional Study

Background. Venous thromboembolism (VTE) is referred to as formation of clots in a deep vein or lodging of thrombus towards the lungs which could be fatal yet preventable. The risk of developing VTE can be increased by various factors. Where there are innumerable acquired causes, the possibility of inherited thrombophilia cannot be ignored. In view of this, we have evaluated all patients with venous thromboembolism for inherited thrombophilia. Objective. To evaluate the frequencies of antithrombin (AT) deficiency, protein C and S deficiencies, Factor V Leiden, and prothrombin gene mutations in patients harboring venous thromboembolism. Materials and Methods. A study comprising of 880 patients who were presented with manifestations of venous thromboembolism was conducted from July 2016 to June 2017. A blood sample collected from patients was screened for thrombophilia defects encompassing AT, protein C and S deficiencies, Factor V Leiden, and prothrombin gene mutations. All acquired causes of thrombosis were excluded. Results. Of 880 patients who underwent screening for thrombophilia, 182 patients demonstrated VTE history. Their age ranged from 1 to 58 years. Males constituted a predominant group. About 45 (24.7%) patients had evidence of heritable thrombophilia. Of these, 20 (10.9%) had AT deficiency, 9 (4.9%) had Factor V Leiden mutation, 6 (3.2%) had protein C deficiency, whereas protein S deficiency and prothrombin gene mutation both were found in 5 (2.7%) patients. Conclusion. Our study illustrated the highest frequency of antithrombin deficiency among other investigated thrombophilia defects.

Impact of thrombophilia and waist circumference on the risk of venousthromboembolism

Background Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE) represents a major health problem. In the general population, the absolute risk of any kind of VTE is 0.1%–0.2% per year, and it increases with age. VTE is an important and preventable cause of morbidity and mortality, with almost a third of survivors experiencing long term effects. Obesity is well-known risk factor of VTE. The extent of the effects of obesity on VTE depends not only on total body fat, but also on the distribution of adipose tissue (e.g., central obesity) and the interplay among risk factors for VTE, such as genetic mutations, and other risk factors. Thrombophilia, venous thromboembolism, obesity, waist circumference Purpose The aim of this study is to investigate the impact of waist circumference on the risk of venous thromboembolism Methodology The study involved 68 patients with VTE (33 females and 34 males, mean age 56.8 years ±15.3) and 84 patients without VTE (38 males and 46 females, 44.4 years±18.6). From 2015 to 2017, data have been collected from records of patients admitted to department of internal medicine. All subjects were recruited to the study during their stay in the hospital. The reasons for hospitalization were: acute event of DVT or PE for the main group, the absence of acute event or history of VTE for the control group. DVT was diagnosed by ultrasonic Doppler examination, and PE was confirmed by intravenous radiocontrast computed tomography. Anthropometric measures were performed with subjects wearing short-sleeved garments and no shoes; waist circumference was measured in centimeters at the umbilical line. For all patients genetic testing for inherited thrombophilia – Factor V Leiden G1691A, Prothrombin G20210A, MTHFR C677T polymorphism, PAI-1 (SERPIN1) 4G/5G polymorphism – was performed by real-time PCR technique. Results Factor V Leiden G1691A increase the risk of VTE in 2.11 (CI: 1.79–2.48), p=0.049, prothrombin G20210A in 3.21 (CI: 1.66–6.211), p=0.049. MTHFR C677T polymorphism, PAI-1 (SERPIN1) 4G/5G polymorphism also increase the risk of VTE, but it was no significant. Study have shown that waist circumference >80 cm increase the risk of VTE in 3.19 (CI: 1.35–7.58), p=0.019. Combination of inherited thrombophilia (Factor V Leiden G1691A, Prothrombin G20210A, MTHFR C677T polymorphism, PAI-1 (SERPIN1) 4G/5G polymorphism) and waist circumference >80 cm increase the risk of VTE in 3.51 (CI: 1.76–7.04), p<0.001. Conclusion Previous results of our work indicate influence of waist circumference >80 cm on the risk of VTE, especially risk of thrombosis is higher in patients with combination inherited thrombophilia and waist circumference >80 cm. FUNDunding Acknowledgement Type of funding sources: None.

Midbrain infarction in inherited protein S deficiency: a rare association

Inherited thrombophilic disorders are well‐established predisposing factors for venous thromboembolism, but their role in arterial ischaemic stroke is uncertain. The exact mechanism of arterial thrombosis in thrombophilias remains elusive. Herein, we report a case of a 30-year-old woman who was admitted to our facility with sudden-onset right-sided ptosis and ophthalmoplegia. Detailed clinical features, neuroimaging and laboratory evaluation clinched the diagnosis of ischaemic stroke in midbrain due to microvascular obstruction associated with isolated protein S deficiency. She was treated with oral anticoagulant (warfarin) and physiotherapy; without any improvement of her symptoms at 2 months of follow-up. A high index of clinical suspicion is needed in any case of young ischaemic stroke in absence of common cardiac and vascular risk factors, to recognise the presence of inherited thrombophilia.