VTE in OBGYN practice DR ANBU SUBBIAN DGO, DNB, MRCOG, Fellowship in Gyne Oncology CONSULTANT GYNECOLOGIST/GYNE ONCOLOGIST BANGALORE

Aim of this session - Prevention of VTE in pregnancy – Risk assessment and prophylaxis Diagnosis and treatment of VTE in pregnancy Management of women on LMWH in labour Prevention of VTE in gynaecology patients

Incidence in pregnancy – 4 fold increase . 40% of women develop an acquired resistance to activated protein C Reduction in the concentration of protein S, a cofactor required for functioning of activated Protein C Increase in coagulation factors I, VII, VIII, X and XII and vWF Increased circulating concentrations of plasminogen activator inhibitor type 1 (PAI-1), produced in the endothelium and the liver. Reduced fibrinolysis is by the secretion of plasminogen activator inhibitor type 2 (PAI-2) by the placenta Venous stasis in the pelvis is partly due to the enlarging uterus impeding blood flow and the reduced venous return from the lower limbs Changes in the coagulation system begin with conception and do not return to baseline until more than eight weeks postpartum

Risk factors for VTE - Preexisting Previous VTE (except a single event related to major surgery) 4 Previous VTE provoked by major surgery 3 Known high-risk thrombophilia Medical comorbidities e.g. cancer, heart failure; active systemic lupus erythematosus, inflammatory polyarthropathy or inflammatory bowel disease; nephrotic syndrome; type I diabetes mellitus with nephropathy; sickle cell disease; current intravenous drug user Family history of unprovoked or estrogen-related VTE in first-degree relative 1 Known low-risk thrombophilia (no VTE) Age (> 35 years) Obesity 1 or 2 Parity ≥ 3 Smoker Gross varicose veins RCOG Green-top Guideline No. 37a

Transient risk factors Obstetric risk factors Pre-eclampsia in current pregnancy 1 ART/IVF (antenatal only) Multiple pregnancy Caesarean section in labour 2 Elective caesarean section Mid-cavity or rotational operative delivery Prolonged labour (> 24 hours) PPH (> 1 litre or transfusion) Preterm birth < 37+0 weeks in current pregnancy Stillbirth in current pregnancy Transient risk factors Any surgical procedure in pregnancy or puerperium except immediate repair of the perineum, e.g. appendicectomy, postpartum sterilisation 3 Hyperemesis OHSS (first trimester only) 4 Current systemic infection 1 Immobility, dehydration

Risk assessment Pre pregnancy or early pregnancy Admitted to hospital or develops intercurrent problems Labour and immediate post partum

Thrombophilias Heritable Acquired Antithrombin deficiency Protein C deficiency Protein S deficiency Factor V Leiden Prothrombin gene mutation Acquired Antiphospholipid antibodies Persistent lupus anticoagulant and/or persistent moderate/high titre anticardiolipin antibodies and/or β2-glycoprotein 1 antibodies No evidence for universal screening Selective screening in women with a personal or family history of thrombosis (if known antithrombin deficiency or unknown) or a history of poor pregnancy outcome (for APS) (Around 50% of such women will have a thrombophilia) The Obstetrician & Gynaecologist 2006;8:215–221

Antepartum thromboprophylaxis May be on oral anticoagulants - warfarin Need to be switched over to LMWH prior to pregnancy ( preferably) Very High risk group Antithrombin deficiency APS associated with VTE Prev VTE with long term anticoagulation Thromboprophylaxis with higher dose LMWH (either 50%, 75% or full treatment dose) Started antenatally and for 6 weeks postpartum Require specialist management by experts

Asymptomatic thrombophilias Heterozygosity for factor V Leiden or prothrombin gene mutation or antiphospholipid antibodies + three other risk factors - antenatal thromboprophylaxis, + two other risk factors thromboprophylaxis - prophylaxis from 28 weeks + one other risk factor postnatal thromboprophylaxis for 10 days Asymptomatic Antithrombin deficiency, Protein C or S deficiency, combination of defects Antenatal + post natal 6 weeks prophylaxis

Intermediate risk

INTERMEDIATE RISK If total score ≥ 4 antenatally, consider thromboprophylaxis from the first trimester. • If total score 3 antenatally, consider thromboprophylaxis from 28 weeks. • If total score ≥ 2 postnatally, consider thromboprophylaxis for at least 10 days. • If admitted to hospital antenatally consider thromboprophylaxis. • If prolonged admission (≥ 3 days) or readmission to hospital within the puerperium consider thromboprophylaxis.

LMW Heparin Antenatal and postnatal prophylactic dose Weight < 50 kg = 20 mg enoxaparin/2500 units dalteparin/3500 units tinzaparin daily Weight 50–90 kg = 40 mg enoxaparin/5000 units dalteparin/4500 units tinzaparin daily Weight 91–130 kg = 60 mg enoxaparin/7500 units dalteparin/7000 units tinzaparin daily Weight 131–170 kg = 80 mg enoxaparin/10 000 units dalteparin/9000 units tinzaparin daily Weight > 170 kg = 0.6 mg/kg/day enoxaparin/ 75 u/kg/day dalteparin/ 75 u/kg/day tinzaparin

Adjuvant measures Ambulation Adequate hydration GCS are specialized hosiery that provide graduated pressure on the lower legs and feet to help prevent thrombosis. Tightest at the ankles and gradually become less constrictive towards the knees and thighs. Little evidence supporting the efficacy in the prevention of VTE. May be used in women who undergo elective CS / long travel > 4 hours Ambulation Adequate hydration Graduated compression stockings

Aim of this session - Prevention of VTE in pregnancy – Risk assessment and prophylaxis Diagnosis and treatment of VTE in pregnancy Management of women on LMWH in labour Prevention of VTE in gynaecology patients

DVT in pregnancy Occurs with equal frequency in each trimester and postpartum Diagnosing is difficult during pregnancy. Clinical suspicion confirmed in 10 percent of pregnant women, compared with 25 percent of nonpregnantpatients. Typical symptoms are unilateral leg pain and swelling Left leg Iliofemoral Pregnant 78 to 90% 72% Nonpregnant 55% 9% Initial management Leg elevation Graduated elastic compression stocking to reduce oedema Mobilisation with graduated elastic compression stockings should be encouraged. www.aafp.org/afp Volume 77, Number 12 ◆June 15, 2008

Diagnosis of VTE / PE Acute PE ECG/ CHEST X Ray Compression duplex ultrasound (if DVT suspected) Spiral CTPA Vs V/Q scan

CT PA V/Q scan

Treatment of DVT/ PE LMWH is the treatment of choice Safety and efficacy is proven Dosage is based on booking pregnancy weight Routine platelet / aPTT/ PT/ INR / Factor Xa follow up monitoring not required Continued throughout pregnancy and 6 weeks post partum ( or atleast 3 months of total therapy) Full blood count, coagulation screen, urea and electrolytes, liver function tests. Thrombophilia screen prior to therapy not recommended

Unfractionated heparin Used in VTE close to term Post operative patients with risk of haemorrhage Massive PE with cardiovascular collapse Loading dose of 80 units/kg, followed by a continuous iv infusion of 18 units/kg/hour Mandatory to measure activated partial thromboplastin time (APTT) level 4–6 hours after the loading dose, 6 hours after any dose change and then at least daily Therapeutic target APTT ratio is usually 1.5– 2.5 times the average laboratory control value Platelet counts every 2-3 days

Additional therapies Leg elevation Thrombolytic therapy Graduated compression stockings IVC filters – recurrent PE with massive DVT Thrombolytic therapy Reserved for patients with severe pulmonary thromboembolism with haemodynamic compromise Massive iliofemoral thrombosis with limb/life threatening complications

Management in labour First of all, “ Do not inject if in labour” Prophylactic LMWheparin In planned delivery, discontinue 12 hours prior NO regional anaesthetic or analgesic until at least 12 hours after the last dose No LMWH for 4 hours after the use of spinal anaesthesia or after the epidural catheter has been removed Epidural catheter should not be removed within 12 hours of the most recent injection Therapeutic LMWheparin In planned delivery, discontinue 24 hours prior NO regional anaesthetic or analgesic until at least 24 hours after the last dose No LMWH for 4 hours after the use of spinal anaesthesia or after the epidural catheter has been removed Epidural catheter should not be removed within 12 hours of the most recent injection.

Post natal management Continued for at least 6 weeks postnatally and until at least 3 months of treatment has been given in total. Before discontinuing treatment the continuing risk of thrombosis should be assessed. May be switched over to oral anticoagulant for postnatal therapy Postpartum warfarin should be avoided until at least the fifth day and for longer in women at increased risk of postpartum haemorrhage. Heparin (unfractionated or LMWH) and warfarin NOT contraindicated in breastfeeding. LMWH (more than 12 weeks) is associated with a significantly lower chance of developing post-thrombotic syndrome.

Aim of this session - Prevention of VTE in pregnancy – Risk assessment and prophylaxis Diagnosis and treatment of VTE in pregnancy Management of women on LMWH in labour Prevention of VTE in gynaecology patients

VTE in gynecologic surgery The diagnosis of DVT is approximately 3% when diagnosed clinically, and fatal PE occur in 0.2–0.9% of patients.1 Death from a PE occurs rapidly, with most patients succumbing within 30 minutes of the first clinical symptoms. By I125 fibrinogen leg scanning, about 14% of patients having surgery for benign indications develop thromboembolism compared to 38% of gynecologic oncology patients.

Risk Classification for VTE in Pre op patients Level of Risk Low Surgery lasting <30 minutes in patients younger than 40 years with no additional risk factors Moderate Surgery lasting <30 minutes in patients with additional risk factors; Surgery lasting <30 minutes in patients aged 40 to 60 years with no additional risk factors; Major surgery in patients younger than 40 years with no additional risk factors High Surgery <30 minutes in patients older than 60 years or with additional risk factors Major surgery in patients older than 40 years or with additional risk factors Highest Major surgery in patients older than 60 years plus prior venous thromboembolism, cancer, or hypercoagulable state Modified from Geerts WH et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(suppl):338S–400S.

Venous Thromboembolism Risk Factors Surgery Trauma (major or lower extremity) Immobility, paresis Malignancy Cancer therapy (hormonal, chemotherapy, or radiotherapy) Previous venous thromboembolism Increasing age Pregnancy and the postpartum period Estrogen-containing oral contraception or hormone therapy or SERMSs Acute medical illness Heart or respiratory failure Inflammatory bowel disease Myeloproliferative disorders Paroxysmal nocturnal hemoglobinuria Nephrotic syndrome Obesity Smoking Varicose veins Central venous catheterization Inherited or acquired thrombophilia

Highest risk Alternatives for prophylaxis for highest-risk patients include the following: Combination prophylaxis (such as the combination of pneumatic compression and either low dose unfractionated heparin or low molecular weight heparin) Consideration of continuing low molecular weight heparin prophylaxis as an outpatient for up to 28 days postoperatively If administration of low molecular weight heparin 12 hours before surgery is impractical, initial dosing should commence 6 to 12 hours postoperatively. From NGC-5947

High risk patients Moderate risk patients Pneumatic compression devices placed before surgery and continued until hospital discharge Unfractionated heparin (5,000 units) administered subcutaneously 2 hours before surgery and every 8 hours postoperatively and continued until discharge LMWH (dalteparin 5,000 units or enoxaparin 40 mg) subcutaneously, 12 hours before surgery / once daily postoperatively until discharge Pneumatic compression devices or GCS placed before initiation of surgery and continued until the patient is fully ambulatory Unfractionated heparin (5,000 units) subcutaneously 2 hours before surgery and every 12 hours after surgery until discharge LMWH(dalteparin, 2,500 units, or enoxaparin, 40 mg) subcutaneously, 12 hours before surgery / once a day postoperatively until discharge

Low-risk patients - No specific prophylaxis other than early ambulation. Laparoscopic surgery should be stratified by risk category (and provided prophylaxis) similar to patients undergoing laparotomy

Agnelli G et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project. Ann Surg. 2006 Jan;243(1):89-95. 2000 patients with cancer undergoing surgery 80% of patients received in-hospital prophylaxis 2% rate of clinical VTE Total mortality was 1.72% within 35 days of surgery Despite prophylaxis, 46% of the deaths were caused by VTE.  It is important to identify and treat high-risk patients, as consistent, systematic thromboprophylaxis will help to decrease the risk of a potentially fatal VTE