Thromboembolism PanelDr HommamDr JalilianDr MoosaviDr TorkestaniDr Vafaei

Significance of VTEHighest risk during pregnancy and peurperiumIncidence : 1/10000 ( nonpregnant) …….1/1600 (

pregnant) 6 - 22 XAntepartum = postpartumDVT …..Antepartum ( 74%)PE………Postpartum (60.5%)Cesarean section : 30.3 RR for PE50% due to thrombophiliaResponsible for 20% of pregnancy- related

deaths

Aims of this panelOral presentation Who needs thromboprophylaxy?Who needs screening for thrombophilia?Review of guideline for thromboprophylaxyThromboprophylaxy in cases with previous

history of VTEThromboprophylaxy in cases with

thrombophilia.Thromboprophylaxy in cases with ARTPeripartum thromboprophylaxyEarly diagnosis of VTETreatment of VTE

کشور در موجود گزارشوضع ارا‌‌ئهترکستانی دکتر خانم

Risk Factors

Pregnancy as a prothrombotic state

Virchow triad: stasis, local trauma to the vessel wall, and hypercoagulability

Increased level of factor I, VII, VIII, IX, X , XIII , VWB ( 20-1000%)

Decreased activity of Pr S ( 39%)Decreased level of Pr S after cesarean section and

infectionVenous statsis due to compressionIncreased in deep vein capacitance ( prog.,

Prostacycline and nitric oxide)

Risk factors

Risk factors

Risk factorsObstetrics:

ThrombophiliaReduction in inhibitory proteins for

coagulation15% white people50% TE events in pregnancy ((Lockwood,

2002; Pierangeli, 2011)InheritedAcquired

Inherited thrombophiliaFamily historyVTE before 45 y/oVTE without risk factor VTE with minimal provocation ( long flight,

estrogen)Family history of sudden dead due to PEHistory of multiple family members requiring

long-term anticoagulation therapy because of recurrent thrombosis (Anderson, 2011)

Inherited thrombophiliaAntithrombin Deficiency:Type IType II Autosomal Dominant

Most thrombogenic of the heritable coagulopathiesHomozygous antithrombin deficiency is lethal

Inherited thrombophiliaProtein C Deficiency: >100 different AD mutations prevalence : 2 to 3 per 1000, but many of

these individuals do not have a thrombosis history because the phenotypic expression is highly variable (Anderson, 2011).

Inherited thrombophiliaProtein S Deficiency: Decreased in pregnancy ( 30-24%) Decreased after cesarean and infection

Inherited thrombophiliaFactor V Leiden Mutation:Most prevalent of the known thrombophiliaHeterozygous inheritance for factor V Leiden is the most

common ; 3 to 15 percent of selected European populations and 3 percent of African Americans, but it is virtually absent in African blacks and Asians (Lockwood, 2012).

Diagnosis during pregnancy : DNA analysis for the mutant factor V gene. This is because bioassay is confounded by the fact that resistance is normally

increased after early pregnancy because of alterations in other coagulation proteins

Factor V Leiden Mutation *****Universal prenatal screening for the

Leiden mutation and prophylaxis for carriers without a prior venous thromboembolism is not indicated***

Inherited thrombophiliaProthrombin G20210A Mutation:

Excessive accumulation of prothrombin

Inherited thrombophiliaHyperhomocysteinemia: Most common cause : C667T thermolabile

mutation of the enzyme 5, 10-methylene-tetrahydrofolate reductase (MTHFR)

Deficiency of several enzymes involved in methionine metabolism ( correctible nutritional deficiencies of folic acid, vitamin B6, or vitamin B12)

Autosomal recessiveDecreased in normal pregnancyfasting threshold of > 12 μmol/L

Hyperhomocysteinemia:Elevated homocysteine level is actually a weak

risk factor (ACOG, 2013).The ACOG (2013) has concluded that there is

insufficient evidence to support assessment of

MTHFR polymorphisms or measurement of fasting homocysteine levels in the evaluation for venous thromboembolism.

Other Inherited thrombophilia Protein Zplasminogen activator inhibitor type 1 (PAI-1) *****a paternal thrombophilia could increase the

risk of a maternal thromboembolism. (Galanaud (2010).

Paternal thrombophilia—the PROCR 6936G allele—affects the endothelial protein C receptor. This receptor is expressed by villous trophoblast and thus is exposed to maternal blood.

Acquired thrombophiliaAnticardiolipinLupus anticoagulantβ2-glycoprotein I***In addition to vascular thromboses, these include: (1) at least one otherwise unexplained fetal death at

or beyond 10 weeks; (2) at least one preterm birth before 34 weeks

because of eclampsia, severe preeclampsia, or placental insufficiency; or

(3) at least three unexplained consecutive spontaneous abortions before 10 weeks.

Acquired thrombophiliaArterial VenousUnusual sites

Thrombophilias and Pregnancy Complications

ACOG(2013) : Definitive causal link cannot be made between inherited thrombophilias and adverse pregnancy outcomes.

In contrast, the association between antiphospholipid syndrome and adverse pregnancy outcomes—including fetal loss, recurrent pregnancy loss, and

preeclampsia—is much stronger.

Thrombophilia ScreeningGiven the high incidence of thrombophilia in the

population and the low incidence of venous

thromboembolism, universal screening during

pregnancy is not cost effective

*** If thrombophilia testing is performed, it is done before anticoagulation because heparin induces a decline in antithrombin levels, and warfarin decreases protein C and S concentrations (Lockwood, 2002).

Thrombophilia ScreeningSELECTIVE SCREENING:(1) a personal history of venous

thromboembolism that was associated with a non recurrent risk factor such as fractures, surgery, and/or prolonged immobilization

(2) a first-degree relative (parent or sibling) with a history of high-risk thrombophilia or venous thromboembolism before age 50 years in the absence of other risk factors.

Do we need to test IT in cases with adverse pregnancy outcome?ACOG(2013) : Testing for inherited thrombophilias

in women who have experienced recurrent fetal loss or placental abruption is not recommended because there is insufficient clinical evidence that antepartum heparin prophylaxis prevents recurrence. Similarly, testing is not recommended for women with a history of fetal-growth restriction or preeclampsia

Screening for antiphospholipid antibodies may be appropriate in women who have experienced a fetal loss.

Screening TestsShould be performed at least 6 weeks after the

thrombotic event, while the patient is not pregnant, and when she is not receiving anticoagulation or hormonal therapy.

Lack of association between methylenetetrahydrofolate reductase (MTHFR)

gene mutations—the most common cause of hyperhomocysteinemia—and adverse pregnancy outcomes, screening with fasting homocysteine levels or MTHFR mutation analyses is not recommended (ACOG 2013).

Screening Tests

Thromboprophylaxis

ThromboprophylaxisThere is a lack of overall agreement about which

groups of women should be offered thromboprophylaxis during or after pregnancy or offered testing for thrombophilias

All women should undergo a documented assessment of risk factors for VTE in early pregnancy or before pregnancy.

Basic rules in thromboprophylaxy

Basic rules in thromboprophylaxy

Basic rules in thromboprophylaxy

Post NVD prophylaxy

Post C/S thromboprophylaxy

Thromboprophylaxy in lactation

Thromboprophylaxy in ART

Venous Thrombo -Embli

Early diagnosis of VTE70% iliofemoral veins in pregnancyLeft sided ( 90- 97%) [compression of the left iliac vein

by the right iliac and ovarian artery, both of which cross the vein only on the left side]

Abrupt in onset, Pain, edema Reflex arterial spasm causes a pale, cool extremity

with diminished pulsations.Calf pain, either spontaneous or in response to

squeezing or to Achilles tendon stretching—Homans sign

30 - 60 percent may be asymptomatic …PE

Diagnosis of DVT

Compression US: Noninvasive technique is currently the most-used first-line test; noncompressibility and

typical echoarchitecture of a thrombosed vein.MRI : Excellent delineation of anatomical detail

above the inguinal ligament, The venous system can also be reconstructed using MR Venography

D-Dimer Screening Tests: increases in nl pregnancy, multifetal, cesarean , abruption, PET, sepsis;

***** Negative D-dimer test should be considered

reassuring (Lockwood, 2012; Marik, 2008).****

***Normal findings with venous ultrasonography

results do not always exclude a pulmonary embolism. This is because the thrombosis may have already embolized or because it arose from iliac or other deep-pelvic veins, which are less accessible to ultrasound evaluation

Venography: The gold standard to exclude lower extremity deep-vein thrombosis, NPV = 98%

Fetal radiation exposure without shielding is approximately 3 mGy (Nijkeuter, 2006).

***venography is associated with significant complications, including thrombosis, and it is time consuming and cumbersome

Treatment of VTEBed Rest ( 60% chance of PE reduced to 5% with Rx)LMWH/ UFHACCP Recommend LMWH: Better bioavailability, Longer plasma half-life, More predictable dose response, Reduced risks of osteoporosis and

thrombocytopenia, Less frequent dosing (Bates, 2012).Safe in pregnancy and lactationIncreased risk of hematoma ( < 2 hr of cesarean)

Treatment of VTEAfter symptoms have abated ( almost 7 days), graded

ambulation should be started.Elastic stockings are fittedGraduated compression stockings should be

continued for 2 years after the diagnosis to reduce the incidence of postthrombotic syndrome. This syndrome can include chronic leg paresthesias or pain, intractable edema, skin changes, and leg ulcers.

Duration of RX: 20 weeks therapeutic and then prophylaxis if still pregnant

DVT postpartum : 6 months

Unfractionated HeparinInitial treatment of thromboembolismDelivery Surgery Thrombolysis may be necessary (ACOG 2011).(1) Initial intravenous therapy followed by adjusted-

dose subcutaneous UFH given every 12 hours; (2) Twice-daily, adjusted dose subcutaneous UFH

with doses adjusted to prolong the activated partial thromboplastin time (aPTT) into the therapeutic range 6 hours postinjection (Bates, 2012)

Bolus intravenous dose of 70 to 100 U/kg( 5000 to 10,000 U) followed by

continuous intravenous infusions beginning at 1000 U/hr or 15 to 20 U/kg/hr, titrated to

achieve an aPTT of 1.5 to 2.5 times control values (Brown, 2010).

Intravenous anticoagulation should be maintained for at least 5 to 7 days, after which treatment is converted to subcutaneous heparin to maintain the aPTT to at

least 1.5 to 2.5 times control throughout the dosing interval. APS : aPTT does not accurately assess heparin

anticoagulation, and thus anti-factor Xa levels are preferred.

Low-Molecular-Weight Heparin4000 to 5000 daltonsunfractionated heparin has equivalent activity

against factor Xa and thrombin, but LMWH have greater activity against factor Xa than thrombin

More predictable anticoagulant response Fewer bleeding complications (because of their

better bioavailability, longer half-life, dose-independent clearance, and decreased interference with platelets (Tapson, 2008).

cleared by the kidneys

LMWH (enoxaparin, tinzaparin, anddalteparin.1 mg/kg ( wt of early pregnancy)Target therapeutic level: peak anti-factor Xa

activity 3 hours post- injection, with a target therapeutic range of 0.4–1.0 U/mL.

Assay measurement accuracy and reliability are uncertain; correlations with bleeding and recurrence risks are lacking; and assay costs are high.

So ACCP:

Routine monitoring with anti-Xa levels is difficult to justify.

Labor and DeliveryTherapeutic or prophylactic anticoagulation

should be converted from LMWH to the shorter half-life UFH in the last month of pregnancy or sooner if delivery appears imminent

ACOG (2013): Twice-daily adjusted-dose subcutaneous UFH or LMWH discontinue their heparin 24-36 hours before labor induction or cesarean delivery.

Patients receiving once-daily LMWH should take only 50 percent of their normal dose on the morning of the day before delivery (Bates, 2012).

Labor and DeliveryThe American Society of Regional Anesthesia

and Pain Medicine advises withholding neuraxial

blockade for 10 to 12 hours after the last prophylactic dose of LMWH or 24 hours after the last therapeutic dose (Horlocker, 2010).

Anticoagulation with Warfarin CompoundsWarfarin derivatives are generally contraindicated

because they readily cross the placenta and may cause fetal death and malformations from hemorrhages (. 12 wks)

Warfarin <12 weeks: nasal hypolasia, Stippled epiphyses,ACC, Dandy walker, cerebral atrophy, optic atrophy

To avoid paradoxical thrombosis and skin necrosis from the early anti-protein C effect of warfarin, these

women are maintained on therapeutic doses of UFH or LMWH for 5 days and until the INR is in a therapeutic range (2.0–3.0) for 2 consecutive days (ACOG 2013; Stewart, 2010).

Thromboprophylaxy in mechanical heart Valve

Complications of AnticoagulationHeparin-Induced Thrombocytopenia Nonimmune :Benign, reversible , within

the first few days of therapy and resolves in approximately 5 days without therapy cessation.

Immune reaction: paradoxically causes thrombosis ; monitoring every 2 or 3 days from day 4 until day 14

Replace by danaparoid,

Complications of AnticoagulationHeparin-Induced Osteoporosis: Long term users: 6 mo or >

Bleeding

SUPERFICIAL VENOUS THROMBOPHLEBITISAnalgesiaElastic support Heat Rest

Pulmonary Embolism

PULMONARY EMBOLISMDyspnea :82 percent, Chest pain: 49 percent, Cough : 20 percent, Syncope 14 percent, Hemoptysis: 7 percentTachypnea, apprehension, and tachycardiaMassive Pulmonary Embolism:

hemodynamic instability

Nonspecific diagnostic testsCXR: Normal, atelectasis , effusionECG: S1Q3T3, Right axis deviation, p

pulmonale , and T-wave inversion in the anterior chest leads may be evident on the ECG ( mimic nl physiologic changes in Preg.)

ABG: normal, hypoxicEchocardiograpy (TEE):

Specific diagnostic testsV/Q scan: preferred to CTPA in pregnancy ( avoiding

breast irradiation), normal V/Q scan findings do not exclude pulmonary embolism

a fourth of V/Q scans in pregnant women were nondiagnostic

CTPA: first –line in nonpregnant, more accurateMRA ( gadolinium): Relatively contraindicated, high

sensitivity for detection of central pulmonary emboli, the sensitivity for detection of subsegmental emboli is less precise

Pulmonary angiography:

Treatment of PE: Vena Caval FiltersThe woman who has very recently suffered a

pulmonary embolism and who must undergo cesarean delivery presents a particularly serious problem

Heparin therapy fails to prevent recurrent pulmonary embolism from the pelvis or legs, or

when embolism develops from these sites despite heparin treatment

Treatment of PEThrombolysis: risk of recurrence or death was

significantly lower in patients given thrombolytic agents and heparin compared with those given heparin alone

EmbolectomyAnticoagulant

Many thanks for your attention

Many thanks to panelist

Previous VTE

Previous > 1 VTE

No prior VTE

Antiphospholipid antibody

Antiphospholipid antibody