Surgery Block

SECTION VIII: MEDICAL & SURGICAL COMPLICATIONS

2012

CHAPTER 47
Thromboembolic Disorders
Dr. Brillantes

INTRODUCTION RISK FACTORS FOR THROMBOEMBOLIC DISEASE

CATEGORY RISK FACTORS
CS
DM
THROMBOEMBOLIC DISORDERS IN Hemorrhage & Anemia
Pregnancy Hyperemesis
OBSTETRICAL Immobility d/t prolonged bed rest
Multiifetal Gestation
Thromoboembolic Disorders Multiparity
Preeclampsia
RISK of venous thrombosis & pulmonary embolism is HIGHEST
Peurperal Infection
during
CA
 pregnancy > 35 years old
⚜ risk of pulmonary embolism Connective Tissue Disease
 4-6 fold higher Dehydration
 puerperium Immobility d/t Long Distance Travel
INCIDENCE Infection & Inflammatory Diseases
Myeloproliferative Disease
 1 per 1000 pregnancies
Nephrotic Syndrome
 antepartum = puerperium but GENERAL
Obesity
⚜ DVT OCP
 MC antepartum Orthopedic Surgery
 frequency  during the puerperium d/t wide Paraplegia
practice of early ambulation Prior Thromboembolism
Sickle Cell Disease
⚜ pulmonary embolism Smoking
 MC first 6 weeks postpartum Thrombophilia
 leading cause of maternal death in the United GENETIC Family History of Thrombotic Events
States
⚜ anemia
Pathophysiology of Thromoboembolic Disorders ⚜ hyperemesis
VIRCHOW TRIAD ⚜ hemorrhage
 conditions that predispose to the development of venous ⚜ cesarean delivery
thrombosis:  Greater Risk
⚜ (1) Stasis ⚜ postpartum infection.
⚜ (2) Local Trauma To The Vessel Wall RISKS Of Pulmonary Embolism
⚜ (3) Hypercoagulability  RELATIVE
⚜ severe preeclampsia
⚜ cesarean delivery
Endothelial Cell Injury ⚜ diabetes
⚜ multifetal gestation
 SIGNIFICANTLY  risk
⚜ BMI: > 30 kg/m
2

Virchow's ⚜ Multiparity

TRIAD DISEASES

THROMBOPHILIAS IN
Stasis Hypercoagulability Pregnancy

RISK  during normal pregnancy Thrombophilias

 STASIS Inherited or acquired deficiencies of inhibitory proteins thereby
⚜ d/t Compression of the Pelvic Veins & IVC  thromboembolic events
 d/t the enlarging uterus lead to
 renders the venous system of the lower  hypercoagulability
extremities particularly vulnerable to STASIS  recurrent venous thromboembolism
 leads to 50%  in venous flow velocity in the responsible for >50% of all thromboembolic events during
legs that lasts from the early third trimester pregnancy
until 6 weeks postpartum. INHERITED THROMBOPHILIAS
 MOST CONSTANT PREDISPOSING RISK FACTOR  Factor V Leiden
for venous thrombosis. ⚜ Homozygous
 INJURY to VESSEL WALL ⚜ Heterozygous
⚜ d/t Venous stasis and delivery  Prothrombin G20210A
 contribute to endothelial cell injury ⚜ Homozygous
 HYPERCOAGULABILITY ⚜ Heterozygous
⚜ d/t marked  in the synthesis of most clotting  Factor V Leiden & Prothrombin G20201A
factors during pregnancy ⚜ Compound Heterozygous
 favor coagulation.  Hyperhomocystenemia
FACTORS a/w  risk of developing thromboembolism during  Antithrombin Deficiency
pregnancy.  Protein S Deficiency
  2 fold  Protein C Deficiency
⚜ multifetal gestation

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THROMBOPHILIA TESTING/ SCREENING Protein C Deficiency

 INDICATIONS
EFFECTS when THROMBIN is bound to THROMBOMODULIN on
⚜ pregnant ♀ w/ h/o venous thromboembolism a/w Endothelial Cells of Small Vessels
temporary and reversible risk factors  Procoagulant activities are neutralized.
 indication for antepartum thromboprophylaxis.  Activates PROTEIN C
 evaluated for hereditary and acquired ACTIVATED PROTEIN C
thrombophilic disorders.  natural anticoagulant that in the presence of protein S
⚜ ♀ w/ unexplained fetal loss at 20 weeks AOG or later controls thrombin generation
⚜ severe preeclampsia or hemolysis  FUNCTION
⚜ elevated liver enzymes ⚜ Partly inactivates factors
⚜ low platelet count  Va
 HELLP syndrome before 34 weeks  VIIIa
⚜ severe fetal-growth restriction ⚜ INHIBITS the synthesis of Plasminogen-Activator
Inhibitor 1.
PREVALENCE
 3 per 1000
INHERITANCE
 autosomal dominant
DIAGNOSIS
 Functional activity cutoff values of 50 to 60%
⚜ a/w 6 to 12-fold  risk for venous thromboembolism

Protein S Deficiency
PROTEIN S
 circulating anticoagulant
 activated by protein C
 FUNCTION
⚜  thrombin generation
PROTEIN S DEFICIENCY
 PREVALENCE
⚜ 2 per 1000
 deficiency is measured by antigenically determined free,
functional, and total S levels.
⚜ All three of these levels  substantively during
normal gestation, thus the diagnosis in pregnant
women—as well as in those taking certain oral
contraceptives—is difficult
⚜ FREE PROTEIN S ANTIGEN
 levels most closely correlated w/ mutated gene.
 <55% in nonpregnant ♀
 <30% pregnant ♀
 degree of thrombogenicity is modest
Antithrombin Deficiency NEONATAL HOMOZYGOUS PROTEIN C OR S DEFICIENCY
ANTITHROMBIN III  Usually a/w a severe clinical phenotype known as Purpura
 one of the most important inhibitors of thrombin in clot Fulminans
formation. ⚜ Characterized by EXTENSIVE THROMBOSES in the
 FUNCTION microcirculation soon after birth leading to SKIN
⚜ natural anticoagulant NECROSIS
⚜ binds & inactivates
 thrombin
 activated coagulation factors
 IXa
 Xa
 Xia
 XIIa
ANTITHROMBIN DEFICIENCY
 autosomal dominant
 Homozygous antithrombin deficiency is lethal
 INCIDENCE
⚜ Rare
⚜ 1 in 5000 individuals
 the most thrombogenic of the heritable coagulopathies
Activated Protein C Resistance
 RISK OF THROMBOSIS during pregnancy among
MOST PREVALENT of the known thrombophilic syndromes
antithrombin-deficient ♀
CHARACTERISTICS
⚜ WITHOUT personal or family history
 Resistance of plasma to the anticoagulant effects of
 3 to 7%
activated protein C.
⚜ WITH personal or family history CAUSES
 11 to 40%  Factor V Leiden Mutation
 MANAGEMENT  Antiphospholipid Antibody Syndrome
⚜ Heparin  NORMAL  AFTER early pregnancy d/t alterations in other
 RECOMMENDED regardless of whether a prior coagulation proteins
thrombosis has occurred. FACTOR V LEIDEN MUTATION
 OUTCOMES  MC cause of resistance
⚜ thrombosis  MISSENSE MUTATION in the Factor V Gene
⚜ death

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⚜ Substitution of GLUTAMINE for ARGININE at position MISSENSE MUTATION OF PROTHROMBIN

506 in the factor V polypeptide GENE
⚜ confers resistance to degradation by activated
protein C
ACCUMULATION OF PROTHROMBIN
 Unimpeded abnormal factor V protein retains its
procoagulant activity and predisposes to thrombosis
 Heterozygous Inheritance Of Factor V Leiden Mutation ACCUMULATED PROTHROMBIN CONVERTED
TO THROMBIN
⚜ MC heritable thrombophilia
⚜ INCIDENCE
 3 to 15% of select European populations ACCUMULATION OF THROMBIN
 3% African American
 virtually absent in INCREASED RISK of THROMBOEMBOLIC
 African blacks EVENTS
 Asians
 50% nonpregnant individuals with
thromboembolic disease. INCIDENCE
 Homozygous Inheritance Of Two Aberrant Copies  2% of the white population
⚜ Rare  extremely UNCOMMON in nonwhites
⚜ >10-fold  risk of thrombosis during pregnancy RISKS
 RELATIVE RISK of thromboembolism
⚜ 3 to 15-FOLD  during pregnancy
 GREATER RISK OF THROMBOEMBOLISM
⚜ Homozygous patients
⚜ G20210A mutation Co-inheritance w/ factor V
Leiden mutation
 RECURRENCE
⚜ Doubly Heterozygous Individuals
 2.6-fold  risk of recurrence relative to those
with the homozygous Leiden mutation alone.
MANAGEMENT
 Carriers of both mutations are candidates for lifelong
anticoagulation after a first thrombotic episode

Hyperhomocystenemia
HOMOCYSTEINE
 A NONPROTEIN amino acid
CAUSES
 C667T Thermolabile Mutation Of Enzyme 5,10-
Methylene-Tetrahydrofolate Reductase (MTHFR)
DIAGNOSIS ⚜ MC cause of elevated homocysteine
 BIOASSAY  Deficiency of other enzymes involved in methionine
⚜ Measures resistance to activated protein C metabolism
⚜ CAVEAT ⚜ Methionine Synthetase
 activated protein C resistance can also be caused ⚜ Cystationine Beta Synthase
by the Antiphospholipid Antibody Syndrome  Nutritional deficiencies of
 Regulatory Proteins resistance is normally  ⚜ folic acid
AFTER early pregnancy d/t alterations in other ⚜ vitamin B6
coagulation proteins ⚜ vitamin B12
 DNA ANALYSIS
⚜ Tested DURING pregnancy
⚜ DNA analysis for the mutant factor V gene
⚜ used to CONFIRM the diagnosis.
 Universal Prenatal Screening For The Leiden Mutation And
Prophylaxis
⚜ NOT INDICATED for CARRIERS WITHOUT a prior
venous thromboembolism
⚜ NOT COST EFFECTIVE
PREGNANCY OUTCOMES
 RISKS of THROMBOEMBOLIC EVENTS
⚜ 4 to 8-FOLD  risk of a first-episode venous
thromboembolism during pregnancy
 NO  RISK IN HETEROZYGOUS ♀:
⚜ Preeclampsia INHERITANCE
 Autosomal recessive
⚜ placental abruption
PREVALENCE
⚜ fetal-growth restriction
 homozygote
⚜ pregnancy loss
⚜ 8 percent in normally pregnant ♀.
PREGNANCY
Prothrombin G20210a Mutation  NORMAL pregnancy
MISSENSE MUTATION in the prothrombin gene ⚜ mean homocysteine plasma concentrations are 
Cause  accumulation of prothrombin  converted to  DIAGNOSIS in PREGNANCY
thrombin. ⚜ Fasting cutoff level of >12 μmol/L
 DEFINE hyperhomocysteinemia.

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PATHOPHYSIOLOGY  splenic veins

 The precise pathological mechanism(s) by which high  subclavian veins
levels of homocysteine  the risk of thromboembolism  cerebral veins
remains UNDEFINED. ⚜ ARTERIES
 Possible pathways include  Retinal arteries
⚜  activation of protein C  Subclavian arteries
⚜ interference with the ability of activated protein C  Brachial arteries
(APC) to inactivate factor Va  Digital arteries.
RISK for THROMBOEMBOLISM  MECHANISM(S) IN PROMOTING THROMBOSIS
  risk of venous thromboembolism in nonpregnant ⚜ Interfere with the normal function of phospholipids
 UNCLEAR whether MTHFR C667T homozygotes have an  or phospholipid-binding proteins involved in
risk during pregnancy coagulation regulation, including
⚜  risk is r/t physiologically lower homocysteine levels  Prothrombin
during pregnancy  Protein C
⚜ most pregnant women take Folic Acid Supplements  Annexin V
 folic acid serves as a cofactor in the  Tissue factor
remethylation reaction of homocysteine to ⚜ Promote thrombosis through AUGMENTED platelet
methionine. and/or complement activation
FETAL OUTCOMES
  lifetime risk of having a fetus with PREGNANCY COMPLICATIONS & PROPHYLAXIS
⚜ Neural-tube defect
⚜ Premature atherosclerosis
THROMBOPHILIAS & COMPLICATIONS IN
Pregnancy
Protein Z Deficiency
PROTEIN Z
 vitamin K-dependent protein
 COFACTOR in the inactivation of factor Xa Pregnancy Complications
PROTEIN Z DEFICIENCY heterozygous factor V Leiden & prothrombin gene mutations
  levels of protein Z are a/w  risk of thromboembolism  consistently a/w most adverse outcomes
 PREGNANCY OUTCOME NO  risk for EARLY-ONSET or SEVERE preeclampsia:
⚜ early pregnancy losses  factor V Leiden mutation
⚜ preterm labor  prothrombin G20210A mutation
⚜ fetal-growth restriction  MTHFR C677T polymorphism or hyperhomocysteinemia.
⚜ late-pregnancy fetal demise

ANTIPHOSPHOLIPID ANTIBODIES IN
Pregnancy

Antiphospholipid Antibodies Syndrome

ANTIPHOSPHOLIPID ANTIBODIES
 Detected in about 2% of patients who have
NONTRAUMATIC venous thrombosis.
 DIRECTED AGAINST
⚜ cardiolipin
⚜ phospholipid-binding proteins
 β2-glycoprotein I
 function as a natural anticoagulant
 COMMONLY found in
⚜ SLE
 LEVELS
⚜ moderate-to-high levels of antibodies
 May have Antiphospholipid Syndrome
 PREDISPOSING FACTOR FOR
⚜ Vein Thromboses
⚜ Arterial Thromboses
 5% of arterial strokes in healthy young ♀
ANTIPHOSPHOLIPID ANTIBODIES SYNDROME
 clinical features
⚜ thromboembolism recurrent preeclampsia
 venous or arterial  more common in ITALIAN women diagnosed with a
 most commonly involves the lower extremities thrombophilia.
⚜ obstetrical complications ASSOCIATED CONDITIONS & Pregnancy Complication
 at least 1 otherwise unexplained FETAL DEATH at  preeclampsia
or beyond 10 weeks  HELLP syndrome
 at least 1 PRETERM BIRTH BEFORE 34 weeks  fetal-growth restriction
 at least 3 consecutive SPONTANEOUS  placental abruption
ABORTIONS BEFORE 10 weeks  recurrent miscarriage
 considered in women with thromboses in unusual sites,  stillbirth
such as the  placental findings of intervillous or spiral artery
⚜ VEINS thrombosis.
 portal veins
 mesenteric veins

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 typically involves much of the deep venous system to the

THROMBOPHILIAS PROPHYLAXIS IN iliofemoral region
Pregnancy  reflex arterial spasm causes a pale, cool extremity with
diminished pulsations.
 there may be appreciable clot, yet little pain, heat, or
swelling
Thrombophilia Prophylaxis  Calf pain
GOAL: ⚜ PRESENTATION
 Prevent adverse pregnancy outcomes  Spontaneous
empirical TREATMENT  Response to squeezing or to stretching the
 aspirin Achilles tendon
 low-molecular-weight heparin  Homans Sign
⚜ enoxaparin ☀ Differential Diagnosis
 INDICATIONS ❧ strained muscle
 previous pregnancy complications ❧ contusion.
 40 mg daily
 prior thromboembolic event
 60 mg daily
 Dalteparin + Low dose Aspirin
VARIOUS OUTCOMES
  term delivery
 no thromboembolic events
  rate of historical fetal loss in ♀ w/
⚜ Antithrombin deficiency
⚜ protein C deficiency
⚜ protein S deficiency
  risk for placental abruption
  risk for early-onset severe preeclampsia
  risk for fetal-growth restriction
 NO improved perinatal outcome

THROMBOEMBOLIC EVENTS

THROMBOEMBOLIC EVENTS IN
Pregnancy
 COMPLICATION if UNTREATED
⚜ pulmonary embolism
 Anticoagulation risk to <5%
DVT During Pregnancy
DIAGNOSIS
Most cases confined to the deep veins of the lower extremity.  INVASIVE CONTRAST VENOGRAPHY
 iliac vein thrombosis
⚜ STANDARD TEST to exclude LE DVT
⚜ frequent in those after cesarean delivery
⚜ negative-predictive value of 98 percent
 left leg
⚜ fetal radiation exposure without shielding is only
⚜ MC side affected during pregnancy
about 300 mrad
⚜ HYPOTHESIS
⚜ COMPLICATIONS/ DISADVANTAGES
 May Thurner Syndrome
 Cause thrombosis
 d/t compression of the Left Common Iliac
 time consuming and cumbersome
Vein by arteries that cross the vein only on
the left side ⚜ Other noninvasive methods are usually used to
confirm the clinical diagnosis.
☀ Right Common Iliac Artery
 IMPEDANCE PLETHYSMOGRAPHY
☀ Ovarian Artery
⚜ EXTREMELY ACCURATE TEST
⚜ Assess thromboses in
 lower iliac veins
 femoral veins
 popliteal veins
⚜ Observes alterations in venous return in the calf,
produced by inflation and deflation of a pneumatic
thigh cuff
 result in changes in electrical resistance detected
at the skin surface.
 changes occur when the popliteal or more
proximal veins are obstructed
⚜ only 50% sensitive for detection of clots in the small
calf veins
⚜ LIMITATIONS
  false-positive results during pregnancy
SIGNS & SYMPTOMS  d/t  venous return of the lower
 vary greatly extremities
 depends in
⚜ SELDOM USED TODAY
⚜ degree of occlusion  COMPRESSION ULTRASONOGRAPHY
⚜ intensity of the inflammatory response. ⚜ noninvasive technique
DVT in LE
⚜ MOST-USED FIRST-LINE TEST to detect deep-venous
 abrupt in onset
thrombosis
 pain and edema of the leg and thigh


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⚜ Fetal radiation exposure is NEGLIGIBLE unless the

pelvic veins are imaged
 MAGNETIC RESONANCE (MR) IMAGING
⚜ USES
 allows EXCELLENT delineation of ANATOMICAL
DETAIL above the INGUINAL LIGAMENT.
 immensely useful for diagnosis of
☀ iliofemoral thrombosis
☀ pelvic vein thrombosis
 venous system can also be reconstructed using
MR venography
 Can detect NONTHROMBOTIC conditions to
explain the clinical findings
 Cellulitis
 Myositis
 Edema
 Hematomas
 Superficial phlebitis
⚜ FINDINGS
 (+) Hyperluscent area indicates clot
⚜ ADVANTAGES
 100% sensitive & 90% specific for detection of
venographically proven DVT in NONPREGNANT
♀
 LOW Interobserver Variability
 D-DIMER SCREENING TESTS
⚜ DVT FINDINGS ⚜ D-DIMERS
 noncompressibility of thrombosed vein  specific fibrin degradation products
 typical echoarchitecture of a thrombosed vein  generated when fibrinolysin degrades fibrin, as
⚜ AREAS Examined occurs in thromboembolism.
 Femoral vein ⚜ NONPREGNANT PATIENTS
 Popliteal vein  Measurement is frequently incorporated into
 Calf trifurcation veins diagnostic algorithms for venous
⚜ ADVANTAGES thromboembolism
 90% sensitive & >99% specific for proximal  D-DIMER CONCENTRATION <0.50 mg/L
thrombosis.  conventional cut-off used to exclude
 negative-predictive value of 98 percent thromboembolism
⚜ NONPREGNANT ♀ w/ suspected thrombosis ⚜ PREGNANCY
 isolated calf thromboses extend into the  Screening w/ D-dimer test is problematic d/t:
proximal veins in up to a fourth of cases.  D-dimer serum levels  w/ AOG w
 detected by serial ultrasonographic substantively  plasma fibrinogen
compression. concentrations
 Safety of withholding anticoagulation with ☀ 22% in midpregnancy & NO ♀ in 3
rd

negative compression ultrasonography is trimester had a D-dimer concentration

ESTABLISHED <0.50 mg/L
⚜ PREGNANT ♀  D-Dimer concentrations can also be  in
 IMPORTANT CAVEAT certain pregnancy complications
 NORMAL findings w/ venous ☀ placental abruption
ultrasonography results DO NOT always
☀ preeclampsia
exclude a Pulmonary Embolism
☀ sepsis syndrome
☀ CAUSES
 use during pregnancy remains UNCERTAIN
❧ Thrombosis may have already  However, a NEGATIVE D-dimer test should be
embolized considered REASSURING
❧ Embolus arose from deep pelvic  CONCLUSION
veins inaccessible to ultrasound  (+) D-DIMER TEST
evaluation ☀ DOES NOT confirm for DVT d/t several
☀ thrombosis a/w pulmonary embolism differential diagnoses
frequently originates in the ILIAC  (-) D-DIMER TEST
VEINS. ☀ RULES OUT Thromboembolism
 natural history of calf deep-venous MANAGEMENT
thrombosis during pregnancy is UNKNOWN.  Thrombophilia testing
 Safety of withholding anticoagulation with
⚜ done before anticoagulation
negative compression ultrasonography has NOT
 heparin
BEEN EVALUATED in pregnant women who may
 induces a  in antithrombin levels
have an isolated iliac vein thrombosis that is less
 warfarin
accessible for imaging
  protein C and S concentrations
 SPIRAL COMPUTED TOMOGRAPHY
 Anticoagulation
⚜ widely available
⚜ initiated with either unfractionated or low-
⚜ very useful for detecting molecular-weight heparin
 LE DVT
⚜ Depends on AOG
 vena cava Thrombosis
 During pregnancy
 Iliac and pelvic venous systems Thrombosis
 heparin therapy is continued
⚜ radiation and contrast agents are required  POSTPARTUM women
⚜ benefits of CT outweigh any theoretical risks if lead  Heparin + Warfarin
shielding is used

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
full anticoagulation be continued for at
least 20 weeks followed by prophylactic
doses if the woman is still pregnant.
 Prophylactic doses of subcutaneous
unfractionated heparin
☀ 5000 to 10,000 units every 12 hours
titrated
❧ to maintain an antifactor Xa level
of 0.1 to 0.2 units
☘ measured 6 hours after the
last injection
 If (+) venous thromboembolism postpartum
☀ minimum of 6 months of
anticoagulation treatment.
 LOW-MOLECULAR-WEIGHT HEPARIN
⚜ molecular weights average 4000 to 5000 daltons
compared with 12,000 to 16,000 daltons for
conventional heparin.
⚜ PRIMARY DIFFERENCE
 relative inhibitory activity against factor Xa and
thrombin

PROPERTIES OF HEPARIN
⚜  RISK of UNFRACTIONATED LOW MOLECULAR
PARAMETERS
 pulmonary embolism HEPARIN WEIGHT HEPARIN
 develops in 25% of patients w/ untreated ANTITHROMBOTIC PROPERTY
venous thrombosis Anti-Factor Xa Activity + ++
Anti-Thrombin Activuty + +
 anticoagulation  risk to <5%
ANTICOAGULANT RESPONSE Less Predictable MORE predictable
 mortality rate <1% percent in DOSE-DEPENDENT
YES
NONPREGNANT ♀ CLEARANCE
 Graded ambulation  INTERFERENCE W/
YES
PLATELETS
⚜ Started AFTER symptoms have abated COST CHEAPER EXPENSIVE
⚜ Elastic stockings are fitted and anticoagulation is EFFECTIVENESS as
LESS EFFECTIVE MORE EFFECTIVE
continued. ANTICOAGULANT
⚜ Recovery to this stage usually takes 7 to 10 days BREASTFEEDING SAFE SAFE
COMPLICATIONS
HEPARINIZATION
Osteopenia More Likely Less Likely
 HEPARIN Bleeding MORE FEW
⚜ DOES NOT cross the placenta
⚜ ANTICOAGULANT ACTIVITY
⚜ OTHER DIFFERENCES
 Activates antithrombin.
 fewer bleeding complications than
 Heparin Used DURING pregnancy
unfractionated heparin d/t better bioavailability,
⚜ Unfractionated Heparin
longer half-life
⚜ Low-molecular-weight heparin.  more effective than the unfractionated form in
 most recommended reducing thrombus size w/o mortality rates or
 Grade 2C level of evidence as ANTICOAGULANT major bleeding complications.
⚜ the lowest quality ⚜ MAJOR DRAWBACK
 UNFRACTIONATED HEPARIN (UFH)  EXPENSIVE
⚜ IV heparin bolus followed by continuous infusion ⚜ Pharmacokinetics in Pregnancy
titrated to achieve full anticoagulation.  LOW-MOLECULAR-WEIGHT HEPARINS
 Initial Bolus: 80 units/kg  include
 Continuous Infusion: 30,000 IU for 24 hours
☀ Enoxaparin (Lovenox)
 titrated to achieve an activated partial
❧ given 40 mg SQ daily
thromboplastin time (aPTT) of 1.5 to 2.5
times control values. ❧ Measure anti-factor Xa activity
during:
⚜ IV anticoagulation should be maintained for at least 5
to 7 days, after which, treatment is converted to ☘ early pregnancy
SUBCUTANEOUS HEPARIN ☘ third trimester
 Injections are then given every 8 hours to ☘ postpartum
maintain the aPTT to at least 1.5 to 2.5 times ❧ d/t  renal clearance, 1 mg/kg
control throughout the dosing interval. BID dosing necessary to maintain
⚜ For women with antiphospholipid syndrome anti-factor Xa activity >0.1 U/mL.
 aPTT does not accurately assess heparin ❧ OPTIMAL DOSING
anticoagulation ☘ best achieved w/ periodic
 anti-factor Xa levels are preferred monitoring of peak activity
⚜ The duration of full anticoagulation varies, and there ❅ 3.5 hours after a dose
are several acceptable schemes. ❅ predose anti-factor Xa
⚜ RECOMENDATIONS activity.
 AAP & ACOG RECOMMENDATION ❧ target therapeutic range
 therapeutic anticoagulation for at least 3 ☘ 0.4–1.0 U/mL.
months after the acute event ☀ Dalteparin (Fragmin)
 ACCP RECOMMEDNATION
❧ once-daily SQ
 anticoagulation throughout pregnancy and
☀ Tinzaparin (Innohep)
for 6 weeks postpartum but for a minimum
total duration of 6 months. ❧ once-daily 50 U/kg dose
 Lockwood (2007) RECOMMENDATION  Monitoring anti-Xa levels during pregnancy

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☀ Measurement important in women  Complete anticoagulation w/ a minimum of

who: 6 weeks
❧ have impaired renal or hepatic  If w/ DVT, minimum of 6 months of
function anticoagulation
❧ weigh <50 kg or >100 kg COMPLICATIONS OF ANTICOAGULATION
 3 significant complications associated with anticoagulation
❧ have risk factors for bleeding
⚜ Hemorrhage
☀ peak anti-factor Xa level:
 most serious complication
❧ 0.5 to 1.2 U/mL.
 more likely if the heparin dosage is excessive
☀ NOT RECOMMENDED in women given
⚜ Thrombocytopenia
thromboprophylaxis,
 unique to heparin
⚜ SAFETY IN PREGNANCY  risk may be reduced with low-molecular-weight
 GENERALLY safe and effective heparins
 Lovenox
⚜ Osteoporosis
 use in pregnancy a/w
 unique to heparin
☀ congenital anomalies  risk may be reduced with low-molecular-weight
☀  risk of hemorrhage heparins
 risks were rare  HEPARIN-INDUCED THROMBOCYTOPENIA (HIT)
⚜ CAVEATS ⚜ 2 types
 SHOULD NOT be used in women with prosthetic  NONIMMUNE HIT
heart valves because of reports of valvular  MC
thrombosis  Benign
 SHOULD BE AVOIDED in women with renal  reversible form
failure  occurs w/in the 1st few days of therapy
  risk of wound hematoma when given within 2  resolves in about 5 days w/o cessation of
hours of cesarean delivery therapy
 massive subchorionic hematoma a/w  IMMUNE HIT
enoxaparin  more severe form
 spontaneous thoracolumbar epidural  results from an reaction involving IgG
hematoma antibodies directed against complexes of
☀ low-molecular-weight heparin SHOULD platelet factor 4 & heparin
BE WITHHELD for at least 2 hours  when severe, HIT paradoxically causes
AFTER removal of epidural catheter. thrombosis
  risk of spinal hematoma a/w regional ☀ MC presentation
analgesia ⚜ DIAGNOSIS
 SHOULD NOT offer regional analgesia until   platelet count 50% b/t 5 & 14 days AFTER the
at least 10 to 12 hours AFTER the last initiation of heparin therapy
heparin injection.  platelet counts be measured on day 5 and
⚜ ANTIDOTE then periodically for the first 2 weeks of
 Protamine Sulfate heparin therapy.
 may help partially reverse the effects of  If unchanged, further platelet counts are
low-molecular-weight heparin not indicated because most cases manifest
ANTICOAGULATION W/ WARFARIN within 15 days of standard heparin
 Warfarin derivatives initiation.
⚜ generally CONTRAINDICATED ⚜ INCIDENCE
 cross the placenta  ~ 3 to 5% nonpregnant individuals
 cause fetal death and malformations from ⚜ MANAGEMENT
hemorrhages  STOP HEPARIN
 BREASTFEEDING  If thrombocytopenia is severe
⚜ safe  alternative anticoagulation
 POSTPARTUM venous thrombosis  Low-molecular-weight heparin
⚜ TREATMENT ☀ NOT A SAFE ALTERNATIVE
 IV heparin + oral warfarin ☀ Can have some CROSS REACTIVITY w/
 COMPLICATION unfractionated heparin
⚜ Warfarin Induced Skin Necrosis  Danaparoid
 paradoxical thrombosis and skin necrosis from ☀ sulfated glycosaminoglycan heparinoid
the early anti-protein C effect of warfarin ☀ reasonable alternative
 PREVENTION  Direct Thrombin Inhibitors
st
 1 give therapeutic doses of unfractionated ☀ Examples
or low-molecular-weight heparin for 5 days
❧ Hirudin
until the international normalized ratio
☘ crosses the placenta
(INR) is in a therapeutic range
 When INR is in therapeutic range ☘ fetotoxic
☀ initial dose of warfarin is usually 5 to ❧ Argatroban
10 mg for the first 2 days ❧ Lepirudin
☀ Subsequent doses are titrated to ☀ used as a heparin alternative
achieve an INR of 2 to 3.  Fondaparinux
 DURATION OF THERAPY ☀ pentasaccharide factor Xa inhibitor
⚜ optimal duration: uncertain ☀ recommended for PREGNANT ♀ for
⚜ RECOMMENDATIONS whom there are no alternatives.
 ACCP RECOMMENDATION  HEPARIN-INDUCED OSTEOPOROSIS
 warfarin anticoagulation be given for at ⚜ Bone loss may develop with long-term heparin
least 6 weeks postpartum administration
 complete a minimum 6-month course  > 6 months
following the initial episode ⚜ more prevalent in CIGARETTE smokers
 Lockwood (2007) RECOMMENDATION ⚜ Low-molecular-weight heparins

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 can cause osteopenia CLINICAL PRESENTATION

 less likely than with unfractionated heparin.  Signs & Symptoms
⚜ PREVENTIVE APPROACH ⚜ dyspnea
 Daily Calcium Supplement of 1500 mg  MC complaint
ANTICOAGULATION & ABORTION ⚜ chest pain
 Treatment of deep-venous thrombosis with heparin DOES ⚜ cough
NOT preclude termination of pregnancy by careful ⚜ syncope
curettage.
⚜ hemoptysis
 After the products are removed without trauma to the
⚜ tachypnea
reproductive tract, full-dose heparin can be restarted in
several hours. ⚜ apprehension
ANTICOAGULATION & DELIVERY ⚜ tachycardia
 The effects of heparin on blood loss at delivery depend on DIAGNOSIS
a number of variables  Auscultation
⚜ Dose, route, & time of administration ⚜ accentuated pulmonic closure sound
⚜ Number & severity of incisions and lacerations ⚜ rales,
⚜ Intensity of postpartum myometrial contractions ⚜ friction rub.
⚜ Presence of other coagulation defects  ECG
 Blood loss ⚜ Right axis deviation
⚜ VAGINAL DELIVERY ⚜ T-wave inversion in the anterior chest leads
 should not be greatly  if  Chest XRAY
 midline episiotomy is modest in depth ⚜ loss of vascular markings in the region of the lungs
 there are no lacerations supplied by the obstructed artery
 uterus promptly contracts  ABG
⚜ CS ⚜ most women are hypoxemic
 Serious bleeding likely when heparin in usual ⚜ However, a normal arterial blood gas analysis DOES
therapeutic doses is administered w/in 24 to 48 NOT EXCLUDE pulmonary embolism.
hours PRIOR to CS  Alveolar-Arterial Oxygen Tension Difference
 heparin therapy ⚜ more useful indicator of disease
⚜ STOPPED during labor and delivery. ⚜ >86% w/ acute pulmonary embolism will have an
⚜ RESTARTED after about 12 hours POSTpartum if: alveolar-arterial difference of > 20 mm Hg
 uterus is well contracted ⚜ (Lockwood, 2007). Even with massive pulmonary
 negligible trauma to the lower genital tract embolism, signs, symptoms, and laboratory data to
⚜ DELAY 1 or 2 days support the diagnosis may be deceptively nonspecific.
 If above 2 parameters are not met MASSIVE PULMONARY EMBOLISM
 Protamine sulfate  embolism causing hemodynamic instability
⚜ administered slowly IV  most acutely symptomatic emboli are large and likely a
⚜ generally reverses the effect of heparin promptly and saddle embolism.
effectively. ⚜ suspected w/ substantively  Pulmonary Artery
⚜ should not be given in excess of the amount needed Pressure as estimated by echocardiography
to neutralize the heparin, because it also has an ⚜ can be lodged at the Pulmonary Trunk & Pulmonary
anticoagulant effect. Arteries
 SEQUELAE
⚜ Acute mechanical obstruction of the pulmonary
Superficial Venous Thrombophlebitis vasculature
Thrombosis limited strictly to the superficial veins of the ⚜  vascular resistance
saphenous system
⚜ pulmonary hypertension
TREATMENT
 does not develop until 60 to 75 percent of the
 Analgesia
pulmonary vascular tree is occluded
 elastic support
⚜ Acute right ventricular dilatation follows.
 rest
If it does not soon subside, or if deep-venous involvement is
suspected, appropriate diagnostic measures are performed. MASSIVE Pulmonary
 Heparin Embolism
⚜ given if deep-venous involvement is confirmed. Acute Mechanical Obstruction of
typically seen in a/w Pulmonary Blood Vessels
 varicosities
 indwelling intravenous catheter sequelae
Increased Vascular
Resitance Pulmonary
Pulmonary Embolism Hypertension

EPIDEMIOLOGY
 relatively uncommon during pregnancy and the
puerperium.
 INCIDENCE ACUTE RIGHT
VENTRICULAR DILATATION
⚜ 1 in 7000 pregnancies
 PREVALENCE
⚜ antepartum = postpartum embolism ⚜ circulatory collapse
MORTALITY  requires 75- to 80-percent obstruction
 causes about 10% of maternal deaths ⚜ right ventricular dysfunction
 postpartum embolism > antepartum embolism  mortality rate 25 percent
ASSOCIATED FINDINGS MANAGEMENT
 70% has clinical evidence of DVT  DONE prior to thrombolysis
⚜ In ♀ w/ DVT, almost ½ will have a silent pulmonary ⚜ infuse crystalloids carefully
embolism. ⚜ support blood pressure with vasopressors
⚜ Oxygen treatment

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 FIRST-LINE EVALUATION of pregnant women

 better resolution allows detection of previously
inaccessible smaller distal emboli that have
uncertain clinical significance.
 FACTORS that Lead to NONDIAGNOSTIC results
in Pregnancy
 hyperdynamic circulation
  plasma volume
 VENTILATION–PERFUSION SCINTIGRAPHY—LUNG SCAN
⚜ may be used if compression ultrasonography results
are negative.
⚜ Use small dose of radiotracer
 Examples
99m
 IV technetium-macroaggregated
albumin
 inhaled xenon-133
 PURPOSE
 to detect abnormal areas of ventilation in
areas with normal perfusion such as with
pneumonia or hypoventilation
⚜ negligible fetal radiation exposure
⚜ scan may not provide a definite diagnosis because
many other conditions
⚜ tracheal intubation  pneumonia or local bronchospasm
⚜ mechanical ventilation  cause perfusion defects
 filter placement ⚜ method is not precise
 embolectomy ⚜ ABNORMAL FINDINGS
DIAGNOSIS  large perfusion defects
 high index of suspicion  ventilation mismatches
 objective testing  CAVEAT
⚜ Ventilation-Perfusion Scintigraphy ☀ normal V/Q scan findings DO NOT
⚜ Computed Tomography EXCLUDE pulmonary embolism.
⚜ Bilateral Compression Ultrasonography ⚜ INTERPRETATION
⚜ Chest Radiograph  high-probability scan
⚜ Multidetector-Row Spiral Computed Tomography  usually indicates pulmonary embolism
Pulmonary Angiography (MDCT)  low-probability scan
 combined with a strong clinical impression
 embolism is unlikely
 near-normal or normal scans
 Pulmoary Embolism very unlikely
 intermediate-probability scan
 no help in establishing the diagnosis.
⚜ V/Q lung scan + clinical assessment
 permits a noninvasive diagnosis or exclusion of
pulmonary embolism for only a minority of
patients.
rd
 2/3 of nonpregnant patients with a suspected
pulmonary embolism have a NONDIAGNOSTIC
scan and require additional testing
 MAGNETIC RESONANCE ANGIOGRAPHY (MRA)
⚜ SENSITIVITY
 high sensitivity for detection of
 CENTRAL or LOBAR Pulmonary Emboli
(100%)
 Segmental Pulmonary Emboli (84%)
 LESS PRECISE sensitivity for
 Subsegmental Pulmonary Emboli (40%)
 COMPUTED TOMOGRAPHIC PULMONARY ANGIOGRAPHY  PULMONARY ANGIOGRAPHY
⚜ Multidetector Spiral CT ⚜ requires catheterization of the RIGHT side of the
 likey will replace pulmonary angiography as the heart
gold standard for diagnosis of pulmonary ⚜ Most definitive study for pulmonary embolism
embolism ⚜ DISADVANTAGES
 fetal x-ray exposure is less than with V/Q  Invasive
scanning  time consuming
 uncomfortable
 dye-induced allergy and renal failure
⚜ procedure-related mortality rate
 1 in 200
⚜ INDICATIONS
 If absolutely necessary for confirmation when
less invasive tests are equivocal
MANAGEMENT
 Anticoagulation
⚜ Given Immediately
 Complementary Procedure
⚜ Vena Caval Filters

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 Routine filter placement has no added

advantage to heparin given alone
 INDICATIONS
 ♀ w/ pulmonary embolism and who must
undergo cesarean delivery
☀ RATIONALE
❧ Reversal of anticoagulation may
be followed by another embolus
❧ surgery while fully anticoagulated
frequently results in life-
threatening hemorrhage or
troublesome hematomas
☀ vena caval filter should be considered
BEFORE surgery
 If heparin therapy fails to prevent recurrent
pulmonary embolism from the pelvis or
legs, or when embolism develops from
these sites despite heparin treatment
 massive emboli in patients who are not
candidates for thrombolysis
 SITES INSERTED
 Jugular Vein
 Femoral Vein.
 Retrievable filters
 may be used as short-term protection
against embolism.
 may be removed before they become
endothelialized, or they can be left in place
permanently
 EXAMPLES
☀ Gunther Tulip filter
⚜ Thrombolytic Agents
 provide more rapid lysis of pulmonary clots and
improvement of pulmonary hypertension
 thrombolytic agents
 alteplase
☀ recombinant tissue plasminogen
activator
  risk of recurrence or death compared
with those given heparin alone
 DOES NOT CROSS THE PLACENTA
⚜ Embolectomy
 uncommonly indicated with use of thrombolysis
and filters.
 stillbirth rate is 20 to 40 percent.

PROPHYLAXIS

THROMBOPHYLAXIS IN
Pregnancy

Thromboembolism Antedating Pregnancy

ANTEPARTUM & POSTPARTUM PROPHYLAXIS
 Optimal management: unclear
 Use Various UFH and LMWH regimens:
 INDICATIONS
⚜ prior thrombosis in association with a thrombophilia
⚜ prior venous thromboembolism

Cesarean Delivery & Antepartum Bed Rest

thromboprophylaxis for women undergoing cesarean delivery
or antepartum bed rest is NOT WIDELY EMPLOYED.
 Grade 2C level of recommendation d/t "low- or very-low
quality evidence."
Thromboprophylaxis approaches for women undergoing
cesarean delivery
 compression boots
 stockings
 heparin
RISK for DVT and especially for fatal thromboembolism is 
manyfold following cesarean compared with vaginal delivery.
pulmonary embolism
 major cause of maternal mortality

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