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Osama Warda,MD Osama Warda,MD

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Deep Vein Thrombosis ( DVT )Deep Vein Thrombosis ( DVT )in Pregnancyin Pregnancy

( ( ( ( ( ( ( ( AN OVERVIEW OF THE LITERATURE )AN OVERVIEW OF THE LITERATURE )

By By

OSAMA M.WARDA, MDOSAMA M.WARDA, MDOSAMA M.WARDA, MDOSAMA M.WARDA, MDOSAMA M.WARDA, MDOSAMA M.WARDA, MDOSAMA M.WARDA, MDOSAMA M.WARDA, MDObstetrics and Gynecology Dept.Obstetrics and Gynecology Dept.

Faculty of MedicineFaculty of Medicine--Mansoura UniversityMansoura University

EpidemiologyEpidemiology�� DVT of the lower limbs during pregnancy occurs in DVT of the lower limbs during pregnancy occurs in

00..13 13 to to 00..61 61 per thousand pregnancyper thousand pregnancy..

�� Despite its relatively low incidence, DVT may lead Despite its relatively low incidence, DVT may lead to pulmonary embolism; the most common cause of to pulmonary embolism; the most common cause of maternal death in developed countries.maternal death in developed countries.


maternal death in developed countries.maternal death in developed countries.

�� DVT occurs with relatively equal frequency in all DVT occurs with relatively equal frequency in all trimesterstrimesters. . However, in the past it was most However, in the past it was most common in the postcommon in the post--partum period due to medical partum period due to medical practices as instrumental deliveries, prescription of practices as instrumental deliveries, prescription of prolonged bed rest after delivery, and use of prolonged bed rest after delivery, and use of estrogens to stop lactationestrogens to stop lactation..

Risk Factors for DVT in Risk Factors for DVT in PregnancyPregnancy

PregnancyPregnancyPregnancyPregnancy itselfitselfitselfitself; DVT is ; DVT is 5 5 times more in pregnant than nontimes more in pregnant than non--pregnant agepregnant age--matched female.matched female.

VVirchowirchow’’s triad:s triad: ( ( hypercoagulabilityhypercoagulability, stasis, and endothelial , stasis, and endothelial


VVirchowirchow’’s triad:s triad: ( ( hypercoagulabilityhypercoagulability, stasis, and endothelial , stasis, and endothelial

injury) operates during pregnancy and puerperium.injury) operates during pregnancy and puerperium.

11-- HYPERHYPER--COAGULABILITYCOAGULABILITY: Increased levels of clotting factors : Increased levels of clotting factors (factor I,II,VII,IX, and X) .Decreased fibrinolysis and (factor I,II,VII,IX, and X) .Decreased fibrinolysis and reduced levels of natural anticoagulants (e.g. proteinreduced levels of natural anticoagulants (e.g. protein-- S) S) contribute to this state of hypercoagulability during contribute to this state of hypercoagulability during pregnancy .pregnancy .

Risk factorsRisk factors (continued)(continued)

VVirchowirchow’’s triad:s triad: ( ( hypercoagulabilityhypercoagulability, , stasisstasis, and endothelial , and endothelial

injury) operates during pregnancy and puerperium.injury) operates during pregnancy and puerperium.

22-- STASISSTASIS: Venous stasis due to pressure of the : Venous stasis due to pressure of the gravid uterus on the IVC and decreased venous gravid uterus on the IVC and decreased venous


gravid uterus on the IVC and decreased venous gravid uterus on the IVC and decreased venous tone are further predisposing factors present in all tone are further predisposing factors present in all pregnant women. At term, flow velocity of the pregnant women. At term, flow velocity of the femoral vein slows to less than femoral vein slows to less than 11//33rdrd of the velocity of the velocity in the first trimester, and subsequently in the postin the first trimester, and subsequently in the post--partum period. Moreover, the vessel diameter of partum period. Moreover, the vessel diameter of the deep leg vein increases during pregnancy. the deep leg vein increases during pregnancy.

Risk factorsRisk factors (continued)(continued)

VVirchowirchow’’s triad:s triad: ( ( hypercoagulabilityhypercoagulability, stasis, and , stasis, and endothelial endothelial

injuryinjury) operates during pregnancy and puerperium.) operates during pregnancy and puerperium.

33-- ENDOTHELIAL VASCULAR INJURY: ENDOTHELIAL VASCULAR INJURY: Although pregnancy Although pregnancy


33-- ENDOTHELIAL VASCULAR INJURY: ENDOTHELIAL VASCULAR INJURY: Although pregnancy Although pregnancy itself is not associated with endothelial injury, the itself is not associated with endothelial injury, the trauma of operative delivery may result vascular trauma of operative delivery may result vascular injury, leading to postinjury, leading to post--partum DVT.partum DVT.

Risk factorsRisk factors ((continued)continued)

OtherOther RiskRisk FactorsFactors include:include:

�� Increased parity (Increased parity (> > 44).).

�� Obesity .Obesity .


�� Obesity .Obesity .

�� Operative or difficult instrumental delivery.Operative or difficult instrumental delivery.

�� Prolonged immobility.Prolonged immobility.

�� Previous thromboPrevious thrombo--embolism or DVT.embolism or DVT.

�� Thrombophilias.Thrombophilias.

Pathogenesis:Pathogenesis:

Multiple risk factors are often present Multiple risk factors are often present in women who develop DVT during in women who develop DVT during pregnancy and these risk factors are pregnancy and these risk factors are


pregnancy and these risk factors are pregnancy and these risk factors are cumulative.cumulative.

In addition, an occult thrombophilia In addition, an occult thrombophilia such as such as FactorFactor--VV-- Leiden mutationLeiden mutationmay become unmasked during an may become unmasked during an otherwise normal pregnancy.otherwise normal pregnancy.

PPathogenesis: athogenesis: (continued)(continued)

WWhich side is more prone during pregnancy for DVT ?hich side is more prone during pregnancy for DVT ?

During pregnancy venous thrombosis begins most During pregnancy venous thrombosis begins most frequently frequently either in the calf veins or in the ilioeither in the calf veins or in the ilio--femoral segmentfemoral segment of the deep venous system.of the deep venous system.


There is a striking propensity for the There is a striking propensity for the leftleft legleg, with , with 8080% of DVT in pregnancy occurring on this side. % of DVT in pregnancy occurring on this side. This may be due to the fact that the venous This may be due to the fact that the venous drainage of the left leg flows a more tortuous drainage of the left leg flows a more tortuous course through the pelvis, with the left common course through the pelvis, with the left common iliac vein traversed by the right common iliac artery.iliac vein traversed by the right common iliac artery.

DDiagnosis : iagnosis : Clinical picture;Clinical picture;

Clinical diagnosis of DVT and thromboembolism is Clinical diagnosis of DVT and thromboembolism is notoriously notoriously unreliable because:unreliable because:

�� The intensity of the classical symptoms of pain, tenderness, The intensity of the classical symptoms of pain, tenderness, and swelling of the affected limb depends on the extent of the and swelling of the affected limb depends on the extent of the vascular occlusion, existing collateral circulation, and the vascular occlusion, existing collateral circulation, and the associated inflammatory response.associated inflammatory response.


vascular occlusion, existing collateral circulation, and the vascular occlusion, existing collateral circulation, and the associated inflammatory response.associated inflammatory response.

�� The physiological changes of pregnancy further complicate The physiological changes of pregnancy further complicate interpretation of the patientinterpretation of the patient’’s history, physical findings, and s history, physical findings, and test results.test results.

�� DVT in pregnancy may present atypically with diffuse DVT in pregnancy may present atypically with diffuse abdominal pain.abdominal pain.

�� Dyspnea, a common symptom of DVT, is experienced in Dyspnea, a common symptom of DVT, is experienced in 7575% % of females during normal pregnancy. of females during normal pregnancy.

DDiagnosis : iagnosis : NonNon--invasive tests;invasive tests;

In the late In the late 19901990--ies, nonies, non--invasive diagnostic studies invasive diagnostic studies such as such as impedanceimpedance plethysmographyplethysmography, , realreal timetime B B mode U/Smode U/S, and , and duplex doppler scanningduplex doppler scanning have have replaced venography as replaced venography as the initial screening testthe initial screening test in in


replaced venography as replaced venography as the initial screening testthe initial screening test in in the diagnosis of DVT. the diagnosis of DVT.

These diagnostic tests have high sensitivity for These diagnostic tests have high sensitivity for detection of thrombosis in the iliodetection of thrombosis in the ilio--femoral veins femoral veins but but notnot in the distal deep veins of the lower limbs. in the distal deep veins of the lower limbs.


Impedance Impedance PPlethysmography : lethysmography :

�� Measures changes in electric resistance Measures changes in electric resistance measured by measured by 2 2 electrodes wrapped around electrodes wrapped around the calf in relation to changes in venous the calf in relation to changes in venous the calf in relation to changes in venous the calf in relation to changes in venous volume.volume.

�� Serial normal studies are Serial normal studies are sufficient to sufficient to withhold therapywithhold therapy in both nonin both non--pregnant and pregnant and pregnant patientspregnant patients


Doppler ultrasonography:Doppler ultrasonography:�� This technique has become the diagnostic test of This technique has become the diagnostic test of

choice in cases of suspected choice in cases of suspected proximal veinproximal veinocclusion.occlusion.


occlusion.occlusion.

�� With expert sonographer, a correct diagnosis with With expert sonographer, a correct diagnosis with high sensitivity and specificity (high sensitivity and specificity (9191% and % and 9999% % respectively) in evaluation of proximal vein respectively) in evaluation of proximal vein thrombosis is obtained. thrombosis is obtained.

�� Limitations includeLimitations include: less effectiveness in calf vein : less effectiveness in calf vein thrombosis, and less sensitivity for diagnosis of thrombosis, and less sensitivity for diagnosis of asymptomatic thrombosis.asymptomatic thrombosis.

DDiagnosis ; iagnosis ; V V e n o g r a p h y:e n o g r a p h y:

What is the role?What is the role?

�� Venography remains the diagnostic standard Venography remains the diagnostic standard for DVT in both pregnant and nonfor DVT in both pregnant and non--pregnant pregnant patients.patients.

�� It has the advantage of It has the advantage of accuratelyaccurately


�� It has the advantage of It has the advantage of accuratelyaccuratelyevaluating the evaluating the entireentire lower limb from the lower limb from the calf veins to the common iliac vessels.calf veins to the common iliac vessels.

�� Although Although invasiveinvasive, it is still more reliable , it is still more reliable than the nonthan the non--invasive techniques in invasive techniques in differentiating between differentiating between intraintra--luminalluminal defects defects and and externalexternal venous compression.venous compression.


HHow safe is it?ow safe is it?

�� Potential side effects include:Potential side effects include:1.1. Chemical phlebitis,Chemical phlebitis,

2.2. Leg swelling, leg painLeg swelling, leg pain


3.3. Skin necrosis due to dye extraSkin necrosis due to dye extra--vasationvasation

�� Procedure is invasive & associated with Procedure is invasive & associated with risks of provoking thrombosis and contrast risks of provoking thrombosis and contrast reaction.reaction.

�� Procedure is relatively expensive & the Procedure is relatively expensive & the results can be difficult to interpret. results can be difficult to interpret.


HHow safe is it? (contd.)ow safe is it? (contd.)

�� Estimated fetal radiation exposure is Estimated fetal radiation exposure is negligible; approximately negligible; approximately 00..314 314 rad for a rad for a unilateral procedure without abdominal unilateral procedure without abdominal shielding.shielding.


shielding.shielding.

�� Limited venography, using an abdominal Limited venography, using an abdominal shield, can reduce the estimated fetal shield, can reduce the estimated fetal exposure to less than exposure to less than 00..05 05 rad.rad.


CONCLUSIONCONCLUSIONCONCLUSIONCONCLUSION

��The role of venography in diagnosing The role of venography in diagnosing DVT in pregnancy remains unresolved.DVT in pregnancy remains unresolved.


��Venography may be helpful when the Venography may be helpful when the results of nonresults of non--invasive imaging studies invasive imaging studies are equivocal OR serial scanning is are equivocal OR serial scanning is impractical.impractical.

D D D D D D D D I A G N O S I SI A G N O S I SI A G N O S I SI A G N O S I SI A G N O S I SI A G N O S I SI A G N O S I SI A G N O S I SRecent Advances:Recent Advances:

MAGNETICMAGNETIC RESONANCERESONANCE IMAGINGIMAGING::�� MRI has been established to be reliable method MRI has been established to be reliable method

for diagnosing pelvic and lower limb venous for diagnosing pelvic and lower limb venous thrombosis.thrombosis.


thrombosis.thrombosis.

�� Despite its cost it has the following advantages: Despite its cost it has the following advantages:

1.1. At least it is as accurate as venography for At least it is as accurate as venography for proximal thrombosis in the lower limb and even proximal thrombosis in the lower limb and even more sensitive for pelvic vein thrombosis.more sensitive for pelvic vein thrombosis.

2.2. Advantages in pregnancy; nonAdvantages in pregnancy; non--invasive, no invasive, no ionizing radiation, and excellent resolution of the ionizing radiation, and excellent resolution of the IVC and pelvic veins. IVC and pelvic veins.

D D D D D D D D I A G N O S I SI A G N O S I SI A G N O S I SI A G N O S I SI A G N O S I SI A G N O S I SI A G N O S I SI A G N O S I SRecent Advances: Recent Advances: (contd.,)(contd.,)

B L O O D T E S T SB L O O D T E S T S�� Several tests are available that reflect the formation of Several tests are available that reflect the formation of

intravascular fibrin. Results are invariably intravascular fibrin. Results are invariably +ve when +ve when thrombosis has occurred.thrombosis has occurred.


�� The most important tests are assays for fibrinopeptide A (FPA) The most important tests are assays for fibrinopeptide A (FPA) and fibrin degradation products (FDP); Dand fibrin degradation products (FDP); D--dimers are the most dimers are the most sensitive.sensitive.

�� Elevations in DElevations in D--dimer levels are found even in uncomplicated dimer levels are found even in uncomplicated pregnancy, in levels increasing during the course of pregnancy, in levels increasing during the course of pregnancy.pregnancy.

�� However, a finding of normal level of these, essentially rules However, a finding of normal level of these, essentially rules out DVT. out DVT.

D D D D D D D D I A G N O S I SI A G N O S I SI A G N O S I SI A G N O S I SI A G N O S I SI A G N O S I SI A G N O S I SI A G N O S I SRecent Advances: Recent Advances: (contd.,)(contd.,)

B L O O D T E S T SB L O O D T E S T SDIAGNOSTIC WORK UP FOR CONGENITALTHROMBOPHILIASDIAGNOSTIC WORK UP FOR CONGENITALTHROMBOPHILIAS

� Activated protein-C resistance due to factor V Leiden mutation is the commonest thrombophilia. The defect is rare in Africans, and Asians. So, diagnostic work-up for


rare in Africans, and Asians. So, diagnostic work-up for thrombophilia is not indicated in all cases of DVT in pregnancy, but only in selected cases with clinical indicators of hypercoagulable state which include:

1. Family history of thrombosis, Recurrent thrombosis, or idiopathic thrombosis

2. Thrombosis at unusual sites (e.g., axillary, cerebral, mesenteric, portal, hepatic veins)

3. Skin necrosis after starting warfarin therapy

M A N A G E M E N T M A N A G E M E N T M A N A G E M E N T M A N A G E M E N T M A N A G E M E N T M A N A G E M E N T M A N A G E M E N T M A N A G E M E N T

The Aims of TreatmentThe Aims of Treatment

1.1. To prevent extension of the thrombusTo prevent extension of the thrombus

2.2. To restore venous patency To restore venous patency ----------»»prevent prevent postpost--phlebitic syndrome (chronic pain, phlebitic syndrome (chronic pain, swelling, ulceration) due to venous swelling, ulceration) due to venous


swelling, ulceration) due to venous swelling, ulceration) due to venous insufficiencyinsufficiency

3.3. The most important aim is to prevent The most important aim is to prevent pulmonary embolism or its recurrencepulmonary embolism or its recurrence

M A N A G E M E N TM A N A G E M E N TM A N A G E M E N TM A N A G E M E N TM A N A G E M E N TM A N A G E M E N TM A N A G E M E N TM A N A G E M E N TIsIsIsIsIsIsIsIs bed rest absolutely necessary in all cases of acute bed rest absolutely necessary in all cases of acute bed rest absolutely necessary in all cases of acute bed rest absolutely necessary in all cases of acute bed rest absolutely necessary in all cases of acute bed rest absolutely necessary in all cases of acute bed rest absolutely necessary in all cases of acute bed rest absolutely necessary in all cases of acute

DVT?DVT?DVT?DVT?DVT?DVT?DVT?DVT?

�� Bed rest with elevation of the affected limb is Bed rest with elevation of the affected limb is invaluable initially because it promotes venous invaluable initially because it promotes venous return & decrease edema.return & decrease edema.

�� As soon as symptoms permit, the patient should be As soon as symptoms permit, the patient should be


�� As soon as symptoms permit, the patient should be As soon as symptoms permit, the patient should be encouraged to ambulate, since bed rest itself may encouraged to ambulate, since bed rest itself may enhance venous stasis.enhance venous stasis.

�� There is no evidence that bed rest will prevent There is no evidence that bed rest will prevent embolus detachment .embolus detachment .

�� Sitting with legs dependant is contraindicated. Sitting with legs dependant is contraindicated.

M A N A G E M E N TM A N A G E M E N TM A N A G E M E N TM A N A G E M E N TM A N A G E M E N TM A N A G E M E N TM A N A G E M E N TM A N A G E M E N TSSSSSSSShould hould hould hould hould hould hould hould wwwwwwwweeeeeeee Advocate Elastic Bandage Advocate Elastic Bandage Advocate Elastic Bandage Advocate Elastic Bandage Advocate Elastic Bandage Advocate Elastic Bandage Advocate Elastic Bandage Advocate Elastic Bandage / / / / / / / / Stocking?Stocking?Stocking?Stocking?Stocking?Stocking?Stocking?Stocking?

�� When correctly designed, elastic stockings increase When correctly designed, elastic stockings increase the velocity of venous return.the velocity of venous return.


�� The pressure gradient should decrease from ankle The pressure gradient should decrease from ankle to thigh without a constricting garter at the top.to thigh without a constricting garter at the top.

�� Elastic bandages once in vogue, are best avoided Elastic bandages once in vogue, are best avoided because they are easily wrapped incorrectly with because they are easily wrapped incorrectly with the greatest pressure ending up at the top, thus the greatest pressure ending up at the top, thus impeding venous return. impeding venous return.

M A N A G E M E N TM A N A G E M E N TM A N A G E M E N TM A N A G E M E N TM A N A G E M E N TM A N A G E M E N TM A N A G E M E N TM A N A G E M E N TDoes DVT limited to the Does DVT limited to the Does DVT limited to the Does DVT limited to the Does DVT limited to the Does DVT limited to the Does DVT limited to the Does DVT limited to the calfcalfcalfcalfcalfcalfcalfcalf require treatment? require treatment? require treatment? require treatment? require treatment? require treatment? require treatment? require treatment?

�� The need for treatment of thrombosis below the The need for treatment of thrombosis below the level of popliteal fossa remains disputable as risk of level of popliteal fossa remains disputable as risk of pulmonary embolism in such cases is very low(pulmonary embolism in such cases is very low(11%).%).

�� However, because about However, because about 2020% of lower DVT% of lower DVT’’s s


�� However, because about However, because about 2020% of lower DVT% of lower DVT’’s s extend proximally and anticoagulants can prevent extend proximally and anticoagulants can prevent this spread, many believe that treatment is this spread, many believe that treatment is required.required.

�� An alternative is frequent doppler flow studies to An alternative is frequent doppler flow studies to detect extension and then treat. detect extension and then treat.

MANAGEMENT MANAGEMENT MANAGEMENT MANAGEMENT MANAGEMENT MANAGEMENT MANAGEMENT MANAGEMENT

Anticoagulant TherapyAnticoagulant Therapy

How safe are the anticoagulants in pregnancyHow safe are the anticoagulants in pregnancy

FDA categoryFDA categoryAgentAgent

DDWarfarin Warfarin

CCUnfractionated heparinUnfractionated heparin


BBDalteparin sodium (LMWH)Dalteparin sodium (LMWH)

BBEnoxaparin sodium (LMWH)Enoxaparin sodium (LMWH)

CCStreptokinaseStreptokinase

BBUrokinase Urokinase

MANAGEMENT MANAGEMENT MANAGEMENT MANAGEMENT MANAGEMENT MANAGEMENT MANAGEMENT MANAGEMENT Anticoagulant TherapyAnticoagulant Therapy (cont’d.)(cont’d.)(cont’d.)(cont’d.)(cont’d.)(cont’d.)(cont’d.)(cont’d.)

W A R F A R I NW A R F A R I N

�� It is the most widely used coumarin derivative for It is the most widely used coumarin derivative for oraloralanticoagulation. Its therapeutic efficacy lies in its ability to anticoagulation. Its therapeutic efficacy lies in its ability to inhibit the action of vitamin K, which is a cofactor for the inhibit the action of vitamin K, which is a cofactor for the synthesis of synthesis of 4 4 essential clotting factors in the liver (essential clotting factors in the liver (factor VII, factor VII, IX, X, prothrombinIX, X, prothrombin). ).


IX, X, prothrombinIX, X, prothrombin). ).

�� DOSAGE: usual dose=DOSAGE: usual dose=1010--15 15 mg daily until therapeutic mg daily until therapeutic prolongation of PT is achieved (INR=prolongation of PT is achieved (INR=22--33). Heparin is ). Heparin is continued for the continued for the 11stst week of warfarin therapy as its action is week of warfarin therapy as its action is not immediate.not immediate.

�� MONITOURING: PT daily for MONITOURING: PT daily for 7 7 days, then days, then 22/week for /week for 22w,then w,then

weekly for several months depending on the response.weekly for several months depending on the response.



�� Avoid large loading dose as it may cause overAvoid large loading dose as it may cause over--coagulation coagulation due to excessive protein C inhibition.due to excessive protein C inhibition.

�� Warfarin use during pregnancy is limited as it crosses the Warfarin use during pregnancy is limited as it crosses the placenta with the following fetal hazards:placenta with the following fetal hazards:

Risk of embryopathy(Risk of embryopathy(55%) if taken between %) if taken between 66thth and and 1212thth


1.1. Risk of embryopathy(Risk of embryopathy(55%) if taken between %) if taken between 66thth and and 1212thth

weeks of gestation. (nasal, epiphysealweeks of gestation. (nasal, epiphyseal--limb hypoplasia).limb hypoplasia).

2.2. If taken after If taken after 11stst trimester of pregnancy it may cause trimester of pregnancy it may cause neurological & ophthalmic anomalies. Also can cause fetal& neurological & ophthalmic anomalies. Also can cause fetal& neonatal hemorrhage, and placental abruptionneonatal hemorrhage, and placental abruption

�� It can cause major maternal hemorrhage & its action is not It can cause major maternal hemorrhage & its action is not as easily reversed as that of heparin. as easily reversed as that of heparin.



For its risks, Warfarin:For its risks, Warfarin:

Is absolutely contraIs absolutely contra--indicated during first trimester.indicated during first trimester.

Its use in Its use in 22ndnd & & 33rdrd trimesters is controversial.trimesters is controversial.

If its use during pregnancy is specifically indicated; If its use during pregnancy is specifically indicated;


If its use during pregnancy is specifically indicated; If its use during pregnancy is specifically indicated; it should replace heparin after the it should replace heparin after the 1212thth week, and week, and replaced by heparin after the replaced by heparin after the 3636thth week or at the week or at the onset of labor.onset of labor.

If labor started while using it, parenteral vitamin K If labor started while using it, parenteral vitamin K and fresh frozen plasma can reverse its effect.and fresh frozen plasma can reverse its effect.


WHAT IS THE MOST COMMONLY USED ANTICOAGULANT WHAT IS THE MOST COMMONLY USED ANTICOAGULANT WHAT IS THE MOST COMMONLY USED ANTICOAGULANT WHAT IS THE MOST COMMONLY USED ANTICOAGULANT WHAT IS THE MOST COMMONLY USED ANTICOAGULANT WHAT IS THE MOST COMMONLY USED ANTICOAGULANT WHAT IS THE MOST COMMONLY USED ANTICOAGULANT WHAT IS THE MOST COMMONLY USED ANTICOAGULANT DURING PREGNANCY?DURING PREGNANCY?DURING PREGNANCY?DURING PREGNANCY?DURING PREGNANCY?DURING PREGNANCY?DURING PREGNANCY?DURING PREGNANCY?

Unfractionated heparin(UFH):Unfractionated heparin(UFH):

�� Naturally occurring mucopolysaccharide.Naturally occurring mucopolysaccharide.

�� In plasma, it combines with antiIn plasma, it combines with anti--thrombin III to thrombin III to become a potent inhibitor of thrombin& to increase become a potent inhibitor of thrombin& to increase


become a potent inhibitor of thrombin& to increase become a potent inhibitor of thrombin& to increase the circulating levels of activated factor X inhibitor.the circulating levels of activated factor X inhibitor.

�� ANTIDOTE :ANTIDOTE :If necessary heparin effects can be If necessary heparin effects can be reversed rapidly with reversed rapidly with protamine sulfateprotamine sulfate in a dose of in a dose of 11mg/mg/100 100 units of administered heparin. No more units of administered heparin. No more than than 5050mg should be given over any mg should be given over any 10 10 min. period min. period because itself can cause bleeding.because itself can cause bleeding.


WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?

�� Lack of adequate anticoagulation increase the risk Lack of adequate anticoagulation increase the risk of recurrence of thrombosis by of recurrence of thrombosis by 1111--15 15 folds.folds.

�� Optimal anticoagulation is obtained with an APTT of Optimal anticoagulation is obtained with an APTT of 6060--80 80 sec (sec (11..55--22..5 5 times control).times control).


�� PrePre--treatment : CBC, Platelet count, PT, APTT, treatment : CBC, Platelet count, PT, APTT, Urine analysis.Urine analysis.

�� Loading dose: Loading dose: 100 100 u/kg u/kg with minimum of with minimum of 5000 5000 u. u. following it, the initial infusion rate should be following it, the initial infusion rate should be 1515--2525u/kg/hr. u/kg/hr.

�� APTT should be obtained after the loading dose and APTT should be obtained after the loading dose and appropriate adjustment should be made.appropriate adjustment should be made.


WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?WHAT ARE THE THERAPEUTIC DOSES OF HEPARIN?

�� MAINTENANCE DOSAGE: continuous IV infusion for MAINTENANCE DOSAGE: continuous IV infusion for 33--5 5 days for active thromboembolism or symptoms resolved & days for active thromboembolism or symptoms resolved & there is no recurrence.there is no recurrence.

�� It is followed by adjusted dose regimen of heparin for It is followed by adjusted dose regimen of heparin for 4 4 months followed by a prophylactic dose for the remainder of months followed by a prophylactic dose for the remainder of


months followed by a prophylactic dose for the remainder of months followed by a prophylactic dose for the remainder of pregnancy and pregnancy and 66--12 12 weeks postpartum.weeks postpartum.

�� Adjusted dose regimen: Adjusted dose regimen: S.C.S.C. heparin /heparin /1212hrs. Dose adjusted to hrs. Dose adjusted to obtain APTT=obtain APTT=11..55--22..0 0 times control at times control at 66hrs. Once a stable hrs. Once a stable dose reached, middose reached, mid--interval APTT done weekly at the antenatal interval APTT done weekly at the antenatal visits.visits.

�� Heparin requirements should be anticipated to increase during Heparin requirements should be anticipated to increase during pregnancy until term. pregnancy until term.


SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?

�� If DVT occurred If DVT occurred ≥ ≥ 33months before the EDD, months before the EDD, anticoagulation during labor is NOT indicated. anticoagulation during labor is NOT indicated. Patient instructed to discontinue therapy with onset Patient instructed to discontinue therapy with onset of labor. The morning dose should not be taken by of labor. The morning dose should not be taken by


of labor. The morning dose should not be taken by of labor. The morning dose should not be taken by those who are planned for cesarean delivery. those who are planned for cesarean delivery. Heparin is resumed Heparin is resumed 44--6 6 hours postpartum.hours postpartum.

�� Regional anesthesia is not contraindicated if APTT Regional anesthesia is not contraindicated if APTT is normal and heparin not given in last is normal and heparin not given in last 44--66hrs.hrs.


SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?SHOULD ANTICOAGULANT BE GIVEN DURING LABOR?

�� If heparin is required during labor, the dose should If heparin is required during labor, the dose should be adjusted to achieve an APTT of be adjusted to achieve an APTT of 11..5 5 times control times control during labor and delivery.during labor and delivery.


�� Conduction anesthesia is contraindicated in these Conduction anesthesia is contraindicated in these patients.patients.

�� With this dose the incidence of PPHge.is not With this dose the incidence of PPHge.is not increased in a normal labor, but the incidence of increased in a normal labor, but the incidence of episiotomy hematoma is increased. episiotomy hematoma is increased.


WHAT ARE THE COMPLICATIONS OF HEPARIN THERAPY?WHAT ARE THE COMPLICATIONS OF HEPARIN THERAPY?WHAT ARE THE COMPLICATIONS OF HEPARIN THERAPY?WHAT ARE THE COMPLICATIONS OF HEPARIN THERAPY?WHAT ARE THE COMPLICATIONS OF HEPARIN THERAPY?WHAT ARE THE COMPLICATIONS OF HEPARIN THERAPY?WHAT ARE THE COMPLICATIONS OF HEPARIN THERAPY?WHAT ARE THE COMPLICATIONS OF HEPARIN THERAPY?

�� Heparin does not cross placenta, so Heparin does not cross placenta, so no fetal hazardsno fetal hazards. All . All complications are maternal;complications are maternal;

1.1. BleedingBleeding: not significantly more in pregnant than non : not significantly more in pregnant than non pregnant. SC heparin may cause persistent anticoagulation pregnant. SC heparin may cause persistent anticoagulation after cessation of use, so it is recommended to convert to after cessation of use, so it is recommended to convert to IV heparin IV heparin 24 24 hrs before elective induction of labor.hrs before elective induction of labor.


IV heparin IV heparin 24 24 hrs before elective induction of labor.hrs before elective induction of labor.2.2. Osteoporosis;Osteoporosis; reversible, more in pregnant than non reversible, more in pregnant than non

pregnant (prolonged therapy, pregnancy & lactation pregnant (prolonged therapy, pregnancy & lactation demineralization.demineralization.

3.3. ThrombocytopeniaThrombocytopenia; ; 2 2 forms forms (a)(a) early benignearly benign, mild occurs , mild occurs 11--6 6 days of treatment days of treatment (b)(b) delayed severedelayed severe, , immuneimmune--mediated, occurs mediated, occurs 66--10 10 days of treatment. The days of treatment. The 22ndnd form may form may be associated with paradoxical arterial and venous be associated with paradoxical arterial and venous thrombosis. Requires immediate heparin withdrawal. thrombosis. Requires immediate heparin withdrawal.


WHAT IS HEPARIN RESISTANCE?WHAT IS HEPARIN RESISTANCE?WHAT IS HEPARIN RESISTANCE?WHAT IS HEPARIN RESISTANCE?WHAT IS HEPARIN RESISTANCE?WHAT IS HEPARIN RESISTANCE?WHAT IS HEPARIN RESISTANCE?WHAT IS HEPARIN RESISTANCE?

�� Defined as the need for more than Defined as the need for more than 2020,,000 000 units units of heparin/day. Mainly occurs in patients with of heparin/day. Mainly occurs in patients with large venous thrombolarge venous thrombo--emboli.emboli.

�� Mechanism of resistance:Mechanism of resistance:1.1. Inherited or acquired decrease in AT III levels.Inherited or acquired decrease in AT III levels.


1.1. Inherited or acquired decrease in AT III levels.Inherited or acquired decrease in AT III levels.2.2. Increased plasma levels of factor VIII.Increased plasma levels of factor VIII.3.3. Increased plasma levels of heparin binding Increased plasma levels of heparin binding

proteins.proteins.�� Monitoring here is not with APTT, but with antiMonitoring here is not with APTT, but with anti--

factor Xa assay.factor Xa assay.�� Low molecular weight heparin should be used Low molecular weight heparin should be used Low molecular weight heparin should be used Low molecular weight heparin should be used Low molecular weight heparin should be used Low molecular weight heparin should be used Low molecular weight heparin should be used Low molecular weight heparin should be used

alternatively as they have less protein binding. alternatively as they have less protein binding. alternatively as they have less protein binding. alternatively as they have less protein binding. alternatively as they have less protein binding. alternatively as they have less protein binding. alternatively as they have less protein binding. alternatively as they have less protein binding.


WHAT ARE LOW MOLECULAR WEIGHT HEPARINWHAT ARE LOW MOLECULAR WEIGHT HEPARINWHAT ARE LOW MOLECULAR WEIGHT HEPARINWHAT ARE LOW MOLECULAR WEIGHT HEPARINWHAT ARE LOW MOLECULAR WEIGHT HEPARINWHAT ARE LOW MOLECULAR WEIGHT HEPARINWHAT ARE LOW MOLECULAR WEIGHT HEPARINWHAT ARE LOW MOLECULAR WEIGHT HEPARINS (LMWH)S (LMWH)S (LMWH)S (LMWH)S (LMWH)S (LMWH)S (LMWH)S (LMWH)????????

�� Are fragments of conventional heparin produced by Are fragments of conventional heparin produced by enzymatic or chemical breakdown.enzymatic or chemical breakdown.

�� Like heparin, they donLike heparin, they don’’t cross the placenta, are t cross the placenta, are


�� Like heparin, they donLike heparin, they don’’t cross the placenta, are t cross the placenta, are

nonnon--teratogenic, and not secreted in milk.teratogenic, and not secreted in milk.

�� By virtue of their shorter & lighter structures, By virtue of their shorter & lighter structures, LMWHs produce predominantly antiLMWHs produce predominantly anti--thrombotic thrombotic effect through their inhibition of factor Xa with little effect through their inhibition of factor Xa with little anticoagulant activity.anticoagulant activity.


ARE DIFFERENT LMWHs SIMILAR IN ACTION?ARE DIFFERENT LMWHs SIMILAR IN ACTION?ARE DIFFERENT LMWHs SIMILAR IN ACTION?ARE DIFFERENT LMWHs SIMILAR IN ACTION?ARE DIFFERENT LMWHs SIMILAR IN ACTION?ARE DIFFERENT LMWHs SIMILAR IN ACTION?ARE DIFFERENT LMWHs SIMILAR IN ACTION?ARE DIFFERENT LMWHs SIMILAR IN ACTION?

�� LMWs have a molecular weight between LMWs have a molecular weight between 44,,000 000 to to 66,,000000. Various formulations differ . Various formulations differ in mean MW, glucosaminoglycan content, in mean MW, glucosaminoglycan content, and anticoagulant activity.and anticoagulant activity.


and anticoagulant activity.and anticoagulant activity.

�� Each LMWH has its own bioavailability, Each LMWH has its own bioavailability, plasma clearance, and release of tissue plasma clearance, and release of tissue factor inhibitor. So properties of a particular factor inhibitor. So properties of a particular LMWH are not applicable to another.LMWH are not applicable to another.


WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?

LMWHsLMWHsUFHUFHEffect Effect

33,,000000--99,,0000001515,,000000--3030,,000000Mean MWt. [dalton]Mean MWt. [dalton]

22--44::1111::11Anti Xa : Antithrombin ratio Anti Xa : Antithrombin ratio


22--44::1111::11Anti Xa : Antithrombin ratio Anti Xa : Antithrombin ratio

Minimal Minimal Significant Significant Protein bindingProtein binding

Rare Rare Not rareNot rareThrombocytopenia Thrombocytopenia

±±9090%%±±3030%%Bioavailability Bioavailability

scscSc or ivSc or ivRoute of administrationRoute of administration


WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?WHAT ARE THE ADVANTAGES OF LMWHs OVER UFH?

1.1. Less hemorrhagic complications.Less hemorrhagic complications.

2.2. Lower risk of heparin induced thrombocytopenia.Lower risk of heparin induced thrombocytopenia.

3.3. Less frequent dosages [increased bioavailability& Less frequent dosages [increased bioavailability& longer half life].longer half life].


longer half life].longer half life].

4.4. No heparin induced osteoporosis.No heparin induced osteoporosis.

5.5. Anti Xa, activity is correlated with body weight, Anti Xa, activity is correlated with body weight, this allows administration in fixed dose.this allows administration in fixed dose.

6.6. No need for lab. Monitoring for coagulation tests No need for lab. Monitoring for coagulation tests like PT and APTT.like PT and APTT.


CAN LMWHs BE USED FOR ACUTE TREATMENT OF D.V.T?CAN LMWHs BE USED FOR ACUTE TREATMENT OF D.V.T?CAN LMWHs BE USED FOR ACUTE TREATMENT OF D.V.T?CAN LMWHs BE USED FOR ACUTE TREATMENT OF D.V.T?CAN LMWHs BE USED FOR ACUTE TREATMENT OF D.V.T?CAN LMWHs BE USED FOR ACUTE TREATMENT OF D.V.T?CAN LMWHs BE USED FOR ACUTE TREATMENT OF D.V.T?CAN LMWHs BE USED FOR ACUTE TREATMENT OF D.V.T?

�� Until recently, the use of LMWHs in pregnancy was Until recently, the use of LMWHs in pregnancy was limited to chronic phase of the disease &for limited to chronic phase of the disease &for prophylaxis.prophylaxis.

�� Intravenous unfractionated heparin is gradually Intravenous unfractionated heparin is gradually being replaced in modern practice by s.c. LMWs, being replaced in modern practice by s.c. LMWs,


being replaced in modern practice by s.c. LMWs, being replaced in modern practice by s.c. LMWs, granting equal or even better efficacy; granting equal or even better efficacy; much easier much easier dosing, a wider therapeutic window, fewer bleeding dosing, a wider therapeutic window, fewer bleeding complications, and faster and more reliable resultscomplications, and faster and more reliable results..

� Full anticoagulation dose of LMWHs:ENOXAPARIN=ENOXAPARIN=11mg/kg SC bdmg/kg SC bdDALTEPARIN=DALTEPARIN=100 100 iu/kg SC bdiu/kg SC bd


DO ALL PATIENTS WITH DVT REQUIRE HOSPITALIZATION?DO ALL PATIENTS WITH DVT REQUIRE HOSPITALIZATION?DO ALL PATIENTS WITH DVT REQUIRE HOSPITALIZATION?DO ALL PATIENTS WITH DVT REQUIRE HOSPITALIZATION?DO ALL PATIENTS WITH DVT REQUIRE HOSPITALIZATION?DO ALL PATIENTS WITH DVT REQUIRE HOSPITALIZATION?DO ALL PATIENTS WITH DVT REQUIRE HOSPITALIZATION?DO ALL PATIENTS WITH DVT REQUIRE HOSPITALIZATION?

Advent of LMWHs for treatment of DVT Advent of LMWHs for treatment of DVT with advantages of sc once or twice with advantages of sc once or twice daily dosage without monitoring has daily dosage without monitoring has


daily dosage without monitoring has daily dosage without monitoring has made it possible to treat patients in an made it possible to treat patients in an outpatient setting. outpatient setting. But pregnant state But pregnant state is a contraindication for such is a contraindication for such treatment.treatment.

MANAGEMENT MANAGEMENT MANAGEMENT MANAGEMENT MANAGEMENT MANAGEMENT MANAGEMENT MANAGEMENT Thrombolytic TherapyThrombolytic Therapy

No controlled trials on the safety and efficacy No controlled trials on the safety and efficacy of thrombolytics in pregnant patients have of thrombolytics in pregnant patients have been done. been done.

Because of the risks of maternal hge. and fetal Because of the risks of maternal hge. and fetal loss, thrombolytic therapy should be loss, thrombolytic therapy should be


Because of the risks of maternal hge. and fetal Because of the risks of maternal hge. and fetal loss, thrombolytic therapy should be loss, thrombolytic therapy should be reserved to the following:reserved to the following:

1.1. Massive PE with hemodynamic instability.Massive PE with hemodynamic instability.2.2. The affected limb viability is in jeopardy, The affected limb viability is in jeopardy,

eg. Phlegmasia alba dolens & phlegmasia eg. Phlegmasia alba dolens & phlegmasia cerulae dolenscerulae dolens. .

MANAGEMENTMANAGEMENTMANAGEMENTMANAGEMENTMANAGEMENTMANAGEMENTMANAGEMENTMANAGEMENTThromboThrombo--prophylaxisprophylaxis

�� Risk of recurrent DVT in pregnancy is about Risk of recurrent DVT in pregnancy is about 44--1515%.%.

�� Prophylaxis: (sc heparin Prophylaxis: (sc heparin 77..500500::1010..000 000 U/bd)U/bd)

1.1. H/O DVT + risk factor (eg, thrombophilia, H/O DVT + risk factor (eg, thrombophilia,


1.1. H/O DVT + risk factor (eg, thrombophilia, H/O DVT + risk factor (eg, thrombophilia, APLAS): start in APLAS): start in 11stst trimestertrimester-- toto-- 6 6 weeks postweeks post--partum.partum.

2.2. Only H/O DVT:Only H/O DVT:

a) clinical surveillance followed by warfarin a) clinical surveillance followed by warfarin postpartum x postpartum x 44--6 6 weeks.weeks.

b) UFH or LMWHs throughout pregnancy followed b) UFH or LMWHs throughout pregnancy followed by warfarin/LMWHs x by warfarin/LMWHs x 44--6 6 wks.wks.

REFFERENCES REFFERENCES

Brandjes DP, Heijboer H, Buller HR, et al: Acenocoumarol and heparin compared Brandjes DP, Heijboer H, Buller HR, et al: Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximalwith acenocoumarol alone in the initial treatment of proximal--vein vein

. . [Medline][Medline]99--14851485): ): 2121((327327; ; 1919Nov Nov 1992 1992 thrombosis. N Engl J Med thrombosis. N Engl J Med Feied CF: Pulmonary embolism. In: Rosen P, Barkin RM, eds. Emergency Feied CF: Pulmonary embolism. In: Rosen P, Barkin RM, eds. Emergency Medicine Principles and Practice. Vol Medicine Principles and Practice. Vol 33. . 44th ed. St. Louis, Mo: Mosby; th ed. St. Louis, Mo: Mosby; 19981998: : Chapter Chapter 111111. . Feied CF: Peripheral venous disease. In: Rosen P, Barkin RM, eds. Emergency Feied CF: Peripheral venous disease. In: Rosen P, Barkin RM, eds. Emergency


Feied CF: Peripheral venous disease. In: Rosen P, Barkin RM, eds. Emergency Feied CF: Peripheral venous disease. In: Rosen P, Barkin RM, eds. Emergency Medicine Principles and Practice. Vol Medicine Principles and Practice. Vol 33. . 44th ed. St. Louis, Mo: Mosby; th ed. St. Louis, Mo: Mosby; 19981998: : Chapter Chapter 107107. . Feied CF: Deep Vein Thrombosis and Pulmonary Embolism. In: Rosen P, Barkin Feied CF: Deep Vein Thrombosis and Pulmonary Embolism. In: Rosen P, Barkin RM eds. Emergency Medicine: Concepts and clinical practice . RM eds. Emergency Medicine: Concepts and clinical practice . 55th ed. St. th ed. St. Louis, MO: Mosby; Louis, MO: Mosby; 20012001: Chapter : Chapter 8383. . Havig O: Deep vein thrombosis and pulmonary embolism. An autopsy study with Havig O: Deep vein thrombosis and pulmonary embolism. An autopsy study with multiple regression analysis of possible risk factors. Acta Chir Scand Suppl multiple regression analysis of possible risk factors. Acta Chir Scand Suppl

. . [Medline][Medline]120120--11: : 478478; ; 19771977Konstantinides S, Geibel A, Olschewski M, et al: Association between thrombolytic Konstantinides S, Geibel A, Olschewski M, et al: Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry. Circulation pulmonary embolism: results of a multicenter registry. Circulation 1997 1997 Aug Aug

. . [Medline][Medline]88--882882): ): 33((9696; ; 55

Kucher N, Koo S, Quiroz R: Electronic alerts to prevent venous Kucher N, Koo S, Quiroz R: Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med thromboembolism among hospitalized patients. N Engl J Med 2005 2005

. . [Medline][Medline]7777--969969): ): 1010((352352; ; 1010Mar Mar Nakamura M, Nakanishi N, Yamada N: Effectiveness and safety of the Nakamura M, Nakanishi N, Yamada N: Effectiveness and safety of the thrombolytic therapy for acute pulmonary thromboembolism: results thrombolytic therapy for acute pulmonary thromboembolism: results of a multicenter registry in the Japanese Society of Pulmonary of a multicenter registry in the Japanese Society of Pulmonary

. . [Medline][Medline]99--8383): ): 11((9999Mar; Mar; 2005 2005 Embolism Research. Int J Cardiol Embolism Research. Int J Cardiol


. . [Medline][Medline]99--8383): ): 11((9999Mar; Mar; 2005 2005 Embolism Research. Int J Cardiol Embolism Research. Int J Cardiol Tretbar LL: Venous Disorders of the Legs. Tretbar LL: Venous Disorders of the Legs. 11st ed. New York, NY: st ed. New York, NY: SpringerSpringer--Verlag; Verlag; 19981998: : 11--138138. . Vossen CY, Conard J, Fontcuberta J: Risk of a first venous thrombotic Vossen CY, Conard J, Fontcuberta J: Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost

. . [Medline][Medline]6464--459459): ): 33((33Mar; Mar; 2005 2005 Weiss RA, Feied CF, Weiss MA, eds: Vein Diagnosis & Treatment: A Weiss RA, Feied CF, Weiss MA, eds: Vein Diagnosis & Treatment: A Comprehensive Approach. Comprehensive Approach. 11st ed. New York, NY: McGrawst ed. New York, NY: McGraw--Hill; Hill; 20012001: : 11--304304. .

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Dvt.warda [compatibility mode]

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