inherited thrombophilia is associated with: n recurrent pregnancy losses n preeclampsia n...
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Inherited Thrombophilia is Inherited Thrombophilia is Associated with:Associated with:
Recurrent pregnancy lossesRecurrent pregnancy losses PreeclampsiaPreeclampsia Intrauterine growth retardationIntrauterine growth retardation StillbirthsStillbirths Preterm laborsPreterm labors Maternal deathsMaternal deaths
Recurrent Miscarriage Recurrent Miscarriage Predisposes Women to:Predisposes Women to:
Preterm laborPreterm labor Intrauterine growth retardationIntrauterine growth retardation PreeclampsiaPreeclampsia Fetal anomaliesFetal anomalies
New Actions of New Actions of Antiphospholipid AntibodiesAntiphospholipid Antibodies
Cause increased serum tumor Cause increased serum tumor necrosis factor (TNF) alphanecrosis factor (TNF) alpha
Alters the TH1:TH2 balance Alters the TH1:TH2 balance towards TH1towards TH1
Decreases Decreases interleukin-3 interleukin-3 (IL-3)(IL-3) TNF alpha can initiate the release TNF alpha can initiate the release
of tissue factor and initiate the of tissue factor and initiate the clotting cascadeclotting cascade
Inherited ThrombophiliasInherited Thrombophilias
Rey et al. in a meta-analysis found:Rey et al. in a meta-analysis found:• Increased incidence of factor V Leiden mutationIncreased incidence of factor V Leiden mutation• Prothrombin gene mutation factor IIProthrombin gene mutation factor II• MTHFR gene mutation in patients with MTHFR gene mutation in patients with
recurrent miscarriagerecurrent miscarriage Screening for inherited thrombophilia Screening for inherited thrombophilia
in women with recurrent spontaneous in women with recurrent spontaneous abortion (RSA), infertility and abortion (RSA), infertility and implantation failure is indicatedimplantation failure is indicated
Heparins 1Heparins 1
Heparin increases serum TNF Heparin increases serum TNF binding protein protecting against binding protein protecting against harmful systemic manifestationsharmful systemic manifestations
Low molecular weight (LMW) Low molecular weight (LMW) heparins inhibit TNF alpha heparins inhibit TNF alpha productionproduction
Heparin and LMW heparin are Heparin and LMW heparin are antiinflammatoryantiinflammatory
Heparins 2Heparins 2
LMW heparin limits neutrophil LMW heparin limits neutrophil extravasionextravasion
LMW heparin decreases vein wall LMW heparin decreases vein wall permeabiolitypermeabiolity
Prevents accumulation of Prevents accumulation of proliferating vascular smooth proliferating vascular smooth muscle that encroaches on the muscle that encroaches on the lumen of arterieslumen of arteries
Inherited and Acquired Inherited and Acquired ThrombophiliaThrombophilia
Pregnancy is a hypercoagulable state Pregnancy is a hypercoagulable state (Stirling et al., 1984)(Stirling et al., 1984)
Antiphospholipid antibodies (aPL), an Antiphospholipid antibodies (aPL), an acquired thrombophilic defect, are an acquired thrombophilic defect, are an important and treatable cause for important and treatable cause for pregnancy losses at all gestational ages pregnancy losses at all gestational ages (Rai et al., 1997)(Rai et al., 1997)
Inherited thrombophilias are a greater Inherited thrombophilias are a greater cause for pregnancy losses and cause for pregnancy losses and complications at all gestational agescomplications at all gestational ages(Rai et al., 2002)(Rai et al., 2002)
Factor V Leiden and RSA Factor V Leiden and RSA Outcome of Untreated Outcome of Untreated
PregnanciesPregnancies
Early Losses FVLEarly Losses FVL ++ 37.5%37.5%
Early Losses FVLEarly Losses FVL -- 69.3%69.3%
Late Losses FVLLate Losses FVL ++ 11.1%11.1%
Late Losses FVLLate Losses FVL -- 48.9%48.9%
Factor V Leiden TreatmentFactor V Leiden Treatment
Increase LMW heparin to twice daily Increase LMW heparin to twice daily with a positive pregnancy testwith a positive pregnancy test
LMW Heparin 30 or 40 mg once LMW Heparin 30 or 40 mg once daily started on cycle day 6daily started on cycle day 6
Continue until 6 weeks postpartumContinue until 6 weeks postpartum Aspirin 81 mg daily starting cycle Aspirin 81 mg daily starting cycle
day one of conception cycleday one of conception cycle
Factor V Leiden Outcome Factor V Leiden Outcome with Treatment on RSA with Treatment on RSA
WomenWomen
Carp et al., 2002Carp et al., 2002
Without Without treatmenttreatment 33.2%33.2%
With treatmentWith treatment 85.7%85.7%
Recommended TestsRecommended Tests
LAC screen APTT and dRVVTLAC screen APTT and dRVVT Antiphospholipid antibodiesAntiphospholipid antibodies Factor V Leiden gene mutationFactor V Leiden gene mutation Prothrombin gene factor II gene Prothrombin gene factor II gene
mutationmutation Methylenetetrahydrofolate Methylenetetrahydrofolate
reductase reductase (MTHFR) gene mutation(MTHFR) gene mutation Antinuclear Antibody (ANA)Antinuclear Antibody (ANA)
Importance of ANA TestingImportance of ANA TestingInfertility, RSAInfertility, RSA
Ogasawara et al., 1999Ogasawara et al., 1999• 25% of RSA patients have low titer 25% of RSA patients have low titer
positive ANA with speckled patternpositive ANA with speckled pattern• 21% of Infertility patients have low 21% of Infertility patients have low
titer positive ANA with speckled titer positive ANA with speckled patternpattern
• A positive ANA mandates a full A positive ANA mandates a full immunological workupimmunological workup
Mechanisms of ThrombosisMechanisms of Thrombosis
Protein C and S and AT III slow Protein C and S and AT III slow down the forward momentum of down the forward momentum of clot formationclot formation
Factor V Leiden is a mutated Factor V Leiden is a mutated variant of factor V that is partially variant of factor V that is partially resistant to inactivation by resistant to inactivation by activated protein Cactivated protein C
Mechanisms of Thrombosis in Mechanisms of Thrombosis in Placenta AntibodiesPlacenta Antibodies
Stern et al., 1998Stern et al., 1998• Increased localization of Increased localization of
prothrombotic proteinsprothrombotic proteins• Blocking of natural anticoagulantsBlocking of natural anticoagulants• Transmembrane signalingTransmembrane signaling
Treatment for MTHFR Hetero Treatment for MTHFR Hetero and Homozygous Women and Homozygous Women
Folgard RXFolgard RXTMTM 2.2 daily (lifetime) 2.2 daily (lifetime) Aspirin 81 mg daily (lifetime)Aspirin 81 mg daily (lifetime) LMW heparin 30 – 40 mg daily, LMW heparin 30 – 40 mg daily,
cycle day 6, increasing to twice cycle day 6, increasing to twice daily until 6 weeks postpartumdaily until 6 weeks postpartum
Treatment of Prothrombin Treatment of Prothrombin Gene Factor II VariantGene Factor II Variant
Aspirin 81 mg daily Aspirin 81 mg daily LMW heparin 30 – 40 mg daily, LMW heparin 30 – 40 mg daily,
cycle day 6, increasing to twice cycle day 6, increasing to twice daily until 6 weeks postpartumdaily until 6 weeks postpartum
MTHFR Outcome with and MTHFR Outcome with and Without TreatmentWithout Treatment
Carp et al., 2004Carp et al., 2004
With treatmentWith treatment 66.7%66.7%
Without Without treatmenttreatment
3.5%3.5%
Factor VII+ Tissue Factor VII+ Tissue Factor Factor
Coagulation Coagulation CascadeCascade
ThrombiThrombinn
PlateletPlateletss
Fibrinogen Fibrinogen FibrinFibrin
Factors V and Factors V and VIII VIII
Activated Factors V and VIII (Va and Activated Factors V and VIII (Va and VIIIa)VIIIa)
Further Coagulation Further Coagulation ActivationActivation
Different direction in intact vessels...Different direction in intact vessels...
Vessel Vessel WoundWound
Protein C System ActivationProtein C System Activation
Activated C (APC) and Protein S and Factor VActivated C (APC) and Protein S and Factor V
Deactivation of Va & VIIIaDeactivation of Va & VIIIa
Normal conditions Normal conditions Anticoagulant mechanisms Anticoagulant mechanisms Procoagulant mechanisms Procoagulant mechanisms
Wound conditions Wound conditions Procoagulant mechanisms Procoagulant mechanisms Anticoagulant mechanisms Anticoagulant mechanisms
Thrombin + Thrombomodulin (Endothelial Surface)Thrombin + Thrombomodulin (Endothelial Surface)
Intact Blood VesselIntact Blood Vessel
European Prospective European Prospective Cohort on Thrombophilia Cohort on Thrombophilia (Lancet 1996)(Lancet 1996)
n=1384n=1384 PregnanciPregnancieses
FetalFetal
LossLoss
Stillbirth/Stillbirth/
MiscarriaMiscarriagege
Stillbirth,Stillbirth,
CombineCombinedd
DefectsDefects
StillbirtStillbirth,h,
Factor V Factor V LeidenLeiden
ThrombophiliaThrombophilia
(n=843)(n=843)n=1524n=1524 1.351.35 3.63.6 14.314.3 22
ControlControl
(n=541)(n=541)n=1019n=1019 11 11 11 11
Position 1691, leading to Arg506Gln protein Position 1691, leading to Arg506Gln protein (factor V Leiden) (factor V Leiden)
Most frequent genetic defect associated with Most frequent genetic defect associated with diseasedisease
In Europe 3-7% with APC-R, 1% homozygotesIn Europe 3-7% with APC-R, 1% homozygotes ““Mitera” study: 4.5% carriers (Greek blood Mitera” study: 4.5% carriers (Greek blood
donors)donors)
Missense Mutation G to A in the Missense Mutation G to A in the FV GeneFV Gene
Hypercoagulability has Positive Hypercoagulability has Positive Genetic (Natural) Selection Genetic (Natural) Selection
EffectsEffects
In the past In the past survival advantage survival advantage (war and hunting wounds, (war and hunting wounds, deliveries)deliveries)
Now Now artifacts of modern life style artifacts of modern life style
Mutated Factor Va (FV Leiden) Mutated Factor Va (FV Leiden) Less Sensitive to APC Less Sensitive to APC
DeactivationDeactivation
APC-Resistance APC-Resistance frequent to frequent to general population, 3-5%general population, 3-5%
Carriers have an increased risk for Carriers have an increased risk for thrombosesthromboses
Most important factor of venous Most important factor of venous thromboembolismthromboembolism
More than half of the patients with More than half of the patients with hereditary thrombophiliahereditary thrombophilia
SevereSevere
Pre-Pre-eclampsieclampsi
aa
NormotensiNormotensiveve
Women onWomen on
Oral Oral ContraceptiContracepti
on and on and ThrombosesThromboses
Women onWomen on
Oral Oral ContraceptiContracepti
on and on and Cerebral-Cerebral-
Vein Vein ThrombosesThromboses
Stroke Stroke in in
Young Young WomenWomen
FV FV Leiden Leiden SubjectsSubjects
8.9%8.9% 4.2%4.2% 30%30% 20%20% 0.9%0.9%
No No MutatioMutationn
10%10% 3%3% 4.1%4.1%1.1. Domna S. Dizon-Townson et al, Salt Lake City, Utah, Am J Obstet Domna S. Dizon-Townson et al, Salt Lake City, Utah, Am J Obstet
Gynecol, 1996Gynecol, 1996
2.2. Margareta Hellgren et al, Mohndal and Malmo, Sweden, Am J Obstet Margareta Hellgren et al, Mohndal and Malmo, Sweden, Am J Obstet Gynecol, 1994Gynecol, 1994
3.3. Longstreth WT Jr et al, Washington, Seattle, Stroke, 1998Longstreth WT Jr et al, Washington, Seattle, Stroke, 1998
4.4. Martinelli I et al, Milan, N Engl J Med, 1998Martinelli I et al, Milan, N Engl J Med, 1998
Br J Haematol, 1997Br J Haematol, 1997Brenner B et al., Bruce Brenner B et al., Bruce Rappaport Faculty of Medicine, Rappaport Faculty of Medicine, Haifa, IsraelHaifa, Israel
Women Women with Fetal with Fetal Losses Losses (n=39)(n=39)
PregnanciPregnancieses
First First TrimesteTrimeste
r r AbortionAbortion
ss
Late Late AbortionAbortion
ss
IntrauterinIntrauterine Deathe Death
Live Live BirthsBirths
FV Leiden FV Leiden (n=19)(n=19) 128128
50%50% 17%17% 47%47% 18%18%With APC-With APC-R (n=9)R (n=9) 5656
Prothrombin Gene G20210A Prothrombin Gene G20210A VariantVariant
Inherited in an autosomal dominant Inherited in an autosomal dominant mannermanner
Gene on chromosome 11p11-q12 (21kb, Gene on chromosome 11p11-q12 (21kb, 14 exons) encodes a plasma 14 exons) encodes a plasma glycoprotein, activated to thrombin by glycoprotein, activated to thrombin by FXa and FvaFXa and Fva
Point mutation G20210A in the 3' Point mutation G20210A in the 3' untranslated region is associated with untranslated region is associated with elevated prothrombin levelselevated prothrombin levels
Title Needed???Title Needed???
Accounts for ~18% of inherited Accounts for ~18% of inherited thrombophiliathrombophilia
Accounts for ~6% of unselected Accounts for ~6% of unselected patients with deep-vein thrombosispatients with deep-vein thrombosis
Frequently co-inherited with other Frequently co-inherited with other genetic risk factors like factor V genetic risk factors like factor V LeidenLeiden
Title Needed???Title Needed???
Carriers have a 2 to 5 fold Carriers have a 2 to 5 fold increased risk of venous increased risk of venous thrombosis, including cerebral-vein thrombosis, including cerebral-vein thrombosisthrombosis
Carriers using oral contraceptives Carriers using oral contraceptives have a highly elevated risk of have a highly elevated risk of cerebral-vein thrombosiscerebral-vein thrombosis
1.1. Longstreth WT Jr et al., Washington, Seattle, Stroke, 1998Longstreth WT Jr et al., Washington, Seattle, Stroke, 1998
2.2. Rosendaal FR et al., Leiden, Netherlands, Blood, 1997Rosendaal FR et al., Leiden, Netherlands, Blood, 1997
3.3. Martinelli I et al., Milan, N Engl J Med, 1998Martinelli I et al., Milan, N Engl J Med, 1998
Women with Women with Myocardial Myocardial InfarctionInfarction
Women on Oral Women on Oral Contraception Contraception and Cerebral-and Cerebral-
Vein Vein ThrombosesThromboses
Stroke in Young Stroke in Young WomenWomen
Prothrombin Prothrombin Gene Variant Gene Variant SubjectsSubjects
5.15.1 20%20% 1.9%1.9%
No MutationNo Mutation 1.61.6 3%3% 1.6%1.6%
Title Needed???Title Needed???
Carrier frequency of 1 to 4% in different Carrier frequency of 1 to 4% in different populationspopulations
Carrier frequency in southern Europe is Carrier frequency in southern Europe is nearly twicenearly twice
As high as in northern EuropeAs high as in northern Europe "Mitera" study: 3.8 % among healthy "Mitera" study: 3.8 % among healthy
Greek blood donorsGreek blood donors Geographical distribution probably due Geographical distribution probably due
to founder effectto founder effect
HyperhomocysteinemiaHyperhomocysteinemia
Cystathionine ß-synthase (CBS) Cystathionine ß-synthase (CBS) deficiency causes the metabolic deficiency causes the metabolic disorder "homocystinuria" (including disorder "homocystinuria" (including premature arteriosclerosis and premature arteriosclerosis and thrombosis)thrombosis)
MTHFR deficiency is an inborn error of MTHFR deficiency is an inborn error of folate metabolism (with increased risk folate metabolism (with increased risk of arteriosclerosis and thrombosis) of arteriosclerosis and thrombosis)
HyperhomocysteinemiaHyperhomocysteinemia(Cont.)(Cont.)
Mild hyperhomocysteinemia has been Mild hyperhomocysteinemia has been recognized as a risk factor for recognized as a risk factor for arteriosclerosis and thrombosisarteriosclerosis and thrombosis
Mild hyperhomocysteinemia due to a Mild hyperhomocysteinemia due to a thermolabile variant of the MTHFR thermolabile variant of the MTHFR enzyme has been associated with enzyme has been associated with premature vascular diseasepremature vascular disease
Homocysteine is presumed to damage Homocysteine is presumed to damage the endothelial cell, but the exact the endothelial cell, but the exact mechanism of its toxicity is unknownmechanism of its toxicity is unknown
Title Needed???Title Needed???
Homozygous individuals show Homozygous individuals show reduced MTHFR activity, increased reduced MTHFR activity, increased thermolability and thermolability and hyperhomocysteinemiahyperhomocysteinemia
Homozygotes may have an Homozygotes may have an increased risk of cardiovascular increased risk of cardiovascular disease and neural tube defectsdisease and neural tube defects
Title Needed???Title Needed???
Relatively high frequency Relatively high frequency throughout the world: allele throughout the world: allele frequency from 6% in Africa to frequency from 6% in Africa to 40% in some European populations40% in some European populations
Selective advantage to explain Selective advantage to explain high frequencyhigh frequency
1.1. J. I. P. de Vries et al., Amsterdam British Journal of J. I. P. de Vries et al., Amsterdam British Journal of Obstetrics and Gynaecology, 1997Obstetrics and Gynaecology, 1997
Placental Placental AbruptionAbruption
(n=31)(n=31)
IntrauterinIntrauterine Fetal e Fetal Death Death (n=18)(n=18)
Small for Small for Gestational Gestational Age Infants Age Infants
(n=13)(n=13)
Women with Mild Women with Mild HyperhomocysteineHyperhomocysteinemiamia
25%25% 8%8% 38%38%
““Mitera” Study, ASH 1998Mitera” Study, ASH 1998Haematology Dept, Haemostasis LabHaematology Dept, Haemostasis Lab
GroupGroup Aborters > 2, Aborters > 2, (n=37)(n=37)
Non-Aborters, Non-Aborters, (n=102)(n=102)
Age Median (range)Age Median (range) 34 (19-51)34 (19-51) 34 (20-54)34 (20-54)
PlateletsPlatelets All NormalAll Normal All NormalAll Normal
PTPT All NormalAll Normal All NormalAll Normal
INRINR All NormalAll Normal All NormalAll Normal
APTTAPTT All NormalAll Normal All NormalAll Normal
Fibrinogen > 400 mg/dlFibrinogen > 400 mg/dl 30%, n=1130%, n=11 14%, n=1414%, n=14
Fibrinogen < 400 mg/dlFibrinogen < 400 mg/dl 70%, n=2670%, n=26 86%, n=8886%, n=88
LA Positive (by confirmative LA Positive (by confirmative test)test) 16%, n=1616%, n=16 9%, n=99%, n=9
AT III < 75%AT III < 75% 3%, n=13%, n=1 3%, n=33%, n=3
PC < 75%PC < 75% All NormalAll Normal All NormalAll Normal
PS < 75%PS < 75% Unreliable TestUnreliable Test Unreliable TestUnreliable Test
Increased APC-R (suggesting Increased APC-R (suggesting FV Leiden)FV Leiden) 22%, n=822%, n=8 11%, n=1111%, n=11
ConsultationConsultation
Extended family screeningExtended family screening Anticoagulant prophylaxis in Anticoagulant prophylaxis in
selected casesselected cases
Inherited Thrombophilia Inherited Thrombophilia (Prothrombotic Gene (Prothrombotic Gene
Mutation)Mutation)
Acquired Acquired ThrombophiliaThrombophilia
HypercoagulabilityHypercoagulability
ThrombosiThrombosiss
LMW HeparinLMW Heparin
Given subcutaneously to maintain Given subcutaneously to maintain trough anti-Xa activity of 0.15-trough anti-Xa activity of 0.15-0.2U/ml and 2 h post injection 0.2U/ml and 2 h post injection levels of 0.4-0.6 U/mllevels of 0.4-0.6 U/ml
Checking of levels are no longer Checking of levels are no longer recommendedrecommended
May check monthly during May check monthly during pregnancypregnancy
LMW Heparin ComplicationsLMW Heparin Complications
Epidural anesthesia is managed by Epidural anesthesia is managed by omitting a dose or inserting the omitting a dose or inserting the needle 6 hours after the previous doseneedle 6 hours after the previous dose
There were no thromboembolic events There were no thromboembolic events or excessive hemorrhagesor excessive hemorrhages
There is one report of osteoporotic There is one report of osteoporotic vertebral collapse post partumvertebral collapse post partum
Hunt BJ et al., Hunt BJ et al., 19971997
LMW Heparin ComplicationsLMW Heparin Complications
No local or systemic side effects reportedNo local or systemic side effects reported No excessive intrapartum or postpartum No excessive intrapartum or postpartum
bleeding in vaginally or c-sectioned bleeding in vaginally or c-sectioned delivered patientsdelivered patients
Epidural was done without complicationsEpidural was done without complications No intraventricular hemorrhages in any No intraventricular hemorrhages in any
infantinfant No effect on platelet countNo effect on platelet count
Dulitzke M. et al., Dulitzke M. et al., 19961996