(PROF.) DR. SRIMANTA KUMAR PAL (SENIOR GYNECOLOGIST): Thrombocytopenia

ABC of Inherited thrombophilia :-- Inherited thrombophilic diseases often remain undiagnosed in clinical practice as A) clinical expression of the diseases is dependent on degree of mutation or deletion of different factors which lead to thrombosis-therefore diag often remain unsuspected B) The lab tests are costly.

Prevalence:-Thromboembolic disease in pregnancy is seen in 0.2-0.3% of pregnancies. Inherited thrombophilias are genetic conditions that increase the risk of thromboembolic disease.. Increasingly, thrombophilias have been identified as underlying contributors to thromboembolic disease in pregnancy. Thrombotic events in pregnancy have not only been associated with poor maternal outcomes but also with a myriad of fetal and obstetrical complications.

Hit Wicket!!! Preg invites many harms to own foetus, sometimes but not always:-Thrombogenic potential increases in Preg:-During pregnancy the thrombogenic potential of these inherited disorders is enhanced because of pregnancy associated changes in several coagulation factors:.

What other changes assuming the concerned woman are suffering from Inherited/ Congenital coagulable disorders (Thrombo-philia)?? Changes are A) What happens to activated protein C ?? Resistance to activated protein C increase in the second and third trimesters , B) But so far as protein S activity is concerned it decreases due to estrogen induced decreases in total protein S and increases in the complement 4B binding protein which binds protein S

What about other common procoagulants?. Ans:-Fibrinogen and factors II, VII, VIII and X increase in preg.

.What preg changes occurs in factors controlling the process of Fibrinolysis:-Levels and activity of the fibrinolytic inhibitors, thrombin activatable fibrinolytic inhibitor PAI-1 and PAI-2 increase in pregnacy.

So take home message will be:-The net effect of these pregnancy induced changes is to produce a hypercogulable state in normal women. The inherited thrombophilias can compound this increase in hypercoagulability and thus increase risk of thromboembolic complications during pregnancy.

How one can classify different types of THROMBOPHILIAS?

1) Inherited Thrombophilias 2) Abnormalities of pro-coagulant factors 3) .Factor V Leiden mutation causing activated protein C resistance (APCR),4). Prothrombin gene mutation (prothrombin G 20210A). 5) . Plasminogen activator inhibitor-1(PAI-1) gene mutation

Single point mutation is very common in inherited Thrombophilia:-What are Coagulation Cascade ??:What are the different factors” –“deficiencies of endogenous proteins”- in the Coagulation Cascade “:-Such are 1). Protein C 2) Protein S 3). Anti thrombin 4) Factor V Leiden 5) Factor V Leiden. All these collectively or individually occur as result of a single point mutation in the factor V gene at the cleavage site (position 506) where protein C acts. Factor Leiden mutation (FVL) is the most common cause of activated prone C resistance. The most cost efficient way of screening for FVL is to check for the abnormal phenotype.

More Recent news on Factor V Leiden mutation on the evening of Independence Day:-Heterozygostiy for the FVL mutation is present in 20 to 40 % of nonpregnant individuals with venous thromboembolism. What is the risk if someone has Factor V Leiden mutation?? Homozygosity for the FVL mutation carries an 80 fold risk of VTE.Incidence: Occurs in 5 to 15 % of ethnic European population:: Fortunately this mutation is rare in Asian or African populations

Not only Fact IV mutation there are other associated Risks for thrombosis .Such is also applicable for endometrial venous thrombosis(missed abortion), Second and third trimester fetal loss.severe intrauterine growth restriction , placental vas thrombosis , Abruption placenta:-So given the low prevalence of VTE in pregnancy the risk of VTE in asymptomatic FVL carriers is only 0.2%

. Abruption

. Severe early onset pre-eclampsia

. Preterm delivery

When compared with non- carriers, FVL carriers demonstrate an increased proportion of pathological Doppler measurements including bilateral uterine artery notches.

What about “Prothrombin Gene Mutation”:-A mutation at nucleotide 20210 occurs in the gene encoding prothrombin resulting in higher circulating levels of prothrombin the precursor of thrombin. Incidence: Prevalence of the gene in the general populations is 2 to 5 % more prevalent in Casucasian women. Associated Risks:. Threefold increased risk of venous thrombosis. Controversy remains about whether prothrombin gene mutation is associated with A) preeclampsia B) . Intrauterine growth restriction C). Placental abruption.

Prothrombin gene mutation –How to test by lab means?? Laboratory investigations: Evaluation for the prothrombin gene mutation is best performed through direct genetic analysis to identify the G20210A transition.

Protein It can result from protean mutations producing two primary phenotypes: Type I: Both immunoreactivity protein levels and protein C activity are reduced. Type II: Immunoreactivity levels are normal but activity is reduced.

ABC of Protein C:- Protein C is highly sensitive to consumption as may be caused by systemic thrombosis or surgery. Protein C levels are reduced in women with disseminated intravascular coagulation liver disease and women that use vitamin K antagonists.

Protein S deficiency :: Are you aware in details of Protein S :-There are three subtypes are found:

Type 1: Characterized by reduced total and free immunoreactivity protein levels and activity.

Type II. Characterized by normal total and free immunoreactivity protein S levels but reduced activity

Type III: Normal total immunoreactivity levels but reduced free immunoreactivity levels and activity because of increased binding to the C4b-BP carrier protein.

Although the currently used free proteins assay is more robust than its predecessors it still is a vulnerable test. To diagnose a woman with protein S deficiency 2 separate measurements outside pregnancy are require. Free protein S shows a marked physiological apt resistance. Protein S should not be measured during pregnancy.

Prof Pal, tell me some salient points on Antithrombin & its functions:- Antithrombin can result from a myriad of possible mutations and is rarest and most thrombogenic of the inherited Thrombophilia. There are two primary types:Type 1: Characterized by reductions in both circulating immunoreactive protein levels and activity:: Type II: Characterized by normal immunoreactive protein levels but decreased activity.::In uncomplicated pregnancy anti thrombin activity levels show no change or a marginal decrease. Decreased anti thrombin activity levels have been demonstrated in women with pre-eclampsia and DIC.

Incidence of different hypercogulable factors:- :The prevalence of PC deficiency is 0.3% ;The prevalence of PS deficiency is 0.1%

The prevalence of anti thrombin deficiency is low .But the associated Risks are Protein C and Protein S, . Venous thrombo embolism,. Increased risk of stillbirth,. Fetal loss ,. Increased rates of pre-eclampsia, abruption and IUGR .

Anyone interested to know about “Anti thrombin Deficiency”?

. Antithrombin deficiency can lead to A)Early fetal loss B) IUGR C) stillbirth D) abruption E) severe pre- eclampsia.

. Women with anti thrombin deficiency are at a particularly high-risk of thromboembolic complication. At deficiency is the only Thrombophilia that ‘always’ will require thrombo prophylaxis during pregnancy and postpartum.

All of these are inherited in an autosomal dominant pattern meaning that an affected person needs to inherit the gene from only one parent. Each child of an affected parent has a 50 percent chance of inheriting the Thrombophilia.

We have so long discussed about Congenital Acquired Thrombophilias :Now let me discussed about acquired hypercogulable diseases:- The most common acquired thrombophilia is 1) Antiphospholipid syndrome, But there are other causes of hypercogulable tests:-2) Mixed inherited and acquired 3)Hyperhomocysteinemia (elevated plasma homocysteine).

Hyperhomocysteinemia

A) The Antiphospholipid syndrome which includes:

. Anticardiolipin antibodies.

. Lupus anticoagulant antibodies

The most common acquired thrombophilia is antiphospholipid syndrome. APS occurs in up to 5 percent of pregnant women. In APS the body makes antibodies that attack certain phospholipids that line the blood vessels sometimes leading to blood clots. APS is an autoimmune disorder. Up to 40 percent of women with SLE have antiphospholipid antibodies in their blood which may contribute to their increased risk of pregnancy complications.

Mixed inherited and acquired

Hyperhomocysteinemia (elevated plasma homocysteine)

Hyperhomocysteinemia

Hyperhomocysteinemia can be inherited or acquired. Defects in either the trans- suplhuration pathway or remethylation pathway will lead to increased blood concentrations of homocysteine known as hyperhomocysteinemia.

The thermolabiles C677T variant of the gene for MTHFR has been associated with a tendency to mild to moderate hyperhomocysteinemia especially in the presence of folic acid deficiency.

It is the phenotype of hyperhomocysteinemia that is associated with a high frequency of early onset preeclampsia rather than any associated genotype e.g. MTHFR. The severe form results from extremely rare homozygous deficiencies in either cystathionine B- synthase or Methylene tetrahydrofolate reductase enzymes.

Blood homocysteine levels are:

Severe; >100 mol/L

Moderate: 25-100 mol/L

Mild: 16-24 mol/L

Incidence: Homozygosity for the 667C- T MTHFR thermolabile mutant is present in up to 11% of ethnic European populations and is the leading cause of mild and moderate hyperhomocysteinemia.

Associated Risks of H.Hcyst (hyperhomocysteinemia / or aPL syndrome:-

. 1) Early onset pre-eclampsia placental abruption2) . Fetal neural tube defects 3). Stillbirth 4). Intrauterine growth restriction 5) .Vascular disease, e.g. coronary artery disease

.6) Recurrent VTE 7) unexplained .fetal loss What are the possible compl of aPL syndrome :- Complications of H.Hcyst have been duly explained by Prof S K Pal but Dr Pal can U tell us what will be possible compl of aPL syndrome ,which by its rigid International defn is difficult repeat, reproduce and therefore the remains difficult to diagnose with 100 % confirmation?? May that what it may be: thrombophilia may contribute to pregnancy complications including;

.A) Repeated miscarriage usually occurring after the tenth week of pregnancy). Stillbirth in the second or third trimesters C) . Placental abruption D) .Pre- eclampsia E) .Poor fetal growth

E).Premature delivery.

. Thromboembolism in pregnancy as in the nonpregnant state is linked to thrombophilia. A recently described guanine 20210 adenine mutation in prothrombin is associated with higher plasma prothrombin concentrations and increased risk for venous thromboembolism and cerebral-vein thrombosis. Heterozygosity for the factor v (FV) leaden mutation is found in about 5% of the population and the mutation is responsible of 20 to 30% of venous thromboembolism events. Homozygosity for the cytosine 677 thymine mutations in methylenetetrahydrofolate reductase results in decreased synthesis of 5 methyltetrahydrofolate the primary methyl donor in the conversion of homocysteine to Methionine and the resulting increase in plasma homocysteine concentrations is a risk factor for thrombosis.

Why Hematologist in Obstetric ward? Hematologists sometimes in some very busy overcrowded Medicals Colleges routinely visit Obstetric OPD (ANC clinic OPD ) twice a month !! But it is equally true that sometimes heaemtologists attend indoor or even Labor room or Operating Theater on emergency basis whenever requested by Call Book:-Why Hematologist in Obstetric ward?

Why hematologist they come rushing and desperately more welcome than a genl surgeon or Urosurgeon or cardiologist? The reasons are to save a life in “Near Miss Mat Death” Like 1) diff types of severe amemia,2) Thalassaemia 3) PPH & DIC 4) VTE & P embolism 5) Platelate dysfunction, 6) ITP 7 ) APL syn & H,H.Cyt group of disorders which we were taking off 9) Bleeding disorders in pregnancy which mainly includes thrombocytopenia, Cong & Acqd deficiencies of clotting factors & abnormal Thrombomodulation, à resultant Abruption, 2)Amniotic Fluid Embolism 3) IUFD-retained for weeks-consumptive coagulopathy, s 4) septic abortion induced bleeding disorders 5) Acute Fatty Liver(AFLP), 6) Preeclampsia.

Time has come when we should seriously how we the Obstetricians & Gynecologist Compl of Blood Tr /component product is another reason why hematologist are summoned at delivery suits on an emergency basis also sometimes in ARF, Care for theses complex patients should be provided in collaboration with a hematologist or maternal fetal medicine specialist.

My dearm students “Diagnosis of Inherited Thrombophilia “?

The role of specific genes is different in etiology of early and late pregnancy loss. Inherited Thrombophilia is now view as multicausal model clinical manifestation can be heterogeneous result of gene –gene and gene environment interactions. Therefore the criteria for genetic screening affected women with history of fetal loss should not be very stringent. The implication of screening for thrombophilic mutations allow to find women at risk of thrombosis and vascular gestational abnormalities in which antithrombotic drugs may have potential therapeutic benefit.

The tests to be done are:

1. Lieden factor V mutation R560Q

2. Hyperhomocysteinemia MTHFR

3. Prothrombin gene mutation 20210 DNA test by PCR

4. Protein C levels

5. Protein S levels and

6. Activated protein C activity

7. PAI-1 gene mutation

8. Factor XIII mutation

Tests for diagnosis of acquired Thrombophilia

1 Antibodies to six phospholipids of the IgM, IgG and IgA classes

2 Lupus anticoagulant antibodies

3 Russell viper venom time

4 Activated partial thromboplastin time

5 Prothrombin time partial prothrombin time.

Evaluation of the placenta from complicated pregnancies

Clotting in the placenta or the blood vessels to the uterus can be diagnosed by doing immune pathology. This study should be done before embarking on another pregnancy since the most effective treatment must be initiated during the cycle of conception before the baby is conceived.

MANAGEMENT OF THROMBOPHILIC PREGNANT WOMEN

Management of thrombophilic pregnant woman demands a multidisciplinary approach. Women with a thrombophilia who have a history of blood clots are usually treated with anticoagulant during pregnancy and the postpartum period. Women with certain severe inherited thrombophilias also are usually treated even if they have not experienced blot clots. During pregnancy these women are generally treated with anticoagulant heparin which do not cross the placenta and are safe for the baby. After delivery some women with a thrombophilia may be treated for about 6 weeks with oral anticoagulant warfarin in addition to or instead of heparin. Warfarin is safe to take during breastfeeding but it is not recommended during pregnancy because it crosses the placenta and can cause birth defects. Treatment may not be recommended for pregnant women with one of the less severe thrombophilias who have no personal or family history of blood clots. In some cases treatment may be recommended after a cesarean delivery.

Antenatal Care

. Early dating Scan in the first trimester

. Close surveillance with regular bold pressure checks and urinalysis to detect early onset pre- eclampsia

. Uterine artery waveforms at 20 and 24 weeks of gestation

. Growth scans every 2-3 weeks for pregnancies with evidence of early diastolic notch

. Consider vitamins C and E if previous PE or bilateral notches

. Ultrasound every 4 weeks to assess growth and amniotic fluids volume

.Uterine artery Doppler studies as indicated to allow timely intervention for fetal reasons

.Develop a management plans for intrapartum and postpartum care and documentations to be done.

Obstetric Management

The gold standard therapy to prevent miscarriages and obstetrical complications is represented by the association of low dose aspirin and heparin. The combination of aspirin and heparin or low molecular weight heparin is effective in recurrent fetal loss in APS syndrome and could be considered for women with inherited thrombophilia and history of severe pre-eclampsia IUGR abruption placentae or fetal loss. The use of corticosteroids in women with APS is limited to maternal thrombocytopenia or coexisting systemic lupus erythematosus ensure regular blood glucose monitoring for women on long term steroids.

Intravenous immunoglobulin has been used in pregnant women with APS but a recent controlled study found no benefit in comparison to the aspirin heparin treatment.

Use of heparin in different cases of thrombophilias is given below:

Recurrent pre-eclampsia and /or embryonic loss without history of thrombotic events:

1. Standard heparin: 5,000-7,500 U every 12 hours in the first trimester 5,000-10,000 U every 12 hours in the second and third trimesters.

2. Low molecular weight heparin:

3. a Enoxaparin 40 mg/day or dalteparin 5,000 U/day or

b. Enoxaparin 30 mg every 12 hours or dalteparin 5000 U every 12 hours.

Fetal death or severe early pre-eclampsia or severe placental insufficiency without history of thrombotic events:

1. Standard heparin;7,500 -10000 U every 8-12 hours adjusted to maintain the mid -interval heparin levels in the therapeutic range

2. Low molecular weight heparin:

A Weight adjusted or

B Intermediate dosage

LWMH offers important advantages over unfractionated heparin; heparin –induced thrombocytopenia and ospeopenia are rarely seen. For treatment doses of LMWH dosage adjustment based on anti Xa levels in usually required as pregnancy progresses. The aim is a plasma Anti-Xa level at 0.6-1.0 U/ml

Intrapartum

Aspirin can be continued until birth. Heparin subcutaneous discontinued 6 hours before and IV Heparin 6 hours before induction or regional anesthesia.

Invasive fetal monitoring and instrumental deliveries should be avoided unless fetus is known to be unaffected.

Placenta to be sent for histopathology if there is pre-eclampsia, IUGR previous stillbirth or miscarriages.

Postpartum

.The leg should be elevated and elastic compression stocking applied to reduce edema.

.Mobilization should be encouraged.

. Drug treatment: Women with a history of previous thrombosis should receive LMWH or warfarin for 6 weeks postpartum. Women without previous history of thrombosis who have other risk factors for venous thrombosis should receive postpartum LMWH for 5 days.

Women Recommencing Warfarin

Recommence warfarin treatment on day 2-3 for women on long term warfarin treatment

Discontinue LMWH when the international normalized ratio is >2.0

Breastfeeding

Breastfeeding should be encouraged. There is minimal excretion of warfarin into breast milk.

Advice

Since patients with inherited thrombophilia suffer clotting complications throughout life with a higher frequency than those without monitoring for this complication is essential. The incidence of clotting disorders if from 8 to 40 times higher than in patients without the thrombophilia disorder. Women with thrombophilia should:

. Have their children tested so that lifestyle or dietary changes can be made from the beginning.

. Choose contraception other than birth control pills.

. Advise the woman to reduce lifestyle variants known to increase homocysteine levels, e.g. smoking coffee and alcohol consumption.

. Encourage well-balance diet. Hyperhomocysteinemia is exacerbated by deficiencies in vitaminB6 B12 and folic acid.

.See a hematologist and check if you need anticoagulation treatment

Alert other female family members of the inherited and urge testing of relatives prior to initiating a pregnancy.

Future research should focus on more studies to roves a causative link between thrombophilia and pregnancy complication in particular the role of placental pathogenic mechanisms require further evaluation as recent reports suggest that placental pathological changes are often nonspecific. Better understanding will unfold many unknown facts of thrombophilias in pregnancy.

Antiphospholipid Antibody syndrome in pregnancy

The Antiphospholipid syndrome was first described by Hughes et al in 1986 as acquired thrombophilia in which autoantibodies are produced to a variety of phospholipids and phospholipid binding proteins.

It is the most commonly occurring acquired thrombophilia. Primary APS has been defined as the presence of Antiphospholipid antibodies in patients with idiopathic thrombosis existing as an isolated immunologic derangement or any other precipitating factor such as infection malignancy hemodialysis or drug induced Antiphospholipid syndrome. The term secondary Antiphospholipid syndrome has been used when patients with other autoimmune disorders and thrombosis are also found to have Antiphospholipid antibodies. The clinical manifestations of thrombosis are similar whether the Antiphospholipid syndrome is primary or secondary.

Diagnosis

The 1999 Sapporo International Consensus statement on Preliminary Criteria for the classification of Antiphospholipid syndrome provides simplified criteria for the diagnosis of Antiphospholipid syndrome. A definite diagnosis requires the presence of at least one of the two clinical criteria and one laboratory criteria

Clinical Criteria

.Vascular thrombosis

- One or more clinical episodes of arterial venous or small vessel thrombosis occurring within any tissue or organ.

- . Complications of pregnancy

- -One or more unexplained deaths of morphologically normal fetuses at or after ten weeks of gestation one or more premature births of morphologically normal neonates at or before 34 weeks of gestation or three or more unexplained consecutive spontaneous abortions before ten weeks gestation.

- Laboratory Criteria

. Anticardiolipin antibodies: Anticardiolipin IgG or IgM antibodies present at moderate or high levels in the blood on two or more occasions at least 6 weeks apart.

. Lupus anticoagulant antibodies: Lupus anticoagulant antibodies detected in the blood on two or more occasions at least 6 weeks apart.

Pathophysiology

The first Antiphospholipid antibody was detected about a century ago in patient of syphilis. The relevant antigen cardiolipin and mitochondrial phospholipids were identified later.

Antiphospholipid antibodies that are important in recurrent miscarriage are anticardiolipin antibodies and lupus anticoagulant.

In young apparently healthy individuals the prevalence of both LA and aCL is about 1-5% . It increases with age especially in elderly patients with chronic diseases. In patients with SLE the prevalence of APLA is much higher ranges from 30-35% .The prevalence of APLA among women with recurrent miscarriage are 15%.

The association between Antiphospholipid antibodies and thrombosis is stronger with lupus anticoagulant than with anticardiolipin antibodies.

Several hypotheses have been proposed to explain the cellular and molecular mechanism by which APA promote thrombosis. These include effects on coagulation pathway, on endothelium and on platelets.

Proposed mechanism of thrombosis of Antiphospholipid antibodies:

1. Interference with endothelial phospholipids and thus prostacyclin release

2. Inhibition of prekallikrein and thus inhibition of fibrinolysis

3. Inhibition of thrombomodulin and thus protein C/S activity

4. Acquired protein C resistance

5. Interaction with platelet membrane phospholipids

6. Inhibition of endothelial tissue plasminogen activator release

7. Direct inhibition of protein S

8. Inhibition of annexin -V, a cell surface protein that inhibits tissue factor also referred to as placental anticoagulant protein

9. Induction of the release of monocytes tissue factor.

Mechanisms of Adverse pregnancy outcomes

Though poorly understood various workers have implicated the following mechanisms in altering pregnancy outcomes.

1. Early pregnancy failure may result from impaired development of the trophoblast and failure to establish effective foetomatrnal circulation .

2. Thrombosis of uteroplacental vasculature as a result of displacement of

3. No thrombotic mechanisms include autoantibody mediated failure of implantation or failure of development of normal uteroplacental vasculature as a result of autoantibody binding to the trophoblast or maternal spiral arteries.

4. Late losses are due to massive thrombosis in the placenta.

5. Vascular thrombosis has also been implicated in development of complications such as pre eclampsia.

INVESTIGATIONS FOR ANTIPHOSPHOLIPID ANTIBODIES

The most commonly performed Antiphospholipid antibody assays are for lupus anticoagulant and anticardiolipin antibodies. The assay for anticardiolipin antibodies is more sensitive test for detection of APS; the assay for lupus anticoagulant is more specific. It is imperative to test for both LA and aCL.

It should ideally be performed preconceptionally as maternal Antiphospholipid antibodies are down regulated during pregnancy.

Antiphospholipid antibody detection is subject to widespread interlaboratory variation . Therefore laboratory assays should be performed according to international guidelines. Although no single test detects all lupus anticoagulant the dilute Russell viper venom time test together with platelet neutralization is more sensitive and specific than either the activated partial thromboplastin time or the kaolin clotting time test. Medium to high titre of anticardiolipin antibody are more specific for the diagnosis of APS as is the specificity of IgG isotope than the IgM isotope.

All test results should be confirmed by repeat samples at least 6 weeks.

Antibodies to phosphatidylglyserine phosphatidylglycerol phosphatidylcholilnes and phophatidic acid have also been linked with poor obstetrical outcome in patients with APS. However testing for these antibodies do not increase the yield for APS and these alterative phospholipid assays have not been standardized.

The antibodies to cardiolipin are directed against beta-2- glycoprotein. The use of B2 GPI assay is reserved for patients who are strongly suspected of having APS but in whom standard Antiphospholipid assays are negative.

Management

Patient should be treated only if there is evidence that their risk of APLA mediated complications exceeds the risk of the proposed treatments. Factors that seem to predict adverse outcomes during pregnancy include anticardiolipin antibody titre and previous obstetric history.

Aims of Treatment during pregnancy

1. Improvement in maternal fetal and neonatal outcome by preventing pregnancy loss pre-eclampsia placental insufficiency and preterm birth.

2. Reduction or elimination os risk of thromboembolism.

Drugs

Aspirin inhibits thromboxane formation reducing the risk of platelet- mediated vascular thrombosis. Aspirin may be used throughout pregnancy and has minimal maternal and fetal complications . It can be continued until delivery and the use of low dose aspirin does not affect the use of regional anesthesia during labor because there is no evidence that it increases the risk of epidural hemorrhage. Most of the studies have proved that low dose aspirin is safe in pregnancy.

Heparin may improve outcomes in women who have APS. In addition to direct effect of heparin on coagulation cascade heparin might protect pregnancies by reducing the binding of antiphospholipid antibodies reducing inflammation facilitating implantation and or inhibiting complement activation. Combination of aspirin and unfractionated heparin has been found to be associated with improved outcomes when compared with aspirin alone in women who had recurrent miscarriages. Heparin does not cross the placenta and has no adverse effect on fetus.

It is recommended that women with APA syndrome should receive prophylaxis with LDA plus subcutaneous heparin once fetal cardiac activity is documented.

LMWH is as good as or better than UFH for the prevention or treatment of thromboembolism . Neither UFH nor LMWH cross the placenta thus any form of heparin is safe for the fetus . However LMWH is safer alterative to UFH and is associated with lower incidence of heparin induced thrombocytopenia and osteoporosis in mother. Women treated with UFH should be prescribed daily calcium and vitamin D supplementation and advised weighbearing exercises.

Management of patients who have APLA and prior objectively confirmed arterial or venous thrombosis during pregnancy usually consists of conversion from therapeutic dose of warfarin at the time of a positive pregnancy test to therapeutic dose LMWH carried on throughout the pregnancy. Warfarin can be reinstituted after delivery as it is safe during nursing.

Warfarin should be avoided during pregnancy especially during the first trimester because it crosses the placenta and is potentially teratogenic. Maternal and fetal bleeding is also matter of concern with its use and is directly related to the intensity of anticoagulation as measured by INR.

Corticosteroids have been abandoned as a modality for treatment of APS since its use has been associated with increased maternal morbidity without improved fetal outcome. They are reserved for women who have APS complicated by clinically important thrombocytopenia or co –existent SLE. Patients on long term corticosteroids should be monitored for the development of complications such as gestational diabetes or hypertension.

Intravenous immunoglobulin is not recommended for pregnant women who have APS as there is no evidence of benefit in reducing adverse obstetrical outcome.

Management Options

. Pregnant women with APS and history of prior thromboembolism

. Such women require lifetime anticoagulation with warfarin. These patients require antithrombotic therapy with UH or LMWH throughout the whole pregnancy. Patients already on warfarin should be switched over to Heparin as soon as pregnancy is confirmed. The antithrombotic therapy should be continued for atleast six weeks postpartum and oral anticoagulants can be reinstituted after delivery. Concomitant treatment with low dose aspirin is generally recommended.

. Pregnant women with poor obstetrical outcome with APS and no thromboembolism

Low dose heparin in combination with heparin is he first line treatment pregnant women with APS. Aspirin and unfractionated subcutaneous heparin or low molecular weight heparin is started after confirmation of viability of pregnancy and this should be continued upto 34 completed weeks of pregnancy. This regimen improves the live birth rates but the risks of late complication like pre-eclampsia preterm intrauterine growth restriction abruption placentae still remains.

. Healthy women with recurrent pregnancy loss and low titre of APA do not require treatment.

.Women with APS seeking pre-pregnancy care: Preconception counseling involves explaining the risks of thromboembolism pregnancy loss and pregnancy complications . Anti coagulation prophylaxis options are discussed and risks of heparin therapy are explained. Some authorities recommend instituting daily low dose aspiring prior to conception.

Antenatal Management

An early transvaginal ultrasound is recommended to confirm an intrauterine pregnancy the viability and to provide accurate dating. Frequent antenatal visits every 2-4 weeks upto 24 weeks and two weekly thereafter should be planned.

At every visit the patient should be monitored for fetal wellbeing and assessed for the development of pre-eclampsia and intrauterine growth restriction. Serial ultrasound examination should be performed every 3-4 weeks after 17-18 weeks of gestation to detect oligohydramnios or growth restriction.

Strict antepartum fetal surveillance should be initiated at 30-32 weeks gestation .

Calcium supplementation and weight bearing exercises are advised.

LABOR AND DELVERY

Time of delivery is guided by the associated complications and postdates should be avoided.

Patients with spontaneous labor are at high risk of postpartum hemorrhage. Protamine sulphate is the antidote for UFH and is administered in the event of surgical intervention or near delivery if aPPT is prolonged.

Anticoagulation should be withheld 24 hours prior to induction of labor or cesarean delivery because of risk of postpartum hemorrhage. Current guidelines recommend that regional anesthesia should not be used until atleast 12 hours after the ;previous prophylactic dose of low molecular weight heparin and 6 hours after a dose of unfractionated heparin . If full doses of heparin are used then the interval of last dose and needle placement should be minimum 24 hours. Heparin should not be given for atleast 4 hours after the epidural catheter is removed.

Monitoring of labor should be as per the protocols for pre-eclampsia and intrauterine growth restriction . Continuous electronic fetal heart rate monitoring during labor is recommended.

POSTPARTUM

Postpartum anticoagulation is recommended in patients with previous history of thromboembolism. Anticoagulation therapy should be resumed 4-6 hour after vaginal delivery and 12 hours after cesarean and continued till six weeks.

. Both heparin and warfarin are safe for breastfeeding mothers.

.Oral contraceptives containing estrogens are absolutely contraindicated.

What about other common procoagulants?. Ans:-Fibrinogen and factors II, VII, VIII and X increase in preg.

How one can classify different types of THROMBOPHILIAS?

2) Inherited Thrombophilias 2) Abnormalities of pro-coagulant factors 3) .Factor V Leiden mutation causing activated protein C resistance (APCR),4). Prothrombin gene mutation (prothrombin G 20210A). 5) . Plasminogen activator inhibitor-1(PAI-1) gene mutation