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C.) Three
D.) Four
Inherited
Hyperhomocysteinemia (C677T) mutation Factor V Leiden mutation (A506G) mutation Mutation in prothrombin ( G 20210 A) Prothrombin II (PTII) mutation
Protein S deficiency
Protein C deficiency
All these conditions should be investigated for APLA except : A.) Early onset severe preeclampsia
B.) Arterial or venous thrombosis C.) Unexplained fetal growth restriction
Diagnosis of APLA
Challenging !!!
Due to fluctuating titers of the antibodies,
Lack of agreement between laboratories concerning standardization of the assays Debates among researchers & clinicians concerning which antibodies to measure.
Patient typically has a prolonged APTT that does not correct in 80:20 mixture with normal human plasma Prolonged Dilute Russel viper venom time (DRVVT), Kaolin clotting test (KCT),(TDT/DTT) or prothombin time Due to heterogeneous nature of LA ,minimum of 2 tests required, 6 weeks apart & should be positive each time showing persistent positivity to confirm diagnosis of APLA Caution : patients with transient positive tests (due to infection etc) can be diagnosed as positive.
B.)
C.) D.)
Anticardiolipin Antibodies
Were thought to react against cardiolipin but it is now thought to interact with B2GP1 85% of APS pts have both LA & aCL These can be detected using an (ELISA)
Screens for the presence of 2 glycoprotein 1 dependent anticardiolipin antibodies (ACA) A low platelet count & positivity for antibodies against 2-glycoprotein 1 or phosphatidylserine may also be observed in a positive diagnosis
B2GP1 has anticoagulant activity through the inhibition of the conversion of prothrombinthrombin, regulation of protein S, & /or activation of platelets.
Sapporo criteria
International Consensus Conference held in Sapporo (98)
Clinical criteria of ( APAS ) Thrombosis, one or more confirmed episodes of venous, arterial, or small vessels disease Coexisting inherited or acquired thrombotic risk factors are not reasons for excluding patients from a diagnosis of APS trials.
Transient elevations common. Elevations common in autoimmune disease & infections ex. HIV, Hep C, syphilis
Interference with : a.) Trophoblast cells: Reduction of proliferation & differentiation; Gonadotrophin secretion impairment
Aneuploidy
Aneuploid fetus risk in women > 35yr. age Inherent risk of fetal loss after amniocentesis
1/80
1/200
Definition
A recurrent pregnancy loss (RPL) is 3 or more consecutive, spontaneous pregnancy losses, under 20 week gestation from the last menstrual period by the same partner.
Primary recurrent pregnancy loss" refers to couples that have never had a live birth Secondary RPL" refers to those who have had repetitive losses following a successful pregnancy
Special Investigations
LAC tested by prolonged coagulation time (inhibition of phospholipids) APTT , KCT , TTIT Most accurate - Dilute russel viper venom test (DRVVT) ACL - ELISA - IgG (GPL) IgM (MPL) IgG/ IgM isotypes of anticardiolipin & antiphosphotidyl serine antibodies In c/o low titres-repeat after 6-8wks (can revert to normal) Transient low titres can be found in viral fever If autoimmune disorders are suspected ANA, anti nDNA, antiSm, anti-Ro/SSA antibody, anti La (SSP)
General guidelines for anticoagulation in Pregnancy with APS leading to recurrent pregnancy loss
Very controversial issue !
Trials
Heparin vs Aspirin + prednisolone Live birth 75% Pre-eclampsia, preterm delivery more in latter group L.S. + LDA Vs Heparin + LDA (n=20) No placebo Large multicentric trials needed Cowchock et al .1994
Randomised controlled trial of LDA versus LDA plus heparin in pregnant women with APS
90 women with APS were randomized into two groups with 1st group receiving 75mg of LDA & 2nd group LDA & Heparin 5000u subcut, every 12 hourly Outcomes measured were number of live births & miscarriages
Antiphospolipid antibodies
Presence of Antiphosholipid antibodies may cause recurrent pregnancy loss Are antibodies directly responsible ?
Women with APLA are advised to take LDA & to start LMWH Rx after pregnancy is diagnosed (80% success)
In case of H/o thrombotic symptoms, Warfarin is used as anticoagulant .Maintain INR between 3.0 - 4.0. Patients with APLA have minor elevations of PT & are difficult to manage with warfarin. During pregnancy, LMWH & LDA are preferred to Warfarin (teratogenic effects )
If previous H/o thrombosis use LMWH in therapeutic doses throughout pregnancy :dose 1mg/kg subcut. If UFH is used dose is 10,000 u 12 hourly
Since APLA reacts with phospholipids both aPTT & PT can be affected. If UFH used to anticoagulate patients with APLA monitor heparin levels ( 0.35 - 0.70 anti-Xa units 6 hours post injectiont ). With LMWH , monitoring is easier : predictable dosing & anticoagulant effect . Measure LMW heparin levels in these patients for long term Rx (0.7 - 1.0 anti-Xa units) Perform prothrombin & proconvertin times ("P&P") to follow anticoagulation. Being less dependent on phospholipids & one can monitor therapy. If miscarriage occurs with heparin & aspirin & there is a pregnancy again IVIG can be tried (RCT did not show benefit) In refractory cases plasmapheresis may be used
Recommendation
Surveillance, or mini-dose heparin, or prophylactic LMWH, & /or aspirin
Grade
2C
1C
B.P, platelets, complement levels , renal function test (to asses target organ damage )
Future Possibilities
PAPRE warfarin intensity PRECLUDE primary prevention
What to do with the patient with APLA but no thrombotic manifestations ? Although some of these patients are at risk, especially those with SLE, many will never develop thrombosis The current recommendation would be to do very careful search for thrombosis. Brain MRI in patients with SLE & in patients with any neurological symptom If this work-up is negative follow the patient very closely Does immunosuppression work ? APLA seems like an autoimmune disease, but immunosuppression does not prevent recurrent thrombosis, fetal loss, or neurological syndromes & so no role in the Rx of thrombotic APLA
In"catastrophic APLA" plasmapheresis may play a crucial role. Low intensity anticoagulation with warfarin appears to be mostly effective in APLA (except patients with venous thrombosis) Many patients will fail low intensity warfarin & need more aggressive anticoagulation.
Heparin anticoagulation appears more effective. Arterial Thrombosis: Warfarin to an INR of 2.0 - 3.0 Venous Thrombosis: Warfarin to an INR of 3.0 - 3.5. Patients who "break through" warfarin should receive heparin.
Inherited Thrombophilia
Inherited Thrombophilia
Three important inherited thrombophilias : Mutation in factor V Leiden causing resistance to
activated protein C (responsible of 2030% of venous
thromboembolism events.)
Mutation in prothrombin (guanine 20210 adenine ) Mutation in methylene tetrahydrofolate reductase (MTHFR) (cytosine 677 thymine (C677T) ) This is responsible for reduced MTHFR activity & is most
It has been linked with an increased risk for venous thromboembolism due to resistance to activated protein C & is responsible of 2030% of venous thromboembolism events
Protein S deficiency
Protein S deficiency (PSD), present in up to 2% of general population.
Women with unexplained recurrent miscarriage have an excellent prognosis for future pregnancy outcome without pharmacological intervention if offered supportive care alone in the setting of a dedicated early pregnancy assessment unit. After all these investigations 50% of recurrent aborters will have no abnormalities & these should be attributed to chromosomal defect in the conceptus.
Conclusion
In cases of adverse pregnancy outcomes APLA should be kept in mind
Risk factors
-Prev. TED -Prev TED+APLA -Prev TED+ family history of TED -Recurrent TED -TED in current preg.
Prophylaxis
ANC:s/c UH or LMWH Intrapartum:s/c UH or LMWH Post partum:s/c UH or LMWH for 3-7 days f/b UH or LMWH or warfarin for 3-7 days ANC: g odd Intrapartum or post partum:as above
Low risk
Diagnosis of APLA can be challenging, due to fluctuating titers of the antibodies, a lack of agreement between laboratories concerning standardization of the assays, and debates among researchers and clinicians concerning which antibodies to measure. Although multiple APLAs might eventually be considered pathologic to pregnancies, anti-cardiolipin, antiphosphotidylserine, and the 'lupus anticoagulant' are generally believed to be culprits when identified in women with pregnancy losses.
Rx APLA syndrome generally requires daily baby aspirin prior to conception & the use of baby aspirin & heparin as soon as pregnancy is diagnosed One recently published study demonstrated an 80% success rate for treatment of APLA by this approach. The 20% failure rate is likely accounted for in large part by genetically-abnormal losses. More aggressive treatment of APLA occasionally involves the use of human intravenous immunoglobulin. This is an expensive therapy that has less clear-cut efficacy demonstrated. The use of empiric intravenous immunoglobulin should generally be discouraged, and is not endorsed by the American College of Obstetricans and Gynecologists.