thrombocytopenia in pregnancy.pptx

Overview of thrombocytopenia in pregnancy

1. Thrombocytopenia in pregnancy DR BISWAJIT BHUYAN

2. Introduction Thrombocytopenia in pregnancy is the 2 nd most common hematological finding after anemia. Platelet count below lower limit of normal range(1,50,000/cu mm). Can be physiological or pathological. Affects 7-10% of all pregnant women. 1 Platelets 120-150*10 3 are frequent in the 3 rd trimester. 1 1 . Perepu U, Rosenstein L. Maternal thrombocytopenia in pregnancy. Proceedings in Obstetrics and Gynecology . 2013;3(1):1-5.

3. Normal pregnancy is associated with a decline in platelet count primarily because of Hemodilution Pooling in splenic and placental circulation. Increased platelet consumption. Increased platelet aggregation driven by increased levels of thromboxane A 2 .

4. Causes 21% 4% 1% 74% Ciobanu AM, Colibaba S, Cimpoca B, Peltecu G, Panaitescu AM. Thrombocytopenia in pregnancy. Maedica . 2016 Mar;11(1):55 .

5. Normal pregnancy is associated with a decline in platelet count primarily because of Hemodilution Pooling in splenic and placental circulation. Increased platelet consumption. Increased platelet aggregation driven by increased levels of thromboxane A 2 .

6. Gestational thrombocytopenia (GT) Accounts for 75% of cases of thrombocytopenia in pregnancy. Mild to moderate thrombocytopenia (>70,000/ cumm ). Generally occurs in the 2 nd & 3 rd trimester. No maternal bleeding risk No fetal or neonatal thrombocytopenia or bleeding risk. Platelets are normal before pregnancy and return to normal within 2-12 weeks postpartum.

7. No confirmatory laboratory tests are available, and the diagnosis is one of exclusion. GT is unlikely if the platelet count is below 50,000 cu mm with very few cases having been described with counts 40,000 -50,000 cu mm. Should have no past history of thrombocytopenia (except during a previous pregnancy). Needs to be differentiated from ITP which can cause bleeding in foetus and mother. Check the platelet count at the time of each routine prenatal visit.

8. GT ITP Onset 2 nd 3 rd trimester Any time Platelet >50000/ cumm Any <100000/ cumm Thrombocytopenia outside pregnancy - + Fetal / neonatal thrombopenia - + Normal platelets in post- partum + - Gestational thrombocytopenia (GT) vs ITP

9. Immune thrombocytopenic thrombopenia (ITP) in pregnancy 3-4% of thrombocytopenia in pregnancy Platelet counts is variable with severe thrombocytopenia(<50000/ cumm ) Auto-immune disorder : antibodies ( IgG ) against platelet glycoproteins ( GPIIb / IIIa and GPIb /IX→ destruction in reticuloendothelial system (spleen). Exclusion diagnosis Risk of maternal bleeding and fetal thrombopenia ( IgG cross the placenta ) Check the platelet count at the time of each routine prenatal visit.

10. Mandatory investigations CBC with peripheral smear LFT TFT ANA HB S AG HIV HCV

11. Other Investigations DCT LDH Kidney function test Lupus Anticoagulant Type 2 Vwd testing Bone aspiration ,biopsy.

12. When to treat Plt count <30,000/ cumm . Associated bleeding. Planned intervention

13. Management Pregnant women with ITP require careful monitoring, and should be seen monthly in the first and second trimester, every 2 weeks after 28 weeks, and weekly after 36 weeks First line of management Ivig —1-2g/kg in 2 divided doses. Steriods –oral or i.v. i.v. only in severe cases or no response to oral Ivig plus steriods Dose of steriods – 20-30mg/day for 10 days 1 mg /kg followed by taper Forceps, vacuum extraction, and fetal scalp electrode should be avoided.

14. Other 2 nd line agents Rituximab– usally avoided in pregnancy because of neonatal B cell depletion and low efficacy. Cyclophosphamide, MMF,Vinca , Danazol are contraindicated in pregnancy.(Category X) TPO agonist– no large scale data available. Azathioprine— has been used safely in pregnant patients. neonatal hematologic and immune impairment have been reported in some cases.( CatD ) Anti D – safety in this setting has not been clearly established,risk of hemolysis

15. Role of splenectomy Splenectomy may be considered as another option for patients who fail to adequately respond to corticosteroids or IVIg . Should be performed in the second trimester, as surgery earlier in pregnancy may induce premature labor, and later in pregnancy splenectomy may be technically difficult due to obstruction of the surgical field by the gravid uterus . Bone marrow studies should be done before spleenectomy .

16. Following delivery, serial platelet counts should be obtained in all newborns at birth and during the first week postpartum. ASH guidelines suggest that infants with a platelet count below 20,000/ μl , or those with hemorrhage, receive treatment. IVIg at a dose of 1gm/kg . The concurrent use of corticosteroids is controversial due to a possible predisposition to neonatal sepsis. Imaging of the brain withUSG , CTor MRI should be performed in all newborns with platelet counts of less than 50,000/ μl to exclude the possibility of occult intracranial hemorrhage that may require prompt intervention. Platelet counts 50 109/L occur in 10% of newborns of mothers with ITP, whereas platelet counts 20 109/L occur in 5% of cases The best predictor of severe thrombocytopenia at birth is its occurrence in an older sibling

17. Bleeding (intra-cranial haemorrhage ) is uncommon Evaluation of the fetal platelet count by cordocentesis or fetal scalp sampling are not recommended (risks >> benefits)

18. ASH AND BCSH GUIDELINES ASH BCSH T/t indications Plt <10,000/ cumm (1 st trimester) Plt 10,000-30,000(2 nd ,3 rd tm) Bleeding Plt <20000 , untill delivery imminent Safe plt count for delivery 50,000/ cumm Vaginal delivery 50,000/ cumm C.S. -80,000/ cumm Epidural Anaesthesia-80,000/ cumm First line T/t IVIG IVIG and corticosteriods Cesarean indiaction Obstetric indications Appropriate if fetal platelet count is <20000/ cumm Obstetric indication Splenectomy 2 nd trimester, platelets <10000/ cumm,bleeding 2nd trimester, platelets <10000/ cumm,bleeding

19. Hypertensive disorders of pregnancy Preeclampsia is the second most frequent cause of thrombocytopenia developing in the late second or third trimester, accounting for 21% of cases of thrombocytopenia at the time of delivery. hypertension + proteinuria + oedema Thrombocytopenia may be the only initial manifestation of preeclampsia. (50,000/ cumm ). Red cell fragmentation can accompany severe preeclampsia but is usually not a prominent feature Transaminases and LDH levels may be elevated, although less than seen in the HELLP syndrome. Platelets transfusion if bleeding or platelets < 50 x10 9 /l

20. HELLP Syndrome HELLP ( hemolysis , elevated liver enzymes, low platelets) The triad of microangiopathic hemolytic anemia (MAHA), abnormal liver function (SGOT ≥70 U/L), and thrombocytopenia with a platelet count less than 100,000/ μ l constitutes the diagnostic criteria of HELLP levated LDH (≥600 IU/L), and increased bilirubin levels (≥1.2mg/ dL ). Platelet consumption (adhesion to damaged endothelium) Treatement : MgSO4, delivery Platelets transfusion if bleeding or platelets < 50 x10 9 / l

21. Thrombotic microangiopathies of pregnancy

22. Classical pentad : 1) Thrombocytopenia 2) MAHA 70% 40% 3) Neurologic dysfunction 4) Renal failure 5) Fever Thrombotic microangiopathies (TTP-HUS)

23. TTP in pregnancy Acquired TTP in remission—higher risk of relapse during pregnancy. Significant proportion of patients with heriditary TTP (Upshaw Schulman syndrome) presents first during pregnancy. 30-60% of women with new onset TTP during pregnancy

24. Complications – IUGR ,fetal death,Preeclampsia Common presentaion in 2 nd ,3 rd trimester and post partum period. Worst outcomes when diagnosed in 2 nd trimester. Clinical course of TTP is not affected by delivery ,needs specific treatment.

25. Presumptive diagnosis MAHA plus thrombocytopenia without another obvious case in appropriate clinical setting. Confirmed diagnsosis ADAMTS 13 activity <10% of normal. Heriditary TTP Mutation studies Early diagnosis of TTP/HUS is essential to institute treatment promptly because most fatal events occur within 24 hours from presentation in untreated subjects

26. A percentage of schistocytes above 1% is a robust cytomorphological indicator for the diagnosis of TMA in adults. If schistocytes are absent and there is a high suspicionof TMA, blood smear screening for schistocytes shouldbe repeated daily, as the appearance of schistocytes canoccasionally be delayed for several days. Burns, Louand Pathak (2004) have found an upper limit of 0.2%in normal individuals, 0.6% in patients with renalfailure 0.45% in pre- eclamptic women, 0.48% in patients with normally functioning prosthetic valves

27. Lab tests before plasma exchange Test Expected results Differentials Cbc with PS Anemia,thrombocytopenia,Schistocytes Leucopenia– autoimmune,b12def. PT.Aptt,fibrinogen Normal Abnormal –DIC Direct Coombs test - ve Positive – evans syndrome LFT WNL Abnormal – HELLP LDH Raised -- RFT Mild Impairment Severe – HUS HIV , HbsAg,HepC should be performed before doing plasmapharesis .

28. PLASMIC SCORE

29. Plasma exchange guidelines Should be initiated within 4-8 hours in patients with MAHA and thrombocytopenia without any identifiable cause. Plasma exchange is initially performed daily until the platelet count is 150 109/L for at least 3 days and serum LDH concentrations have returned to normal, or nearly normal levels. Replacement produts —100%FFP Or cryopoor plasma

30. Steriods Can be used with plasma exchange High risk (neurological involvement and e TropI ) Iv methylprednisolone 1g*3 days followed by prednisolone 1mg/kg. Low risk– prednisolone 1mg/kg till platelet recovery and taper over 2-3 weeks.

31. Rituximab Established efficacy as second line agent. Recommendations in pregnancy Upfront – neuro /cardiac involvement. Refractory ,relapsing immune ITP. Safe in 1 st trimester of pregnancy. 375mg/m 2 4 days. Large scale data are lacking. Plasma infusion– Can be started as a initial therapy only in cases of hereditary TTP.

32. Platelet transfusions are contrindicated . Folate supplementation. PRBC transfusions are indicated Response – Platelet count >1,50,000/ cumm for 2 consecutive days. Remission– Normal platelet count for 30 days after stopping PLEX.

33. Worsening of pre‐existing thrombocytopenia is the most im ‐ portant change observed in type 2B VWD women during pregnancy because an increased release of abnormal multimers with enhanced affinity for glycoprotein Ib on platelet surface occurs. in type 2B, use of DDAVP can exacerbate thrombocytopenia, leading to an additional risk of bleeding; this agent is contraindicated if a persistent decrease in platelet count has been documented Replacement products are needed for type 2B and 3 vWD

34. Derivation and Prospective Validation of a Predictive Score for the Rapid Diagnosis of Thrombotic Thrombocytopenic Purpura : The Plasmic Score Pavan K Bendapudi , MD,Ang Li, MD,Ayad Hamdan , MD,Ashley Michelle Fry, MD,Lynne Uhl , MD,Marisa Marques, MD,Richard Kaufman, MD,Christopher P. Stowell , MD PhD,Walter Sunny Dzik , MD,Robert S Makar , MD PhD, Derivation and Prospective Validation of a Predictive Score for the Rapid Diagnosis of Thrombotic Thrombocytopenic Purpura : The Plasmic Score, Blood, 2014, Table 1 Copyright © 2020 American Society of Hematology

35. With regard to inherited TTP, plasma infusions (10-15 mL/kg) in mothers may be sufficient TTP/HUS during pregnancy does not differ from that of the nonpregnant patient. Delivery does not generally cause resolution of TTP and is not routinely indicated. Plasma exchange is the most effective therapy and should be initiated as soon as possible. Plasma exchange is initially performed daily until the platelet count is 150 109/L for at least 3 days and serum LDH concentrations have returned to normal, or nearly normal, levels

36. The mainstay of treatment of preeclampsia/ eclampsia , HELLP syndrome, and AFLP is delivery of the fetus. Prompt delivery is indicated for pregnancies 34 weeks of gestation, evidence of fetal distress (based on fetal heart rate monitoring and biophysical profile), or severe maternal disease (Figure 2). Reversal of coagulopathy ( eg , transfusion of fresh frozen plasma, cryoprecipitate, packed red blood cells, and platelets) may be required before delivery and/or in the immediate postnatal period

37. Haema t ological physiologic changes during pregnancy

38. Haematological physiologic changes during pregnancy Anemia < hemodilution ( ’ plasma volume up to 40%) < iron deficiency < folic acid deficiency Normal hemoglobin level : > 11 g/dl during pregnancy Mild elevation of neutrophils Platelet count decreases by 10%  Left shift of the whole distribution of platelet counts at term  Platelets 120-150 x10 9 /l are frequent at the 3rd trimester

39. Thrombocytopenia during pregnancy

40. Thrombocytopenia during pregnancy The most common haematological abnomality during pregnancy : 7-15% 74% 21% 4% 1%

41. Thrombocytopenia during pregnancy 75% of thrombocytopenia during pregnancy are gestational thrombocytopenia, a benign phenomenon with no significant bleeding-risk for the mother or the fœtus. BUT Difficult to distinguish from ITP Thrombopenia can be an indicator of severe complications like eclampsia, DIC, TTP… Ð assessment is required to exclude severe complications and evaluate de bleeding risk for the mother and the fœtus, especially when platelets < 100 x10 9 /l

42. Differential diagnosis of thrombocytopenia in pregnancy Isolated thrombocytopenia Gestational ITP Drug-induced Type IIb von Willebrand disease Thrombocytopenia associated with systemic disorders Pregnancy specific Preeclampsia HELLP Acute fatty liver Not pregnancy specific Thrombotic microangiopathies : TTP, HUS Systemic lupus Antiphospholipid antibodies Disseminated intra-vascular coagulation (DIC) Viral infection (HIV, CMV, EBV) Bone marrow dysfuction Nutrionnal deficiency (folate deficiency)

43. Gestational thrombocytopenia (GT) 5-8% of healthy pregnant women Mild to moderate thrombopenia (>70-80 x10 9 /l) Cause : accelerated platelet consumption + increased plasma volume ? Generally occurs in the 3rd trimester No maternal bleeding risk No fetal or neonatal thrombopenia or bleeding risk Platelets are normal before pregnancy and return to normal within 2-12 weeks postpartum Anti-platelet antibodies can be present (screening not recommanded)

44. Immune thrombopenic thrombopenia (ITP) in pregnancy 3% of thrombocytopenia in pregnancy Moderate thrombopenia : 50-100 x10 9 /l but lower Auto-immune disorder : antibodies (IgG) against platelet glycoproteins (GPIIb/IIIa and GPIb/IX→ destruction in reticuloendothelial system (spleen) Detection of antibodies is possible but not recommended Thrombopenia can be present before conception or early in pregnancy Normal bone marrow biopsy and spleen size Exclusion diagnosis Risk of maternal bleeding and fetal thrombopenia (IgG cross the placenta)

45. Pathophysiology of ITP

46. Gestational thrombocytopenia versus ITP Important to distinguish GT from ITP to optimize management GT ITP Before pregnancy - + Mild Moderate (< 50 x10 9 /l ) ++ - -/+ ++ Antiplatelets antibodies + ++ Fetal / neonatal thrombopenia - + Normal platelets in post- partum + - Early in pregnancy Late in pregnancy -/+ + ++ +

47. Treatment of ITP during pregnancy

48. Corticosteroids – IVIG Similar response for both treatments No effect on fetal platelet count Splenectomy has been performed during 1st or 2d trimester Immunosupressive agents avoided if possible (azathioprine is safe, ciclosporine ) Rituximab (used in case reports) contra-indicated in pregnancy The risk for thrombopenia in the neonates remains in splenectomized mothers (persistance of IgG). T rea t ment of IT P during pregnancy

49. Treatment of ITP during pregnancy Corticosteroids 1-2 mg/kg prednisone Response within 7 days Tapering after 2-3 weeks Side effects: hypertension, hyperglycemia, weight gain, psychosis, osteoporosis Indicated if platelets <50 x10 9 /l I V I G 0.4 g/kg/d for 5 days Response within 1-3 days • Response duration 2-3 weeks Side effects : headache, anaphylactic choc, oedema Indicated if : platelets < 50 x10 9 /l pre-operatively bleeding with platelets < 30 x10 9 /l Cortico-resistance Costs !

50. Delivery in women with ITP

51. Epidural analgesia in patients with ITP

52. Management of neonate of a mother with ITP Antiplatelets antibodies can cross the placenta→ fetal thrombopenia ( 5% of neonates have platelets <20.000/mm3) and 10-15% <50.000) Bleeding (intra-cranial haemorrhage) is uncommon Evaluation of the fetal platelet count by cordocentesis or fetal scalp sampling are not recommended (risks >> benefits) Avoid scalp electrodes, forceps, ventouse Mesure cord platelets count and monitor platelets until nadir (2-5 days after delivery) If neonate’s platelet < 30-50 x10 9 /l : IVIG 1g/kg No treatement if neonate’s platelets >50 x10 9 /l If life-threatening haemorraghe : IVIG + platelet transfusion

53. Neonatal alloimmune thrombocytopenia Maternal antibodies against alloantigens carried on fetal platelets. Cause of severe thrombocytopenia in the fetus and neonate, can produce serious bleeding, intracranial haemorrhage and death P latelet GPs are polymorphic, classified in a system of Human Platelet Antigen (HPA) Maternal-fetal incompatibility for HPA-1a is the most common cause of NAIT A first affected neonate with NAIT is suspected when signs of bleeding are evident at or shortly after birth Treatment : PS transfusion +/- IVIG

54. Management of subsequent pregnancies Test the HPA phenotype of the father and the mother Estimate the degree of fetal thrombocytopenia to gauge the risk of antenatal intracranial haemorrhage. Platelet count on a fetal blood sample. (invasive) Mother’s seric titre of the anti-HPA antibody Consider the severity of disease in affected siblings. Antenatal therapy to the mother to improve fetal thrombocytopenia and reduce the risk of pre and postnatal bleeding. High dose IVIG with or without corticosteroids Neonatal alloimmune thrombocytopenia

55. M. Kamphuis Prénat Diagn 2011

56. Hypertensive disorders Preeclampsia : hypertension + proteinuria + oedema Occurs in 6% of all pregnancies Thrombopenia in 20-50% Platelet consumption (adhesion to damaged endothelium) Haemorrhage is uncommon unless DIC develops HELLP (hemolysis, elevated liver enzymes, low platelets) Moderate thrombopenia Treatement : MgSO4, delivery Platelets transfusion if bleeding or platelets < 50 x10 9 /l

57. Endothelial dysfunction Abnormal insertion of the placenta ™ utero-placental perfusion hypoxia Vasoconstriction NO+prostacyclins TXA2 + angiotensin II Platelets activation Hemostasis disturbancies Fibrin formation and patelets consumption Possible mecanism of thrombopenia in eclampsia and HELLP

58. Thrombotic microangiopathies (TTP-HUS) Classical pentade : Thrombocytopenia Microangiopathic hemolytic anemia Neurologic dysfunction Renal failure Fever Biological findings Thrombocytopenia < 20 x10 9 /l Anemia < 10 g/dl, hemolysis (elevated reticulocytosis, LDH, indirect bilirubin, haptoglobine) Schistocytes Treatment : plasmapheresis, fresh frozen plasma, corticoids, immunosuppresive agents, rituximab…

59. Pathophysiology of TTP Blood Flow Adhesion, Rolling, Activation, Recruitment Normal Mul t imers Protease No Protease Thrombus “Ultra-Large” Multimers ( TT P ? )

60. Disseminated intravascular coagulation (DIC)

61. DIC Causes of DIC during pregnancy Placenta abruptio Eclampsia and preeclampsia Abortion Acute fatty liver (3rd trimester, abdominal pain, mental disturbancies, cholestasis, DIC, hypoglycemia) Intra uterine fetal death (IUFD) Sepsis Amniotic embolism Biological findings ’ prothrombin time and APTT ™ fibrinogen Severe thrombopenia Microangiopathic hemolytic anaemia (schistocytes) – ’ fibrin and degradation fibrin product (D-dimers), TAT

62. Treat basic disease Delivery Control hypertension Antibiotics Maintain and restore blood volume Transfusion : red blood cell, platelets, FFP Fluids perfusion Heparin if thrombosis, antithrombin Tranexamic acid if bleeding (with caution) DIC : treatment

63. Other causes of thrombocytopenia during pregnancy Infection: Viral : EBV, CMV, HIV Mycoplasma Bacteria Parasites (malaria) Mycobacteria, rickettsia Systemic lupus and antiphospholipid syndrome (APS) Haematological malignancies Congenital : May-Hegglin von Willebrand type IIb Familial

64. Drug-induced thrombocytopenia during pregnancy Drug induced : recovery of platelets 5-7 days after withdrawn

65. Thrombocytopenia induced by heparin UFH > LMWH Score « 4T » 2 1 Platelets 20-100 or ™ 50% 10-20 or ™30-50% <10 or ™ 30% Timing 5-10 days > 10 days < 4 days Thrombosis Proven Cutaneous necrosis suspected no Other possible cause no possible yes Antibodies against PF4+ or platelets aggregation with heparin Stop heparin Hirudin or daparinoïd

66. Work-up of thrombocytopenia during pregnancy summary Medical and familial history Timing of thrombopenia: before pregnancy ? Gestational age Risk for HIV Bleeding (bruising, gingivorragia, menometrorraghia, purpura) Drug use Physical examination (blood pressure, oedema, splenomegaly, adenopathy, signs of systemic disease…) Blood count and peripheral smear Liver and renal function, auto-immune, viral serology Antiphospholipid antibodies Hemostasis tests : APTT, PT, INR, fibrinogen, D-Dimers Proteinuria

67. Pseudothrombopenia In vitro artefact usually caused by antibodies antiplatelets against the cryptic site IIb-IIIa unmasked by EDTA Control platelets counts with citrate and heparin Control platelets count on blood smear (clumps)

68. Thrombopenia during pregnancy Exclude pseudothrombocytopenia No history of ITP, drug, medical disorders Peripheral smear Follow platelets monthly Repeat screening if < 75 History of ITP Pl < 50 Prednisone IVIG Pl > 75 Only low Pl APL AAN HIV, virus Normal, Pl > 75 probable ITP Drugs, medical disorder Stop drugs, treat medical disorder Hemolytic anemia Hypertension Proteinuria Liver enzymes Fever Neurological Purpura Bleeding T hrombosis Hemos t asis Preeclampsia HELLP TTP DIC Delivery MgSO4 Delivery transfusion Plasma pheresis

69. Haemostasis in normal pregnancy

70. PREGNANCY = HYPERC O A G ULAB I L IT Y Protection from haemorrhage during delivery Predisposes to t hromboembolism

71. Effets of pregnancy on the clotting system Increase of clotting factors –  FVIII,  FVII,  FX,  Fibrinogen,  von willebrand factor Reduction of coagulation inhibitors  Proteins S  Antithrombin Protein C remains stable Reduction of fibrinolysis inhibition (hypofibrinolysis)  PAI-1 Factors II, V , IX, XI are stable

72. Pregnancy in women with inherited bleeding disorder

73. Inherited bleeding disorders Carriers of Haemophilia Von Willebrand disease Other coagulation factor deficiency (FXI,….)

74. Issues related to inherited bleeding disorders in pregnancy Miscarriages Follow-up of pregnancy Labour Epidural analgaesia Delivery Fetal complications Post-partum haemorrhage

75. Carriers of haemophilia Carriers of haemophilia may have a factor (VIII or IX) deficiency → check factor VIII level at 3rd trimester (FIX will nor raise) Determine the gender of the baby in case of hemophilia (if male fetus, prenatal diagnosis and genetic counselling should be offered Need for treatment with factor concentrate during pregnancy is rare For labour,delivery and postpartum, if factor level < 50 iu/dl Factor concentrate (FVIII, vWF+FVIII, FIX) Desmopressin for HA - VWD Tranexamic acid

76. VWD during pregnancy Variable and unpredictable increase of : FVIII von Willebrand factor : > 12 weeks, not in vWD type 3 → factors levels should be checked during the last trimester Miscarriages Similar incidence in women with vWD (10-20 %) and without vWD (12-15%) Miscarriages or abor t ion early in pregnancy carry an increased risk of maternal haemorrhage Vaginal bleeding During first trimester : 33% in VWD 33% > mothers without vWD (16%) Antepartum : frequency not higher than normal

77. Epidural analgaesia Limited reported experience Many anesthaetists are reluctant to preform the procedure Can be safely performed if FVIII and von Willebrand factor (VWF) antigen and activity levels are above 50 % at time of delivery Von Willebrand factor concentrates or DDAVP should be administered if FVIII and VWF levels below 50 % Any other clotting abnormality should be excluded (low platelets) Individualised assessment is required

78. vWD and delivery Primary post-partum haemorrhage Blood loss > 500 ml during 24 hrs after birth of the infant 3 to 5 % in normal vaginal delivery 15 to 18.5 % in women with vWD Secondary post-partum haemorrhage 1.3 % in normal individuals 20-25 % in patients with vWD (rapid fall of FVIII and VWF) Always check VWF and FVIII before delivery and factors + haemoglobin on discharge

79. Management of peri- and post-partum haemorrhage Minimise genital and peritoneal trauma at delivery Factor levels should be kept > 50 % for 3-4 days after vaginal delivery and 4-5 days after cesarean section At time of delivery, a sample of cord-blood should be collected and carried promptly to the lab to exclude severe deficiency Good communication between anesthaesiologist, obstetrician and bleeding expert is mandatory

80. Management of the fetus born to a mother with a bleeding disorder Determine the gender of the baby in case of hemophilia Reduce the risk of bleeding complications at delivery by avoiding : Instrumental deliveries (vacuum extractions, forceps) Prolonged deliveries Invasive monitoring techniques Desmopressin do not contra-indicate breast feeding After birth, avoid IM injection of Vit K, IM immunisations and post- pone surgery when possible (circumcision)

81. Ohter rare bleeding disorders in pregnancy Global management like hemophilia and vWD Afibrinogenaemia Infusion of fibrinogen or FFP → Fg level > 100 mg/dl Factor XI deficiency No raise during pregancy Correlation between factor level and bleeding is difficult (< 15 iu/dl) Fresh frozen plasma if required Factor VII deficiency Tranexamic acid, Novoseven 

82. Management of pregnancies in women with inherited bleeding disorders Control factor level Prepare management plan with anaesthestist, gynecologist and paediatrician Genetic counseling ? Risk of t ransmission De t ermine fetus sex Conception Before concep t ion Mesure factor level Delivery Week 34 Post-partum Control haemoglobin level Control neaonate’s factor level on blood cord

83. Gestational venous thrombo-embolism (diagnosis, prevention and treatment)

84. Embol ism Venous thrombo-embolic disease (VTED) Pulmonary embolism Deep venous thrombosis Migrati on Thrombus 1. Pesavento R, et al. Minerva Cardioangiologica 1997;45:369-375. 2. Girard P, et al. Chest 1999;116:903-908.

85. Pregnancy and VTE Risk of DVT/PE : 5-10 X during pregnancy Incidence : 0.86/1000 pregnancies (0.71: DVT - 0.15 : PE) 80 % DVT : left lower limb Proximal DVT (iliac and/or femoral veins) >> distal DVT during pregnancy

86. Pregnancy and risk factors of VTE STASIS – Mechanical factors Slowdown of blood flow Reduction of vascular tone Compression of veins by uterus (left > right) HYPERCOAGULABILITY Increase of FVIII and VWF Reduction of inhibitors (protein S and antithrombin) Hypofibrinolysis VASCULAR INJURY / LESION Delivery

87. Individual risk factors for VTE BEFORE PREGNANCY Past history of VTE disease (personal and family) Thrombophilia Age > 35 years Obesity Multiparity Venous insufficiency Nephrotic syndrome DURING PREGNANCY Immobility Hyperemesis Dhydratation Ovarian hyperstimulation Pre-eclampsia Air travel Cesarean section Infection or inflammatory process

88. Model of thrombotic risk DVT = multifactorial disease Rick of thrombocic Trechold for DVT/PE Bacal rick Factor V Leiden Pi ll Pregnancy Immobilication Age Adapted from Rocendaal FR : Lancet 353 : 1167, 1999

89. Pulmonary Embolism Recurrent DVT Pos t - t hrombo t ic Syndrome Consequences and sequelae of VTE disease Maternal mortality Venous insufficiency Post-thrombotic syndrome (PTS) Recurrent DVT

90. Antithrombotic agents VKA (Sintrom, Marevan, Marcoumar) contra-indicated (relative CI) Crosses the placenta Risk of bleeding Teratogenic (6-12 weeks) LMWH : anticoagulant agent of choice >> UFH Excellent bioavailability and predictable effect Does not cross the placental barrier Short half-life Well-tolerared (rare thrombocytopaenia, osteoporosis) NOAC : contra-indicated in pregnancy

91. Treatment of VTE during pregnancy Doses and duration : 100 anti-Xa units /kg, twice a day (avoid once a day treatment) If distal DVT : 100 U anti-Xa units /kg, once a day after 3 months of treatment Throughout pregnancy and at least 6 weeks postpartum 24 hours between last injection and epidural at therapeutic concentration Monitoring (anti-Xa and platelets count) : Anti-Xa activity should be measured after one week, then every 6 weeks Expected value : 0.5-1.0 anti-Xa unit / ml (2-4 h post-injection) Mandatory if < body weight <50 or >100 kg, renal insufficiency, increased bleeding risk Platelet count : risk of Heparin Induced Thrombocytopaenia (HIT) low with LMWH during pregnancy, full blood count after a week then 1x/month

92. Pregnant Women With Past DVT/PE Prophylaxis for 6 weeks after delivery (Grade 2B) for all Moderate/high recurrence risk should consider taking prophylactic or intermediate-dose LMWH during pregnancy (Grade 2C). This includes women with a prior DVT or PE that was unprovoked, or related to pregnancy or estrogen use. Low risk for recurrence (because their VTE was provoked by a transient risk factor unrelated to pregnancy or estrogen use) and their doctors should watch carefully for signs or symptoms of DVT or PE during pregnancy, but ACCP suggests they not use LMWH as prophylaxis (Grade 2C). VTE prophylaxis during pregnancy ACCP 2012

93. VTE prophylaxis during pregnancy ACCP 2012 1 episode of VTE with transient risk factor and no thrombophilia → surveillance antepartum and prophylaxis postpartum 1 episode of idiopathic VTE without long term anticoagulation and no thrombophilia → surveillance or prophylaxis antepartum and prophylaxis postpartum 1 episode of VTE with thrombophilia or mulitple episodes of VTE → prophylaxis antepartum and prophylaxis postpartum Prior VTE and long-term anticoaguation → intermediate or full dose LMWH antepartum

94. No prior VTE but severe thrombophilia (homozygous) or combined thrombophilia and familial history of VTE → prophylaxis antepartum and prophylaxis postpartum (grade 2B) No prior VTE and other thrombophilia → surveillance antepartum and prophylaxis postpartum (grade 2C) Prior VTE and long-term anticoaguation → intermediate or full dose LMWH antepartum VTE prophylaxis during pregnancy ACCP 2012

95. Epidural analgaesia and LMWH Insertion of the needle when the anticoagulant effect is minimal (8-12 hours after last prophylactic injection and 24 hours after last therapeutic injection) Prophylactic dose should be given at least 4-6 hours after insertion/removal of catheter

96. Thrombophilia Inherited or acquired predicpocition towardc thrombocic Primarily accociated with an increaced rick of venouc thromboembolic diceace Can be accociated with adverce pregnancy outcomec (APL)

97. Thrombophilia screening : recommendations Avoid pregnancy (< 12 weeks) and hormonal treatment Has a screening already been performed in the past ? Known thrombophilic trait in the family ?? Informed consent and appropriate information regarding personal and family implications (insurance) Is screening useful and indicated ? Eligibility for re-imbursement (cost > 400-800 euros)

98. Family history of VTE Idiopathic VTE (or after a trivial provocation) VTE < 60 years old Recurrent VTE Unusual VTE Suspicion of APS A screening makes sense only if the care of the patient or her/his family will be modified Who sould be screened for thrombophilia

99. Thrombophilia and risk of DVT during pregnancy Basal risk : 1/1500 FV Leiden : 1/500 – 1/437 G20210A FII mutation : 1/200 FVL + FII mutations : 4.6/100 Protein C deficiency : 1/113 Antithrombin deficiency (quantitative defect ) : 1 / 2.8 Antithrombin deficiency (qualitative defect) : 1 / 42

100. Ovarian stimulation Thromboprophylaxis with LMWH (3800 à 5000 anti/ Xa units /day) : Past history of DVT/PE Risk factors for DVT-PE Known thrombophilia Ovarian hyperstimulation

101. Cerebral venous sinus thrombosis Incidence : 4/1.000.000 /yr Common caucec : trauma, auto-immune, pregnancy, puerperium, OC Rick increaced by OC (20 x) Rick = two-fold rick with 3 rd vc 2nd generation pillc Rick higher in women with thrombophilia Factor V Leiden : X 34 Prothrombin mutation : X 149.3 (31-711)

102. Prosthetic heart valves Anticoagulation is required throughou t pregnancy in women with mechanical heart valve(s) Treatment should be individualised after careful counselling (valve type, position, VTE history) O p t ions of an t icoagula t ion in pregnant women wi t h pros t he t ic heart valve(s) Ora l anticoagulant s (VKA ) throughou t pregnanc y (ris k of embryopathy) Replace VKA with Heparins (weeks 6-12) (UFH or LMWH) Heparins throughout pregnancy (very few studies on the study and efficacy of LMWH in this setting)

103. Ar t erial t hrombo-embolism in pregnancy

104. Mechanisms of thrombosis Venous t hrombosis Arterial t hrombosis Stasis +++ +  Blood coagulabili t y +++ + Altered vessel + +++ wall

105. Ischaemic stroke Pregnancy is associated with a increased risk of stroke No clear consensus about the incidence 5 cases / 100.000 deliveries Infarctions > haemorrhages Arterial > venous infarctions Risk higher in the post-partum Most common cause = eclampsia and pre-eclampsia

106. Thrombophilia and fetal loss / gestational vascular complications

107. Adverse pregnancy outcomes potentially related to thrombophilia Recurrent unexplained miscarriages (3 or >) Pre-eclampsia Unexplained IUGR (intra-uterine growth retardation) Unexplained IUD (intra-uterine fetal death) Abruptio placentae

108. Placenta vacculopathy and thrombophilia Thrombophilia Miscarriages IUFD Pre- eclampsia HELLP Abruptio placentae Antithrombin deficiency ++ ++ + Protein C deficiency + ++ + Protein S deficiency + ++ + + Dysfibrinogenemia + + APC-resistance ++ ++ ++ + Factor V Leiden ++ ++ ++ + ++ MTHFR C677T + + + + Hyperhomocysteinaemia + + ++ ++ ++ Prothrombin mutation + + + ++ Antiphospholipid syndrome ++ ++ ++ + Combined defects ++ ++ + +

109. Thrombophilia and complicated pregnancy : evidence and controversies With the exception of Anti-Phospholipid antibodies, there is little evidence to support systematic screening for thrombophilia in women with complicated pregnancy In our experience, combined treatment with LMWH and aspirin with close monitoring although not validated is safe and efficient in most cases to prevent recurrent complications For women with past history of eclampsia and/or pre-eclampsia and no thrombophilia, low dose aspirin is recommended

110. Antithrombotic therapy in women with complicated pregnancy and thrombophilia Low-dose enteric coated aspirin + LMWH (prophylactic dose) Dosis : 3800-4000 anti-Xa units / day (injection in the morning in order to allow monitoring with the anti-Xa assay) Stop aspirin at week 34 Continuation of LMWH until delivery and 4 to 6 weeks post-partum For women with past history of eclampsia and/or pre-eclampsia and no thrombophilia, low dose aspirin is recommended

111. Thank you for your attention