Overview of thrombocytopenia in pregnancy

1. Thrombocytopenia in
pregnancy
DR BISWAJIT
BHUYAN

2. Introduction
 Thrombocytopenia in pregnancy is the 2nd 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*103 are frequent in the 3rd 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 A2.

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.

6.  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 A2.

7. Gestational thrombocytopenia (GT)
 Accounts for 75% of cases of thrombocytopenia in
pregnancy.
 Mild to moderate thrombocytopenia
(>70,000/cumm).
 Generally occurs in the 2nd & 3rd 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.

8.  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.

9. GT ITP
Onset 2nd 3rd 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

11. 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→
destructionin 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.

12. Mandatory investigations
 CBC with peripheral smear
 LFT
 TFT
 ANA
 HBSAG
 HIV
 HCV

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

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

17. 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.

19. Other 2nd 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

21. 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.

22.  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

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

24. ASH AND BCSH GUIDELINES
ASH BCSH
T/t indications Plt<10,000/cumm(1st trimester)
Plt 10,000-30,000(2nd ,3rd 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

25. 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 x109 /l

26. 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/μl 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 x109 /l

28. Thrombotic microangiopathies of pregnancy

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

31. 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

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

33.  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

34.  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

35. 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.

36. PLASMIC SCORE

38. 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

39. 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.

40. Rituximab
 Established efficacy as second line agent.
 Recommendations in pregnancy
 Upfront – neuro/cardiac involvement.
 Refractory ,relapsing immune ITP.
 Safe in 1st trimester of pregnancy.
 375mg/m2 4 days.
 Large scale data are lacking.
 Plasma infusion– Can be started as a initial therapy
only in cases of hereditary TTP.

41.  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.

42.  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

43. 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

46.  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

47.  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

48. Haematological physiologic
changes during pregnancy

49. 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 x109 /l are frequent at the 3rdtrimester

50. Thrombocytopenia during
pregnancy

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

52. 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 x109 /l

53. 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)

54. Gestational thrombocytopenia (GT)
• 5-8% of healthy pregnant women
• Mild to moderate thrombopenia (>70-80 x109 /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)

55. Immune thrombopenic thrombopenia
(ITP) in pregnancy
• 3% of thrombocytopenia in pregnancy
• Moderate thrombopenia : 50-100 x109 /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)

56. Pathophysiology of ITP

57. Gestational thrombocytopenia versus ITP
Important to distinguish GT from ITP to optimize management
GT ITP
Before pregnancy - +
Mild
Moderate (< 50 x109 /l )
++
-
-/+
++
Antiplatelets antibodies + ++
Fetal / neonatal
thrombopenia
- +
Normal platelets in post-
partum
+ -
Early in pregnancy
Late in pregnancy
-/+
+
++
+

58. Treatment of ITP during pregnancy

59. • 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).
Treatment of ITP during
pregnancy

60. 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 x109 /l
IVIG
• 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 x109 /l
– pre-operatively
– bleeding with platelets < 30 x109 /l
– Cortico-resistance
• Costs !

61. Delivery in women with ITP

62. Epidural analgesia in patients with ITP

63. 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 x109 /l : IVIG 1g/kg
• No treatement if neonate’s platelets >50 x109 /l
• If life-threatening haemorraghe : IVIG + platelet transfusion

64. 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
• Platelet 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

65. 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

66. M. Kamphuis Prénat Diagn 2011

67. 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 x109 /l

68. 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

69. Thrombotic microangiopathies (TTP-HUS)
• Classical pentade :
– Thrombocytopenia
– Microangiopathic hemolytic anemia
– Neurologic dysfunction
– Renal failure
– Fever
• Biological findings
– Thrombocytopenia < 20 x109 /l
– Anemia < 10 g/dl, hemolysis (elevated reticulocytosis, LDH,
indirect bilirubin, haptoglobine)
– Schistocytes
• Treatment : plasmapheresis, fresh frozen plasma,
corticoids, immunosuppresive agents, rituximab…

70. Pathophysiology of TTP
Blood Flow
Adhesion, Rolling,
Activation, Recruitment
Normal
Multimers
Protease
No Protease Thrombus
“Ultra-Large”
Multimers
(TTP?)

71. Disseminated intravascular coagulation
(DIC)

72. 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

73. • 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

74. 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

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

76. Thrombocytopenia induced by heparin
• UFH > LMWH
Score « 4T » 2 1 0
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

77. 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

78. 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)

79. 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
Thrombosis
Hemostasis
Preeclampsia
HELLP TTP DIC
Delivery
MgSO4
Delivery
transfusion
Plasma
pheresis

80. Haemostasis in
normal pregnancy

81. PREGNANCY =
HYPERCOAGULABILITY
Protection from
haemorrhage during
delivery
Predisposes to
thromboembolism

82. 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

83. Pregnancy in women
with inherited bleeding disorder

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

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

86. 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

87. 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 abortion 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

88. 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

89. 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

90. 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

91. 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)

92. 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

93. Management of pregnancies in women
with inherited bleeding disorders
- Control factor level
-Prepare management
plan with anaesthestist,
gynecologist and
paediatrician
Genetic
counseling
? Risk of
transmission
Determine
fetus sex
Conception
Before
conception
Mesure
factor
level
Delivery
Week 34 Post-partum
-Control
haemoglobin level
-Control neaonate’s
factor level on blood
cord

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

95. Embolism
Venous thrombo-embolic disease (VTED)
Pulmonary embolism
Deep venous thrombosis
Migration
Thrombus
1. Pesavento R, et al. Minerva Cardioangiologica1997;45:369-375.
2. Girard P, et al. Chest 1999;116:903-908.

96. 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

97. 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

98. 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

99. Model of thrombotic risk
DVT = multifactorial disease
Rick
of
thrombocic
Trecholdfor DVT/PE
Bacalrick
FactorV Leiden
Pill
Pregnancy
Immobilication
Age
Adapted from Rocendaal FR : Lancet 353 : 1167, 1999

100. Pulmonary
Embolism Recurrent DVT
Post-thrombotic
Syndrome
Consequences and sequelae of VTE
disease
• Maternal mortality
• Venous insufficiency
• Post-thrombotic syndrome (PTS)
• Recurrent DVT

101. 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

102. 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

103. 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

104. 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

105. • 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

106. 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

107. Thrombophilia
• Inheritedoracquiredpredicpocitiontowardc
thrombocic
• Primarilyaccociatedwithanincreacedrickof venouc
thromboembolicdiceace
• Canbeaccociatedwithadvercepregnancyoutcomec
(APL)

108. 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)

109. • 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

110. 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

111. 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

112. Cerebral venous sinus thrombosis
• Incidence: 4/1.000.000 /yr
• Commoncaucec: trauma,auto-immune,pregnancy,
puerperium, OC
• RickincreacedbyOC (20 x)
• Rick= two-foldrick with 3rd vc2nd generation pillc
• Rickhigherinwomenwith thrombophilia
– FactorVLeiden: X 34
– Prothrombinmutation: X149.3(31-711)

113. Prosthetic heart valves
• Anticoagulation is required throughout pregnancy in women with
mechanical heart valve(s)
• Treatment should be individualised after careful counselling (valve type,
position, VTE history)
• Options of anticoagulation in pregnant women with prosthetic heart
valve(s)
– Oral anticoagulants (VKA) throughout pregnancy (risk 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)

114. Arterial thrombo-embolism
in pregnancy

115. Mechanisms of thrombosis
Venous
thrombosis
Arterial
thrombosis
Stasis +++ +
 Blood
coagulability
+++ +
Altered vessel + +++
wall

116. 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

117. Thrombophilia and fetal loss /
gestational vascular complications

118. 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

119. 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 ++ ++ + +

120. 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

121. 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

122. Thank you for your attention