BBSSHH OOBBSSTTEETTRRIICC HHAAEEMMAATTOOLLOOGGYY GGRROOUUPP Meeting focus: Interaction with the obstetric anaesthetist Am- obstetric haemorrhage PM – Obesity, Regional Anaesthesia Venue: Robens Suite, 29th Floor, Tower Wing, Guy’s Hospital Great Maze Pond, London SE1 9RT Date: Monday 19th November 2012

PROGRAMME

CHAIR: Dr Sue Pavord 10.00 -10.30 Guidelines on blood usage in obstetric haemorrhage

Laura Green, Haematologist, Barts and the London 10.30- 10.50 Update on the WOMAN study and use of tranexamic acid in

obstetric haemorrhage Beverley Hunt 10.50 - 11.00 Review of the role for rVIIa in Obstetric haemorrhage Sue Pavord, Haematologist, Leicester 11.00 – 11.30 Use of fibrinogen concentrate in Obstetric haemorrhage Peter Collins, Haematologist, Cardiff (TBC) 11.30 – 11.45 Coffee

11.45 – 12.05 Assessment of Fibrinogen Speaker TBC

12.05 – 12.30 Use of thromboelastography in obstetric practice

Helena Maybury, Obstetrician, Leicester

12.30 – 13.10 Open forum - Case studies of difficult Obstetric haemorrhage / regional anaesthesia including managing obesity (Jason Scott)

13.10 -13.50 Lunch CHAIR: Professor Beverley Hunt 13.50 – 14.20 Obesity-an anaethetist’s perspective

Dr Claire Nightingale, Anaesthetist, Buckshealthcare NHS Trust

14.20 – 14.40 Pharmacokinetics of LMWH in pregnancy Jig Patel 14.40 – 15.20 Debate: This house believes the coagulation criteria for

permitting spinal/epidural anaesthesia in labour are too strict. Proposer Will Lester, Haematologist Against Anaesthetist TBC 15.20 Close

Prof Beverley Hunt MB ChB, FRCP, FRCPath, MD

Consultant, Guy’s & St Thomas’ Trust

Medical Director of Lifeblood: the thrombosis charity

Haematology problems in the maternity HDU

Maternal triennial enquiry Centre for Maternal and Child enquires

1997-99 2000-2 2003-5 2006-8

VTE 35 30 41 18

Preeclamp & eclampsia

16 14 18 19

Haemorrhage 7 17 14 9

Plus TTP is killing one mother a year

Haematology in maternal critical care

•  VTE prevention/management/APS •  Pre eclampsia/HELLP (consider TTP)

•  Thrombocytopenia •  Bleeding management

•  Sickle –exchange! Aim for sickle% of <30%

Thromboprophylaxis in obesity

•  Obesity doubles the risk of VTE •  An epidemic •  Larger plasma volume to anticoagulate •  Adipocytes produce additional prothrombotic factors-

PAI-1, increased fibrinogen due ot IL-6 etc

•  …..So adjusting dose to lean body weight is not appropriate…..

Obesity  in  pregnancy:  Improving  care  and  effecting  change,  Dec  2010  

Weight    

Enoxaparin    

Dalteparin    

Tinzaparin   (75u/kg/day)    <50kg  

 20mg  daily    

2500  units  daily    

3500  units  daily    

50-­‐90kg    

40mg  daily    

5000  units  daily    

4500  units  daily    

91-­‐130kg      

60  mg  daily*    

7 5 0 0   u n i t s  daily*    

7000units  daily*    

131-­‐170kg    

80  mg  daily*      

1 0 0 0 0   u n i t s  daily*      

9000  units  daily*      

>170kg    

0.6mg/kg/day*    

75u/kg/day*    

75u/kg/day*    

High  prophylactic  (intermediate)  dose  for  women  weighing  50-­‐90kg    

40mg  12  hourly    

5000   units   12  hourly    

4 5 0 0   u n i t s   1 2  hourly    

Treatment  dose    

1mg/kg/12  hourly  antenatal  1.5mg/kg/daily  postnatal    

1 0 0 u / k g / 1 2  hourly   or   200u/k g / d a i l y  postnatal    

175u/kg/daily  (antenatal  and  post  natal)    

Diagnosis & treatment of VTE in pregnancy is different from normal

•  V/Q Spect new technique, about 10 centres in UK. Same specificity and sensitivity as CT PA BUT lower radiaotion dose to the breast (combined V/QSPECT/CT on the way).

•  If a ?PE then perform a Doppler of legs and if confirmed no further invest required

•  D –dimer is not validated in pregnancy •  Dose of LMWH is larger (plasma volumes and better

renal excretion) Clexane 1mg/Kg BD versus 1.5mg/Kg

•  Rivaroxaban is licensed and NICE approved, can be used postpartum in the non breast feeding mother?

Other agents for thromboprophylaxis and treatments of VTE in pregnancy

• UFH -need larger doses than non-parous, 2% risk of osteoporotic fracture • Danaparoid — monitor with anti-Xa levels, safe to breastfeed (one report) • Recombinant hirudin- case report in pregnancy, no adverse outcome • Fondaparinux — minor transplancental passage- case reports, increasingly being used, increasingly being used • Oral direct thrombin inhibitors & anti Xas— no human data •  IVC filters — temporary please

Antithrombin (III)

•  Present in plasma in inactive form •  Activated by heparinoids -up to

10,000 fold •  produced by the liver •  antithrombin deficiency -

heterozygotes 1 in 5,000, homozygous incompatible with life

•  Risk of VTE in pregnancy is 50%

Protamine binds to sulphated UH only

Classification Criteria for definite antiphospholipid syndrome

•  Antiphospholipid antibody (aPL) plus •  Thrombosis in ANY vessel (thrombotic APS) AND/OR •  One or more unexplained deaths of a morphologically normal fetus BEYOND the

10th week of gestation, OR •  One or more premature births of a morphologically normal neonate at or before

34th week of gestation because of PET, eclampsia or severe placental insufficiency

•  THREE or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomical or hormonal abnormalities and

paternal and maternal chromosomal causes excluded

Antiphospholipid antibodies and pregnancy Lupus pregnancy clinic, St Thomas

RECURRENT PREGNANCY LOSS •  Aspirin •  Aspirin & enoxaparin 40mg if

failure on aspirin, or 2/3rd trimester loss

PREVIOUS THROMBOSIS Venous •  Aspirin & enoxaparin 40mg od to

16-20 weeks then bd •  Drop to 40mg 3/7 post op Arterial •  Aspirin & enoxaparin 40mg BD •  Option of warfarin in 2/3rd trimester if

recurrent cerebral events

37 year old woman

•  Known thrombotic APS. •  Developed PET/eclampsia at 28/40 •  Delivered by C/S, problems with C/S •  Septic, ventilated and haemodialysis •  BP required help •  CT scan of abdomen showed infarction of adrenals,

splenic wedge infarcts, ? bowel infarct

•  Diagnosis and management?

Catastrophic APS •  Multiple thromboses in any organ associated with

aPL (lupus anticoagulant &/or ACA &/or anti beta2 glycoprotein 1)

•  50% mortality •  Often precipitated by infection &/or surgery •  Ideally prevent •  Rx- no trials. Plasma exchange, IV Igs, steroids,

anticoagulation (hirudin). New anticomplement monoclonals??

Maternal mortality

Ratio per 100 000 live births in 2005: World Health Statistics (2008) http://www.who.int/whosis/whostat/2008/en/index.html

Each year, world-wide about 530,000 women die from causes related to pregnancy and childbirth

The WOMAN study aiming to recruit 15,000 with PPH

The WOMAN study Trial Treatment

TREATMENT AMPOULES DOSE (TRANEXAMIC ACID OR PLACEBO) ADMINISTRATION INSTRUCTION

DOSE 1 2 1gram To be administered by intravenous injection at an approximate rate of 1mL/

minute to all randomised women as soon as possible after randomisation.

DOSE 2 2 1gram If after 30 minutes bleeding continues, or if it stops and restarts within 24

hours after the first dose, a second dose may be given. To be administered

by intravenous injection at an approximate rate of 1mL/minute.

The trial treatment injections should not be mixed with blood for transfusion, or infusion solutions containing

penicillin or mannitol.

Thrombocytopenia in pregnancy

Pregnancy-related •  Gestational •  PET/HELLP/DIC •  Folate deficiency

Other •  Spurious •  Autoimmune •  HIV -1% of pregnancies in

South London •  HUS/TTP •  Congenital/ marrow disease/

hypersplenism •  Drugs- NOT LMWH!

Haemostasis in PET Activated maternal endothelium •  Activated coagulation-↑TAT, & decreased antithrombin

•  Fibrinolytic activity (D-dimers) despite ↑ PAI-1& PAI-2

•  Fibrin in maternal spiral arteries and renal glomeruli

•  Thrombocytopenia in 18% •  Activated platelets

•  DIC in up to 10%,

•  HELLP and HUS in a minority

Blood film & renal biopsy specimen from a patient with DIC

Thrombotic microangiopathic haemolytic anaemias in pregnancy

Haemolysis, Elevated Liver enzymes and Thrombocytopenia

•  No standardised definition •  Up to 10% of severe pre-eclampsia •  Severe thrombocytopenia and deranged LFTs can occur

without hypertension & proteinuria. •  Exacerbations can occur post-partum (up to 6 days) •  Recurrence risk in future pregnancies of 3% •  Complication –DIC (20%), abruption (16%)

TTP, essentially a clinical diagnosis

Fever

MAHA microangiopathic haemolytic anaemia, red cell fragments

Neurological symptoms

Renal impairment Severe

Thrombocytopenia

NB. HUS, also a thrombotic microangiopathy, is a tetrad, with different pathophysiology.

Thrombotic Thrombocytopenic Purpura

•  Rare: 4-6/million •  Female: 70% cases. •  Peak incidence: 4th decade •  Acute, life threatening disorder •  >70% cases-due to an acquired TTP- an antibody to

vWF-CP/ADAMTS 13. •  IgG primarily, IgM/IgA described. •  Significant minority have congenital TTP, which can

present for the first time in pregnancy •  Mortality 90% without treatment, <10% with Rx.

The South East England Thrombotic Thrombocytopenic Purpura Registry

5% 5%7%

2%2%2%

77%

CongenitalPreg/COCPHIVPancreatitisOtherCa/Txidiopathic

April 2002-December 2006

TTP: a deficiency of von Willebrand-cleaving protease = ADAMTS 13: a disintegrin and metalloprotease with

thrombospondin type 1 motif 13

TTP in pregnancy

Rare but vital diagnosis because disease is fatal in the absence of treatment

•  1% of all maternal deaths- missed or treated too late •  50% present before 24 weeks. •  Maternal outcome same as non-pregnant •  Placental infarcts → poor fetal outcome –(IUGR/intrauterine

death/preeclampsia) → fetal monitoring. •  No fetal disease reported •  Termination of pregnancy does not alter clinical course of

disease •  Pregnancy does not impair response to plasma exchange, but

increases plasma requirements •  90% mortality without URGENT plasma exchange

Preventing maternal deaths due to acquired thrombotic thrombocytopenic purpura.

Hunt BJ, Thomas-Dewing RR, Bramham K, Lucas SB. J Obstet Gynaecol Res. 2012 J

Anti-CD61

Three cases of TTP that died in pregnancy/puerperium in the UK 2003-7

1  31 caucasian, 4 days post partum with low platelets, MAHA, liver & renal impairment, & confusion

Diagnosis made late & died before Rx started 2 29 afrocaribbean second pregnancy, 5 days post partum with low

platelets, blurred vision, hypertension, proteinuria (+), mild liver impairment, MAHA, cardiomegaly on CXR, confusion

Late diagnosis and died before Rx started 3 35 afrocaribbean third pregnancy, 24 weeks gestation, gestational

diabetes in second pregnancy SLE – mesangiocapillary glomerular nephritis low platelets, central chest

pain, headaches, visual floaters, arthralgia, proteinuria (+++),haematuria(+++), hypertension, renal impairment

Diagnosis not considered & Rx as SLE and died

Key points on TTP if in doubt treat until alternative diagnosis

confirmed 1.  TTP is rare BUT 2.  In view of the high risk of preventable, early death in

TTP, treatment with plasma exchange (PEX) should be initiated if a patient presents with a MAHA and thrombocytopenia in the absence of any other identifiable clinical cause.

3.  Pregnancy: If a thrombotic microangiopathy cannot be fully explained by a non-TTP pregnancy-related TMA then the diagnosis of TTP must be considered and PEX should be started.

4.  The diagnosis of TTP is a medical emergency. Patients must be offered plasma exchange as soon as the diagnosis is made, preferably within at least 4-8 hours of presentation, whatever time of day they present.

TTP HUS PET HELLP

Weeks of onset

<24 Post-partum Usually >34 Usually>34

Histopath Platelet thrombi

“Normal” thrombi in glomeruli

Accelerated atheroma

Hepatic necrosis, fibrin in sinusoids

Effect on fetus Placental infarcts

None Placental ischaemia

Placental ischaemia

Effect of delivery

None None Recovery

Recovery

Rx Plasma exchange

supportive Deliver! Deliver!

ITP in pregnancy

•  1-2 in 10,000, 3% of thrombocytopenia in pregnancy •  No positive diagnostic tests •  Platelet autoantibody has high false positive and false negative rate •  Platelet autoantibody has no predictive value for maternal & fetal outcome. Lescale, Am J Obstet Gynaecol 1996; 174: 1014

• Fetal thrombocytopenia in 5-10%, nadir day 2-5

Healthy pregnant woman

Normal woman

Gestational Thrombocytopenia Message: High fibrinogen of pregnancy more than compensate for low platelet counts: women can tolerate lower Plt counts when pregnant

Summary messages

•  Please use dose appropriate LMWH in obesity •  If you have a MAHA (red cell fragments) and low plt,

please consider TTP •  Fibrinogen is a critical protein in bleeding PPH- needs

supplementing in addition to FFP! •  Women in pregnancy can tolerate lower platelet

counts because of their high fibrinogens

Trials Coordinating Centre, Room 180 London School of Hygiene & Tropical Medicine

Keppel Street, London WC1E 7HT

Tel +44(0)20 7299 4684, Fax +44(0)20 7299 4663 Email: thewomantrial@Lshtm.ac.uk

www.womantrial.Lshtm.ac.uk

BBSSHH OOBBSSTTEETTRRIICC HHAAEEMMAATTOOLLOOGGYY GGRROOUUPP Meeting focus: Interaction with the obstetric anaesthetist Am- obstetric haemorrhage PM – Obesity, Regional Anaesthesia Venue: Robens Suite, 29th Floor, Tower Wing, Guy’s Hospital Great Maze Pond, London SE1 9RT Date: Monday 19th November 2012

PROGRAMME

CHAIR: Dr Sue Pavord 10.00 -10.30 Guidelines on blood usage in obstetric haemorrhage

Laura Green, Haematologist, Barts and the London 10.30- 10.50 Update on the WOMAN study and use of tranexamic acid in

obstetric haemorrhage Beverley Hunt 10.50 - 11.00 Review of the role for rVIIa in Obstetric haemorrhage Sue Pavord, Haematologist, Leicester 11.00 – 11.30 Use of fibrinogen concentrate in Obstetric haemorrhage Peter Collins, Haematologist, Cardiff (TBC) 11.30 – 11.45 Coffee

11.45 – 12.05 Assessment of Fibrinogen Speaker TBC

12.05 – 12.30 Use of thromboelastography in obstetric practice

Helena Maybury, Obstetrician, Leicester

12.30 – 13.10 Open forum - Case studies of difficult Obstetric haemorrhage / regional anaesthesia including managing obesity (Jason Scott)

13.10 -13.50 Lunch CHAIR: Professor Beverley Hunt 13.50 – 14.20 Obesity-an anaethetist’s perspective

Dr Claire Nightingale, Anaesthetist, Buckshealthcare NHS Trust

14.20 – 14.40 Pharmacokinetics of LMWH in pregnancy Jig Patel 14.40 – 15.20 Debate: This house believes the coagulation criteria for

permitting spinal/epidural anaesthesia in labour are too strict. Proposer Will Lester, Haematologist Against Anaesthetist TBC 15.20 Close