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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