1. Hematologic management of massive PPH
Mehran Karimi
Professor of Pediatric Hematology- Oncology Shiraz University of Medical Science
29 Khordad,Shiraz

2. postpartum hemorrhage (PPH)
PPH is the loss of 500 ml or more of blood from the genital tract within 24 hours of the birth of a baby
PPH can be minor (500–1000 ml) or major (more than 1000 ml)
PPH is the most common cause of maternal death worldwide
PPH is responsible for 25% of the deaths of an estimated women world-wide each year
WHO guidelines for the management of postpartum haemorrhage and retained placenta, 2009

3. Severe PPH Pale, sweating PR > systolic blood pressure
Blood loss: watery, non clot
Decreased Hb more than 2-4 gr/dl from baseline (anemia is a risk factor for PPH)
Decreased HR + decreased BP when blood loss > 1500 mls

4. Hematological Changes in Pregnancy
Non pregnant: < 1% of her cardiac output flows through her uterus but at the end of pregnancy uterine blood flow accounts for 15% of CO
40% expansion of blood volume by 30 weeks
600 ml/min of blood flows through intervillous space
Appreciable increase in concentration of Factors I (fibrinogen), VII, VIII, IX, X
Plasminogen appreciably increased
Plasmin activity decreased
Decreased colloid oncotic pressure secondary to 25% reduction in serum albumin

5. Blood Products Utilization
Local protocols are helpful
Don’t wait for lab abnormalities if actively bleeding!
Massive hemorrhage without replacement of coagulation factors (FFP) will result in coagulation abnormalities

6. Causes and treatment of massive PPH
Uterine atony: The most common cause of PPH that bleeding leading to coagulopathy
Incisions and lacerations
Hemostatsis defect
Massage, remove clot, uterotonic agent, uterine tamponade
Surgical repaire
Factor replacement
Early hysterectomy indications : 1- Placenta accreta
2- Uterine rupture

7. Goals in management of a postpartum hemorrhage
Journal of Thrombosis and Haemostasis, 2011; 9: 1441–1451

8. Blood components for prevention of massive bleeding
Whole blood and RBC
Fresh frozen plasma (FFP)
Cryopercipitate
Platelets
Fibrinogen
rFVIIa

9. Main therapeutic goals of management of massive blood loss
crystalloid ,colloid , blood transfusion
Restore circulating volume
Early surgical or obstetric intervention
Arrest bleeding
> 8g/dl
Haemoglobin
> 75000/µ/
Platelets count
< 1.5 x mean control
Prothrombin Time (PT)
Activated Partial Thromboplastin time (PTT)
> 1.5 g/l
Fibrinogen
Treat underlying cause (shock, hypothermia, acidosis, hypotension)
Avoid DIC

10. Blood Product Utilization
Contents
Volume
Effect
Whole Blood
500ml
↑ Hct 3%
PRBCs
RBCs, WBCs, few plasma proteins
300ml
Platelets
Pooled concentrate
1 unit = 6 pack
50ml
↑ PLT 5000
30000
FFP
Fibrinogen, ATIII, clotting factors, plasma
250ml
↑ fibrinogen 5-10mg/dl
Cryoprecipitate
Fibrinogen, Factor VIII, XIII, vWF
40ml

11. blood components
When the blood loss reaches about 4.5 liters (80% of blood volume) and large volumes of replacement fluids have been given, there will be clotting factor defects and blood components should be given
transfusion of coagulation factors, up to 1 liter of FFP and 10 units of cryoprecipitate may be prevent bleeding
Critical levels of fibrinogen rich after a loss only 140% of the calculated blood volume
Critical levels of prothrombin, FV, FVII and PLT rich after a loss only 200% of the calculated blood volume

12. Fluid therapy and blood products transfusion
Crystalloid
Up to 2 liters Hartmann's solution
Colloid
Up to 1–2 liters colloid until blood arrives
Blood
Crossmatched. If crossmatched blood is still unavailable, give uncrossmatched group-specific blood OR give 'O RhD negative' blood
Fresh frozen plasma
4 units for every 6 units* of red cells or prothrombin time/activated partial thromboplastin time >1.5 x normal (12–15 ml/kg or total 1 litre)
Platelets concentrates
If platelet count <50 x 109
Cryoprecipitate
If fibrinogen <1 g/l
FFP/RBC ratio mortality: 1/4: 19%, 2/5: 34%, /8: 65%

13. Fibrinogen concentrate
Acquired hypofibrinogenaemia develops early in relation to fluid resuscitation, imbalanced transfusion of blood components and bleeding
This state of impaired hemostasis also develops in relation to PPH
Fibrinogen concentrate is a commercially available drug produced from human plasma
It seems that early fibrinogen substitution in cases of PPH is benefit in prevention PPH
The FIB-PPH trial is investigator-initiated and aims to provide an evidence-based platform for the recommendations of the early use of fibrinogen concentrate in PPH (Wikkelsoe et al. Trials 2012, 13:110)
If fibrinogen less than 2 gr/lit severe PPH

14. Fluid replacement
By consensus, total volume of 3.5 liters of clear fluids (up to 2 liters of warmed Hartmann’s solution as rapidly as possible, followed by up to a further 1.5 liters of warmed colloid if blood still not available) comprises the maximum that should be infused while awaiting compatible blood
The choice of fluid to be infused is controversial but of greater importance is rapid administration and warming of the infusion
The woman needs to be kept warm using appropriate measures

15. Blood transfusion
If fully cross-matched blood is unavailable by the time that 3.5 liters of clear fluid have been infused, the best available alternative should be given to restore oxygen-carrying capacity
Group O RhD-negative blood may be the safest way to avoid a mismatched transfusion in an acute emergency

16. Antifibrinolytic agents (Tranexamic acid)
Treatment with TXA is effective in reducing blood loss in patients undergoing CS
Although the study was not adequately powered to address safety issues, the observed side effects were mild and transient
TXA given in the dose of 0.5 to 1 g intravenously was effective in reducing postpartum haemorrhage after vaginal birth and caesarean section with minimal side effects
Arch Gynecol Obstet 2012 Oct 13
2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

17. Tranexamic acid Reduction of amount of blood loss
TA and Pregnancy & Post-partum – Systematic review
6 RCT, 7 Observational studies
Peitsidis et al 2011
Waiting for lab results may be too late – so point of care
Cyril Huissoud et al showed FIBTEM amplitude so fast than 5 minutes after the beginning of the test to be a good reflect of fibrinogen plasma level in non hemorrhagic PPH and in PPH patients.
Thus FIBTEM is useful to predict without delay the decrease of fibrinogen.
Reduction of amount of blood loss
TXA seems to be safe and effective
Lack of prospective trial

18. Tranexamic acid Blood loss – significantly less
Waiting for lab results may be too late – so point of care
Cyril Huissoud et al showed FIBTEM amplitude so fast than 5 minutes after the beginning of the test to be a good reflect of fibrinogen plasma level in non hemorrhagic PPH and in PPH patients.
Thus FIBTEM is useful to predict without delay the decrease of fibrinogen.
Blood loss – significantly less
Duration of bleeding less
BT – significantly less
Less interventions required to stop the bleeding
Loading 4 gr over 1 hr then infusion of 1 gr/hr over 6 hrs
Ducloy-Bouthers et al 2011

19. Recombinant activated factor VII (rFVIIa)
rFVIIa was developed for the treatment of haemophilia

20. rFVIIa North European Registry – 2000-2004
128 women – 33 hysterectomy prior rFVIIa
80% improvement after rFVIIa – 13(14%) required hysterectomy
4 cases of VTE + one myocardial infarction
Death – 5 cases - none due to VTE
Australian and New Zealand Registry –
110 cases - 78% of cases single dose (median dose 92 µg/kg
76% positive response
Hysterectomy 41% before rFVIIa
21% required hysterectomy after rFVIIa
2 cases of VTE
Death – 9 cases - none related directly to rFVIIa

21. rFVIIa rVIIa – should be considered in management of massive PPH
Timing ?
Prior to hysterectomy – unless bleeding surgical
Optimal dose ?
– 90mcg/Kg – two doses minutes apart
Ensure
Platelet > 50 and Fibrinogen > 2gm/l
Grade C-IV evidence

22. Algorithm approach of rFVIIa in PPH
P/E: R/O GYN problem If : -PLT > FIB> 1 gr/dl - Normal PT - PH ≥ Temp ≥35 Hematology consult : rFVIIa: μg/kg *By: MOH

23. Conclusion
Severe bleeding because of placenta accreta or uterine rupture cause early hysterectomy (HST)
Before early hysterectomy: compression suture or balloon tomponade is indicated
Uterine Atony: bleeding persist in spite of correction:
Coagulopathy
Hypothermia rFVIIa (max: 2 doses)
Acidosis and hypocalcemia µg/kg before HST

24. The patient was a 37 years old women
Case presentation
The patient was a 37 years old women
She had normal first vaginal delivery without history of coagulation disorders
Three months after second normal vaginal delivery she developed severe skin ecchymosis and bleeding of right upper and lower extremities (compartment syndrome)

25. What is your next evaluation for definite diagnosis?
VWF Ag
Factor IX assay
Factor XI assay
Inhibitor assay
Inhibitor assay

26. Case presentation
Many works up was done to finding the cause of her bleeding tendency
Coagulation tests were:
PT: 13 sec, INR: 1
PTT: 55 sec (mixing PTT:51 sec)
Serum FVIII level: 0.14%
Serum FVIII inhibitor level: 145 BU
Serum FIX inhibitor level: normal
Serum FX inhibitor level: normal
ANA: neg
dsDNA: neg

27. What is your definite diagnosis in this case?
Hemophilia A
Hemophilia B
Acquired Hemophilia A
VWD
Acquired Hemophilia A

28. What is treatment of bleeding in this case?
FVIII concentrate
IVIG
Recombinant FVIIa
FEIBA
3 and 4
All
Recombinant FVIIa
&
FEIBA

29. Case presentation (treatment)
The patient admitted in the hospital and the recombinant FVII 90 u/kg (every 4 hrs for three times) with partial response
So the frequency was changed to every 2 hrs for 24 hrs with complete response and then every 4-6 hours for the second day
The plasmapheresis was also done without any response
Immune suppressive treatment was started with prednisolon 1 mg/kg/d and cyclophosphamide 2 mg/kg/d at the same time.
The coagulation tests resulted to normalization after completion of treatment

30. Case presentation (follow up)
The bleeding symptom was stopped after 2 days of acute treatment
FVIII level: 30%
FVIII inhibitor: 40 BU
PTT: 45 sec
The patient was discharged with continue prednisolone and cyclophosphamide for a period of 6 weeks with complete response

31. Thank you