Hematologic management of massive PPH

Mehran KarimiProfessor of Pediatric Hematology-

Oncology Shiraz University of Medical Science

29 Khordad,Shiraz

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 358000 women world-wide each year

WHO guidelines for the management of postpartum haemorrhage and retained placenta, 2009

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

Hematological Changesin 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

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

Causes and treatment of massive PPH

Causes• Uterine atony: The most

common cause of PPH that bleeding leading to coagulopathy

• Incisions and lacerations • Hemostatsis defect

Treatment• Massage, remove clot,

uterotonic agent, uterine tamponade

• Surgical repaire• Factor replacement

Early hysterectomy indications : 1- Placenta accreta 2- Uterine rupture

Goals in management of a postpartum hemorrhage

Journal of Thrombosis and Haemostasis, 2011; 9: 1441–1451

Blood components for prevention of massive bleeding

• Whole blood and RBC• Fresh frozen plasma (FFP)• Cryopercipitate• Platelets• Fibrinogen• rFVIIa

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)

< 1.5 x mean control Activated Partial Thromboplastin time (PTT)

> 1.5 g/l Fibrinogen

Treat underlying cause (shock, hypothermia, acidosis, hypotension)

Avoid DIC

Blood Product UtilizationProduct Contents Volume Effect

Whole Blood 500ml ↑ Hct 3%

PRBCs RBCs, WBCs, few plasma proteins

300ml ↑ Hct 3%

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 ↑ fibrinogen 5-10mg/dl

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

Fluid therapy and blood products transfusionCrystalloid 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%, 1/8: 65%

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

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

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

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 effectsArch Gynecol Obstet 2012 Oct 132011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Tranexamic acid

• Reduction of amount of blood loss• TXA seems to be safe and effective• Lack of prospective trial

Peitsidis et al 2011

TA and Pregnancy & Post-partum – Systematic review 6 RCT, 7 Observational studies

Tranexamic acid

Ducloy-Bouthers et al 2011

• 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

Recombinant activated factor VII (rFVIIa)

• rFVIIa was developed for the treatment of haemophilia

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 – 2002-2008• 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

rFVIIa

rVIIa – should be considered in management of massive PPH

• Timing ?Prior to hysterectomy – unless bleeding surgical • Optimal dose ? – 90mcg/Kg – two doses 15-30 minutes apart

Ensure Platelet > 50 and Fibrinogen > 2gm/l

Grade C-IV evidence

Algorithm approach of rFVIIa in PPH

P/E: R/O GYN problem

If : -PLT > 50000 - FIB> 1 gr/dl - Normal PT - PH ≥ 7.2 -Temp ≥35

Hematology consult : rFVIIa: 40-60 μg/kg

*By: MOH

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:

I. CoagulopathyII. Hypothermia rFVIIa (max: 2 doses)

III. Acidosis and hypocalcemia 90 µg/kg before HST

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)

What is your next evaluation for definite diagnosis ?

.1VWF Ag

.2Factor IX assay

.3Factor XI assay

.4Inhibitor assayInhibitor assay

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

What is your definite diagnosis in this case?

.1Hemophilia A

.2Hemophilia B

.3Acquired Hemophilia A

.4VWDAcquired Hemophilia A

What is treatment of bleeding in this case?

1. FVIII concentrate

2. IVIG

3. Recombinant FVIIa

4. FEIBA

5. 3 and 4

6. All

Recombinant FVIIa&

FEIBA

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

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

Thank youkarimim@sums.ac.ir