Hematologic management of massive PPH Mehran Karimi Professor 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 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

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 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

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) Activated Partial Thromboplastin time (PTT) > 1.5 g/l Fibrinogen Treat underlying cause (shock, hypothermia, acidosis, hypotension) Avoid DIC

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

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 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%, 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 effects Arch Gynecol Obstet 2012 Oct 13 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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

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

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: Coagulopathy Hypothermia rFVIIa (max: 2 doses) Acidosis and hypocalcemia 90 µg/kg before HST

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)

What is your next evaluation for definite diagnosis? VWF Ag Factor IX assay Factor XI assay Inhibitor assay Inhibitor 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? Hemophilia A Hemophilia B Acquired Hemophilia A VWD Acquired Hemophilia A

What is treatment of bleeding in this case? FVIII concentrate IVIG Recombinant FVIIa FEIBA 3 and 4 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 you karimim@sums.ac.ir