Postpartum hemorrhage: Blood product management and massive transfusion

Abstract

Blood product transfusion capabilities are crucial for appropriate response to postpartum hemorrhage. Novel treatments are continually being sought to improve maternal morbidity and mortality associated with massive hemorrhage.

Introduction

Hallmark signs of massive hemorrhage, such as tachycardia and hypotension, may not be readily apparent in healthy postpartum women until blood loss approaches 25% of total blood volume (1.5 L in a term, pregnant female).^1,2 Once hemorrhage is recognized, determining the etiology is of primary importance as treatment strategies vary tremendously.

Management

When postpartum hemorrhage is encountered, care should be taken to accurately diagnose the source of bleeding as treatment strategies vary. Close inspection of the placenta to ensure that it is intact and completely extracted, as well as appropriate visualization of the cervix and birth canal to rule out laceration is integral. Once the source of the bleeding has been identified, appropriate steps to swiftly address the etiology should ensue.

The leading cause of postpartum hemorrhage is uterine atony, which accounts for 80% the incidence of postpartum hemorrhage.³ The mainstay of therapy is uterotonics (discussed in detail in medical and surgical management of postpartum hemorrhage chapters) and active management of the third stage of labor with bimanual massage, uterine compression, and Pitocin.³ If acute hemorrhage persists, the most important next clinical step is a rapid and appropriate response to the hemorrhage, as recommended by National Maternal Health initiative postpartum hemorrhage bundles, which calls for unit standard obstetric hemorrhage protocols in addition to several other components discussed below. Other components of the postpartum hemorrhage bundle include hospital wide massive transfusion protocols (MTP), hemorrhage carts, and assessment of blood loss.

Blood products

Transfusion of blood products is a critical component of resuscitation in response to postpartum hemorrhage. Transfusion medicine was altered tremendously when it was discovered that blood can be divided into individual components and transfused separately, which is crucial given that blood is a limited resource. A donor contributes whole blood to a bank, but this 1 unit of whole blood has the potential to yield four distinct blood products: packed red blood cells, platelets, fresh frozen plasma, and cryoprecipitate (Fig. 1). Table 1 describes the common blood therapy components including their volume, preparation time, expiratory time, etc.⁴

Fig. 1 –

Blood component processing summary.

Table 1 –

Blood component therapy.

Component	Volume of blood needed for preparation	Volume of product yielded	Shelf-life	Storage conditions	Preparation time	Corresponding increase in blood parameter	Matching
1 unit Red Blood cells	450–500 mL of Whole blood	200 mL + 100 mL of preservative solutiona	35 days vs. 42 daysa	1–6 °C	None. Blood warmer can be used if appropriate.	Hgb 1–1.5 g/dL Hct 3–5%	ABO and Rh
1 unit Platelets	450–500 mL of whole blood	50 mLb	5 days	Room temperature (20–24 °C) with gentle agitation	None	20,000–40,000 platelets/uL	Unmatchedc
1 unit Plasma	450–500 mL of whole blood	250 mL	1 year	−18 °C	Time for thawing at 37 °C	Decreases PT/INR by giving factors II, VII, IX, X	ABO and Rh
1 unit Cryoprecipitate	450–500 mL of whole blood	15 mLd	1 year	−18 °C	Time for thawing at 37 °C	5–10 mg/dL of fibrinogen, Contains Factor VIII, vWF	ABO suggested

^aDepending on the preservative solution (CPDA-1 vs. ADSOL).

^bTypically pooled with 4–6 additional units prior to transfusion.

^cPlatelets only contain 5% of ABO antigens contained in RBC units, which is clinically insignificant.

^dOften pooled with 8–10 units of cryoprecipitate.

Massive transfusion protocols (MTP)

In certain circumstances, when maternal blood loss is drastic, or the rate of bleeding is rapid, several units of blood products will not suffice to insure avoidance of maternal morbidity or even mortality. In these circumstances, massive transfusion protocols were developed. Massive transfusion is defined as greater than 10 units of packed red blood cells (pRBCs) in a 24-h period,⁵ and has resulted in a reduction in mortality from hemorrhage.⁶ Exsanguinating hemorrhage results in acidosis, hypothermia, and coagulopathy, commonly referred to in the trauma literature as “the lethal triad” ⁷ and aggressive correction of coagulopathy improves outcomes and increases survivorship.^8–10 Therefore, reduction in mortality is achieved with decreased fresh frozen plasma to packed red blood cell ratios, with most MTP protocols prescribing a 1:1 or 1:1.5 ratio (Table 2).¹¹

Table 2 –

Example of massive transfusion protocol.

Container	pRBCs	Thawed plasma	Platelet pheresis	Cryoprecipitate (Pool × 10)
Initial	6	5	1	–
2	6	5	1	–
3	6	5	1	1
4	6	5	1	–
5	6	5	1	–
6	6	5	1	1
7	6	5	1	–
8	6	5	1	–
9	6	5	1	1

Adapted from the Johns Hopkins Massive Transfusion Protocol.

In survey studies of obstetric units across the county, 95% of labor and delivery units had an MTP protocol. However, most institutions with the protocol lacked a standardized initiation causing variability in use. Most institutions that had an initiation standard used a cut-off of 1500 mL with uncontrolled bleeding. Although institutions develop their own MTP protocols; many have adopted a 1:1:1 strategy (1 unit pRBCs, 1 unit of fresh frozen plasma [FFP], and 1 U of platelets). Once MTP is activated, the blood products are typically provided in a “cooler” or “container”, which contains the multiple blood products in the prescribed ratio to be transfused, with a typical cooler consisting of 6 units pRBCs, 6 units FFP, and one unit of pooled (6 packs) platelets.

Adjuncts to massive transfusion

Tranexamic acid, fibrinogen concentrate, and plasma concentrate

It is always important to understand the basic principles and management of obstetric hemorrhage. However, it is imperative that obstetric practitioners continue to understand and evaluate new therapies of combating postpartum hemorrhages within safety bundles and massive transfusion protocols. Maternal death from hemorrhage can occur within hours of onset especially in settings without robust blood banks or the ability to initiate or collaborate with a nearby blood bank. Medications recently described such as Tranexamic acid (TXA), fibrinogen concentrate, and plasma concentrate may aid in both high and low blood bank resource settings as adjuncts to massive transfusion protocols.

TXA is an antifibrinolytic drug that serves as a lysine analogue and inhibits the breakdown of fibrinogen and fibrin by plasmin. The WOMAN trial has generated more interest in the utilization of TXA for postpartum hemorrhage. In traumatic injury, TXA reduced death secondary to hemorrhage without increase in thrombotic events.¹² Further, the WOMAN trial showed similarly that women given TXA within 3 h of birth (or hemorrhage) had significantly reduced mortality from bleeding when compared to controls (1.2% versus 1.7%, RR 0.69, CI 0 52–0.91, p = 0.008). Interestingly there was no difference in hysterectomy, use of intrauterine tamponade, embolization, and manual removal of placenta between groups.¹³ In continued, hemorrhage after 30 min the medication can be re-dosed until surgical or procedural control is achieved.

Other medical adjuncts to hemorrhage include the use of concentrated fibrinogen and plasma concentrates. Disseminated intravascular coagulopathy (DIC) can occur soon after hemorrhage especially in trauma or surgical injury. Augmentation of the fibrinogen, a plasma glycoprotein, allows clot formation through its conversion to fibrin and is an independent predictor of mortality.¹⁴ Cryoprecipitate is needed in massive transfusion protocols to augment survival as fresh frozen plasma alone is often a suboptimal source of fibrinogen and large volume required to reach adequate levels place patient at risk of transfusion related lung injury (TRALI), pulmonary edema, and blood transfusion reactions.¹⁵ While “fresh frozen” cryoprecipitate is prepared by controlled thawing, fibrinogen concentrate can be stored as a lyophilized powder at room temperature and theoretically, removes the time lag of thaw in emergent hemorrhages.¹⁶ The powder allows for quick reconstitution with sterile water an infusion with low volumes. In contrast to FFP and traditional cryoprecipitate, fibrinogen concentrates also decreases the risk of a viral transmission as well as delay in administration.¹⁵

Fibrinogen concentrate is considered the standard of care for conditions such as congenital afibrinogenemia,¹⁷ and has shown promise in retrospective studies including traumatic injury, cardiac surgery, and obstetric hemorrhage. In one respective cohort study, it was found that when over 18 units of red cells were utilized in severe hemorrhage, fibrinogen concentrate increased fibrinogen supplementation along with reducing the need for FFP; and thereby avoiding volume overload and causing a reduction in pulmonary edema.¹⁸ However, this study was done using FFP alone versus FFP with concentrated fibrinogen. When using cryoprecipitate versus concentrated fibrinogen, studies do not find a significant difference in mortality large hemorrhages.^19,20 Either way, during massive hemorrhage and transfusion, fibrinogen concentrate could serve as an expeditious adjunct to protocols and help limit delay in fibrinogen containing blood products and decrease complications of volume overload. Although fibrinogen concentrate is becoming option in some hospitals across the country, it is not widely used. Practitioners should discuss with their blood bank and hematology departments the availability of fibrinogen concentrate, and its use in the hospital system

A similar adjunct to hemorrhage is prothrombin complex concentrates (PCC). PCCs contain vitamin K dependent clotting factors (Factors II, VII, IX, and X) as well as Protein C and Protein S. When it comes to PCC, there are 3 and 4 factor coagulants. The three factor coagulants contain factors II, IX, X as well as Protein C and S. The 4 factor PCCs contain factors II, VI, IX, and X. The PCCs are further characterized as activated and inactivated. Activated PCCs are coagulant products that contain factor VII in its active form of Factor VIIa and these factors can be used in cases such as Hemophilia A, acquired Hemophilia, and other forms of severe bleeding. Inactivated PCCs are used in individuals with Vitamin K deficiency or in the urgent reversal of Vitamin K antagonist.

PCCs have also been used as adjuncts in cases of severe bleeding. In the setting of vitamin K antagonist and reversal, administration of PCC was associated with reduction in severity of bleeding and seven-day mortality.^21,22 Many women with obstetric hemorrhage are not on vitamin K antagonist secondary to concerns about teratogenicity. However, PCCs could be of benefit in women with severe liver disease (i.e., cirrhosis, HELLP syndrome, etc.) or with acquired, factor-deficient bleeding disorders. Randomized prospective studies need to be done to show true benefit.

In hospital settings that do not have high volume blood banks, TXA, fibrinogen concentrate, and PCCs could serve as lifesaving medications in the prevention of DIC and hemorrhage when 1:1 massive transfusion cannot be achieved.

Whole blood in massive transfusion

After being discarded by civilian medicine for several decades, the use of whole blood is becoming en-vogue in MTP. After World War II, academic institutions felt that blood could be used more effectively and efficiently if its components were separated into RBC, FFP, platelets, and fibrinogen and then frozen.²³ Currently, fractionated blood must be “reconstitutionalized” in a ratio-balanced component during hemostatic resuscitations. However, “re-constituted” blood is associated with anemia, thrombocytopenia, and coagulopathy when compared to fresh whole blood.²⁴ Although whole blood has had promising studies within the military, safety concerns have hastened its use in the civilian population.

Continued use of whole blood in the military setting is necessary because of the lack of platelets and frozen components in the environment of war. Platelets must be separated from whole blood by centrifuge or harvested by apheresis and are only viable for 5 days; FFP and cryoprecipitate can be stored for one year but must be a −20 °C and require thawing.²⁴ Although these feats can be accomplished with ease in major academic centers and resource rich hospital settings the grim environment of war is neither feasible nor sensible for such an accomplishment.²³ Therefore, the military augments its own blood back with whole blood in combat military hospitals. In both civilian and military populations, the use of fresh whole blood has been shown to reduce potassium overload, electrolyte abnormalities, and hyperbilirubinemia, and to improve O2 carrying capacity and mortality in hypotensive traumatic injury patients.²³ The use of whole blood has also been studied in obstetric patients. In a population-based study, women transfused with fresh whole blood had acute organ dysfunction in the setting of acute tubular necrosis when compared to the packed cell group; albeit there was more pulmonary edema.²⁵

Although whole blood has been shown to be superior in large volume hemorrhagic resuscitations of certain patient populations, it does have some disadvantages. While warm fresh blood used within 8 h maintains factor integrity, stored whole blood can have lability in Factor V and VIII within 12–18 h of storage at 4 °C.²⁶ Aside from factor break down, other risk of fresh warm blood includes increased risk of infections, bacterial growth in stored specimens, and microchimerism, which is harboring genetically different cells in one’s own system.²⁶ Whole blood can be used as a viable supplement and/or replacement in hospital settings, especially in hypovolemic hemorrhagic shock. However, its use should be chaperoned by appropriate experts to limit risk to the patients.

Multiple antibodies and transfusion of incompatible blood

Red blood cell transfusion is vital and lifesaving to patient populations such as sickle cell disease, thalassemia, and hemophilia, but these women have higher rates of blood antibodies. These women are still susceptible to the risk of obstetric hemorrhage and need for transfusion. These women can be vexing to practitioners especially if there is not an adequate blood bank at the delivery institution. Usually, every effort is made to avoid transfusing incompatible blood such as prophylactic preparation of cross-matched blood up to 48 h before induction of labor, use of cell-saver, and early interventions for hemorrhages such as uterine artery embolization and hysterectomy to obtain hemorrhage control.

However, in severe cases of obstetric hemorrhage, the transfusion of incompatible blood may be necessary. Overcoming this quandary to avoid acute hemolytic transfusion reactions has been described in the literature. One case report advised the administration of methylprednisone 1 mg/kg/day and intravenous immunoglobulin 1 g/kg/day for three days prior to scheduled interventions where blood loss may occur²⁷ (i.e., induction of labor or cesarean section). Also, when using incompatible units, the provider should transfuse in ascending order of clinical hemolytic severity of the antibody of concern. The blood bank, hematology, and maternal fetal medicine should be involved if transfusion of known incompatible blood is to take place.

In cases of multiple antibodies, unexpected incompatibility can occur and result in acute hemolytic reactions. Acute hemolytic reactions usually occur during or within 24 h of blood transfusion and clinically present with fever, chills, hypotension, hemoglobinuria, renal failure, back pain, and signs of DIC.²⁸ In the most severe form the recipient can have hyper-hemolysis syndrome where both donor and recipient blood cells are destroyed. The destruction of the red cells can be intravascular, via the complement pathway of membrane attack complexes, and extravascular via the sequestration and phagocytosis of red cells by macrophages.²⁹ These hemolytic reactions are a medical emergency, and evaluations occur at the bedside. The initial management includes stopping the current transfusion and stabilization of the patient via supplemental oxygenation, hemodynamic support with vasopressors if needed, and contacting transfusion medicine or the blood bank for further guidance. During initial stabilization laboratory tests should include: Repeat ABo compatibility testing, additional antibody studies and titers, Direct antiglobulin (Coombs) testing which can be positive for acute hemolytic transfusion reaction (AHTR) but negative for ABo incompatibility, visual inspection of serum and urine, testing for hemolysis (LDH and haptoglobin), DIC testing (PT, PTT, INR, Fibrinogen, CBC), and electrolyte testing.^30,31 These patients should also receive consultation with hematology and be taken to a higher level of care that has cardiac monitoring available. In severe cases with hyper-hemolysis syndrome; other measures aside from support, may need to be taken. In these cases, patients may need plasma exchange, high dose steroids, intravenous immunoglobulin and anti-C5 monoclonal antibody therapy. Even in these setting, mortality remain high.^32,33 Therefore, a swift multidisciplinary approach is needed.

Additional transfusion related complications include Transfusion Related Acute Lung Injury (TRALI) and transfusion associated circulatory overload (TACO). TRALI is a potential transfusion related complication that is caused by antibodies in the plasma against antigens on recipient leukocytes.^34,35 Leukocyte antigens are more common in females due to exposure to previous pregnancies; therefore, TRALI is a particularly relevant complication of transfusion to postpartum hemorrhage. TRALI is more commonly encountered with transfusion of plasma, however it can occur with transfusion of any blood product. Because of its leukocyte and inflammatory nature, TRALI typically clinically presents with inflammatory changes such as hypotension, fever, leukocytosis, alongside a classic presentation of bilateral infiltrates and severe hypoxemia.³⁶ These clinical changes typically occur within the first 6 h of transfusion but can take longer. TACo is a transfusion related reaction in which pulmonary edema develops secondary to volume overload. This typically occurs in patients who receive a large volume of transfusion products and/or cardiovascular or renal impairment, and should be suspected in any patient that develops signs of respiratory distress, elevated brain natriuretic peptide, and hypertension with six hours of initiation of a blood transfusion.³⁷ Whether the diagnosis is TACO or TRALI management is typically supportive care with supplemental oxygen and gentle diuresis. Sometimes TACO and TRALI may require intubation and ICU admission.

Guidance and endpoints of resuscitation

Clinical endpoints of a successful resuscitation include maintained mean arterial pressure greater than 65, sustained mental status, urine output and acid-base status. Serum pH, lactate, base deficit, and bicarbonate have all been extensively studied as clinical markers of resuscitation success in shock.^38–41 Although there are many parameters to measure, lactate and its clearance is the most adopted surrogate marker of tissue perfusion.⁴² Because the half-life of lactate is approximately 20 min, a persistent lactic acidosis (>2 mmol/L) is indicative of persistent tissue hypoperfusion. Therefore, the use of serial lactates have been useful in predicting mortality in both septic shock and traumatic injury.⁴³ Therefore, lactate levels should be initially collected at recognition of hemorrhage and can be followed during resuscitation as an adjunct to ensure tissue perfusion while insuring hemostatic control.

Additional adjuncts to resuscitation are the use of thromboelastography (TEG) and rotational thromboelastometry (ROTEM). TEG provides a qualitative assessment of hemostasis in a patient’s whole blood by testing both platelet function and coagulation by assaying several parameters of clot formation within whole blood. The test is rapid and can be done at the bedside.⁴⁴ TEG has been validated and used in obstetric hemorrhage and can help guide the resuscitator in which factor products are most needed to avoid DIC.^45,46 Similarly, ROTEM provides the same results as TEG, however the mechanism at which it arrives at those results differs slightly: In TEG, a pin rotates within a cup, however in ROTEM, the cup rotates around a stationary pin.

Another adjunct to resuscitation is electrolyte repletion. During large resuscitations, patients can experience hyperkalemia from RBC overload, hypocalcemia from citrate in blood products, and hypomagnesemia.⁴⁷ During large resuscitation, serial electrolytes should be drawn and repleted accordingly. Without the repletion of electrolyte, the patient could suffer from severe cardiac arrhythmias. The citrate used to store blood products can bind with calcium in the blood leading to severe hypocalcemia. With severe hypocalcemia patients can have hypotension, myocardial dysfunction with decreased performance, and prolong the QT interval placing the patient at risk of dangerous arrhythmias such as Torsades de pointes (polymorphic ventricular tachycardia).⁴⁸ Hyperkalemia may also develop with massive blood transfusion especially in the setting of renal disease. Hyperkalemia can result in worsening acidosis along with ECG changes.⁴⁹ ECG changes are generally peaked T waves, bundle branch blocks, bi-fascicular blocks, and atrioventricular blocks. This can ultimately lead to non-perfusable rhythms leading to cardiac arrest.^50,51 In both treatment of hypocalcemia and severe hyperkalemia, 1–2 g of calcium chloride or gluconate (10 mL of a 10% solution) should be used to stable the myocardium to prevent such severe and life-threatening arrhythmias. In the setting of hyperkalemia other measures such as insulin and glucose, and sodium bicarbonate, and renal replacement therapy will need to be considered.⁵²

Conclusion

Massive hemorrhage is a form of shock which is unavoidable for most obstetric providers. In extremis, blood product transfusion is often lifesaving. Obstetric providers should become familiar with MTP protocols in their institutions and understand adjuncts to resuscitation for these patients to reduce the risk for severe morbidity and mortality. Particularly in settings without access to MTP and large quantities of blood products, hemostatic adjuncts may play a vital role in decreasing the risk for life-threatening hemorrhage. Other forms of resuscitation such as use of whole blood or incompatible blood may be considered in extreme cases and only under expert supervision. The provider can use goal endpoints such as clinical improvement and serial lactates and should remain vigilant for evidence of electrolyte abnormalities and circulatory overload.