Cryoprecipitate, Fibrinogen Concentrates and New Pathogen Reduced Cryo Product Vie for Use in Massive Hemorrhage

WHETHER THE result of severe trauma, major surgery, childbirth or some other acute event, massive hemorrhage requires the earliest possible replacement of shed blood components, ideally through transfusion of packed red blood cells (pRBCs), plasma and platelets or, where available, low-titer type O whole blood. But an added common concern for massively bleeding patients is acquired hypofibrinogenemia, secondary to fibrinogen consumption and hemodilution from any replacement of lost blood with coagulation factor-deficient fluids, as well as a dynamic fluid shift from the interstitial to the intravascular compartment. 

The next most plentiful plasma protein after human albumin, fibrinogen is converted by thrombin (factor II) at sites of vascular injury to form a tough, insoluble fibrin mesh-like clot, which in turn stabilizes and strengthens primary platelet and retained RBC hemostatic plug (Figure 1). Because fibrinogen is the key effector protein in the coagulation process, it is also the first coagulation protein to reach critically low levels during severe hemorrhage. Impaired hemostasis due to hypofibrinogenemia in turn results in increased ongoing bleeding, which in turn increases the risk of multiorgan failure and death. 

The causal association between low fibrinogen level and increased transfusion requirements and mortality risk is well-established. In the controlled setting of cardiopulmonary bypass (CPB) surgery, for example, a large single-center study found that the risk-adjusted odds of requiring large-volume transfusion (≥5 units of pRBCs) was 80 percent higher for patients with a post-CPB fibrinogen level <2.0 g/L relative to those with a post-CPB level of >2.0 g/L.¹ A recent Australian trauma registry study evaluating nearly 4,800 patients confirmed that low circulating fibrinogen was a strong independent risk factor for massive transfusion, as well as increased in-hospital mortality: The mortality odds for patients with a fibrinogen nadir less than 1 g/L and 1-1.5 gram/liter (g/L) were, respectively, 3.28 and 2.08 times that of patients whose fibrinogen levels remained in the normal range (2 to 4 g/L).² 

Does Fibrinogen Replacement Work?

Since it was first developed in the 1960s, fibrinogen-rich human cryoprecipitate* (cryo) has been administered in an effort to restore fibrinogen levels in extensively bleeding surgical, trauma and obstetric patients with laboratory-confirmed or presumptive hypofibrinogenemia. Prepared by thawing fresh frozen plasma (FFP) and recovering the cold-insoluble centrifugate, each bag of cryo contains a minimum of 150 mg of fibrinogen suspended in 5 mL to 20 mL of added plasma, as well as significant levels of factor VIII, factor XIII and von Willebrand factor.³ Typically, five or 10 cryo units are pooled into a single bag for frozen storage and, once thawed, must be transfused within six hours. 

Over the last decade, two purified fibrinogen concentrates (FCs) approved as replacement therapies for treatment of congenital fibrinogen deficiency — CSL Behring’s RiaSTAP and Octapharma’s Fibryga — have also been widely used off-label in lieu of cryo to treat hypofibrinogenemia in massively bleeding coagulopathic patients. The lyophilized protein powder is simply reconstituted with sterile water for injection, implying that FCs can be ready to infuse much faster than cryo.

But while there is a straightforward therapeutic rationale for using either cryo or FCs to replete fibrinogen massively bleeding hypofibrinogenemic patients, there is limited and conflicting evidence to support the ability of either product to reduce transfusion requirements or mortality.

A recent systematic review of 26 clinical studies and a meta-analysis of five randomized controlled trials evaluating the use of FCs for trauma-related hemorrhage found no benefit from the use of FCs with respect to mortality or usage of packed RBCs, FFP or platelet transfusion requirements. The study authors acknowledged that the quality of evidence was graded as low to moderate, and called out the need for high-quality, adequately powered clinical trials.⁴ And they astutely added that new trials need to prioritize administration of FCs “as early as possible from the point of entry into the trauma system of care.” 

A two-year analysis of the American College of Surgeons-Trauma Quality Improvement Program data set came to a very different conclusion. The investigators examined records of 4,945 massively transfused patients who received cryo and 14,698 others who did not receive cryo. Patients in the cryo group received a lower volume of plasma and pRBCs, and on multivariate logistic regression, the use of cryo was associated with decreased odds of in-hospital mortality (odds ratio, 0.79 [95% confidence interval, 0.77-0.87]; p=0.01).

A separate 2017 sub-analysis of the landmark PROPPR study demonstrated that mortality declines with fewer elapsed minutes between massive transfusion protocol (MTP) activation and delivery of blood-containing coolers.⁵ While this study focused on blood component therapy generally, it and similar reports have convinced many surgeons and anesthesiologists that each minute of delay to administration of fibrinogen concentrates translates into prolonged coagulopathic hemorrhage and increased risk of death.

Accordingly, a growing consensus is now aligned behind a simple explanation for why some massive transfusion studies report survival and transfusion avoidance benefits with use of fibrinogen-containing products and some do not: The infusion-ready product must arrive and be administered very early to rapidly restore hemostasis and limit further bleeding-related complications. 

Delivery Timing of FCs vs. Cryo: No Contest

Prompted by wider awareness that earlier blood product administration saves more lives, investigators are now focusing on how much time actually transpires before FC or cryo is on hand and ready to infuse.

Published in 2021, the “Fibrinogen Early In Severe Trauma studY” (FEISTY), conducted at four major Australian trauma centers, examined the time interval in minutes from the blood draw for fibrinogen level testing to the commencement of first administration of either FC or cryo.⁶ A total of 100 major trauma patients were identified based on clinical evidence or suspicion of major active hemorrhage, and were randomly assigned to the FC or cryo arms. Sixty-two of these patients were determined to be hypofibrinogenemic and received either FC (n=35) or cryo (n=25). Dosing was guided by the degree of hypofibrinogenemia.

The median time to initiation of FC administration from the time of blood sampling for functional fibrinogen testing was 29 minutes, compared to 60 minutes for cryo administration. Within 30 minutes, more than half of patients in the FC replacement had started to receive their infusions. By contrast, no patient in the cryo group had been started at 30 minutes (Figure 2). Further, the median duration of FC administration was four minutes (interquartile range [IQR] two to eight minutes), compared to 12.5 minutes (IQR eight to 24 minutes) for cryo. 

This same Australian team separately reported that, in 36 consecutive severe hemorrhagic trauma patients who received FCs, it took a median of 22 minutes (IQR 17 to 30 minutes) from the time that thromboelastometry results confirming hypofibrinogenemia triggered an order for FC to its administration,⁷ during which the product was reconstituted and pooled.

Their findings are consistent with a report from a Canadian tertiary care hospital, where aseptic reconstitution and pooling of 1-gram FC concentrates to prepare a 6-gram dose was completed in about 20 minutes by trained blood bank technologists.⁸ A pilot trial at five United Kingdom (UK) hospitals separately showed that FC could be ordered, prepared and administered to most severe hemorrhagic trauma patients within 45 minutes of admission (a median of 37.5 minutes for all participants).⁹

By contrast, reported real-world experience with cryo reveals that it often arrives for administration long after the first units of RBCs and plasma have been transfused, if it arrives at all before the patient exsanguinates or dies from other causes. In a prospective observational study of 146 massively hemorrhaging patients in 22 UK hospitals, the median time to delivery of cryo after arrival was 2.2 hours — long after the first unit of pRBCs was transfused at a median of 41 minutes after admission. Just under 50 percent of patients with massive hemorrhage did not receive any cryo within the first 24 hours.¹⁰ In a secondary analysis of the much-referenced U.S. PROMMTT trial, the median time from admission to first cryo unit was 2.7 hours (IQR 1.7 to 4.5 hours) — similar to the median time of 2.6 hours to hemorrhagic death. By the median time that cryo was finally administered, patients had already received a median of eight units of pRBCs. 

Nevertheless, some clinicians continue to prefer cryo over purified FCs, citing its high concentrations of other clotting factors, in particular factor FXIII, which both acts to cross-link fibrin strands and stabilize the clot by cross-linking fibrinolytic inhibitors into the forming fibrin network.¹¹ But recent findings from a large head-to-head trial in Canada cast doubt on the presumptive inherent superiority of cryo relative to FCs: Investigators randomized 827 bleeding hypofibrinogenemic patients following cardiac surgery to FC or cryo and found that FC was noninferior to cryo; the mean numbers of 24-hour post-bypass allogeneic transfusions were 16.³ in the FC group and 17.0 in the cryo group (P<0.001 for noninferiority).¹² 

However, this apparent therapeutic equivalency of FC and cryo in the controlled, typically non-emergent postoperative cardiac surgery setting has little if any bearing on the “is FC or cryo better” question for patients experiencing massive acute hemorrhage, who may arrive or very quickly become hypofibrinogenemic and seriously coagulopathic, and who need fibrinogen replacement therapy as quickly as possible. 

Additionally, thanks to the recent arrival of an entirely new cryo-like product with remarkable post-thaw stability and storage flexibility, standard cryoprecipitate could soon be obsolete, making the “FC  vs. cryo” question for massive transfusion moot.

The Newest Option: A Ready-to-Use Cryo

In late 2020, California-based Cerus Corp. received FDA approval for a process that now enables community blood centers to manufacture a new pathogen-inactivated version of cryo, formally known as the INTERCEPT Pathogen Reduced Cryoprecipitated Fibrinogen Complex (INTERCEPT Fibrinogen Complex, or IFC). IFC can be supplied as single or pre-pooled units from up to 10 donors. In addition to a fibrinogen content comparable to standard cryo, IFC contains high concentrations of factor XIII and von Willebrand factor.

Like standard cryo, IFC is intended for the treatment and control of bleeding, including massive hemorrhage, associated with fibrinogen deficiency.** But unlike cryo, which must be transfused within six hours of thawing, IFC can be stored in a thawed state at room temperature for up to five days (120 hours), which entirely eliminates the roughly 20- to 30-minute thawing time and need for transfer from the hospital blood bank. 

Now, instead of an average of an hour or more from admission to delivery of cryo, the immediate availability of IFC could cut that time down to as little as 30 minutes while awaiting confirmatory fibrinogen and/or clot strength testing results. In circumstances in which the physician suspects the patient is hypofibrinogenemic based on presenting signs and symptoms, IFC can be transfused contemporaneously with the first round of blood component products instead of waiting until a later transfusion round while cryo is thawing in the blood bank.¹³ IFC additionally offers the opportunity to reduce product wastage: In instances where it is ordered but not transfused, IFC’s five-day shelf life allows it to be used for a different patient, instead of being discarded as sometimes occurs with six-hour shelf life standard cryo. 

Which Fibrinogen Product: New Trials Needed 

In the design and conduct of clinical investigations in the hemorrhagic trauma population, choices of patient inclusion criteria, fibrinogen-containing product(s) and dosage protocol may yield results that answer the research question posed by the investigators, but which may not help to define what is optimal therapy for every patient. A prime example is the recently reported 26-center randomized CRYOSTAT-2 trial, which evaluated the addition of “early” empiric high-dose cryo (three five-unit pools; six grams) to standard resuscitative care in 1,604 patients with trauma and bleeding who required activation of a major hemorrhage protocol.¹⁴ 

The investigators found no difference in all-cause 28-day mortality between standard care and standard care plus “early” empiric high-dose cryo (26.1 percent vs. 25.3 percent). Nor was there a significant difference in transfusion requirements across the two study groups. While the intention was to administer cryo as early as possible, the study authors acknowledged that “multiple challenges in rapidly delivering the intervention led to variability of timing of cryoprecipitate administration.” Of 665 patients in the cryo group who received cryo within 24 hours of hospital admission, only about 11 percent received it within 45 minutes, and under one-third within an hour of admission. All the rest waited for between one and two hours or longer to receive their cryo infusions, hardly what one would characterize as “early.” Further, the lack of a placebo group, as well as low patient numbers, precluded an assessment of mortality in the minority of patients who did receive cryo within the first 45 minutes or hour of admission.

“Although the study aimed for early cryoprecipitate administration,” the co-authors admitted, “the median time to first transfusion was more than an hour after arrival, reflecting the logistical challenge of preparing and administering a frozen blood component stored in a blood laboratory remote from the patient.”¹⁴

Now, with the availability of a pathogen-reduced IFC product that can be transfused immediately, one could argue that it is no longer necessary or justifiable for any U.S. hospital to provide only standard cryo for empiric treatment of any trauma, obstetric or other patient experiencing severe acute hemorrhage and suspected hypofibrinogenemia. A case for use of IFC in lieu of standard cryo can also be made for any patient for whom fibrinogen and/or clot strength testing  is ordered: Why risk a potential delay in treatment to resolve low fibrinogen in an actively bleeding patient in the event that blood bank staff need extra time to prepare standard cryo? 

Does the relatively short preparation time for fibrinogen concentrates make them a reasonable option in lieu of IFC in defined patient populations experiencing massive hemorrhage? This question can only be answered by large-scale clinical trials. Given the life-and-death stakes involved, the earlier such trials can be organized, completed and reported out, the better.

* Technically called cryoprecipitated antihemophilic factor (cryoprecipitated AHF).

** As it contains significant levels of factor XIII and von Willebrand factor (vWF), INTERCEPT pathogen reduced cryoprecipitated fibrinogen complex (IFC) is also intended for control of bleeding when recombinant and/or specific virally inactivated preparations of factor XIII or vWF are not available, and as second-line therapy for von Willebrand disease. This product should not be used for replacement of factor VIII.