Tag Archives: platelets

Resuscitation

Artificial Platelets Under Development!

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Uncontrolled bleeding is the bane of trauma professionals everywhere. Early in a resuscitation, we focus on identifying potential sources. We’ve developed numerous techniques for plugging them up. And we have processes in place to replace the blood that’s been lost.

Unfortunately, blood products are a perishable item. Packed red blood cells have a typical shelf-life of 42 days. Whole blood lasts only 21-35 days. Plasma is only suitable for up to five days once thawed. However, it can be frozen and used only when needed.

Platelets are another short-lifespan product, typically lasting only five days. This is a major reason for the relative lack of availability, especially at smaller hospitals. Unfortunately, freezing them or attempting cold storage renders them less active. For this reason, the platelet shortage persists.

As you know, platelets are fragments of cells produced by the bone marrow that have a major function in hemostasis. They bind to injured surfaces of disrupted blood vessels. Seconds later, they become activated and begin to clump with other platelets. They also release factors that result in fibrin deposition, creating a clot that helps stop bleeding.

Researchers have been trying to develop artificial blood substitutes for decades. I remember reading about rat experiments using these products in the 1980s. Unfortunately, they remain experimental to this day.

I found a recent article describing recent work on artificial platelets that piqued my interest. It was published by the biomedical engineering groups at North Carolina State University and UNC Chapel Hill. They used nanoparticles made of an ultrasoft microgel that were similar in size and shape to natural platelets. Fibrin-binding antibody fragments were embedded on the surface. These were selected to target only activated fibrin and not circulating fibrinogen.

Source: Science Translational Medicine

The groups devised a rat and pig trauma model by creating a liver laceration and then infusing varying doses of the artificial platelets (AP). Postmortem analysis of the wounds showed:

  • The APs did home in on the injured sites and were found in the injured areas
  • There was increased fibrin deposition at the wound site when compared to saline controls
  • Less bleeding was seen in the animals that received the APs vs saline
  • No significant deposition of APs was found in other tissues
  • The APs were excreted in the urine of the animals

Bottom line: This is very exciting, if preliminary, work. These artificial platelets are relatively easy to produce and can be frozen or stored at room temperature for extended periods. They appear harmless to the animals and decrease bleeding from the liver injury.

I am still somewhat cautious in my assessment. This same excitement was present 40 years ago in the early years of artificial hemoglobin solutions. And look where we are now. But, fingers crossed, there may be a solution to our chronic platelet shortage at some point in the future.

Reference: Ultrasoft platelet-like particles stop bleeding in rodent and porcine models of trauma. Sci Transl Med. 2024 Apr 10;16(742):eadi4490. doi: 10.1126/scitranslmed.adi4490. Epub 2024 Apr 10. PMID: 38598613.

Abstracts, Resuscitation

Best Of AAST #7: How Do You Like Your Platelets – Warm Or Cold?

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Until the last few years, massive transfusion in trauma consisted of component therapy, an admixture of packed red cells, plasma, and platelets. Whole blood transfusion is making inroads again, but it is used in a minority of centers.

Of the three components, platelets have classically required different handling than the others. They are generally kept at room temperature, while the red cells and plasma are kept very cold to preserve their shelf life. A few centers have toyed with the use of cold platelets, but there have been concerns about their ability to clot and their useful life after transfusion.

Researchers from the US Army performed a retrospective registry study on a sample of military casualties over four years. They identified soldiers who received either room-temperature or cold-stored platelets. The primary outcome was mortality, and secondary outcomes included the need for surgery, fluid and blood infusions, and the use of a massive transfusion protocol.

Here are the factoids:

  • A total of 300 patients were identified, nearly equally split between room temp platelets and cold-stored
  • Demographics of the two groups were similar, but the ISS was somewhat higher in the cold-stored platelet group
  • Significantly fewer cold-stored platelet patients underwent surgery (13% vs. 24%)
  • Survival was the same at 87-88%
  • Blood and product administration was significantly higher in the cold-stored group, as was the use of the MTP (54% vs. 34%)

The authors concluded that the use of cold-stored platelets were not inferior to room temperature platelets.

Bottom line: Huh?? Yes, survival was the same despite a higher ISS in the cold platelet group. But they required more blood and needed massive transfusion significantly more often.

I see two major issues with this study. The most important is that it is a non-inferiority study. To believe that both arms are equal, a power analysis is required. The sample size here is too small to achieve significance unless differences are extreme, like the transfusion and MTP numbers.

The second problem is that this is an association study. Attempting to show that the type of platelets used is a major determinant of survival, need for surgery, or blood product use is shortsighted. There are a myriad of other factors that have more of an impact.

Far more subjects need to be studied, and a retrospective study with limited data points is not enough. I’m surprised that a military registry could only come up with 75 patients a year to analyze. These low numbers and the nature of this particular registry could inject significant bias as well.

Stay with the room temp platelets for now, and wait for a well-powered prospective analysis before changing your MTP.

Reference: An analysis of the use of cold-stored platelets in combat trauma. AAST 2023 Plenary paper #29.

Resuscitation

Best Of EAST #2: Pay Attention To Platelet Ratios In Your MTP!

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More MTP stuff! Every trauma center has a massive transfusion protocol, and current literature encourages them to try to achieve an “optimal” transfusion ratio. The literature has converged on a red cell to plasma ratio of somewhere between 1:1 and 2:1. Less has been written about platelet ratios, and trauma centers often don’t pay as much attention to this ratio when reviewing MTPs.

But is it important? The trauma group at the Massachusetts General Hospital examined the impact of platelet ratios on mortality in patients undergoing MTP. This was another TQIP data analysis, performed over a nine year period.

The authors defined massive transfusion as ten or more units of PRBC in the first 24 hours, or any number of units of red cells, plasma, or platelets given within the first four hours. They also defined “balanced” as a ratio of RBC to FFP and RBC to platelets <2. Multivariate regression analysis was performed to gauge the impact of ratios and achievement of a balanced resuscitation on 24-hour mortality.

Here are the factoids:

  • A total of 7,520 patients in the dataset underwent MTP
  • Nearly 83% achieved RBC to FFP balance, but only 6% had RBC to platelet balance (!)
  • Patients with both balanced FFP and platelets had the lowest mortality at 24 hours
  • Mortality increased by 2x with unbalanced plasma, a little more than 2x with unbalanced platelets, and 3x if both were out of balance (see figure)

The authors concluded that the platelet component of the MTP was frequently out of balance, and that it is associated with mortality to a greater degree than with unbalanced plasma.

Bottom line: This paper confirms my observations that trauma centers pay a lot more attention to the red cell to plasma ratio and don’t get as excited when the platelets are out of line. Part of this is probably due to confusion over how to count platelet packs. Typically they are delivered in packs called “pheresis” or “apheresis.” Each is the equivalent of about 6 units of platelets (check with your blood bank for more exact numbers). This means that a ratio of 6 RBC to 5 plasma to 1 platelets would be considered balanced. But a ratio of 28:28:2 would not.

According to this abstract, the use of sufficient platelets is important. This makes sense. However, the exact mechanism cannot be determined from this type of study. It could be a direct effect of not having enough platelets to form good clot. Or it could be something completely outside the clotting mechanism, just an association with something in the care processes that occurs as these patients undergo resuscitation. 

The why doesn’t matter so much, though. This abstract presents compelling data that suggests that we really need to pay attention to the platelet ratios given during the MTP. They should be analyzed just as closely as plasma ratios during PI review, and changes to the MTP process implemented to normalize this important ratio.

Here are my questions for the authors and presenter:

  • There is a statement in the methods section that is not clear. “only patients with steady RBC/PLT and RBC/FFP ratios between 4-and 24-hr were analyzed.” What is your definition of “steady?”
  • Did you see any mortality patterns in the data you analyzed that might suggest why lower platelet volumes were more deadly?

This was a nicely done abstract, and I look forward to the live presentation and the finished manuscript!

Reference: DON’T FORGET THE PLATELETS: BALANCED TRANSFUSION AND THE INDEPENDENT IMPACT OF RBC/PLT RATIO ON MORTALITY IN MASSIVELY TRANSFUSED TRAUMA PATIENTS. EAST 25th ASA, Oral abstract #1.

Abstracts

Best Of EAST 2020 #2: Do Platelet Transfusions Fix Sad Platelets?

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The next abstract from EAST tackles the question of how we can treat platelets that don’t work right in trauma patients. The literature on using platelet transfusions in patients who are taking anti-platelet agents is getting fairly clear: they don’t work. But what about for platelets that don’t work right due to traumatic hemorrhage?

The trauma group at Penn attacked this problem by performing a prospective study at their Level I trauma center. They investigated platelet function using thromboelastography (TEG) with platelet mapping on trauma patients admitted to the intensive care unit over a two year period. They analyzed platelet function and counts at 3, 6, 9, 12, and 24 hours after admission. Platelet function in patients given platelets during any of the intervals were compared to those who were not. Outcomes studied were improvement in platelet function and mortality.

Here are the factoids:

  • A total of 93 patients were entered into the study
  • About half (57%) had platelet dysfunction detected by TEG
  • Mortality was not different between the groups
  • Neither platelet count nor function improved with transfusion

The authors concluded that platelet dysfunction is common in these patients and that platelet transfusions do not appear to restore platelet function.

My comment: This abstract is a bit hard to follow. Hopefully the manuscript will have more detailed tables that break down which patients got platelets and at what times. It appears that patients could have gotten platelets at various times (any, all, or none) after admission to the ICU, and that pre- and post-transfusion TEG runs were analyzedfor each. It’s also not clear if every patient with dysfunction got a transfusion.

The most obvious issue here is that the total number of patients is small, and the numbers getting platelets at each time interval is even smaller (10-49). The statistical power of such a study is very low. It’s not surprising that no significant differences could be detected. This means that failing to see significance doesn’t means it’s not necessarily there, just that many more patients are needed. So it’s hard to buy into the assertion that platelet transfusions don’t matter.

Here are my questions/comments for the presenter:

  1. Why didn’t all patients get platelets? From the table, it looks like nearly all patients had significant dysfunction (defined as MAadp < 40mm) until the end of the 24 hour study period. It looks like some selection bias is possible if there was no defined protocol for giving transfusions to those who had an abnormal TEG.
  2. Is your study sufficiently powered to draw the conclusion it did? The number of patients seems small overall, and doing measurements serially every 3 hours would seem to further weaken the statistics. Please comment on your choice of analysis and how likely you are to actually be able to detect significance.
  3. Be sure to clarify the details of when platelets were given and why, how many measurements were taken and when, and exact patient numbers. These are not clear in the abstract due to length limitations.

This paper is very interesting and I look forward to its presentation.

Reference: Platelet infusions do not correct trauma induced platelet dysfunction. EAST Annual Assembly abstract #24, 2020.

Pharmacy

Platelet Transfusion In Patients Taking Anti-Platelet Drugs

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These days, trauma professionals see quite a few patients who take antiplatelet agents for cardiovascular comorbidities. These drugs can be problematic when the patients sustain injuries that result in bleeding in problematic areas like the cranial vault.

Aspirin and clopidogrel are the most common medications, and they irreversibly inhibit platelet aggregation.  All exposed platelets essentially quit working for the remainder of their 10-day lifespan. Platelet aggregation improves slowly over time after cessation of the drug as new platelets are added to the circulation from the bone marrow.

But what can you do if you are concerned that your patient is bleeding after injury because their platelets are not working? It seems logical that you would just transfuse some new platelets. But you should know by now that not everything that makes sense really works. A group in France designed a study to test this premise in patients taking either aspirin or clopidogrel. They performed a prospective, observational study on patients presenting with potentially life-threatening hemorrhage.

The authors used the Verify Now device to measure platelet response to the two drugs. Patients who had normal platelet function in the first place (not compliant or not a responder to the therapy) were excluded. All patients had initial platelet counts greater than 100K/ml. They underwent platelet transfusion for management of hemorrhagic shock, intracranial hemorrhage, or an emergent neurosurgical procedure.

Here are the factoids:

  • Only 25 patients were enrolled during the three year study; 13 were receiving only aspirin, 8 clopidogrel only, and 4 combined therapy
  • Average transfusions were 1-2 apheresis packs of platelets (6-12 units)
  • For aspirin patients, all showed significant platelet dysfunction before transfusion, and all but one showed recovery of function post-transfusion
  • For clopidogrel patients, platelet function remained impaired; the percent of inhibited platelets decreased but remained above the study threshold for “normal” of 20%

Bottom line: This is a very small study, but drives home the point that clopidogrel and its relatives may be problematic in bleeding patients. The active metabolites of this drug class are not well understood. But they are most likely still circulating in the blood in patients actively taking them, and deactivate new platelets as soon as they are transfused (assuming that the transfused platelets have good function in the first place). 

This issue requires further study so we can really tease out the actions of the drugs and their effect on transfused platelets. Until then, carefully consider whether platelet transfusion will be helpful in your bleeding patients, and if it is even worthwhile giving them or waiting for them to finish prior to going to the operating room.

Reference: Is platelet transfusion efficient to restore platelet reactivity in patients who are responders to aspirin and/or clopidogrel before emergency surgery? J Trauma 74(5):1367-1369, 2013.