Welcome to ReachMD.
This medical industry feature, titled, Rare Bleeding Disorders: The Path to Diagnosis and Treatment, is sponsored by Novo Nordisk Incorporated.
Here’s your host, Dr Charles Turck.
When a patient presents to the emergency department with an active, uncontrolled bleed, being acutely aware of possible underlying bleeding disorders can help save a life. But how can the busy emergency physician recognize these disorders—even those that are exceedingly rare—and help clear the path toward diagnosis and treatment?
This is ReachMD, and I’m Dr Charles Turck.
Joining me to discuss the management of underlying unknown bleeding disorders are Dr Jesse Pines and Dr Craig Kessler. Dr Pines is the National Director of Clinical Innovation at US Acute Care Solutions based in Canton, Ohio. Dr Pines, thanks for being here today.
Thank you for having me.
And Dr Kessler is a Professor in the Department of Medicine and Pathology’s Division of Hematology and Oncology at the Lombardi Comprehensive Cancer Center in Washington, DC. Dr Kessler, it’s great to have you with us.
It’s a pleasure to be here.
So let’s jump right in. Starting with you, Dr Pines, how do patients with underlying unknown bleeding disorders typically present to the emergency department, or ED for short? And what challenges do physicians face when managing them?
I think about patients in categories. In my opinion, the focus should always be on identifying the cause and severity of the bleed and what specific treatment they may need in coordination with a consult to the hematologist.
First, you have patients where the primary issue is bleeding and/or trauma, but it appears to be more of a bleed than it should be, meaning there may also be some history of spontaneous bruising.
In that case, the challenge is making sure that you spend enough time performing a history and physical with the patient to suspect a bleeding disorder.
Another category would be where it's something that's unrelated to the reason why the patient is at the ED. So they're there for something else and while the physician is going through the review of systems, the patient mentions some spontaneous bleeding and/or a history of bruising.
Again, in my opinion, the key for the busy ED physician is spending enough time with your patient to help make good clinical decisions. We want to take good patient and family histories and make sure we’re treating the patient for the primary issue and making the right referral to a hematologist on the back end if something abnormal is detected in the initial bloodwork screen. When lab results are inconclusive, we should always consult a hematologist to confirm.
Thanks, Dr Pines. Over to you now, Dr Kessler, how important is it for emergency physicians and their extended care team to be aware of bleeding disorders?
Well the question is: why is this individual bleeding? And a rapid response from the care team is important because if there's uncontrolled bleeding, then there can be uncontrolled complications.
For instance, a patient who presents with petechiae will have a completely different workup than someone who presents with an active bleed. And as far as an active bleed is concerned, the hematologist has to determine the type of bleed—perhaps it’s a visceral bleed, mucosal surface bleed, a subcutaneous bleed presenting with ecchymotic lesions, or something else entirely.
Now oftentimes, the bleed occurs only after an intervention, such as an arterial stick, urinary catheter insertion, intubation, or measurement of intracompartmental pressures. And if the bleed is uncontrolled, then that leads the hematologist and the ED physician down a separate algorithmic pathway.
So yes, the hematologist and the ED physician have to be very aware and work together to understand the type and cause of the bleed to determine the appropriate diagnostic algorithm.1
So Dr Pines, with the importance of rapid and accurate diagnosis of unknown bleeding disorders in mind, what specific diagnostic tests would you order and when?
In general, a standard set of lab tests should be ordered in the emergency department, including a hemoglobin, hematocrit, and platelet count, which may lead you to suspect an underlying bleeding disorder.2
Then we have comprehensive metabolic panels where you may not see a direct indicator of a bleeding disorder, but you’ll recognize if there are other problems.
And then we have our coagulation tests, such as prothrombin time test, or PT, or activated partial thromboplastin time test, or aPTT, among others.3 Interestingly, I've moved away from INR in the ED as a regular test that everyone gets if they're getting blood tests, but if there is an undiagnosed bleeding disorder suspected, then that would be a clear indication for that coag.
And like Dr Kessler said, based on these initial coagulation tests, if the results are outside the reference ranges, like a low platelet count or if there's spontaneous bruising that's unexplained by these tests, then I would consult with a hematologist.
I’d also like to point out that we need to be calling on the right patients. On average, I’ve seen anywhere from 20 to 30 percent of patients in the ED with active bleeds, but the care team has to be vigilant enough to spot those unknown bleeding disorders, even for something as rare as acquired hemophilia, for example.1
Thank you, Dr Pines. And if we come back to you, Dr Kessler, can you talk about the importance of early diagnosis for these patients with rare bleeding disorders and the potential consequences of delayed diagnosis?
Yes, so it's critically important to establish an early rare bleeding disorder diagnosis due to the high risk of morbidity and mortality.2,4,5
Dr Pines just mentioned acquired hemophilia, so let's take a deeper look at that.
As the name implies, acquired hemophilia is a factor VIII deficiency that’s not genetic but develops from autoantibody formation during the patient’s lifetime.6
We see most cases in a bimodal age distribution, in the young women of childbearing age and in the elderly population of both sexes.4,6 And many patients present with a background of other medical disorders, mainly autoimmune diseases or malignancies, with acquired hemophilia resulting as a complication of the underlying disorder.4,6
However, up to 50 percent of individuals can present without having an underlying disease.4 It’s also important to note that, in my experience, a typical patient will have no prior knowledge of having a bleeding disorder. In fact, the mortality associated with this disease is up to 22 percent of individuals who present with bleeding complications.4
In addition, 35 percent of patients go undiagnosed for more than seven days following the onset of bleeding,4 and 70 percent experience severe or life-threatening bleeding.4
And if we go back to our coagulation tests, the emergency physician and the hematologist will use a diagnostic algorithm if they see an isolated prolonged activated partial thromboplastin test.7-9
This triggers the laboratory to perform a mixing study of the patient's plasma with normal plasma. If the mixing study corrects the prolonged aPTT, then the patient’s plasma has a clotting factor deficiency that was remedied by the presence of clotting factor in the normal plasma. But if the mixing study doesn’t correct the aPTT, then the patient has formed antibody inhibitors against a clotting factor, which would not be affected by the normal plasma.2,3,10
For those just joining us, this is ReachMD. I’m Dr Charles Turck, and today I’m speaking with Drs Jesse Pines and Craig Kessler about how we can identify and manage rare bleeding disorders, particularly acquired hemophilia.
So Dr Kessler, let’s stay with you just a bit longer. What treatments are available to help stop an active bleed, especially in a case of acquired hemophilia?
Because acquired hemophilia is so rare, it’s probably not the first thought an ED physician has when a patient presents in my opinion. But if we have an abnormal laboratory test that we think is a clotting factor deficiency of a spontaneous nature, usually our first inclination is to turn to fresh frozen plasma.
However, for acquired hemophilia, which is due to autoantibodies that inhibit a clotting factor, fresh frozen plasma won’t have any effect on the patient’s bleeding complication.8 When this happens, I think it’s important to know what your blood bank has available to treat a coagulopathy created by an acquired autoantibody.
In this situation, we have to use one of the bypassing agents available to us7,9 that generate thrombin by activating clotting factors distal to the clotting factor deficiency in the coagulation pathway.12,13 Treatment options include anti-inhibitor coagulant complex and antihemophilic factor (recombinant porcine sequence).7,9
We also have NovoSeven® RT, otherwise known as recombinant coagulation factor VIIa, that activates factor X to Xa without relying on the presence of a normal factor VIII molecule to activate the coagulation pathway.12,13
Now we will talk about NovoSeven® RT. You can find the full Prescribing Information, including Boxed Warning, on this episode’s landing page on ReachMD. Please listen to the Important Safety Information throughout this video.
So in my opinion, NovoSeven® RT is an agent that ED physicians might be familiar with. And if there's uncontrolled bleeding related to acquired hemophilia, this bypassing agent can be used. The last thing that I’d like to mention is that NovoSeven® RT can be administered rapidly to treat these bleeding episodes.
Thank you, Dr Kessler.
Now let’s review the Indications and Usage of NovoSeven® RT.
Indications and Usage
NovoSeven® RT (coagulation Factor VIIa, recombinant) is a coagulation factor indicated for:
- Treatment of bleeding episodes and perioperative management in adults and children with hemophilia A or B with inhibitors, congenital Factor VII (FVII) deficiency, and Glanzmann’s thrombasthenia with refractoriness to platelet transfusions, with or without antibodies to platelets and/or
- Treatment of bleeding episodes and perioperative management in adults with acquired hemophilia
Important Safety Information
- Serious arterial and venous thrombotic events following administration of NovoSeven® RT have been reported
- Discuss the risks and explain the signs and symptoms of thrombotic and thromboembolic events to patients who will receive NovoSeven® RT
- Monitor patients for signs or symptoms of activation of the coagulation system and for thrombosis
Now we’re almost out of time, but before we close, I’d like to hear your final thoughts. Dr Pines, what would you like to leave with our audience today?
I have three final points I want to emphasize. First, make sure that you’re ordering screening tests on all patients with potential undiagnosed bleeding disorders to reveal any detectable abnormalities.3
Second, take good patient and family histories as these help make a more accurate diagnosis.6 In my experience, spending this extra time with patients can be critical despite being in a busy ED with competing priorities.
And finally, it’s important to consult a hematologist if you see abnormal or inconclusive lab results, or have a high suspicion for an undiagnosed bleeding disorder.1
Thanks, Dr Pines. And Dr Kessler, we’ll end with your key takeaways.
So first, I’d like to say that I completely agree with Dr Pines. Consulting a hematologist is a crucial part of the treatment algorithm, especially when we’re dealing with underlying unknown bleeding disorders.1
With that being said, a care team could never make a diagnosis that they didn’t think of, so in my experience, it’s absolutely critical to be aware of rare bleeding disorders if a patient isn’t responding to traditional bleeding reversal approaches, or if a patient begins to bleed in a manner uncharacteristic of the type of intervention.
It’s also important to make sure you’re ordering the correct lab laboratory tests and know how to interpret them for accurate diagnosis.
And last, know what’s available at your blood bank and treat with the right products, such as NovoSeven® RT, for bleeds in cases of acquired hemophilia.1,2
Thank you, Dr Kessler.
Now let’s review some additional Important Safety Information about NovoSeven® RT.
Important Safety Information continued
Warnings and Precautions
- Serious arterial and venous thrombotic events have been reported in clinical trials and postmarketing surveillance
- Patients with congenital hemophilia receiving concomitant treatment with aPCCs (activated prothrombin complex concentrates), older patients particularly with acquired hemophilia and receiving other hemostatic agents, and patients with a history of cardiac and vascular disease may have an increased risk of developing thrombotic events
- Hypersensitivity reactions, including anaphylaxis, can occur with NovoSeven® RT. Patients with a known hypersensitivity to mouse, hamster, or bovine proteins may be at a higher risk of hypersensitivity reactions. Discontinue infusion and administer appropriate treatment when hypersensitivity reactions occur
- Factor VII deficient patients should be monitored for prothrombin time (PT) and factor VII coagulant activity (FVII:C). If FVII:C fails to reach the expected level, or PT is not corrected, or bleeding is not controlled after treatment with the recommended doses, antibody formation may be suspected and analysis for antibodies should be performed
- Laboratory coagulation parameters (PT/INR, aPTT, FVII:C) have shown no direct correlation to achieving hemostasis
- The most common and serious adverse reactions in clinical trials are thrombotic events. Thrombotic adverse reactions following the administration of NovoSeven® RT in clinical trials occurred in four percent of patients with acquired hemophilia and 0.2 percent of bleeding episodes in patients with congenital hemophilia
- Thrombosis may occur if NovoSeven® RT is administered concomitantly with Coagulation Factor XIII
Please use link provided on the landing page for Prescribing Information, including Boxed Warning.
I want to thank my guests for helping us better understand acquired hemophilia and the overall treatment of rare bleeding disorders. Dr Pines, Dr Kessler, it was great speaking with you both today.
Thank you for having me.
It was a pleasure to be here.
This program was sponsored by Novo Nordisk Incorporated. If you missed any part of this discussion, visit reachmd.com/industry-feature. This is ReachMD. Be Part of the Knowledge.
1. Collins PW. Management of acquired haemophilia A. J Thromb Haemost. 2011;9(Suppl 1):226-235.
2. Collins P, Baudo F, Huth-Kuhne A, et al. Consensus recommendations for the diagnosis and treatment of acquired hemophilia A. BMC Research Notes. 2010;3:161.
3. Kitchen S, McCraw A, Echenagucia M. Diagnosis of hemophilia and other bleeding disorders: a laboratory manual. 2nd ed. Montréal, Québec, Canada: World Federation of Hemophilia; 2010.
4. Giangrande P. Acquired hemophilia. Montreal, Quebec, Canada: World Federation of Hemophilia; 2012. Treatment of hemophilia 38:1-7.
5. Collins PW. Treatment of acquired hemophilia A. J Thromb Haemost. 2007 May;5(5):893-900.
6. Knoebl P, Marco P, Baudo F, et al. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost. 2012;10:622-631.
7. Kruse Jarres R, Kempton CL, Baudo F, et al. Acquired hemophilia A: updated review of evidence and treatment guidance. Am J Hematol. 2017;92(7):695-705.
8. Shander A, Walsh CE, Cromwell C. Acquired hemophilia: a rare but life-threatening potential cause of bleeding in the intensive care unit. Intensive Care Med. 2011 Aug;37(8):1240-9.
9. Tiede A, Werwitzke S, Scharf RE. Laboratory diagnosis of acquired hemophilia A: limitations, consequences, and challenges. Semin Thromb Hemost. 2014 Oct;40(7):803-11.
10. Srivastava A, Santagostino E, Dougall A, et al; WFH Guidelines for the Management of Hemophilia panelists and coauthors. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020;(supp l6):1 158.
11. Tiede A, Collins P, Knoebl P, et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica. 2020;105(7):1791-1801.
12. NovoSeven RT [package insert]. Plainsboro, NJ: Novo Nordisk Inc; 2020.
13. Hoffman M, Monroe DM III. A cell based model of hemostasis. Thromb Haemost. 2001;85(6):958-965.
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