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ASH 2014: Diving for pearls in a massive sea of presentations
The combination of 26,000 attendees and a seemingly equal number of abstracts can cause intellectual dissonance, at least in folks my age.
In an attempt to make lemonade from (too many) lemons, I will provide some thoughts provoked by a few particularly interesting presentations from the ASH Annual Meeting and Exposition, held Dec. 6-9 in San Francisco.
Platelet desialylation
Harry S. Jacob
Three papers that demonstrated a novel mechanism by which circulating platelets are removed from circulation were particularly evocative.
The plenary session included intriguing data from a study by Grozovsky and colleagues that showed effete platelets are recognized and destroyed in the liver when their membranes become desialylated.
Sialic acid is a common terminal moiety of many soluble — as well as membrane — glycoproteins. Removal of sialic acid (eg, by neuraminidases) signals Ashwell-Morell receptors on hepatocytes to attach and destroy the desialylated entities. The studies demonstrated that cultured hepatoma cells, when “fed” desialylated platelets, synthesize and secrete thrombopoietin, and that Ashwell-Morell receptors are required.
Several hypotheses evolve.
A commenter inquired whether alcohol might act as a desialylator, explaining perhaps early observations of Louis W. Sullivan, MD, who later served as secretary of HHS. Those studies predicted the existence of a circulating thrombopoietin (TPO) decades before Kenneth Kaushansky, MD, rigorously characterized TPO.
Sullivan noted that severely intoxicated patients admitted to Boston City Hospital were frequently thrombocytopenic. After a few days of sobriety, platelet counts normalized and often rebounded to excessive levels. Plasmas drawn from the rebound periods were collected, stored and reinfused back into the autologous patients weeks later. A rapid increase in platelet counts resulted.
Thus, the proffered hypothesis: Desialylation of platelets is provoked by ethanol. If so, simple exposure of cultured hepatoma cells to “drunken” platelets might induce TPO in vitro, thereby explaining the Sullivan phenomenon.
Another hypothesis generated by these studies was verified by other presentations at the meeting. Could this same mechanism of platelet removal be relevant to idiopathic thrombocytopenic purpura (ITP) platelet destruction?
Indeed, two other abstracts — one by Li and colleagues, the other by Qiu and colleagues — support this proposal in that platelet desialylation was found to be involved in ITP.
Certain — but not all — platelet antibodies (eg, antiplatelet glycoprotein Ib) were shown to cause thrombocytopenia predominantly by this mechanism. By contrast, antibodies to antiplatelet glycoproteins IIb/IIIa provoked accelerated platelet destruction by Fc receptor engagement, previously thought to be the only mechanism underlying immune thrombocytopenia.
It will be interesting to discern whether this dichotomy is reflected in patients with ITP who do — or do not — respond to immunoglobulin G (IgG) infusions. In addition, abundant production of hepatocyte TPO via the Ashwell-Morell mechanism might underlie the curious rapid and salutary increase in platelet counts in those patients with ITP who respond to IgG.
Then there is a third hypothesis: Several bacteria — as well as influenza viruses — that produce septic shock with thrombocytopenia produce neuraminidases. These include pneumococci, Staphylococcus aureus, Pseudomonas and Klebsiella.
Might platelet desialylation be involved in platelet destruction during infections with these microbes? If so, not all platelet decrements in septic patients are due to disseminated intravascular coagulation, and measures to decrease Ashwell-Morell receptor efficiency — such as swamping them with infused, soluble desialylated proteins — might be worth investigation.
Factor XI inhibition
Sticking with hemostasis, the game may be changing in the anticoagulant arena.
One example is the late-breaking abstract presented by Dutch investigator Harry R. Büller, MD, PhD, subsequently published in The New England Journal of Medicine.
Decades-old observations of Oscar D. Ratnoff, MD — who examined John Hageman in 1955 and determined he lacked a previously unidentified clotting factor — served as the foundation for these studies. Hageman’s blood was incoagulable in glass test tubes, yet did not induce untoward hemorrhage in the 37-year-old railroad worker. From this, the contact phase of coagulation was defined, yet considered clinically unimportant.
Coagulation Factor XII (also known as Hageman Factor) and Factor XI were shown to catalyze this pathway — a pathway that seemed anachronistic to many of us because deficiencies in its factors seemed not to cause untoward bleeding (although serious genitourinary hemorrhage may be seen following urethral abrasion attending transurethral surgery in patients with Factor XI deficiency).
That in vivo clotting does occur in contact pathway-deficient patients is evident, because Hageman died of a deep vein thrombosis (DVT) and pulmonary embolism following serious trauma at work. This paradox has led to the hypothesis that the contact pathway may be thrombophilic under certain (eg, traumatic) events, yet cause little hemorrhagic risk when deficient.
Conversely, tissue factor-mediated extrinsic pathway coagulation seems a more relevant clotting mechanism under most circumstances. Several animal studies support this concept.
Thus, Büller and others have postulated that by inhibiting Factor XI (or Factor XII), the “Holy Grail” of therapeutic anticoagulation might be afforded. That is, unwanted thrombosis might be prevented without provoking disastrous hemorrhage.
Büller has now described an antisense oligonucleotide that reduces Factor XI levels to about 20% of normal — levels that do not cause bleeding in modestly traumatized mice. In phase 2 randomized studies of this reagent simultaneously published in The New England Journal of Medicine, 300 patients undergoing knee arthroplasty were followed.
The results were stunning. To some patients, the oligonucleotide FXI-ASO (ISIS 416858, Isis Pharmaceuticals) was serially administered subcutaneously starting 5 weeks before surgery. This reduced Factor XI levels by about 80%. None of these recipients developed significant post-operative DVTs.
In contrast, as expected, more than 15% of patients in the control group — who received traditional post-operative doses of enoxaparin — developed thrombosis. Rates of clinically relevant bleeding were 3% in the GXI-ASO group and 8% in the enoxaparin group.
Thus, the concept is proven. No doubt, less cumbersome methods of intrinsic pathway inhibition now will be explored.
Antidotes for newer anticoagulants
Concern exists that antidotes are lacking if untoward bleeding occurs in patients who take newer oral anticoagulants, such as antithrombins (eg, dabigatran [Pradaxa, Boehringer Ingelheim]) or anti-Factor X drugs (eg, apixaban [Eliquis; Bristol-Myers Squibb, Pfizer]).
A study by Glund and colleagues showed a newly synthesized hybrid antibody, idarucizumab (Boehringer Ingelheim), blocks the active site of dabigatran and — within 5 minutes of infusion — reverses all studied thrombosis parameters in both men and women of different ages and varying renal function.
Importantly, the patients can be safely re-anticoagulated 24 hours later, and the agent is fully efficacious when readministered several weeks thereafter. Apparently no formation of anti-idiotype antibody to the hybrid antibody occurs that could prevent its use in chronically dabigatran-treated patients.
Other studies provide hope that seriously traumatized individuals who take dabigatran can be salvaged from lethal bleeding by immediate infusion of a triad of procoagulants: fibrinogen, prothrombin complex concentrate and tranexamic acid.
Massively traumatized, anesthetized pigs with fractured bones and blunt injury to livers uniformly and rapidly bled to death. However, if treated with all three procoagulants — but not with two alone — bleeding immediately was curtailed and all animals survived. It now will be important to perform more clinically relevant studies of subjects with lesser trauma, and to determine maximum lag times for intervention.
Equally salutary findings regarding possible antidotes for Factor X inhibitor-induced bleeding also were reported. Perlstein and colleagues measured multiple thrombotic parameters in 15 healthy adult subjects who received 10-mg doses of apixaban twice daily. Infusion of either of two non-activated 4-factor prothrombin complex concentrates reversed increased clotting parameters within 30 minutes.
Studies in patients who develop unwanted bleeding with apixaban and similar agents likely are in the works. For the future, we can hope these efficacious antidotes may permit us to be sanguine about replacing warfarin with newer oral anticoagulants.
References:
The following were presented at the ASH Annual Meeting and Exposition; Dec. 6-9, 2014; San Francisco:
Büller HR. Abstract #LBA-1.
Glund S. Abstract #344.
Grozovsky R. Abstract #2.
Li J. Abstract #467.
Perlstein I. Abstract #332.
Qiu J. Abstract #463.
For more information:
Harry S. Jacob, MD, FRCPath(Hon), is HemOnc Today’s Founding Chief Medical Editor and its Consulting Editor for Hematology. He can be reached at jacob002@umn.edu.
Disclosure: Jacob reports no relevant financial disclosures.