February 25, 2016
4 min read

ASH 2015: Several pearls fished from sea of abstracts

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The ASH Annual Meeting and Exposition once again featured some particularly interesting presentations in the field of benign hematology.


Two papers related to thrombotic thrombocytopenic conditions captured my attention.

In the first, Anand Padmanabhan, MBBS, MA, PhD, of Medical Sciences Institute at BloodCenter of Wisconsin, and colleagues report a new, simpler and probably more rapid test for clinically relevant heparin/platelet factor 4 (PF4) antibodies that cause heparin-induced thrombocytopenia (HIT).

Harry S. Jacob

Noting the “gold standard” serotonin-release assay for HIT is cumbersome and only available in a few research laboratories, they have developed an assay that likely could be reproduced easily in routine labs.

Their previous studies demonstrated that HIT antibodies are much more avid for PF4 when it is bound to negatively charged glycosaminoglycans than when PF4 is bound to heparin itself.

Their assay uses PF4-treated target platelets that are then exposed to suspect patient plasma. Platelet activation is determined by increased P-selectin expression.

The assay proves to be more sensitive than serotonin release and just as specific for “true” positivity. Of further interest, the new assay remains positive even with greatly diluted patient sera in contrast to loss of efficacy with dilution in the serotonin assay.

Because patients with suspect HIT are sometimes also treated with large amounts of fresh frozen plasma because of concomitant disseminated intravascular coagulation suspicion, Elisa and serotonin assay values may decrease and be reported as negative.

I suspect the new assay may be just as rapidly performed as Elisa tests and more likely will be sensitive in hemodiluted, post-cardiac or orthopedic surgical patients.

In another study, Wenjing Cao, MD, PhD, of the department of pathology at The University of Alabama at Birmingham, and colleagues presented a novel mechanism for the production and/or worsening of thrombotic thrombocytopenic purpura (TTP).

Noting that TTP may first present in patients with underlying inflammatory disorders or worsen with intercurrent infection, the researchers demonstrate that activated neutrophils inhibit ADAMTS13. Highly polymerized, prothrombotic von Willebrand factor is cleaved by this metalloproteinase, which — when congenitally absent or inhibited by autoantibody — promotes the TTP syndrome.

Activated neutrophils release small peptides (the “defensins,” 29-33 amino acids in length) that protect against invading bacteria, viruses and fungi. Some of these also have been shown to be prothrombotic.

The new studies demonstrate that several of these peptides inhibit the binding of ADAMTS13 to von Willebrand factor and, thereby, prevent cleavage of highly polymerized von Willebrand factor, the “glue” that fosters platelet agglomeration and activation. This substance is thought to promote the microvascular occlusion that characterizes TTP.

The researchers suggest that this mechanism is likely to be particularly relevant in patients with already-diminished ADAMTS13 levels.

Sickle cell anemia

Two papers were evocative in the sickle cell anemia arena.

Vercellotti, Belcher and colleagues have been intensely interested in the role of oxidative damage to endothelium in worsening symptoms of patients with sickle cell anemia — particularly its role in acute chest syndrome.

Their laboratory previously demonstrated that heme — mainly its iron moiety — released from hemoglobin in hemolytic states is a potent catalyst of oxidative damage to endothelium. An inkling as to why high levels of hemopexin — the specific binder of heme — is a prominent mammalian plasma component can be proffered: that is, it is critically important in protecting endothelium from iron-catalyzed oxidant damage.

Noting that hemopexin levels are low in sickle cell anemia, the investigators demonstrated that mice with sickle cell anemia — when depleted of hemopexin — develop marked vaso-occlusion, viewed in dorsal skinfold chambers.

Conversely, this occlusive behavior and its accompanying increase in inflammatory markers — such as NF-kappa B — are markedly suppressed in animals genetically altered to produce high hemopexin levels.


The researchers provide the intriguing suggestion that sickle patients might benefit from hemopexin infusions. Perhaps sicklers who develop early signs of acute chest syndrome should be the first to be so treated.

The plenary session provided another important treatment insight for young patients with sickle cell anemia — specifically those with cerebral vascular damage or likelihood for developing such as detected by transcranial Doppler scanning.

Until now, stroke prophylaxis in patients with sickle cell anemia has required chronic transfusion therapy with AA blood. Significant benefit is well documented, albeit with adverse iron overload and accelerated, alloimmune donor red cell hemolysis (not benign phenomena, considering the studies by Vercellotti and colleagues noted above).

In a multi-institution National Heart, Lung, and Blood Institute-sponsored study, Russell E. Ware, MD, PhD, of the division of hematology at Cincinnati Children’s Hospital Medical Center, and colleagues randomly assigned 121 young folk who had undergone approximately 2 years of transfusion therapy to either continued transfusions or to daily hydroxyurea.

After several months, researchers observed no significant differences in cerebral flow velocities or cerebral symptomatology between groups. Obviously, iron overload requiring chelation or phlebotomy therapy occurred in the continually transfused patients.

The researchers surmise that elevated hemoglobin F levels in the hydroxyurea cohort (approximating 25%) provided the major benefit in this group. However, I would suggest the significant reduction in neutrophil levels in the hydroxyurea group also might be ameliorative.

Thus, as reviewed above, activated neutrophils adhere to — and damage — heme-exposed endothelium. Moreover, their release of defensins that inhibit von Willebrand factor depolymerization and, thus, promote platelet aggregation/activation also might aggravate vaso-occlusive propensity in sickle cell anemia.

Finally, the role of nitric oxide (endothelial relaxing factor) that is generated during metabolic breakdown of hydroxyurea also may play a role in inhibiting cerebral ischemia.


Cao W, et al. Abstract 1147.

Padmanabhan A, et al. Abstract 764.

Vercellotti GM, et al. Abstract 412.

Ware RE, et al. Abstract 3.

For more information:

Harry S. Jacob, MD, DHC, 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.