By David N. Leff

Science Editor

Thrombocytopenia is a potentially life-threatening disorder with almost no perceptible signs or symptoms.

Its barely visible hallmark is a very small set of tiny blood-red dots just under the skin, from pinpoint to pinhead in size. Yet these innocuous petechiae betray what thrombocytopenia is all about, namely a sudden drop in the bloodstream's cargo of platelets, a.k.a. thrombocytes.

Petechiae reflect a leakage of blood out of ruptured or burst small capillaries. They're nature's way of saying: "This wouldn't have happened if there were enough platelets on hand to prevent it."

Platelets are the blood's swat team (special weapons and tactics) for stanching a cut or break in a blood vessel before it gets out of hand. Like a finger in the dike, platelets swarm to the site of a wound, then stick to its edges and to each other until they form a clump or plug to stop the flow. If the injury is large, this first aid is followed by formation of a clot, in which platelets secrete growth factors that mobilize soluble fibrinogen into insoluble fibrin. This meshwork serves as a matrix for platelets to seal over with a mature coagulation.

"Besides petechiae," observed clinical hematologist/oncologist Robert Cohen, at Genentech Inc., of South San Francisco, "thrombocytopenia's warnings can include gum bleeding, bruising of the skin and similar minor bleeds. These are classical presenting signs, but they don't lead to symptoms."

He continued: "The main reason that doctors are concerned about a loss of platelets is the low but finite risk of a spontaneous catastrophic hemorrhage, which could well be on the inside of your brain."

Which is why clinical oncologists keep close track of their patients' platelet counts while treating them with potent anticancer drugs.

A healthy person may have 150,000 to 400,000 platelets per cubic millimeter of blood. Triggered by a cytokine called thrombopoietin, these tiny, colorless cellular fragments pinch off from giant megakaryocyte cells in the bone marrow and shed into the bloodstream.

Cohen, whose research laboratory at Genentech focuses on the mechanisms of tumor metastasis, told BioWorld Today: "Cancer chemotherapy can drive down a normal platelet count from 300,000 to 20,000. If it goes below that nadir, physicians feel compelled to replace them with platelet transfusions."

These transfused replacements totaled more than eight million platelet units in 1992, up from some four million a decade earlier. Besides treating the worrisome thrombocytopenic side effect of cancer chemotherapy, donor platelets play a clinical part in organ and bone marrow transplantation and heart surgery.

But they are extremely expensive and horrendously inconvenient, and transfusion platelets bring along side effects of their own, notably viral contamination and provoking anti-platelet antibodies, which nullify future replacements.

By the mid-1990s, it was high time for a human recombinant thrombopoietin molecule to reach the clinic. Genentech and its competitor, Amgen Inc., of Thousand Oaks, Calif., both filled this gap.

The May 1 issue of Annals of Internal Medicine carries an initial report on a Genentech-sponsored Phase I/II clinical trial of rhTPO. Its title: "Stimulation of megakaryocyte and platelet production by a single dose of recombinant human thrombopoietin in patients with cancer."

Genentech's Robert Cohen is a co-author of that paper. Its lead author is immunotherapist Saroj Vadhan-Raj, of the M.D. Anderson Cancer Center, in Houston.

"We started with this clinical trial, which is still ongoing," Vadhan-Raj told BioWorld Today, "in mid- to late-1995. The study," she added, "is divided into two parts -- treatment with rhTPO before chemotherapy and after. Our report in the Annals describes the first part only, in which we had enrolled 12 adult sarcoma patients, seven men and five women."

Those preliminary results recorded an increase in platelet counts ranging from 61 percent to 213 percent, accompanied by a dose-related increase in bone marrow megakaryocytes (precursors of platelets) of up to fourfold.

By December 1996, Vadhan-Raj was able to inform the American Society of Hematology Meeting, in Orlando, of patient responses to rhTPO, administered by intravenous injection after as well as before a round of two-drug chemotherapy with adriamycin and ifosfamide.

Both of these antineoplastic compounds take a severe toll on bone marrow blood-cell progenitors.

The additional patients enrolled and treated by the Orlando meeting produced platelet and megakaryocyte restoration paralleling the earlier results in the Annals.

"We now have still more patients entered into the trial," Vadhan-Raj observed. Our objective is to define the optimal dose and schedule following chemotherapy, to see how we can reduce thrombocytopenia. The results right now appear to be quite encouraging," she continued, "so the most logical next step would be to pursue Phase III clinical trials."

Chemotherapy: 'Across-The-Board Killer'

Blood-cell biologist Hal Broxmeyer, director of the Walther Oncology Center at the University of Indiana, in Indianapolis, is the Annals article's final co-author.

"One of the things we found in our paper," he told BioWorld Today, "is that rhTPO treatment stimulates proliferation of not only progenitor cells for the megakaryocytes, but also for other blood lineages, such as granulocyte, macrophage and erythroid progenitor cells. It puts them into the active cell cycle so they can divide faster."

Broxmeyer pointed out that "the problem with all chemotherapy is that it's not specific to the tumor. It knocks out the bad cells, but in the process it's also knocking out the normal cells -- not just those involved in platelet formation, but also those that produce the blood's granulocytes, the macrophages, the platelets, the lymphocytes.

"So in fact," he observed, "chemotherapy is an across-the-board killer."

The reason platelets are the focus of replacement therapy, he explained, is that "platelet production usually takes longer to make a comeback than that of the other blood cells. So you could have a prolonged period of time, when the platelets are low, that becomes life-threatening. You could treat it with platelet transfusions," he went on, "but rhTPO allows you the hope of accelerating platelet production earlier, after chemotherapy. So the patient is healthier sooner, and can be released from the hospital sooner."

To which Vadhan-Raj made the point that "rhTPO may be given to normal platelet donors or to patients to collect platelets, to be stored and given later as needed." *