Case Challenges

Normal iron stores, sedimentation rate and cytogenetics are clues

This patient presents with a persistently elevated platelet count. Though she did give birth a number of months ago, her hematocrit and iron stores are within normal limits (transferrin saturation is 20%). There is no evidence of acute inflammation or infection. Of note, an increased number of megakaryocytes with occasional dysplastic forms is found in the bone marrow. Cytogenetics are normal.

Most cases of thrombocytosis are reactive in nature and reflect underlying iron deficiency, inflammation, infection, malignancy, recent blood loss or a combination of these disorders (Table 1). In addition, patients who are post-splenectomy may run platelet counts that are modestly elevated, and may develop more significant elevations of their platelet counts in the setting of acute blood loss or inflammation.

Typical case

An example of a typical case of reactive thrombocytosis is that of a middle-aged male with a history of alcohol abuse who undergoes surgery for repair of a perforated duodenal ulcer. A combination of baseline borderline iron stores, the reactive response to blood loss and recent surgery can lead to an elevated platelet count that may approach or exceed 1,000,000/µl.

In cases of reactive thrombocytosis, treatment should be aimed at resolution of the underlying disturbance. There is no need for the administration of aspirin even at platelet count of over 1,000,000/µl unless perhaps there are special circumstances, such as a history of coronary artery disease, in which case aspirin is likely indicated in any case.

Myelodysplasic syndromes may occasionally be associated with thrombocytosis. This is not uncommonly the case in the 5q-syndrome, which may present with anemia and an elevated platelet count. Diagnosis of a myelodysplastic syndrome, however, requires that at least two bone marrow lineages exhibit dysplastic change. Dysplastic change in a single lineage is non-diagnostic and may be seen in non-malignant disorders or in a myeloproliferative syndrome such as primary thrombocythemia.

chart

The myeloproliferative disorders associated with thrombocytosis include chronic myelogenous leukemia (CML), polycythemia vera, agnogenic myeloid metaplasia, and primary thrombocythemia (essential thrombocytosis) (Table 2).

It is important to note that these syndromes can overlap somewhat, so it is sometimes impossible to assign a given patient to one of the established diagnostic entities. In addition, the diagnosis in a small percentage of patients with primary thrombocythemia will appear to evolve into polycythemia vera. Although there are no pathognomonic features for the diagnosis of polycythemia vera, agnogenic myeloid metaplasia, and primary thrombocythemia, the diagnosis of CML, which eventually invariably transforms to blast crisis if untreated, can be made by sending peripheral blood for bcr-abl molecular diagnostic testing.

Primary thrombocythemia

Primary thrombocythemia, also known as essential thrombocytosis, has a peak incidence at age 50 to 60 in both sexes, with a smaller peak in women around age 30. The diagnosis of primary thrombocythemia rests on ruling out reactive causes of thrombocytosis and eliminating the possibility of other myeloproliferative syndromes or myelodysplasia (Table 3).

Observation is an appropriate management for younger individuals (age < 60) with platelet counts less than 1,500,000/µl. The administration of aspirin to individuals who are asymptomatic can lead to excessive bruising, as the platelets in primary thrombocythemia are abnormal and may have increased or decreased function. Such heterogeneity in the platelet function in primary thrombocythemia means that patients may experience hemorrhagic or thrombotic complications, and either may occur at different times in a given individual (Table 4).

chart

Important recognition

In addition, it is important to recognize that bleeding may be secondary to a thrombotic event: for instance, duodenal arcade thrombosis may present as massive gastrointestinal bleeding. Though aspirin should be used cautiously as noted above, symptomatic individuals who have erythromelagia (a burning sensation in the hands and feet) or who have had thrombotic events may benefit from therapy with aspirin.

The treatment for platelet counts greater that 1,500,000/µl in young individuals and greater than 600,000/µl in older individuals with primary thrombocythemia is usually either hydroxyurea or the platelet-lowering agent anagrelide. Hydroxyurea has been shown in a randomized clinical trial to reduce the number of thrombotic complications in high-risk patients patients with primary thrombocythemia (Cortelazzo et al., N Engl J Med. 1995;332:1132-6). Anagrelide, which selectively inhibits the formation of platelets, is also effective in decreasing the platelet count; however, its effect on reducing thrombotic complications has not yet been demonstrated in a randomized clinical trial. It is a useful agent in patients who do not tolerate hydroxyurea because of myelosuppression or other side effects. It does, however, have its own side effect profile, and is much more expensive (Anagrelide Study Group, Am J Med. 1992;92:69-76).

The patient in this case had no evidence of iron deficiency or an inflammatory process. A myelodysplasic syndrome, though formally possible, is much less likely in a younger individual. This patient’s bone marrow biopsy revealed only increased megakaryocytes with a few dysplastic forms and normal cytogenetics. Whether or not a bone marrow biopsy would have been necessary at all in this case is debatable. Simply sending peripheral blood for bcr-abl molecular diagnostic testing is quite sensitive for the detection of CML, and this would be the most important condition, requiring treatment sooner rather than later, that might be missed. The patient in this case was simply followed over time, and three years later with no therapeutic interventions was still doing well with a platelet count of 735,000/µl.

Splenomegaly, bone marrow hypercellularity with aggregates of megakaryocytes, clonal hematopoiesis in women, or abnormal platelet aggregation to ADP/epinephrine are supportive of the diagnosis.

For more information:
  • Peter Marks, MD, PhD is clinical director of hematology at Brigham and Women’s Hospital and Instructor of Medicine at Harvard Medical School. You may contact him at: hemonctoday@slackinc.com.

This patient presents with a persistently elevated platelet count. Though she did give birth a number of months ago, her hematocrit and iron stores are within normal limits (transferrin saturation is 20%). There is no evidence of acute inflammation or infection. Of note, an increased number of megakaryocytes with occasional dysplastic forms is found in the bone marrow. Cytogenetics are normal.

Most cases of thrombocytosis are reactive in nature and reflect underlying iron deficiency, inflammation, infection, malignancy, recent blood loss or a combination of these disorders (Table 1). In addition, patients who are post-splenectomy may run platelet counts that are modestly elevated, and may develop more significant elevations of their platelet counts in the setting of acute blood loss or inflammation.

Typical case

An example of a typical case of reactive thrombocytosis is that of a middle-aged male with a history of alcohol abuse who undergoes surgery for repair of a perforated duodenal ulcer. A combination of baseline borderline iron stores, the reactive response to blood loss and recent surgery can lead to an elevated platelet count that may approach or exceed 1,000,000/µl.

In cases of reactive thrombocytosis, treatment should be aimed at resolution of the underlying disturbance. There is no need for the administration of aspirin even at platelet count of over 1,000,000/µl unless perhaps there are special circumstances, such as a history of coronary artery disease, in which case aspirin is likely indicated in any case.

Myelodysplasic syndromes may occasionally be associated with thrombocytosis. This is not uncommonly the case in the 5q-syndrome, which may present with anemia and an elevated platelet count. Diagnosis of a myelodysplastic syndrome, however, requires that at least two bone marrow lineages exhibit dysplastic change. Dysplastic change in a single lineage is non-diagnostic and may be seen in non-malignant disorders or in a myeloproliferative syndrome such as primary thrombocythemia.

chart

The myeloproliferative disorders associated with thrombocytosis include chronic myelogenous leukemia (CML), polycythemia vera, agnogenic myeloid metaplasia, and primary thrombocythemia (essential thrombocytosis) (Table 2).

It is important to note that these syndromes can overlap somewhat, so it is sometimes impossible to assign a given patient to one of the established diagnostic entities. In addition, the diagnosis in a small percentage of patients with primary thrombocythemia will appear to evolve into polycythemia vera. Although there are no pathognomonic features for the diagnosis of polycythemia vera, agnogenic myeloid metaplasia, and primary thrombocythemia, the diagnosis of CML, which eventually invariably transforms to blast crisis if untreated, can be made by sending peripheral blood for bcr-abl molecular diagnostic testing.

Primary thrombocythemia

Primary thrombocythemia, also known as essential thrombocytosis, has a peak incidence at age 50 to 60 in both sexes, with a smaller peak in women around age 30. The diagnosis of primary thrombocythemia rests on ruling out reactive causes of thrombocytosis and eliminating the possibility of other myeloproliferative syndromes or myelodysplasia (Table 3).

Observation is an appropriate management for younger individuals (age < 60) with platelet counts less than 1,500,000/µl. The administration of aspirin to individuals who are asymptomatic can lead to excessive bruising, as the platelets in primary thrombocythemia are abnormal and may have increased or decreased function. Such heterogeneity in the platelet function in primary thrombocythemia means that patients may experience hemorrhagic or thrombotic complications, and either may occur at different times in a given individual (Table 4).

chart

Important recognition

In addition, it is important to recognize that bleeding may be secondary to a thrombotic event: for instance, duodenal arcade thrombosis may present as massive gastrointestinal bleeding. Though aspirin should be used cautiously as noted above, symptomatic individuals who have erythromelagia (a burning sensation in the hands and feet) or who have had thrombotic events may benefit from therapy with aspirin.

The treatment for platelet counts greater that 1,500,000/µl in young individuals and greater than 600,000/µl in older individuals with primary thrombocythemia is usually either hydroxyurea or the platelet-lowering agent anagrelide. Hydroxyurea has been shown in a randomized clinical trial to reduce the number of thrombotic complications in high-risk patients patients with primary thrombocythemia (Cortelazzo et al., N Engl J Med. 1995;332:1132-6). Anagrelide, which selectively inhibits the formation of platelets, is also effective in decreasing the platelet count; however, its effect on reducing thrombotic complications has not yet been demonstrated in a randomized clinical trial. It is a useful agent in patients who do not tolerate hydroxyurea because of myelosuppression or other side effects. It does, however, have its own side effect profile, and is much more expensive (Anagrelide Study Group, Am J Med. 1992;92:69-76).

The patient in this case had no evidence of iron deficiency or an inflammatory process. A myelodysplasic syndrome, though formally possible, is much less likely in a younger individual. This patient’s bone marrow biopsy revealed only increased megakaryocytes with a few dysplastic forms and normal cytogenetics. Whether or not a bone marrow biopsy would have been necessary at all in this case is debatable. Simply sending peripheral blood for bcr-abl molecular diagnostic testing is quite sensitive for the detection of CML, and this would be the most important condition, requiring treatment sooner rather than later, that might be missed. The patient in this case was simply followed over time, and three years later with no therapeutic interventions was still doing well with a platelet count of 735,000/µl.

Splenomegaly, bone marrow hypercellularity with aggregates of megakaryocytes, clonal hematopoiesis in women, or abnormal platelet aggregation to ADP/epinephrine are supportive of the diagnosis.

For more information:
  • Peter Marks, MD, PhD is clinical director of hematology at Brigham and Women’s Hospital and Instructor of Medicine at Harvard Medical School. You may contact him at: hemonctoday@slackinc.com.