Thrombocytosis

Overview
Thrombocytosis is the presence of high platelet counts in the blood, and can be either reactive or primary (also termed essential and caused by a myeloproliferative disease). Although often symptomless (particularly when it is a secondary reaction), it can predispose to thrombosis in some patients.

Definition

 * 95% of the population will have a platelet count between 100K and 450K. Thrombocytosis is defined as >500K.  Extreme thrombocytosis is defined as >1,000,000.  Generally, a normal platelet count ranges from 150,000 and 450,000 per mm³. These limits, however, are determined by the 2.5th lower and upper percentile, and a deviation does not necessary imply any form of disease. Nevertheless, counts over 750,000 (and especially over a million) are considered serious enough to warrant investigation and intervention.

Pathophysiology & Etiology
Thrombocytosis is either reactive or autonomous. In one study of 91 patients with platelet count >600K, 70% were reactive and 22% autonomous. In 280 patients with platelet count >1,000,000 82% were reactive and 14% were autonomous. 8% had both. Among reactive causes of thrombocytosis, infection (30%), Post-surgical (15%), Both (30%), Malignancy (10%), Post splenectomy (10%) and acute blood loss/iron deficiency (10%) are the most common causes.

Autonomous causes of thrombocytosis include Essential Thrombocytosis, chronic myolegenous leukemia (CML), Polycythemia Vera, Agnogenic Myeloid Metaplasia and Myelodysplasia. The degree of thrombocytosis does not help determine whether the thrombocytosis is reactive or not.

Signs and symptoms
High platelet levels do not necessarily signal any clinical problems, and are picked up on a routine full blood count. However, it is important that a full medical history be elicited to ensure that the increased platelet count is not due to a secondary process. Often, it occurs in tandem with an inflammatory disease, as the principal stimulants of platelet production (e.g. thrombopoietin) are elevated in these clinical states as part of the acute phase reaction.

High platelet counts can occur in patients with polycythemia vera (high red blood cell counts), and is an additional risk factor for complications.

A very small segment of patients report symptoms of erythromelalgia, a burning sensation and redness of the extremities that resolves with cooling and/or aspirin use.

Vasomotor symptoms including headache, change in vision, lightheadedness, acral dysethesia, and atypical chest pain are more common in autonomous thrombocytosis but can certainly be seen in reactive thrombocytosis and are amenable to aspirin therapy. The rates of thrombosis and/or hemorrhage are higher in autonomous (24%) vs. reactive (1-3%) extreme thrombocytosis.

Diagnosis
Laboratory tests might include: full blood count, liver enzymes, renal function and erythrocyte sedimentation rate.

If the cause for the high platelet count remains unclear, bone marrow biopsy is often undertaken, to differentiate whether the high platelet count is reactive or essential.

Causes
Increase platelet counts can be due to a number of disease processes:
 * Essential (primary)
 * Essential thrombocytosis (a form of myeloproliferative disease)
 * Other myeloproliferative disorders such as chronic myelogenous leukemia, polycythemia vera,  myelofibrosis
 * Reactive (secondary)
 * Inflammation
 * Surgery (which leads to an inflammatory state)
 * Hyposplenism (decreased breakdown due to decreased function of the spleen)
 * Hemorrhage and/or iron deficiency

Treatment
Often, no treatment is required or necessary for reactive thrombocytosis.

However, in primary thrombocytosis, if platelet counts are over 750,000 or 1,000,000, and especially if there are other risk factors for thrombosis. Aspirin at low doses is thought to be protective, and extreme levels are treated with hydroxyurea (a cytoreducing agent). The new agent anagrelide (Agrylin®) has recently been introduced for the treatment of essential thrombocytosis. However, recent studies show that anegrilide is not significantly more effective than traditionally used hydroxyurea (Harrison et al 2005).

Treatment should exclude spurious thrombocytosis secondary to mixed cryoglobulinemia, or cytoplasmic fragments from lymphoma, leukemia, hemolysis and burns. Look for splenomegaly (seen in CML, polycythemia.vera, AMM and myodysplastic syndrome). Consider measurement of ferritin, CRP (C-reactive protein), fibrinogen and ESR (erythrocyte sedimentation rate) as well as DIC (disseminated intravascular coagulation) parameters. Thrombopoeitin levels have not been shown to be helpful yet. Review smear with special attention to the presence/absence of schistocytes (DIC), teardrops/nucleated red blood cells (agnogenic myeloid metaplasia), Howell-Jolly bodies/target cells (post splenectomy), toxic granulations/Dohle bodies/neutrophillia/bands (infection). Essential thrombocytopenia is a diagnosis of exclusion. In these cases, giant clusters of platelets or megakaryocyte clusters may be seen. Less than 5% will have, cytogenetic abnormalities.

Acute Pharmacotherapies
Bleeding should prompt discontinuation of platelet poisons. The patient should also be worked up for DIC. Acquired Factor V deficiency or von Willebrand disease can be seen in association with extreme thrombocytosis and is managed with factor replacement, fresh frozen plasma and/or platelet apheresis coupled with a platelet lowering agent (Hydrea or anagrelide). Rarely, thrombocytosis is associated with thrombosis. For this reason, routine antiplatelet therapy is not necessary (exception post- coronary artery bypass graft-CABG) and has not shown to be effective in preventing thrombosis. Budd-Chiari, portal and splenic vein thrombosis occur and suggest an autonomous cause. Immediate platelet apheresis and a platelet lowering agent are advised for those with counts >800K. Work-up for hypercoagulable state is suggested (Protein C,S, ATIII, anticardiolipin, homocysteine, Factor V and prothrombin gene mutation).

Acknowledgements
The content on this page was first contributed by: BIDMC Resident Report by Duane Pinto, M.D.

Trombocitosis תרומבוציטוזיס Trombocytose Trombocitose