Hospital Medicine

Thrombocytosis

Thrombocytosis

I. Problem/Condition.

Defined as platelet count of greater than 450,000 cells/microliter (cells/μL).

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

The differential includes spurious, reactive (secondary) or autonomous (primary) thrombocytosis.

Always confirm by repeat testing of the platelet count and peripheral smear and exclude false or spurious causes of thrombocytosis. Causes of spurious thrombocytosis include cell fragments (which are increased in the case of leukemia), red cell inclusions (such as Pappenheimer bodies) or schistocytes, as seen in the setting of hemolysis or severe burns. In cryoglobulinemia, platelet counts and white blood cells rise when samples are prepared at cool temperatures.

Secondary or reactive thrombocytosis accounts for 80-90% of cases of thrombocytosis. Causes of secondary thrombocytosis include infection, inflammatory states (for example, inflammatory bowel disease), physical stress (including the post-operative state), acute blood loss, iron deficiency anemia, post-splenectomy and underlying malignancy.

Primary or autonomous thrombocytosis is a clonal bone marrow process. Disorders include essential thrombocythemia (ET), polycythemia vera, primary myelofibrosis and chronic myeloid leukemia.

Familial thrombocytosis is a genetically heterogeneous disorder and a rare entity.

B. Describe a diagnostic approach/method to the patient with this problem.

Confirm by rechecking platelet count and obtain peripheral smear to rule out spurious causes.

If confirmed, review the duration of thrombocytosis and perform a thorough history and physical to evaluate for causes of reactive thrombocytosis. Take note of whether the patient had recent trauma, surgery, infection, or inflammatory disease, history of splenectomy, history of iron deficiency, thrombosis or bleeding, weight loss, fatigue or night sweats suggestive of malignancy. Check ferritin to evaluate for iron deficiency anemia.

Consider an autonomous disorder once reactive processes have been excluded. A bone marrow biopsy with aspiration and cytogenetic testing is required to confirm the diagnosis.

1. Historical information important in the diagnosis of this problem.

  • - Recent trauma;

  • - Recent surgery;

  • - Recent or current infection;

  • - Recent thrombocytopenia (rebound);

  • - Underlying inflammatory disorder (collagen vascular disease, inflammatory bowel disease);

  • - Vigorous exercise;

  • - Medications (EpiPen®, tretinoin);

  • - Splenectomy or splenic disorder;

  • - Acute blood loss;

  • - Iron deficiency anemia;

  • - Thrombosis;

  • - Bleeding;

  • - Recurrent or spontaneous abortion;

  • - Weight loss, fatigue, chills, night sweats;

  • - Erythromyalgia (intense burning or throbbing pain in a patchy distribution in the hands and feet, particularly plantar surfaces).

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

  • - Splenomegaly

  • - Delay in nail bed blanching and nail bed rubor, decrease in palmar crease rubor, and conjunctival pallor (exam findings suggestive of anemia).

  • - Signs of microvascular ischemia (warmth, duskiness, mottled erythema, gangrene).

  • - Focal neurologic signs.

  • - Palpable abdominal mass or tenderness, ascites, varices, jaundice (suggestive of portal or hepatic vein thrombosis).

  • - Unilateral extremity swelling or edema, calf/thigh pain, palpable cord (suggestive of deep vein thrombosis).

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Peripheral blood smear, ferritin, serum iron, serum total iron binding capacity (TIBC), bone marrow biopsy with aspirate and cytogenetic testing, JAK2 serum and/or aspirate testing. Consider evaluating for occult malignancy with review of prior imaging and further testing and imaging as indicated by systemic and localizing signs and symptoms.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Note that the degree of thrombocytosis is not indicative of its etiology. Reactive thrombocytosis still accounts for the majority of cases of extreme thrombocytosis (platelet counts >1,000,000 cells/μL).

In reactive thrombocytosis, platelets are typically small in size and with a normal mean platelet volume. The peripheral smear may provide evidence of an underlying infective or inflammatory process. Acute phase reactants including erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) are often elevated. Bone marrow aspirate or trephine is not required; if it is performed, megakaryocytic hyperplasia with normal mature and left shifted megakaryocyte morphology.

In ET, the platelet count is sustained over 450,000 cells/μL. Reactive causes must be excluded, and iron stores are normal. Peripheral smear may be significant for thrombocytosis with platelet anisocytosis (varying size). Evidence of iron deficiency anemia may be present where erythrocytes are hypochromic and microcytic. Leukoerythroblastosis and poikilocytosis are not seen. Polycythemia vera, chronic myeloid leukemia, primary myelofibrosis and myelodysplastic syndrome must be ruled out. Bone marrow biopsy is typically required for diagnosis.

Clonal genetic markers such as JAK2 V17 or MPL mutations may be detected in up to 60% of patients. If a clonal abnormality is detected in an elderly patient and features of myelodysplastic syndrome or primary myelofibrosis are not present, bone marrow biopsy may not be required. Bone marrow is normocellular for age; the number of megakaryocytes is increased but normal in morphology. Many large megakaryocytes with hyperlobulated nuclei are present. Erythropoeisis and granulopoesis are normal.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Avoid obtaining CRP or ESR if patient has an apparent underlying infectious or inflammatory disorder, as they will be elevated.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Thrombocytosis.

Rule out etiologies of reactive thrombocytosis. If etiology is identified, then treat underlying disease or remove inciting process.

Your patient may have pseudohyperkalemia on serum basic metabolic panel as high as 9 milliequivalents/liter (mEq/L). However, this causes no symptoms as plasma levels of potassium are unaffected. You can confirm by checking a plasma potassium level.

The major complications of thrombocytosis include bleeding, thrombosis or vasomotor symptoms.

Extreme thrombocytosis is sometimes associated with an acquired type II von Willebrand disease (vWD); in this setting, rapid reduction of platelet count with platelet apheresis along with aspirin is required. If the patient is bleeding, stop antiplatelet agents including aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). May require fresh frozen plasma (FFP) or platelet transfusion if actively bleeding and hemodynamically unstable.

Patients with vasomotor symptoms (headache, flushing) may benefit from aspirin 81 milligram (mg) daily.

Consider platelet cytoreductive therapy with hydroxyurea or megakaryocyte inhibitor with anagrelide in patients with essential thrombocytosis and platelets greater than 1.5 million cells/μL, age greater than 60 years, cardiovascular risk factors, or risk of bleeding or thrombosis. Rapid reduction of platelets with platelet apheresis is performed for patients with acute cerebrovascular complications or digital ischemia.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

Check platelet count >450000 cells/μL

  • - review peripheral blood smear, CRP, ESR, iron studies.

  • - 3 paths:

    • if acute phase response, likely reactive thrombocytosis, treat underlying disorder only.

    • if iron deficiency, treat and recheck platelet count after repletion of iron stores.

    • if normal (chronic thrombocytosis, normal iron store and intact spleen):

      • repeat platelet count, if persistent unexplained thrombocytosis.

      • bone marrow biopsy with aspirate and cytogenetic testing, JAK2.

If symptomatic:

  • - if bleeding, stop antiplatelet agents, consider FFP or platelet transfusion. If suspect acquired VWF deficiency, consider emergent platelet apheresis and aspirin 81mg by mouth (po) daily.

  • - if vasomotor symptoms (headache, flushing, pruritus) start aspirin 81mg PO daily.

  • - if thrombosis (hepatic, inferior vena cava, portal, splenic), immediate platelet apheresis if platelet greater than 800k, consider anticoagulation with heparin/warfarin depending on type of thrombosis.

  • - if ET and acute cerebrovascular complications or digital ischemia, immediate platelet apheresis.

VII. What's the Evidence?

Alizadeh, K, Hadjinicolaou, AV, Hadjittofi, C, Shankar, A. "Postsplenectomy thrombocytosis with pseudohyperkalemia". BMJ Case Rep. 2015 Sep 7. pp. 2015.

(This is a case report of unnecessary treatment of pseudohyperkalemia resulting from thrombocytosis in a post-operative patient. I think this is an important clinical laboratory finding for hospitalists to be aware of, because not only is treatment unnecessary for pseudohyperkalemia but it can also result in symptomatic hypokalemia.)

Schafer, A. "Thrombocytosis". JAMA. vol. 314. 2015. pp. 1171-1172.

(This is a recent case report and summary of literature on how to approach a new diagnosis of thrombocytosis in a clinical scenario.)

Tefferi, A, Barbui, T. "Polycythemia Vera and essential thrombocythemia: 2015 update on diagnosis, risk stratification and management". Am. J. Hematol. vol. 90. 2015. pp. 163-173.

(This is an updated guideline for treatment of PV and ET.)

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