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Blood Disorders
(Anemia, Leukopenia, and Thrombocytopenia)

Thrombocytopenia

Thrombocytopenia is a condition characterized by reduced platelets, or thrombocytes. Platelets, which are fragments formed from large bone marrow-derived cells (ie, megakaryocytes), function in blood clotting (MedlinePlus 2012d).

Causes and risk factors

Thrombocytopenia can arise in a variety of clinical situations. For example, reduced megakaryocytes (platelet precursors) are seen in aplastic anemia and leukemia. Aplastic anemia is a condition in which production of all blood cells is reduced (Brodsky 2005). Leukemia is a cancer where abnormal production of leukocytes (white blood cells) affects the synthesis of other blood cells, including platelets (Merck 2012b).

Thrombocytopenia can arise as a result of complex interplay of autoimmune platelet destruction and impaired platelet production. This type of thrombocytopenia was historically referred to as “idiopathic thrombocytopenia,” since its causes were unknown; now that its pathophysiology is better understood, it is deemed “immune thrombocytopenia” or ITP. It is more common in aging populations, and may be a result of the immune system dysregulation associated with aging (McCrae 2011; Rodeghiero 2009). Specifically, ITP is characterized by the presence of immunoglobulin G (IgG) autoantibodies against receptors on the surface of platelets. These autoantibodies “mark” platelets for destruction by the immune system, leading to reduced platelet count. Additionally, these autoantibodies appear to decrease platelet production (McCrae 2011; McMillan 2004).

Thrombocytopenia can be induced by a host of drugs, including those that suppress the synthesis of bone marrow cells, such as hydroxycarbamide and interferon alfa-2b (IntronA®). Hydroxycarbamide is beneficial in treating sickle cell disease through its ability to stimulate fetal hemoglobin synthesis; however, it also reduces platelet production in some individuals (Zamani 2009). Interferon alfa-2b is an antiviral drug used to treat hepatitis B, hepatitis C, and certain cancers; however, it also suppresses platelet production (Roomer 2010; Scaglione 2012; Kelly 2012; Rubin 2012). The list of drugs that can cause thrombocytopenia does not stop there – heparin, quinine, vancomycin, cimetidine, naproxen, and chlorothiazide can all negatively affect platelet number (Aster 2007; Giugliano 1998).

Reduced production of platelets from megakaryocytes can occur due to alcoholism, vitamin B12 and folate deficiency, aplastic anemia, leukemia, and chemotherapy. Similar to anemia and leukopenia, an enlarged spleen can result in enhanced clearance/destruction of platelets (MedlinePlus 2012d).

Symptoms & diagnosis

Clinically, thrombocytopenia is diagnosed as a platelet count of <50 000 per microliter of blood on a standard blood test. Symptoms include multiple small petechiae (or broken blood vessels just beneath the skin), scattered bruising, gastrointestinal or vaginal bleeding, and excessive bleeding after surgery. All of these symptoms reflect the underlying disorder – impaired blood clotting (NHLBI 2012).

Treatment

Non immune-system-mediated thrombocytopenia. In non immune-system-mediated thrombocytopenia, the treatment depends on the underlying cause (MedlinePlus 2012d); however, all patients should avoid drugs that impair clotting (NHLBI 2012).

Thrombocytopenia due to increased platelet destruction (eg, immune thrombocytopenia - ITP). Thrombocytopenia due to increased platelet destruction is typically treated with corticosteroid medications such as prednisolone (Nakazaki 2012). Prednisolone is a glucocorticoid, which acts as an immunosuppressant to reduce the destruction of platelets by the immune system (NHLBI 2012). Splenectomy is a more invasive option that is generally reserved for severe or treatment-resistant thrombocytopenia (Wang 2012).

Immune cells called B-cells can be partly responsible for the destruction of platelets in thrombocytopenia. Rituximab (RituxanTM), a drug that inhibits B-cells, has been shown to be efficacious in certain populations of immune-mediated thrombocytopenia. One review of rituximab trials showed that 72% of patients treated with the drug achieved significant clinical improvements (Cervinek 2012).

If platelets become too low, they can be directly replaced by transfusions (Bercovitz 2012; Wandt 2012).

Thrombocytopenia due to reduced megakaryocyte production. Thrombocytopenia due to reduced megakaryocyte productioncan be treated with Romiplostim (Nplate®), an injectable thrombopoietin-mimetic that has been shown to sustainably improve platelet counts within 14 weeks (Kuter 2008). Thrombopoietin is a liver-derived hormone that stimulates megakaryocyte production in bone marrow (Sharma 2012).

Eltrombopag (Promacta®) is a small molecule that binds to and activates the thrombopoietin receptor. The advantage of eltrombopag over treatments like romiplostim is that it is orally bioavailable and does not require regular self-administered injections. In one double-blind, randomized, placebo-controlled trial in patients with liver disease and thrombocytopenia about to undergo an invasive procedure, pretreatment with 75 mg eltrombopag daily for 2 weeks significantly reduced the need for platelet transfusions (Afdhal 2012).

Despite both drugs targeting the same receptor, patients who are non-responders to eltrombopag may still benefit from romiplostim (Aoki 2012). One review of the two drugs modestly favored romiplostim over eltrombopag (Cooper 2012). Eltrombopag and romiplostim may cause shortness of breath, coughing up blood, accelerated heart rate and breathing, dizziness or lightheadedness, and vision changes. These drugs can also cause bone marrow abnormalities, or may cause the platelet count to increase too much; both of these side effects can be serious (MedlinePlus 2009, 2010).

New/Novel therapies

Avatrombopag. Avatrombopag (a novel analog of eltrombopag), which has shown efficacy in preliminary studies on thrombocytopenia associated with liver disease (Terrault 2012), is being tested in chronic immune thrombocytopenia patients (ClinicalTrials.gov 2012b).