Thrombocytopenia

The number of platelets may be reduced by decreased production, increased destruction, or abnormal distribution. Production may be suppressed by many factors, including radiation, drugs, chemotherapy, alcohol use, malignant invasion of the bone marrow, aplastic anemia, and vitamin B12 or folic acid deficiency.

Thrombocytopenia due to immune destruction Idiopathic thrombocytopenic purpura (ITP) is the result of platelet injury by antiplatelet antibodies. The International Working Group on ITP classifies it into 3 categories: primary ITP; secondary ITP associated with other conditions such as SLE, HIV infection, malignancy, and hepatitis C; and drug-induced thrombocytopenia. The acute form of ITP usually occurs in children and young adults, often following a viral illness, and commonly undergoes spontaneous remission. Chronic ITP is more common in adults and is characterized by mild manifestations; spontaneous remission is uncommon. Initial treatment consists of corticosteroid therapy. Patients with ITP who do not respond to corticosteroid therapy, who are bleeding and require rapid increase in platelet count, or who require surgical intervention should receive intravenous immunoglobulin. Alternatively, anti-D immunoglobulin may be administered in those who are Rh positive. Rituximab or splenectomy is recommended for ITP refractory to corticosteroids and intravenous immunoglobulin. Because spontaneous remission may occur, clinicians often delay splenectomy for at least 6 months. Thrombopoietin receptor agonists (TPO-RAs) such as romiplostim or eltrombopag or immunosuppressive agents such as azathioprine, cyclosporine, or mycophenolate mofetil may also be of benefit. Fostamatinib has also recently received FDA approval for treatment of chronic ITP. Splenectomy, however, has been reported to provide the highest durable remission rate and, in balance, still appears to be the favored second-line treatment over rituximab and TPO-RAs, except in poor surgical candidates or those who prefer a nonsurgical approach.

A neonatal form of the disorder occurs in babies born to women with ITP; this form results from transplacental passage of antiplatelet antibodies. Recovery follows physiologic clearance of the antibodies from the child’s circulation.

Many drugs and other substances, including quinine, quinidine, digitalis, procainamide, thiazide-type diuretics, sulfonamides, phenytoin, aspirin, penicillin, heparin, and gold compounds, have been implicated as causes of immunologic platelet destruction. Drug-induced thrombocytopenia is common, and discontinuation of the offending drug should result in platelet recovery.

Nonimmunologic thrombocytopenia Types of nonimmunologic thrombocytopenia include thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), and the syndromes of disseminated intravascular coagulation (see the section “Disseminated intravascular coagulation” later in the chapter). TTP is caused by an inherited or acquired deficiency of the von Willebrand factor–cleaving protease ADAMTS13. It is characterized by thrombotic microangiopathy and hemolytic anemia. Fever, neurologic symptoms, microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and renal dysfunction occur, often with subacute onset. Death occurs in days to weeks in the majority of untreated cases. However, early treatment with exchange plasmapheresis has improved the survival rate to over 80%, especially when rituximab is given as part of initial therapy. Despite significant thrombocytopenia, bleeding is relatively uncommon. Therefore, platelet transfusions are usually unnecessary because plasma exchange abates the consumption process. However, platelet transfusion may be indicated in patients with severe bleeding or in those who will undergo an invasive procedure. Refractory cases may be treated with antiplatelet drugs, corticosteroids, and immunosuppressive agents. Eculizumab is recommended in complement-mediated TTP.

Hemolytic-uremic syndrome is similar in pathophysiology to TTP in that both are associated with MAHA, thrombocytopenia, and renal involvement. The most common cause of HUS, especially among children, is Shiga toxin–producing Escherichia coli (STEC), which accounts for 90% of cases of HUS. TTP and HUS are similar in clinical appearance, and laboratory confirmation of low ADAMTS13 activity (<10% in patients with TTP) may take several days; these factors complicate the decision whether to initiate plasma exchange or anticomplement therapy emergently. The abnormal distribution of platelets is most commonly caused by splenic sequestration. The usual clinical setting is hepatic cirrhosis, and the level of thrombocytopenia is mild. Patients with severely depressed platelet counts probably also have accelerated platelet destruction in the spleen.

Thrombocytosis and essential thrombocythemia

Thrombocytosis is defined as a platelet count exceeding 450,000. Essential thrombocythemia (ET) refers to an excess of platelets due to a primary bone marrow clonal disorder. Reactive thrombocytosis is secondary to other conditions such as inflammatory disorders. Management of reactive thrombocytosis is aimed at treating the underlying cause such as infection, inflammation (eg, giant cell arteritis), trauma, iron deficiency, congestive heart failure, renal failure, and pancreatitis. In contrast, ET is a clonal myeloproliferative disorder akin to neoplastic disease. Severe autonomous increase in platelet counts may also be caused by other myeloproliferative disorders such as polycythemia vera, primary myelofibrosis with myeloid metaplasia, chronic myeloid leukemia (CML), and myelodysplastic syndromes.

Epidemiologic studies have determined a prevalence rate of ET of 30/100,000 in the general population worldwide with a nearly 2:1 ratio between men and women. Regardless of etiology, severe thrombocytosis can cause both thrombotic and hemorrhagic events. However, thrombohemorrhagic complications are much more common in ET and in other clonal myeloproliferative disorders and include arterial and venous thromboses, cerebrovascular accident, myocardial infarction, and deep venous thrombosis. Hemorrhagic events include ecchymoses, subcutaneous hematomas, epistaxis, and gum bleeding. About 36% of patients, however, are asymptomatic. There is a 2%–5% long-term risk of leukemic transformation into acute myeloid leukemia. Treatment is centered on inhibition of platelet aggregation, especially in patients at high risk of thrombotic events, as well as cytoreduction. Aspirin and other antiplatelet agents such as ticlopidine and clopidogrel inhibit aggregation. Hydroxyurea and interferon alfa reduce platelet counts by bone marrow inhibition. Anagrelide, a phosphodiesterase inhibitor, has both platelet antiaggregating and cytoreductive properties.

• Birgegård G. Advances and challenges in the management of essential thrombocythemia. Ther Adv Hematol. 2015; 6(3):142–156.

  Geyer HL, Kosiorek H, Dueck AC, et al. Associations between gender, disease features and symptom burden in patients with myeloproliferative neoplasms: an analysis by the MPN QOL International Working Group. Haematologica. 2017;102(1):85–93.

Ophthalmic considerations Reported ocular manifestations of ET include ischemic optic neuropathy and retinal vein occlusion. For more information on these conditions, see BCSC Section 5, Neuro-Ophthalmology, and Section 12, Retina and Vitreous.

Platelet dysfunction

Patients with platelet dysfunction usually come to the physician’s attention because of easy bruising, epistaxis, menorrhagia, or excessive bleeding after surgery or dental work. Unlike patients with marked thrombocytopenia, patients with platelet dysfunction rarely have petechiae.

Hereditary disorders of platelet function are rare. Much more important clinically are the acquired forms, of which drug ingestion is the most common cause. As with drugs causing antiplatelet antibodies, the list of causative agents is very long. A single aspirin tablet taken orally irreversibly inhibits platelet aggregation for the life span of the circulating platelets present, causing a modest prolongation of bleeding time for at least 48–72 hours following ingestion. This reaction has remarkably little effect in otherwise healthy individuals, although intraoperative blood loss may be slightly increased. However, bleeding may be significant in patients with hemophilia, severe thrombocytopenia, or uremia and in those on warfarin or heparin therapy.

Nonsteroidal anti-inflammatory drugs cause reversible inhibition of platelet function in the presence of the drug; the effect disappears as the drug is cleared from the blood. Other commonly used drugs that may affect platelet function include ethanol, tricyclic antidepressants, and antihistamines.

In addition to uremia, clinical conditions associated with abnormal platelet function include liver disease, multiple myeloma, SLE, chronic lymphocytic leukemia, and Hermansky-Pudlak syndrome (an autosomal recessive form of oculocutaneous albinism).

Excerpted from BCSC 2020-2021 series: Section 1 - Update on General Medicine. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.