A. Introduction. Thrombocytopenia, a common disorder in hospitalized patients, is defined as a platelet count <150,000 cells/μL.
B. Clinical Manifestations of Thrombocytopenia. Signs and symptoms are related to the degree of thrombocytopenia (in the absence of concomitant disorders of coagulation or platelet dysfunction).
a. Platelet count 50,000–100,000 cells/μL. Usually asymptomatic, but bleeding times may be prolonged on specific laboratory testing.
b. Platelet count 30,000–50,000 cells/μL. Signs and symptoms include easy bruising. Spontaneous bleeding is rare.
c. Platelet count 10,000 to 30,000 cells/μL. Increased risk for bleeding with minimal trauma. Small, but measurable risk for spontaneous bleeding (e.g., petechiae, gastrointestinal bleeding).
d. Platelet count <10,000 cells/μL. Patients are at an increased risk for spontaneous bleeding and typically benefit from transfusion support.
C. Causes of Thrombocytopenia. It is easiest to remember the causes of thrombocytopenia if you classify them according to the underlying mechanism: decreased production, splenic sequestration, or increased destruction (Figure 60.1).
a. Decreased production. Because the bone marrow is involved, there is often a decrease in other cell lines as well. The causes of decreased platelet production are almost identical to those of pancytopenia (see Chapter 59).
i. Paroxysmal nocturnal hemoglobinuria (PNH). Commonly associated with increased platelet destruction but may also be associated with a production defect.
ii. Aplasia. Aplastic anemia due to bone marrow failure can cause pancytopenia.
iii. Neoplasms and bone marrow disorders. Some examples include leukemia, metastatic malignancies, and myelodysplasia.
iv. Vitamin deficiencies. Deficiencies of vitamins such as vitamin B12 and folate are rare causes of isolated thrombocytopenia.
v. Toxins, drugs, and radiation therapy. Many toxins and drugs are implicated in decreased platelet production including ethanol, thiazide diuretics, linezolid, interferon, and chemotherapeutic agents.
vi. Overwhelming infections. Bacterial sepsis, tuberculosis, fungal infections, and viral infections, including viral hepatitis and HIV, can cause thrombocytopenia.
vii. Congenital thrombocytopenia. These include May-Hegglin anomaly, Bernard-Soulier syndrome, Wiskott-Aldrich syndrome, congenital hypoplastic amegakaryocytic thrombocytopenia, and thrombocytopenia and absent radii (TAR syndrome).
c. Increased destruction is the most common cause of isolated thrombocytopenia. Disorders that cause increased destruction of platelets can be classified as nonimmunologic or immunologic.
1. Microangiopathic hemolytic anemia (MAHA) may cause platelet destruction as a result of shearing in small vessels (see Chapter 62).
2. PNH predisposes all cell lines to complement-mediated lysis and is therefore a rare cause of isolated thrombocytopenia.
1. Destruction related to an autoimmune phenomenon (e.g., immune thrombocytopenic purpura [ITP], gestational thrombocytopenia, common variable immune deficiency, lymphoproliferative disorders, infections (e.g., Helicobacter pylori, HIV, hepatitis), or rheumatologic disease (e.g., systemic lupus erythematosus [SLE], antiphospholipid syndrome)].
2. Alloimmune phenomena (e.g., posttransfusion reaction).
3. Drug-dependent antibodies due to medications (i.e., heparin, abciximab, quinine, gold salts, penicillins, vancomycin, nonsteroidal antiinflammatory drugs, and valproic acid). The timing, onset, and degree of thrombocytopenia are important to analyze because they can help identify the offending agent.
a. Heparin-induced thrombocytopenia (HIT) is subdivided into type 1 and type 2. Type 1 HIT—a nonimmune process occurring from a direct effect of heparin on platelet activation—generally occurs within 48 hours after exposure to heparin; the platelet count normalizes despite continued heparin therapy. Type 2 HIT is an immune-mediated disorder—with limb-threatening thrombosis—that typically occurs 5–8 days after heparin exposure and is classically associated with >50% drop from the baseline platelet count at the time of heparin initiation. However, the platelet nadir is usually moderate at about 50,000—60,000 cells/μL.
In clinical practice, the term “HIT” usually refers to type 2 HIT. The main consideration is limb-threatening thrombosis.
b. Other drug-induced thrombocytopenia can be associated with bleeding and platelet nadirs around 10,000 cells/μL.
D. Approach to the Patient
a. Exclude pseudothrombocytopenia. Pseudothrombocytopenia is an artifact of platelet clumping in the test tube in EDTA-anticoagulated blood. Examining the peripheral blood smear will show platelet clumping and will alert you to the problem. Send a citrate or heparinized specimen (because these limit clumping) or ask for a manual count if you suspect pseudothrombocytopenia.
b. Determine the cause of thrombocytopenia.
i. Patient history. Detailed attention to the patient’s medications, infectious risk factors (e.g., viral hepatitis and HIV), and substance abuse (e.g., alcohol) is necessary. A review of systems and assessment of “B” symptoms (i.e., fevers, night sweats, and weight loss) may help reveal an occult malignancy. A bleeding history including questions about menstrual bleeding, surgical complications, and prior transfusions may help elucidate the chronicity of the problem. Family history may help reveal a congenital pattern.
ii. Physical examination. A complete physical examination is always necessary, with particular attention to the following areas:
iii. Diagnostic studies
1. Peripheral blood smear. A peripheral blood smear is essential and can quickly uncover an etiology. Some blood smear findings that aid in diagnosis include:
a. Large platelets. The finding of both normal-sized and large platelets implies increased destruction with increased platelet turnover and early release from the bone marrow. ITP is classically associated with finding both normal and large platelets on the peripheral blood smear. The large platelets are young and hyperfunctional, and as a result, patients with ITP have a lower incidence of bleeding relative to their platelet count. Congenital thrombocytopenia syndromes typically also have large/giant platelets (similar in size to red blood cells [RBC]).
b. Schistocytes. The finding of fragmented RBCs implies microangiopathic hemolytic anemia (MAHA) or intravascular hemolysis (e.g., severe valvular disease).
c. Other abnormalities that may offer clues are discussed in Chapter 59.
2. Laboratory studies
a. Elevated lactate dehydrogenase (LDH) levels may be used to evaluate the possibility of MAHA.
b. Coagulation studies: prolonged prothrombin time (PT), partial thromboplastin time (PTT), and fibrin degradation products (including D-dimer) are seen in disseminated intravascular coagulopathy (DIC).
c. Blood urea nitrogen (BUN) and creatinine levels may help elucidate syndromes such as hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP).
d. Vitamin B12, folate levels and flow cytometry for PNH are sometimes performed, but these disorders are rarely associated with isolated thrombocytopenia.
3. Serologic studies. Disease-specific serologies/molecular studies are useful for evaluating possible etiologies of immunologic destruction of platelets.
a. Infectious serologies/real-time polymerase chain reaction (RT-PCR) testing: HIV, viral hepatitis, Epstein-Barr virus (EBV), cytomegalovirus (CMV), and toxoplasmosis.
b. Serologies to evaluate for SLE.
4. Antiplatelet antibody testing is neither sensitive nor specific and is not a standard test to perform.
iv. Bone marrow biopsy. Performed when it is necessary to assess the production of platelets if and when other, more common etiologies are ruled out. If the cause of thrombocytopenia is readily identifiable (e.g., thiazide diuretic therapy, heparin, other medications), then discontinuation of the offending agent may be both diagnostic and therapeutic—obviating the need for a bone marrow biopsy. Pertinent findings on bone marrow biopsy include the following:
1. Decreased megakaryocytes indicate a platelet production issue. Evidence of the specific cause of the decreased production may also be found (e.g., malignancy, aplasia, infection).
2. Increased megakaryocytes are seen when increased destruction or sequestration is the mechanism of thrombocytopenia. An increased number of megakaryocytes on bone marrow biopsy in the absence of dysplasia, ongoing destruction, or sequestration is diagnostic for ITP.
3. Evidence for myelodysplasia can also be seen on bone marrow biopsy (see Chapter 70) and is characterized by micromegakaryocytes, oligonuclear forms, hypolubulated forms, and hypogranular megakaryocytes.
a. General treatment
i. Treat underlying disorder (e.g., viral etiologies)
ii. Discontinue medications or offending agents that may cause thrombocytopenia.
1. The platelet count will usually return to normal in 7–10 days.
2. Heparin-induced thrombocytopenia and thrombosis (HITT) is a disorder in which immune-mediated thrombocytopenia and, paradoxically, systemic thrombosis coexist (also called HIT type 2 and discussed previously). Increasing the heparin dose in these patients is contraindicated; the therapy involves heparin withdrawal and systemic anticoagulation with a direct thrombin inhibitor to prevent further thrombotic complications. In HITT, platelet counts rarely fall below <50,000 cell/μL.
a. Assessments for HIT should be made by calculating a 4T score and (depending on probability) sending for a HIT enzyme-linked immunosorbent assay (ELISA) and/or a serotonin release assay.
b. A direct thrombin inhibitor such as lepirudin, bivalirudin, or argatroban may be used to anticoagulate patients with confirmed or suspected HIT. Warfarin should not be reinstituted until the patient is stabilized on a direct thrombin inhibitor and the platelet count is ≥150,000 cell/μL.
iii. Platelet transfusions. Unnecessary platelet transfusions should be avoided because they may induce immune resistance to future transfusions, especially in cases of TTP and ITP; if this complication occurs, single-donor platelets or human leukocyte antigen (HLA)-matched platelets can be administered.
1. Platelet transfusions are usually not indicated for patients with platelet counts >10,000–20,000 cells/μL and no evidence of bleeding.
In general, platelet transfusions in patients with TTP but without symptoms should be avoided because transfusions can worsen the patient’s condition.
2. Indications. Platelet transfusions are indicated in the following situations:
a. Before surgery. The platelet count is usually maintained above 50,000 cells/μL when surgery is to be performed, although in patients with ITP, this may be both impossible and unnecessary. When neurosurgery or thoracic surgery is to be performed, the platelet count should be maintained above 80,000–100,000 cells/μL to minimize the risk for bleeding because this may be catastrophic.
b. In a patient with active bleeding
i. Severe bleeding. The platelet count is always maintained above 50,000 cells/μL. Higher thresholds may be required, depending on the clinical situation (e.g., neurosurgical patients).
ii. Mild bleeding or petechiae. The platelet count should be maintained above 20,000 cells/μL, unless an alternative treatment (e.g., directed ITP therapy) can be instituted in a monitored setting.
c. Prevention of spontaneous bleeding. Maintain a platelet count >10,000–20,000 cells/μL, depending on physician preference and clinical history.
b. Specific treatments for ITP (including HIV-associated ITP) are discussed here; specific treatments for other causes are discussed in relevant chapters.
i. Observation is often appropriate for patients with platelet counts >30,000 cells/μL and no evidence of bleeding. Children frequently develop an acute form of ITP that is related to a viral illness and resolves spontaneously over 3–6 months. In adults, ITP usually follows a chronic and recurrent course.
ii. Pharmacologic therapy
1. Steroids will benefit approximately 70% of patients, leading to an increase in platelet count. Counts can increase in as quickly as 3–7 days, but relapses occur in up to 50% of patients after the discontinuation of the therapy.
2. Intravenous immunoglobulin (IVIG) or anti-Rh(D) (anti-D, WinRho) often increases the platelet counts in patients with steroid-refractory disease and can be combined with corticosteroids. As the rate of platelet count recovery is hastened in comparison with either treatment alone, combination therapy can be used to acutely raise platelet counts in medical emergencies or before surgery. However, the relapse rate is significant. Anti-Rh(D) is used in patients who are Rh positive with no preceding evidence of a Coombs test–mediated hemolysis and no prior splenectomy. Response rates can be as high as 70%.
3. Immunosuppressive agents can be used for patients with ITP, including those associated with SLE or other connective tissue disorders, after the failure of steroids or IVIG. The most commonly used agents include cyclophosphamide, azathioprine, mycophenolate mofetil, sirolimus, vincristine, or vinblastine.
4. Rituximab, a monoclonal antibody directed against a B-cell antigen (CD20), has demonstrated responses in approximately 50% of patients with refractory ITP, with some responses lasting more than 5 years.
5. Thrombopoietin receptor agonists. Both agents stimulate megakaryocyte production by binding and activating the thrombopoietin (TPO) receptor.
a. Eltrombopag: Approved for the treatment of ITP, chronic hepatitis C–associated thrombocytopenia, and severe aplastic anemia.
b. Romiplostim: Approved for the treatment of relapsed or refractory ITP, chronic hepatitis C–related thrombocytopenia, and severe aplastic anemia not responding to immunosuppressive therapy.
6. Zidovudine may be useful in patients with HIV-associated ITP. The key is to institute highly active antiretroviral therapy, and ITP typically improves as the viral load is reduced.
iii. Splenectomy is second-line therapy for ITP, reserved for patients in whom steroid therapy fails or for those who experience relapse after a steroid taper. Although predicting which patients might benefit from splenectomy is not well-established, it appears that the highest response rates are seen in younger patients and patients responsive to IVIG. Immunizations for Streptococcus pneumoniae, Haemophilus influenza type b, and Neisseria meningitides are required before splenectomy.
Suggested Further Readings
Aster RH, Curtis BR, McFarland JG, Bougie DW. Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management. J Thromb Haemost 2009;7:911–8.Find this resource:
Cuker A, Neunert CE. How I treat refractory immune thrombocytopenia. Blood 2016;128:1547.Find this resource:
Grace RF, Neunert C. Second-line therapies in immune thrombocytopenia. ASH Education Program Book 2016;2016:698–706.Find this resource:
Greinacher A. Heparin-induced thrombocytopenia. N Engl J Med 2015;373:252–61.Find this resource: