Identifying the cause of thrombocytopenia is crucial because the patient's life may depend on prompt treatment. For example, thrombocytopenia that results from a reaction to quinine requires discontinuation of the drug and symptomatic treatment of bleeding.1 A decreased platelet count can also be a secondary manifestation of serious disease, such as disseminated intravascular coagulation (DIC), hemolytic uremic syndrome (HUS), or leukemia.
The differential diagnosis of thrombocytopenia is extensive and often daunting. As an alternative to sifting through a long list of potential causes, we present here a simplified approach that aorganizes diagnoses into categories and thus narrows the differential. Accompanying cases (see page 114 of this issue) illustrate how this approach can be applied in various clinical settings.
THREE CATEGORIES OF THROMBOCYTOPENIA
Scheme-based problem solving organizes possible diagnoses into categories based on relevant associated data. For example, a scheme-based approach is sometimes used in the differential diagnosis of hypokalemia, which, like thrombocytopenia, has many possible causes.2 The causes of low potassium levels can be grouped by the associated acid-base status. Thus, if potassium depletion is accompanied by normal- anion gap acidemia, the possible causes are limited to renal or gut- related (diarrheal) potassium and bicarbonate wasting.
The differential diagnosis of thrombocytopenia can be condensed into 3 shorter lists based on the status of the other blood cell lines (red and white cells). A low platelet count can be part of any of 3 possible scenarios:
- The decreased number of platelets is an isolated phenomenon.
- Thrombocytopenia is part of a pathologic process that also causes hemolytic destruction (mechanical or immune) of red cells; white cells are unaffected.
- Thrombocytopenia is a manifestation of a single disease process that affects all 3 blood cell lines in some way.
The possibilities included in these 3 categories can be summarized by the mnemonic "VIC G. SAID to TED and SAMMM" (Table). "VIC G. SAID" represents the possible causes of thrombocytopenia as an isolated phenomenon or accompanied by a disease-specific leukocytosis or lymphocytosis (such as that associated with a viral or bacterial infection) but without any changes in the red cell line. "TED" represents the causes of thrombocytopenia associated with hemolytic anemia, and "SAMMM" represents the disease processes that affect all 3 blood cell lines—red and white cells as well as platelets.
A caveat: when using this mnemonic, you need to determine whether disturbances in the red or white blood cell lines that accompany thrombocytopenia are manifestations of the same primary process that caused the decrease in platelet count. For help in discerning whether a disturbance in the red or white blood cell line is related to a patient's thrombocytopenia, see the Box.
The severity of the decrease in platelet number—mild (100,000 to 150,000/µL), moderate (50,000 to 100,000/µL), or severe (less than 50,000/µL)—and the morphologic appearance of red and white cells can help narrow the differential still further. In fact, all data necessary to arrive at a diagnosis are available from the history, physical examination, complete blood cell (CBC) count, and peripheral smear.
THROMBOCYTOPENIA AS AN ISOLATED ABNORMALITY
The differential diagnosis of thrombocytopenia as an isolated abnormality (that is, unaccompanied by hemolytic anemia or bone marrow pathology affecting all 3 cell lines) includes:
- Viral infections.
- Immune-mediated platelet destruction.
- Congenital diseases.
- Gestational thrombocytopenia.
- Antiphospholipid antibody syndrome.
- Infectious diseases of bacterial origin.
Any one of a spectrum of viral infections—including rubella, influenza, and infectious mononucleosis—can cause a drop in platelet count. The decrease usually results from an immune mechanism brought on by the infection.
However, platelet destruction that is immune-mediated also occurs independently of infection. Immune-mediated thrombocytopenia is common. One of the most frequently seen types is idiopathic thrombocytopenic purpura (ITP) (see Case 1 on page 114). In addition, antibodies to platelet surface antigens triggered by a blood transfusion can develop—primarily in multiparous women; this phenomenon is known as post-transfusion purpura. Vasculitis can also produce a decrease in platelet count via an autoimmune mechanism. HIV-induced thrombocytopenia results from an autoimmune mechanism; it can be classed with either immune-mediated causes or viral causes of platelet destruction. Immune-mediated thrombocytopenias can cause severe reductions in platelet count.
Rare congenital diseases, such as thrombocytopenia with absent radii (TWAR) and the May-Hegglin anomaly, are associated with lowered platelet counts.
Gestational thrombocytopenia is one of a number of conditions seen in pregnancy that are characterized by lowered platelet counts. Others include ITP, the HELLP (Hemolysis, Elevated Liver enzyme levels and Low Platelet count) syndrome, and preeclampsia/eclampsia. Of these, only ITP and gestational thrombocytopenia are not associated with changes in the other blood cell lines. The two can be difficult to distinguish; however, the reductions in platelet count seen in gestational thrombocytopenia are typically mild, whereas those seen in ITP that develops during pregnancy tend to be more severe. For a more detailed discussion of the differences between gestational thrombocytopenia and ITP that develops during pregnancy, see Case 1 (page 114).
Splenomegaly can cause a decrease in platelet count, either with or without decreases in the other parameters of the CBC. (Splenomegaly that produces changes in the other blood cell lines along with thrombocytopenia is discussed below.) Splenomegaly causes mild or moderate reductions in platelet count rather than severe thrombocytopenia.
The cause of splenomegaly must be determined. It may be associated with a viral infection, such as infectious mononucleosis, or it may be a clue to other conditions, such as cirrhosis or portal hypertension.
Antiphospholipid antibody syndromes can produce thrombophilia, prolonged partial thromboplastin time (PTT), and thrombocytopenia in some patients.
Infectious diseases that are associated with a reduction in platelet count range from rickettsial infections to more common bacterial illnesses, such as Gram-negative bacteremia. Infection can cause mild as well as moderate to severe thrombocytopenia.
Finally, thrombocytopenia is a prominent potential adverse effect of a number of drugs and medications. In fact, so many drugs are associated with thrombocytopenia that it is prudent to do a quick computer search whenever a patient presents with a lowered platelet count to determine whether any medication he or she is taking should be stopped. In drug-related thrombocytopenia, there is significant variation in both the mechanism of platelet destruction and the resultant degree of reduction in platelet count. For example, in susceptible persons, quinine can cause severe, life-threatening thrombocytopenia, whereas a heparin-induced low platelet count seldom falls below 50,000/µL(see Case 2, page 115). (Because heparin-induced thrombocytopenia lowers the platelet count through an immune mechanism, it can be grouped with immune-mediated causes as well as with drug-related causes.)
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