ABSTRACT: A scheme-based approach, supported by a simple mnemonic, can narrow the broad differential diagnosis of thrombocytopenia. This approach uses findings from the complete blood cell count and the peripheral smear to organize the possible causes of thrombocytopenia into those that affect only platelet count, those that produce both a low platelet count and hemolytic anemia, and those that produce disturbances in all 3 blood cell lines. Causes of isolated thrombocytopenia include viral infections, immune-mediated platelet destruction, congenital diseases, gestational thrombocytopenia, conditions in which splenomegaly is a prominent feature, antiphospholipid antibody syndrome, infectious diseases of bacterial origin, and drugs. Causes of thrombocytopenia in conjunction with hemolytic anemia include hemolytic uremic syndrome, thrombotic thrombocytopenia purpura, and disseminated intravascular coagulation. Disorders that produce disturbances in all 3 blood cell lines include aplastic anemia, myeloproliferative syndromes, myelodysplasia (both primary and secondary), myelofibrosis, myelophthisis, and several other diseases in which splenomegaly is prominent.
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 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:
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.)
THROMBOCYTOPENIA ASSOCIATED WITH HEMOLYTIC ANEMIA
If thrombocytopenia is accompanied by hemolytic anemia, the underlying cause is one of the following:
Because thrombotic microangiopathies and DIC have similar presentations, we will discuss these together and then return to Evans syndrome. Patients with DIC or a thrombotic microangiopathy typically have severe thrombocytopenia, anemia of varying severity that results from mechanical hemolysis (as demonstrated by the presence of schistocytes on the peripheral smear), and renal insufficiency; patients with DIC and those with TTP usually have fever as well.
DIC, unlike TTP and HUS, is a consumptive coagulopathy. However, a battery of tests may be required to establish consumption, since neither the international normalized ratio nor the PTT is particularly sensitive in this regard (see Case 3, page 119).
DIC, like splenomegaly, always results from another significant pathology. Hence, whenever DIC is diagnosed as the cause of thrombocytopenia, it is imperative to search for the primary cause. This might be a bacterial infection with sepsis, cancer, or another serious illness.
Two other thrombocytopenic-hemolytic syndromes that are similar in many ways to TTP, HUS, and DIC are seen only in pregnant women. These are the thrombocytopenia of severe preeclampsia/eclampsia and that of the HELLP syndrome. Both syndromes occur primarily in the third trimester.
Evans syndrome is an autoimmune-mediated decrease in the number of both platelets and red blood cells (a Coombs-positive, warm antibody hemolytic anemia with thrombocytopenia). It usually is the result of systemic lupus erythematosus (SLE) or another stimulus to the production of warm antibodies directed at red cells, such as chronic lymphocytic leukemia or lymphoma.
Occasionally, patients who have SLE make antibodies that target white blood cells in addition to platelets and red blood cells. These patients present with pancytopenia. In such cases, the diagnosis can be made based on clinical and laboratory signs of SLE, Coombs positivity, leukopenia, thrombocytopenia, and the presence of spherocytes on the peripheral smear.
The peripheral smear is often helpful in the identification of Evans syndrome. Red blood cells that are partially destroyed as a result of warm reacting antibodies become spherocytes, not schistocytes. The partial phagocytosis of portions of the antibody-covered red cell membrane decreases the surface area of these cells. Consequently, they morph from their typical dumbbell shape into that of a sphere. Thus, evidence of spherocytes on the peripheral smear is a clue to this diagnosis.
The mean cell hemoglobin concentration (MCHC) can be another clue. Because spherocytes contain the same amount of hemoglobin as normal red cells but have less surface area, the MCHC is often elevated in patients with Evans syndrome.
THROMBOCYTOPENIA ASSOCIATED WITH DISTURBANCES OF BOTH RED AND WHITE BLOOD CELL LINES
A number of conditions can produce thrombocytopenia along with disturbances in both red and white blood cell lines (either pancytopenia or thrombocytopenia with anemia and leukocytosis [the latter often accompanied by abnormal white blood cells]). These include:
In the majority of instances in which splenomegaly accompanies a 3-cell line disturbance, 1 of the last 3 entities in this part of the mnemonic (myelodysplasia, myeloproliferative syndromes, myelofibrosis, or myelophthisis) is the underlying cause. However, there are a few diseases not otherwise covered by the mnemonic in which splenomegaly accompanies disturbances in all 3 blood cell lines. One of these is leishmaniasis; massive splenomegaly and pancytopenia are typical findings.
Aplastic anemia is characterized by pancytopenia. The size of the spleen in affected patients is usually normal.
Myelodysplasia can cause pancytopenia or thrombocytopenia with anemia and leukocytosis3; the condition may be secondary or primary. Secondary myelodysplasia can result from any process or deficiency that interferes with cellular maturation in the marrow (eg, vitamin B12 deficiency). Distinctive features of the CBC count and peripheral smear assist with the diagnosis. In secondary myelodysplasia, the red blood cells are macrocytic (mean corpuscular volume is increased).
If thrombocytopenia is associated with anemia and leukocytosis, the appearance of the white blood cells is key to identification of the specific underlying disease process (see Case 4, page 120). For example, hypersegmented neutrophils are typical of vitamin B12 deficiency, while the presence of blast cells signals leukemia. Interpretation of the peripheral smear can be supplemented by the use of specialized stains and "cluster differentiation" analysis, which can identify the exact source of the abnormal myeloproliferation.
Red blood cell morphology is similar in both myelofibrosis and myelophthisis. Peripheral smears in these 2 diseases show nucleated and "teardrop" red cells because both fibrosis and infiltration of the bone marrow (by either tumor or infection) push red cell precursors into the circulation prematurely and in so doing "pinch" the shape of the cells. Because splenomegaly, disturbances in all 3 blood cell lines, and similar peripheral smear abnormalities are seen in both myelofibrosis and myelophthisis, a bone marrow examination may be necessary to distinguish between the 2 entities. This can establish definitively whether the marrow involvement is primary (myelofibrosis) or secondary to cancer or infection (myelophthisis).
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