Thrombocytopenia

1. 
   

   Does the patient have true thrombocytopenia or pseudothrombocytopenia?

   
   
2. 
   

   What is the timing of onset, progression, and severity of the thrombocytopenia?

   
   
3. 
   

   Is the thrombocytopenia isolated, or is there concomitant anemia, leukopenia, or both?

   
   
4. 
   

   What are the findings of the peripheral blood film?

   
   
5. 
   

   What tests and studies are useful to evaluate each etiology?

   
   
6. 
   

   What is the frequency of specific causes of thrombocytopenia in defined clinical circumstances?

   
   
7. 
   

   Is the thrombocytopenia a marker of bleeding risk, thrombosis risk, or adverse prognosis?

   
   
8. 
   

   What treatments are available for each etiology?

Thrombocytosis

1. 
   

   Is the thrombocytosis newly acquired during the hospitalization?

   
   
2. 
   

   Is there concomitant splenomegaly and/or abnormalities in hemoglobin or white blood cell levels?

   
   
3. 
   

   Does the thrombocytosis predate the hospitalization?

   
   
4. 
   

   Is the red cell size (mean corpuscular volume) increased or decreased?

Introduction

The normal platelet count range is approximately 150 to 400 × 109/L (150,000 to 400,000 per mm3). An individual’s platelet count usually remains relatively constant during life. The platelet count decreases normally during pregnancy (gestational thrombocytopenia). The platelet count increases to above the usual value following an acute self-limited thrombocytopenia (eg, postsurgery thrombocytosis).

Many clinicians equate thrombocytopenia with increased bleeding risk. Indeed, severe immune-mediated thrombocytopenia does pose increased bleeding risk. But certain other thrombocytopenic disorders are associated with greatly increased risk of thrombosis (eg, heparin-induced thrombocytopenia [HIT], antiphospholipid syndrome, cancer-associated hypercoagulability), or increased mortality (thrombocytopenia complicating septicemia or multi-organ system dysfunction).

The various explanations for thrombocytopenia differ depending on the clinical setting. For patients who present to the emergency room with acute, severe thrombocytopenia, certain life-threatening disorders must be considered, such as thrombotic thrombocytopenia purpura (TTP), drug-induced immune thrombocytopenic purpura (D-ITP), and acute leukemia. In postoperative patients, the timing of onset of thrombocytopenia is important since early thrombocytopenia is usually due to postoperative hemodilution, whereas later-onset thrombocytopenia suggests heparin-induced thrombocytopenia, septicemia, or other postoperative complications. Thrombocytopenia in the intensive care unit is often due to poorly defined platelet consumption complicating multiorgan system dysfunction.

The hospitalist may be the first physician called upon to evaluate a thrombocytopenic patient, especially when the platelet count decline begins during hospitalization. The hospitalist needs to appreciate the circumstances when referral to a hematologist is appropriate.

Physical Examination

The physical examination should focus on the presence of signs of bleeding (petechiae, purpura), fever, or chills (infection, anaphylactoid reaction secondary to acute HIT), the presence of invasive catheters and the integrity of the surrounding skin (source of infection), ventilator status (risk for pneumonia, indicator of multiorgan system failure), hemodynamic status (shock with risk of multiorgan failure–associated thrombocytopenia and disseminated intravascular coagulation [DIC]), pulses and distal limb ischemia (HIT-associated arterial or venous thrombosis), lymphadenopathy (lymphoproliferative disorders), hepatosplenomegaly (hypersplenism), and miscellaneous skin lesions (necrotizing skin lesions at heparin injection sites). Note that acral (distal extremity) tissue ischemic necrosis—despite palpable or Doppler-identifiable pulses—is a hallmark of disturbed procoagulant-anticoagulant balance that underlies several hematologic disorders such as overt (decompensated) DIC and HIT-associated venous limb gangrene (usually caused by warfarin).

The hallmark of severe thrombocytopenia is mucocutaneous bleeding, particularly pinpoint intradermal hemorrhages known as petechiae. These are nonpalpable, nonblanching, and indicate bleeding from capillaries. Petechiae are most evident in dependent areas (eg, the legs and feet in outpatients and the back and posterior thighs in bedridden patients) because of the effects of hydrostatic pressure. Generalized “oozing” from mucosal sites (eg, nose and genitourinary and gastrointestinal tracts) can be seen in severe thrombocytopenia. A classic finding is “blood blisters” (hemorrhagic vesicles of the oral mucosa or tongue) when the platelet count is less than 10 × 109/L in the setting of autoimmune, alloimmune, or drug-induced immune thrombocytopenia. Ecchymosis denotes intradermal hemorrhage greater than 2 mm (ie, larger than petechiae); however, ecchymoses are less specific than petechiae for thrombocytopenic bleeding.

Pathophysiology

Table 175-1 lists the five general mechanisms of thrombocytopenia, plus a sixth category of spurious thrombocytopenia (“pseudothrombocytopenia”).

Pseudothrombocytopenia

A key question when evaluating a patient for thrombocytopenia is, Does the patient have true thrombocytopenia or pseudothrombocytopenia? Platelet clumping that occurs ex vivo (ie, only after the blood has been drawn into an anticoagulant) can be caused by naturally occurring antibodies that bind to platelets, resulting in platelet agglutination, but only in the presence of anticoagulant. This is most often seen when blood is collected into the purple tube (containing ethylenediaminetetraacetic acid [EDTA]) for determination of the complete blood count (CBC) (ie, EDTA-induced pseudothrombocytopenia). The thrombocytopenia is spurious because the electronic particle counter fails to detect the clumped platelets. Examination of the blood film reveals platelet clumping. Usually, platelet clumping does not occur, or is less marked, when blood is collected into another anticoagulant (eg, citrate, heparin). Pseudothrombocytopenia is clinically insignificant except when inappropriate treatment results from a wrong diagnosis of thrombocytopenia.

Hemodilution

A decline of 20% to 70% occurs universally in patients following major surgery, a phenomenon that is most dramatic in post–cardiac surgery patients. The platelet count nadir usually occurs between postoperative days 1 and 4 (median, day 2), with a subsequent rise in the platelet count that peaks at approximately day 14, at levels that are usually two to three times the patient’s preoperative baseline (postthrombocytopenia thrombocytosis). The platelet count decline is roughly proportional to the amount of crystalloid, colloid, or blood products administered, plus some component of platelet consumption. Dilutional coagulopathy generally accompanies the thrombocytopenia, accounting for the minor increases in prothrombin time (PT) and activated partial thromboplastin time (APTT) that are commonly seen immediately after surgery. Hemodilution occurs universally after major surgery and represents the most common explanation for thrombocytopenia in the early postoperative period.

The diagnosis of dilutional thrombocytopenia is a good example of considering the key question, What is the timing of onset, progression, and severity of the thrombocytopenia? Here, the timing is abrupt in onset (directly follows surgery), the thrombocytopenia progresses to its usual nadir at approximately day 2 (range, days 1 to 4), and is mild to moderate in severity depending on the nature of the surgery and the amount of fluids and blood products administered. In the case of cardiac surgery utilizing extracorporeal circulation (cardiopulmonary bypass), the maximum decline in platelet count averages 50%, but can be as high as 70%. Furthermore, the natural history of dilutional thrombocytopenia is for the platelet count—after attaining its nadir—to progressively increase to peak levels at approximately day 14 that are considerably greater than the preoperative baseline.

Hypersplenism

When approaching the diagnosis of hypersplenism, consider the following question: Is the thrombocytopenia isolated, or is there concomitant anemia and/or leukopenia? Whereas isolated thrombocytopenia usually indicates consumption or destruction of platelets (eg, DIC or immune thrombocytopenia) or hereditary thrombocytopenia (eg, MYH9-associated thrombocytopenia), thrombocytopenia associated with anemia and leukopenia can indicate hemodilution (discussed previously), hypersplenism, or marrow failure (eg, leukemia, marrow infiltration by metastatic cancer), or the combination of anemia and thrombocytopenia (eg, a disorder such as TTP).

Normally, about one-third of the circulating platelets are exchangeably sequestered within the spleen. Increased spleen size leads to greater splenic pooling (as high as 70–90%) and, thus, thrombocytopenia (“hypersplenism”). Two factors determine the extent of splenic pooling: splenic blood flow and splenic transit time. The most important determinant of splenic blood flow is spleen size, and the most important determinant of splenic transit time is splenic perfusion (spleen blood flow/spleen volume). However, since disorders that alter splenic transit time (eg, congestive heart failure, rheumatologic disorders) usually have counterbalancing effects on splenic blood flow, in practical terms, spleen size itself correlates well with the degree of splenic platelet pooling. Hence, radiologic imaging of spleen size can assess whether thrombocytopenia is caused by hypersplenism. A more recent concept is that reduced hepatic production of thrombopoietin (TPO) also contributes to thrombocytopenia of hypersplenism, in the setting of severe liver disease.

Decreased Platelet Production

Decreased platelet production can be caused by congenital or acquired bone marrow disorders, often manifesting as pancytopenia. However, isolated thrombocytopenia is seen in the MYH9-associated thrombocytopenias. Suspicion of decreased marrow production is often based on the answer to the question, What are the findings of the peripheral blood film? The blood film often points to a diagnosis of a primary bone marrow disorder, eg, primitive cells such as leukoblasts (acute leukemia) or abnormal lymphoid cells (neoplastic lymphoproliferative disorders), dysplastic white cells (myelodysplasia), tear drop red cells (infiltrative marrow disorders such as carcinoma metastatic to the bone marrow, myeloproliferative neoplasms with increased marrow fibrosis), and large red and white cells (megaloblastic anemia of vitamin B12 deficiency). The presence of very large platelets, together with neutrophil inclusions, is suggestive of MYH9-associated thrombocytopenia. Table 175-2 lists some of the findings of the peripheral blood film in patients with decreased platelet production, as well as some other disorders.

Demographics trends, particularly increasing numbers of elderly patients, suggest that clonal marrow disorders such as myelodysplasia (“preleukemia”) and chronic lymphoid leukemia will become more common. These are often “incidental” findings when patients are admitted for nonhematologic problems, and a routine CBC can lead to detection of thrombocytopenia.

Platelet Consumption

Pathological activation of the coagulation system, often termed disseminated intravascular coagulation (DIC) or consumptive coagulopathy, is usually accompanied by thrombocytopenia. Underlying problems can include shock, trauma/burns, septicemia, multiorgan system failure, malignancy, envenomations, severe hemolysis, certain complications of pregnancy (eg, placental abruption, retained products), and so forth. Sometimes, thrombocytopenia due to increased platelet consumption occurs even when the global coagulation assays (PT, PTT) are not markedly elevated; this can be seen in some infections or in multiorgan system failure, and might reflect nonthrombin-mediated mechanisms of accelerated physiologic platelet clearance.

A key question is, What tests and studies are useful in evaluating each etiology? Testing for DIC should include the global coagulation assays (PT, APTT) in addition to fibrinogen and one or more markers of fibrin formation, such as the fibrin d-dimer, fibrin(ogen) degradation products (FDPs), fibrin monomer, and the protamine sulfate paracoagulation test (the last test is infrequently performed nowadays). Blood cultures should be done because bacteremia is a common explanation for consumptive thrombocytopenia (with or without laboratory evidence for DIC) in hospitalized patients; when a consumptive thrombocytopenia occurs in a patient who has received antibiotics for a prolonged period, fungemia becomes an increasingly plausible explanation for a consumptive thrombocytopenia. Table 175-3 lists some of the laboratory tests that can be helpful in evaluating thrombocytopenia.

Platelet Destruction

The term platelet destruction (or destructive thrombocytopenia) refers to disorders in which pathologic factors destroy platelets in a nonphysiologic manner, most often as a direct or indirect result of antibodies. Table 175-4 lists different antibody-mediated thrombocytopenic disorders. Heparin-induced thrombocytopenia (HIT) overlaps the differing concepts of destructive and consumptive thrombocytopenia: it arises from pathologic platelet-activating antibodies (destructive thrombocytopenia) and, in its severe form, can also feature overt DIC (consumptive thrombocytopenia).