Thrombocytopenia Caused by Hypersplenism, Platelet Destruction, or Surgery/Hemodilution

History and Physical Examination

Certain information should be ascertained, including (1) the location and severity of bleeding (if any); (2) the temporal profile of the hemostatic defect (acute, chronic, or relapsing), particularly the temporal relationship with potential proximate triggers (e.g., new drugs, recent infection); (3) the presence of symptoms of a secondary illness, such as a neoplasm, infection, or an autoimmune disorder such as systemic lupus erythematosus (SLE); (4) history of recent medication use, alcohol ingestion, or transfusion; (5) presence of risk factors for certain infections, particularly human immunodeficiency virus (HIV) infection or viral hepatitis; and (6) family history of thrombocytopenia.

As part of the physical examination, evidence of hemostatic impairment should be sought, as well as secondary causes of thrombocytopenia. The signs of platelet-related bleeding include petechiae and purpura. Petechiae typically occur in the dependent regions of the body or on traumatized areas. Spontaneous mucous membrane bleeding (wet purpura), epistaxis, hematuria, and gastrointestinal bleeding indicate a more serious hemostatic defect. Although petechiae are common in patients whose platelet counts are less than 10 to 20 × 10 ⁹ /L, most patients with platelet counts over 50 × 10 ⁹ /L have no signs of hemostatic impairment. The physical examination may provide an explanation for the thrombocytopenia. For example, enlarged lymph nodes may indicate a viral infection, such as infectious mononucleosis or HIV infection, or a neoplastic process. An enlarged spleen raises the possibility of hypersplenism.

Timing of Onset and Severity of Thrombocytopenia

Many thrombocytopenic disorders, particularly those involving an immune pathogenesis, exhibit characteristic temporal features that can aid in the diagnosis. For example, if the platelet count begins to fall 5 to 10 days (median, 6 to 7 days) after starting a new drug or after a blood transfusion and reaches a nadir of less than 20 × 10 ⁹ /L a few days later, the diagnosis of drug-induced immune thrombocytopenia (D-ITP) or posttransfusion purpura (PTP), respectively, should be considered ( Fig. 130.2 ). Patients with these disorders typically have mucocutaneous bleeding and are at risk for fatal intracranial hemorrhage.

A similar temporal profile is also characteristic of typical-onset HIT (see Chapter 130), although in that disorder the platelet count falls below 20 × 10 ⁹ /L in only 5% to 10% of affected patients (see Fig. 130.2 ); in approximately 80% to 90% of patients, the platelet count nadir ranges from 20 to 150 × 10 ⁹ /L; and in the remainder, the platelet count nadir never falls below 150 × 10 ⁹ /L despite a large reduction in the platelet count. When the platelet count falls abruptly after drug administration, the possibility of rapid-onset thrombocytopenia caused by preexisting drug-dependent antibodies should be considered, as is well described with HIT. Indeed, so-called rapid-onset HIT is the presenting feature of this adverse drug reaction in 25% to 30% of cases. Rapid-onset thrombocytopenia is also a feature of glycoprotein (GP) IIb/IIIa (αIIbβ3) antagonist-induced ITP (see Chapter 129 ).

Occasionally, thrombocytopenia worsens in the first few days after surgery; this can occur with multiorgan system failure (e.g., cardiogenic or septic shock, with lactic acidemia) (see Fig. 130.2 ). If the patient develops concomitant DIC and hypotension, there is a high risk for ischemic limb injury secondary to microvascular thrombosis (“symmetric peripheral gangrene”), especially if the patient has “shock liver” (acute ischemic hepatitis), which is a risk factor for severe depletion of protein C and antithrombin, important endogenous anticoagulants (see Chapter 125 ). Another potential contributory factor for severe natural anticoagulant depletion and risk for limb gangrene in susceptible patients is colloid transfusion (albumin, high-dose IVIG), which lacks coagulation factors including protein C and antithrombin. If the platelet count falls to very low levels and is accompanied by microangiopathic hemolysis, the possibility of postoperative thrombotic thrombocytopenic purpura (TTP) should be considered (see Chapter 132 ).

Rarely, abrupt thrombocytopenia, with or without complicating thrombosis, can occur in post-cardiac or vascular surgery patients following protamine administration (to reverse intraoperative heparin anticoagulation). This disorder is caused by platelet-activating anti-protamine (heparin) antibodies (“protamine [heparin]-induced thrombocytopenia”). Because these antibodies are transient, at-risk patients include those with recent exposure to both heparin and protamine, such as patients who previously underwent cardiac or vascular surgery (in the recent past) or who may have received preoperative unfractionated or low-molecular-weight heparin while at the same time receiving protamine-containing insulin products.

Mild to moderate platelet count decreases that occur soon after transfusion of blood products are common and can be explained by hemodilution; however, a marked platelet count fall after transfusion may be the result of passive alloimmune thrombocytopenia (PAT) or sepsis because of contaminated blood products (see Fig. 130.2 ).

Other characteristic temporal features of thrombocytopenia include postenterohemorrhagic Escherichia coli –associated hemolytic uremic syndrome (HUS); thrombocytopenia and microangiopathic hemolysis that begin approximately 1 week after a prodromal diarrheal illness; and fungemia-associated thrombocytopenia (onset, 1 to 3 weeks after complex illness involving indwelling catheters and broad-spectrum antibiotic use). In contrast, thrombocytopenia of insidious onset that progresses over several years suggests chronic liver disease, with evolution to portal hypertension and associated splenomegaly (e.g., cirrhosis secondary to alcohol or hepatitis C) or a slowly progressive BM disorder (e.g., myelodysplasia).

Laboratory Evaluation

Laboratory evaluation of patients with thrombocytopenia includes evaluation of the complete blood count (CBC), examination of the peripheral blood film, and obtaining relevant ancillary studies, which sometimes includes BM aspirate/biopsy.

The blood film is examined to exclude pseudothrombocytopenia, which is characterized by in vitro platelet clumping. This phenomenon, which is evident in approximately 1 in 1000 blood samples, is most often caused by naturally occurring GPIIb/IIIa-reactive autoantibodies that induce aggregation of platelets in the presence of the calcium-chelating anticoagulant ethylenediamine tetraacetic acid (EDTA). Because the platelet aggregates are not counted by the electronic particle counter, the automated platelet count appears falsely low. The correct platelet count usually can be determined by collecting the blood into sodium citrate or heparin or by performing the count on nonanticoagulated finger prick samples; maintaining the blood sample at 37°C often attenuates platelet clumping. EDTA-dependent pseudothrombocytopenia has no pathologic significance other than potentially placing a patient in jeopardy for inappropriate treatment for thrombocytopenia that does not exist. A much less common (1 in 10,000 blood samples) antibody-mediated pseudothrombocytopenic disorder is platelet satellitism, in which rosette-like clusters of platelets surround the neutrophils. This entity is produced by immunoglobulin G (IgG) antibodies that recognize EDTA-induced cryptic epitopes on both platelet GPIIb/IIIa and neutrophil FcγIII receptors.

BM examination can be helpful for platelet production assessment, particularly if megakaryocytes are reduced or abnormal in appearance. Examination of the BM can be diagnostic in some disorders (e.g., leukemia, metastatic tumor, Gaucher disease, megaloblastic anemia).

Besides the CBC, commonly performed blood tests to evaluate thrombocytopenia include: prothrombin time/international normalized ratio (PT/INR), partial thromboplastin time (PTT), fibrinogen, d-dimer (screening tests for DIC), serum enzyme levels such as lactic dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine phosphokinase (CPK) (evaluation of hemolysis, shock liver, muscle injury), blood cultures (bacteremia, fungemia). More specific assays appropriate in selected patients include testing for HIT or non-HIT drug-dependent platelet-reactive antibodies (e.g., using the monoclonal antibody immobilization of platelet antigens [MAIPA] test), platelet-reactive alloantibodies, antiphospholipid antibodies (non-specific inhibitor, anti-cardiolipin antibodies, anti-β ₂ -glycoprotein 1 antibodies), quantitative immunoglobulin determination and serum protein electrophoresis, viral serology (HIV, hepatitis C, etc.), tests for hemolysis (direct Coombs test, haptoglobin levels, etc.).

In exceptional circumstances, when the mechanism of chronic thrombocytopenia is unclear, an autologous platelet survival study using ¹¹¹ In-labeled platelets may be informative. Three patterns can be seen: (1) normal platelet survival and recovery (underproduction), (2) marked reduction in the platelet life span (increased destruction or consumption), and (3) reduced recovery but a normal or near-normal life span (sequestration). However, platelet survival studies are rarely performed.

Therapy

The risk of bleeding in patients with thrombocytopenia can be reduced by avoiding drugs that impair hemostasis (e.g., alcohol, antiplatelet agents, anticoagulants) and invasive procedures (e.g., intramuscular injections). If drug-induced thrombocytopenia is suspected, as many medications as possible, especially those started within the preceding 5 to 14 days, should be stopped. Life-threatening bleeding episodes should be treated with platelet transfusion regardless of the mechanism of the thrombocytopenia.

The underlying cause and anticipated natural history of the thrombocytopenic disorder influence the decision about prophylactic platelet transfusion. As a rule, patients with chronic thrombocytopenic disorders characterized by increased platelet destruction (e.g., chronic immune thrombocytopenia [ITP]) or chronic underproduction (e.g., aplastic anemia or myelodysplasia) can tolerate long periods of severe thrombocytopenia without major bleeding (see Chapter 113 ). In addition, prophylactic platelet transfusions can trigger alloimmunization against human leukocyte antigen (HLA) or platelet antigens, thereby jeopardizing future therapeutic platelet transfusions. Consequently, prophylactic platelet transfusions are seldom indicated for such patients except when they are at risk of bleeding because of trauma or major surgery. When platelets are given, the platelet count should be maintained above 50 × 10 ⁹ /L (>100×10 ⁹ /L, if possible, for central nervous system procedures). Invasive procedures such as thoracentesis, paracentesis, and liver biopsy are not usually associated with excess bleeding if the platelet count is greater than 50 × 10 ⁹ /L.

Prophylactic platelet transfusions should not be given to patients with strongly suspected or confirmed HIT, TTP, HUS, and, possibly, DIC, because they may exacerbate platelet-mediated thrombotic complications, and, particularly with HIT, mucocutaneous bleeding is uncommon. However, bleeding from severe thrombocytopenia, or other patient-specific considerations, may justify platelet transfusion even in these disorders.

The Spleen: Anatomy and Function

The spleen is a small, well-perfused organ that receives about 5% of the total cardiac output. In adults, the spleen weighs between 150 and 200 g and measures approximately 11 cm in length.

The anatomy of the spleen is uniquely suited for its function; progressive branching of the splenic artery into trabecular and central arteries helps separate the plasma from the cellular elements (see Chapter 156 ). The central arteries arise perpendicularly from the trabecular arteries and skim the plasma layer from the cells. Soluble antigens in the plasma are delivered to the white pulp, where phagocytic cells process them and antibody production is initiated.

A cell-rich, hemoconcentrated fraction of the blood is delivered to the red pulp. Some of this blood flows directly to the splenic veins (the closed system), but most moves into the splenic cords (the open system). Here, the cellular elements percolate through a meshwork of reticulum fibers, reticuloendothelial cells, and supporting cells to reach the splenic sinuses. The cells enter the sinuses by passing through narrow fenestrations in the basement membrane of the endothelial cells lining the sinuses. The blood exits through the splenic vein into the portal system. Because the veins in the portal system lack valves, any increase in portal pressure is transmitted to the splenic microcirculation.

The spleen plays many important roles. It is the largest lymphoid organ in the body and contributes to host defense by clearing microorganisms and antibody-coated cells. The spleen is also important for antibody synthesis, especially antibodies directed against soluble antigens. The filtering function of the spleen includes (1) culling (removal of damaged or senescent cells and bacteria), (2) pitting (removal of RBC inclusion bodies or parasites), and (3) remodeling (reticulocyte sequestration and maturation). The spleen also serves as a reservoir of platelets (accommodating about one-third of the platelet mass in normal individuals). By contrast, the human spleen contains less than 2% of the total RBC mass, although in some animals (dogs and cats), the spleen is a much more important RBC reservoir.

Physiologic Platelet Sequestration

Radiolabeled platelet studies have shown that approximately 30% of the total platelet mass exists as a freely exchangeable pool in the spleen. Because the normal platelet life span is 9 to 10 days, platelets spend approximately one-third of their lives, or 3 days, within the spleen. In patients with hypersplenism, up to 90% of the platelets can be found in the spleen.

After labeled platelets are injected, there is accumulation in both the liver and the spleen. An initial, irreversible phase of hepatic uptake occurs. This equilibrates during the first 5 minutes and may reflect hepatic clearance of platelets damaged during the labeling procedure. Simultaneously, there is a slow increase in activity over the spleen that peaks in about 20 minutes. Splenic platelet uptake depends on input (spleen blood flow) and output (clearance).

The splenic platelet pool size can decrease and the platelet count increase with intravenous infusions of epinephrine in normal persons and in patients with splenomegaly. By contrast, isoprenaline increases the splenic pool size. Splenic blood flow increases with increasing spleen size, although perfusion (flow per unit of tissue volume) falls. Blood flow can increase in some inflammatory disorders (e.g., SLE) without an increase in spleen size. A marked increase or decrease in splenic perfusion alters the proportion of platelets within the spleen.

Fig. 130.3 shows why approximately 30% of the platelets are normally present in the spleen. Because about 5% of cardiac output goes to the spleen and because the average splenic transit time (i.e., the time for the platelet to pass through the spleen) is approximately 10 minutes—compared with the usual average time of 1 minute for a platelet to make a complete circulatory pass—approximately one-third of the platelets are within the spleen (i.e., 5%×10 minutes/95%×1 minute, or a ratio of 50 : 95, or ≈1:2). With hypersplenism, the splenic blood flow can increase up to fivefold (i.e., from 5% to 25% of total blood flow). Thus, even without an increase in splenic transit time, 70% or more of the platelets can be reversibly sequestered within the spleen.

The most important determinant of the splenic platelet pool is the spleen size. The measurement of spleen size can thus be helpful in predicting the degree of thrombocytopenia expected from excess platelet pooling in the spleen. For example, if 90% of the platelet pool is in the spleen (i.e., 10% outside the spleen), the platelet count will be reduced by sevenfold because normally, 70% of platelets lie outside the spleen. Consequently and as a general rule, even if the spleen is massively enlarged, severe thrombocytopenia (<20 × 10 ⁹ /L) is unusual. On the other hand, mild thrombocytopenia may be explained by mild splenomegaly that may not be detectible on physical examination but can be seen with imaging studies.