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DISORDERS OF PLATELETS

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THROMBOCYTOPENIA

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Thrombocytopenia results from one or more of three processes: (1) decreased bone marrow production; (2) sequestration, usually in an enlarged spleen; and/or (3) increased platelet destruction. Disorders of production may be either inherited or acquired. In evaluating a patient with thrombocytopenia, a key step is to review the peripheral blood smear and to first rule out “pseudothrombocytopenia,” particularly in a patient without an apparent cause for the thrombocytopenia. Pseudothrombocytopenia (Fig. 140-1B) is an in vitro artifact resulting from platelet agglutination via antibodies (usually IgG, but also IgM and IgA) when the calcium content is decreased by blood collection in ethylenediamine tetraacetic (EDTA) (the anticoagulant present in tubes [purple top] used to collect blood for complete blood counts [CBCs]). If a low platelet count is obtained in EDTA-anticoagulated blood, a blood smear should be evaluated and a platelet count determined in blood collected into sodium citrate (blue top tube) or heparin (green top tube), or a smear of freshly obtained unanticoagulated blood, such as from a finger stick, can be examined.

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FIGURE 140-1

Photomicrographs of peripheral blood smears. A. Normal peripheral blood. B. Platelet clumping in pseudothrombocytopenia. C. Abnormal large platelet in autosomal dominant macrothrombocytopenia. D. Schistocytes and decreased platelets in microangiopathic hemolytic anemia.

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APPROACH TO PATIENT

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APPROACH TO THE PATIENT: Thrombocytopenia

The history and physical examination, results of the CBC, and review of the peripheral blood smear are all critical components in the initial evaluation of thrombocytopenic patients (Fig. 140-2). The overall health of the patient and whether he or she is receiving drug treatment will influence the differential diagnosis. A healthy young adult with thrombocytopenia will have a much more limited differential diagnosis than an ill hospitalized patient who is receiving multiple medications. Except in unusual inherited disorders, decreased platelet production usually results from bone marrow disorders that also affect red blood cell (RBC) and/or white blood cell (WBC) production. Because myelodysplasia can present with isolated thrombocytopenia, the bone marrow should be examined in patients presenting with isolated thrombocytopenia who are older than 60 years of age. While inherited thrombocytopenia is rare, any prior platelet counts should be retrieved and a family history regarding thrombocytopenia obtained. A careful history of drug ingestion should be obtained, including nonprescription and herbal remedies, because drugs are the most common cause of thrombocytopenia.

The physical examination can document an enlarged spleen, evidence of chronic liver disease, and other underlying disorders. Mild to moderate splenomegaly may be difficult to appreciate in many individuals due to body habitus and/or obesity but can be easily assessed by abdominal ultrasound. A platelet count of approximately 5000–10,000 is required to maintain vascular integrity in the microcirculation. When the count is markedly decreased, petechiae first appear in areas of increased venous pressure, the ankles and feet in an ambulatory patient. Petechiae are pinpoint, nonblanching hemorrhages and are usually a sign of a decreased platelet number and not platelet dysfunction. Wet purpura, blood blisters that form on the oral mucosa, are thought to denote an increased risk of life-threatening hemorrhage in the thrombocytopenic patient. Excessive bruising is seen in disorders of both platelet number and function.

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FIGURE 140-2

Algorithm for evaluating the thrombocytopenic patient. DIC, disseminated intravascular coagulation; RBC, red blood cell; TTP, thrombotic thrombocytopenic purpura.

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Infection-Induced Thrombocytopenia
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Many viral and bacterial infections result in thrombocytopenia and are the most common noniatrogenic cause of thrombocytopenia. This may or may not be associated with laboratory evidence of disseminated intravascular coagulation (DIC), which is most commonly seen in patients with systemic infections with gram-negative bacteria. Infections can affect both platelet production and platelet survival. In addition, immune mechanisms can be at work, as in infectious mononucleosis and early HIV infection. Late in HIV infection, pancytopenia and decreased and dysplastic platelet production are more common. Immune-mediated thrombocytopenia in children usually follows a viral infection and almost always resolves spontaneously. This association of infection with immune thrombocytopenic purpura is less clear in adults.

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Bone marrow examination is often requested for evaluation of occult infections. A study evaluating the role of bone marrow examination in fever of unknown origin in HIV-infected patients found that for 86% of patients, the same diagnosis was established by less invasive techniques, notably blood culture. In some instances, however, the diagnosis can be made earlier; thus, a bone marrow examination and culture are recommended when the diagnosis is needed urgently or when other, less invasive methods have been unsuccessful.

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Drug-Induced Thrombocytopenia
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Many drugs have been associated with thrombocytopenia. A predictable decrease in platelet count occurs after treatment with many chemotherapeutic drugs due to bone marrow suppression (Chap. 103e). Drugs that cause isolated thrombocytopenia and have been confirmed with positive laboratory testing are listed in Table 140-1, but all drugs should be suspect in a patient with thrombocytopenia without an apparent cause and should be stopped, or substituted, if possible. A helpful website, Platelets on the Internet (http://www.ouhsc.edu/platelets/ditp.html), lists drugs and supplements reported to have caused thrombocytopenia and the level of evidence supporting the association. Although not as well studied, herbal and over-the-counter preparations may also result in thrombocytopenia and should be discontinued in patients who are thrombocytopenic.

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Classic drug-dependent antibodies are antibodies that react with specific platelet surface antigens and result in thrombocytopenia only when the drug is present. Many drugs are capable of inducing these antibodies, but for some reason, they are more common with quinine and sulfonamides. Drug-dependent antibody binding can be demonstrated by laboratory assays, showing antibody binding in the presence of, but not without, the drug present in the assay. The thrombocytopenia typically occurs after a period of initial exposure (median length 21 days), or upon reexposure, and usually resolves in 7–10 days after drug withdrawal. The thrombocytopenia caused by the platelet Gp IIb/IIIa inhibitory drugs, such as abciximab, differs in that it may occur within 24 h of initial exposure. This appears to be due to the presence of naturally occurring antibodies that cross-react with the drug bound to the platelet.

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Heparin-Induced Thrombocytopenia
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Drug-induced thrombocytopenia due to heparin differs from that seen with other drugs in two major ways. (1) The thrombocytopenia is not usually severe, with nadir counts rarely <20,000/μL. (2) Heparin-induced thrombocytopenia (HIT) is not associated with bleeding and, in fact, markedly increases the risk of thrombosis. HIT results from antibody formation to a complex of the platelet-specific protein platelet factor 4 (PF4) and heparin. The anti-heparin/PF4 antibody can activate platelets through the FcγRIIa receptor and also activate monocytes and endothelial cells. Many patients exposed to heparin develop antibodies to heparin/PF4, but do not appear to have adverse consequences. A fraction of those who develop antibodies will develop HIT, and a portion of those (up to 50%) will develop thrombosis (HITT).

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TABLE 140-1Drugs Reported as Definitely or Probably Causing Isolated Thrombocytopeniaa
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HIT can occur after exposure to low-molecular-weight heparin (LMWH) as well as unfractionated heparin (UFH), although it is more common with the latter. Most patients develop HIT after exposure to heparin for 5–14 days (Fig. 140-3). It occurs before 5 days in those who were exposed to heparin in the prior few weeks or months (<~100 days) and have circulating anti-heparin/PF4 antibodies. Rarely, thrombocytopenia and thrombosis begin several days after all heparin has been stopped (termed delayed-onset HIT). The “4T’s” have been recommended to be used in a diagnostic algorithm for HIT: thrombocytopenia, timing of platelet count drop, thrombosis and other sequelae such as localized skin reactions, and other causes of thrombocytopenia not evident. Application of the 4T scoring system is very useful in excluding a diagnosis of HIT but will result in overdiagnosis of HIT in situations where thrombocytopenia and thrombosis due to other etiologies are common, such as in the intensive care unit. A scoring model based on broad expert opinion (the HIT Expert Probability [HEP] Score) has improved operating characteristics and may provide better utility as a scoring system.

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FIGURE 140-3

Time course of heparin-induced thrombocytopenia (HIT) development after heparin exposure. The timing of development after heparin exposure is a critical factor in determining the likelihood of HIT in a patient. HIT occurs early after heparin exposure in the presence of preexisting heparin/platelet factor 4 (PF4) antibodies, which disappear from circulation by ~100 days following a prior exposure. Rarely, HIT may occur later after heparin exposure (termed delayed-onset HIT). In this setting, heparin/PF4 antibody testing is usually markedly positive. HIT can occur after exposure to either unfractionated (UFH) or low-molecular-weight heparin (LMWH).

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LABORATORY TESTING FOR HIT
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HIT (anti-heparin/PF4) antibodies can be detected using two types of assays. The most widely available is an enzyme-linked immunoassay (ELISA) with PF4/polyanion complex as the antigen. Because many patients develop antibodies but do not develop clinical HIT, the test has a low specificity for the diagnosis of HIT. This is especially true in patients who have undergone cardiopulmonary bypass surgery, where approximately 50% of patients develop these antibodies postoperatively. IgG-specific ELISAs increase specificity but may decrease sensitivity. The other assay is a platelet activation assay, most commonly the serotonin release assay, which measures the ability of the patient’s serum to activate platelets in the presence of heparin in a concentration-dependent manner. This test has lower sensitivity but higher specificity than the ELISA. However, HIT remains a clinical diagnosis.

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TREATMENT
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TREATMENT Heparin-Induced Thrombocytopenia

Early recognition is key in treatment of HIT, with prompt discontinuation of heparin and use of alternative anticoagulants if bleeding risk does not outweigh thrombotic risk. Thrombosis is a common complication of HIT, even after heparin discontinuation, and can occur in both the venous and arterial systems. Patients with higher anti-heparin/PF4 antibody titers may have a higher risk of thrombosis. In patients diagnosed with HIT, imaging studies to evaluate the patient for thrombosis (at least lower extremity duplex Doppler imaging) are recommended. Patients requiring anticoagulation should be switched from heparin to an alternative anticoagulant. The direct thrombin inhibitors (DTIs) argatroban and lepirudin are effective in HITT. The DTI bivalirudin and the antithrombin-binding pentasaccharide fondaparinux are also effective but not yet approved by the U.S. Food and Drug Administration (FDA) for this indication. Danaparoid, a mixture of glycosaminoglycans with anti-Xa activity, has been used extensively for the treatment of HITT; it is no longer available in the United States but is in other countries. HIT antibodies cross-react with LMWH, and these preparations should not be used in the treatment of HIT.

Because of the high rate of thrombosis in patients with HIT, anticoagulation should be considered, even in the absence of thrombosis. In patients with thrombosis, patients can be transitioned to warfarin, with treatment usually for 3–6 months. In patients without thrombosis, the duration of anticoagulation needed is undefined. An increased risk of thrombosis is present for at least 1 month after diagnosis; however, most thromboses occur early, and whether thrombosis occurs later if the patient is initially anticoagulated is unknown. Options include continuing anticoagulation until a few days after platelet recovery or for 1 month. Introduction of warfarin alone in the setting of HIT or HITT may precipitate thrombosis, particularly venous gangrene, presumably due to clotting activation and severely reduced levels of proteins C and S. Warfarin therapy, if started, should be overlapped with a DTI or fondaparinux and started after resolution of the thrombocytopenia and lessening of the prothrombotic state.

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Immune Thrombocytopenic Purpura
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Immune thrombocytopenic purpura (ITP; also termed idiopathic thrombocytopenic purpura) is an acquired disorder in which there is immune-mediated destruction of platelets and possibly inhibition of platelet release from the megakaryocyte. In children, it is usually an acute disease, most commonly following an infection, and with a self-limited course. In adults, it is a more chronic disease, although in some adults, spontaneous remission occurs, usually within months of diagnosis. ITP is termed secondary if it is associated with an underlying disorder; autoimmune disorders, particularly systemic lupus erythematosus (SLE), and infections, such as HIV and hepatitis C, are common causes. The association of ITP with Helicobacter pylori infection is unclear.

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ITP is characterized by mucocutaneous bleeding and a low, often very low, platelet count, with an otherwise normal peripheral blood cells and smear. Patients usually present either with ecchymoses and petechiae, or with thrombocytopenia incidentally found on a routine CBC. Mucocutaneous bleeding, such as oral mucosa, gastrointestinal, or heavy menstrual bleeding, may be present. Rarely, life-threatening, including central nervous system, bleeding can occur. Wet purpura (blood blisters in the mouth) and retinal hemorrhages may herald life-threatening bleeding.

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LABORATORY TESTING IN ITP
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Laboratory testing for antibodies (serologic testing) is usually not helpful due to the low sensitivity and specificity of the current tests. Bone marrow examination can be reserved for those who have other signs or laboratory abnormalities not explained by ITP or in patients who do not respond to initial therapy. The peripheral blood smear may show large platelets, with otherwise normal morphology. Depending on the bleeding history, iron-deficiency anemia may be present.

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Laboratory testing is performed to evaluate for secondary causes of ITP and should include testing for HIV infection and hepatitis C (and other infections if indicated). Serologic testing for SLE, serum protein electrophoresis, immunoglobulin levels to potentially detect hypogammaglobulinemia, selective testing for IgA deficiency or monoclonal gammopathies, and testing for H. pylori infection should be considered, depending on the clinical circumstance. If anemia is present, direct antiglobulin testing (Coombs’ test) should be performed to rule out combined autoimmune hemolytic anemia with ITP (Evans’ syndrome).

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TREATMENT
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TREATMENT Immune Thrombocytopenic Purpura

The treatment of ITP uses drugs that decrease reticuloendothelial uptake of the antibody-bound platelet, decrease antibody production, and/or increase platelet production. The diagnosis of ITP does not necessarily mean that treatment must be instituted. Patients with platelet counts >30,000/μL appear not to have increased mortality related to the thrombocytopenia.

Initial treatment in patients without significant bleeding symptoms, severe thrombocytopenia (<5000/μL), or signs of impending bleeding (such as retinal hemorrhage or large oral mucosal hemorrhages) can be instituted as an outpatient using single agents. Traditionally, this has been prednisone at 1 mg/kg, although Rh0(D) immune globulin therapy (WinRho SDF), at 50–75 μg/kg, is also being used in this setting. Rh0(D) immune globulin must be used only in Rh-positive patients because the mechanism of action is production of limited hemolysis, with antibody-coated cells “saturating” the Fc receptors, inhibiting Fc receptor function. Monitoring patients for 8 h after infusion is now advised by the FDA because of the rare complication of severe intravascular hemolysis. Intravenous gamma globulin (IVIgG), which is pooled, primarily IgG antibodies, also blocks the Fc receptor system, but appears to work primarily through different mechanism(s). IVIgG has more efficacy than anti-Rh0(D) in postsplenectomized patients. IVIgG is dosed at 1–2 g/kg total, given over 1–5 days. Side effects are usually related to the volume of infusion and infrequently include aseptic meningitis and renal failure. All immunoglobulin preparations are derived from human plasma and undergo treatment for viral inactivation.

For patients with severe ITP and/or symptoms of bleeding, hospital admission and combined-modality therapy is given using high-dose glucocorticoids with IVIgG or anti-Rh0(D) therapy and, as needed, additional immunosuppressive agents. Rituximab, an anti-CD20 (B cell) antibody, has shown efficacy in the treatment of refractory ITP, although long-lasting remission only occurs in approximately 30% of patients.

Splenectomy has been used for treatment of patients who relapse after glucocorticoids are tapered. Splenectomy remains an important treatment option; however, more patients than previously thought will go into a remission over time. Observation, if the platelet count is high enough, or intermittent treatment with anti-Rh0(D) or IVIgG, or initiation of treatment with a TPO receptor agonist (see below) may be a reasonable approach to see if the ITP will resolve. Vaccination against encapsulated organisms (especially pneumococcus, but also meningococcus and Haemophilus influenzae, depending on patient age and potential exposure) is recommended before splenectomy. Accessory spleen(s) are a very rare cause of relapse.

TPO receptor agonists are now available for the treatment of ITP. This approach stems from the finding that many patients with ITP do not have increased TPO levels, as was previously hypothesized. TPO levels reflect megakaryocyte mass, which is usually normal in ITP. TPO levels are not increased in the setting of platelet destruction. Two agents, one administered subcutaneously (romiplostim) and another orally (eltrombopag), are effective in raising platelet counts in patients with ITP and are recommended for adults at risk of bleeding who relapse after splenectomy or who have been unresponsive to at least one other therapy, particularly in those who have a contraindication to splenectomy. However, with the recognition that ITP will resolve spontaneously in some adult patients, short-term treatment with a TPO agonist can be considered before splenectomy in patients who need therapy.

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Inherited Thrombocytopenia
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Thrombocytopenia is rarely inherited, either as an isolated finding or as part of a syndrome, and may be inherited in an autosomal dominant, autosomal recessive, or X-linked pattern. Many forms of autosomal dominant thrombocytopenia are now known to be associated with mutations in the nonmuscle myosin heavy chain MYH9 gene. Interestingly, these include the May-Hegglin anomaly, and Sebastian, Epstein’s, and Fechtner syndromes, all of which have distinct distinguishing features. A common feature of these disorders is large platelets (Fig. 140-1C). Autosomal recessive disorders include congenital amegakaryocytic thrombocytopenia, thrombocytopenia with absent radii, and Bernard-Soulier syndrome. The latter is primarily a functional platelet disorder due to absence of Gp Ib-IX-V, the VWF adhesion receptor. X-linked disorders include Wiskott-Aldrich syndrome and a dyshematopoietic syndrome resulting from a mutation in GATA-1, an important transcriptional regulator of hematopoiesis.

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THROMBOTIC THROMBOCYTOPENIC PURPURA AND HEMOLYTIC-UREMIC SYNDROME

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Thrombotic thrombocytopenic microangiopathies are a group of disorders characterized by thrombocytopenia, a microangiopathic hemolytic anemia evident by fragmented RBCs (Fig. 140-1D) and laboratory evidence of hemolysis, and microvascular thrombosis. They include thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS), as well as syndromes complicating bone marrow transplantation, certain medications and infections, pregnancy, and vasculitis. In DIC, although thrombocytopenia and microangiopathy are seen, a coagulopathy predominates, with consumption of clotting factors and fibrinogen resulting in an elevated prothrombin time (PT) and often activated partial thromboplastin time (aPTT). The PT and aPTT are characteristically normal in TTP or HUS.

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Thrombotic Thrombocytopenic Purpura
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TTP and HUS were previously considered overlap syndromes. However, in the past few years, the pathophysiology of inherited and idiopathic TTP has become better understood and clearly differs from HUS. TTP was first described in 1924 by Eli Moschcowitz and characterized by a pentad of findings that include microangiopathic hemolytic anemia, thrombocytopenia, renal failure, neurologic findings, and fever. The full-blown syndrome is less commonly seen now, probably due to earlier diagnosis. The introduction of treatment with plasma exchange markedly improved the prognosis in patients, with a decrease in mortality from 85–100% to 10–30%.

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The pathogenesis of inherited (Upshaw-Schulman syndrome) and idiopathic TTP is related to a deficiency of, or antibodies to, the metalloprotease ADAMTS13, which cleaves VWF. VWF is normally secreted as ultra-large multimers, which are then cleaved by ADAMTS13. The persistence of ultra-large VWF molecules is thought to contribute to pathogenic platelet adhesion and aggregation (Fig. 140-4). This defect alone, however, is not sufficient to result in TTP because individuals with a congenital absence of ADAMTS13 develop TTP only episodically. Additional provocative factors have not been defined. The level of ADAMTS13 activity, as well as antibodies, can now be detected by laboratory assays. Although assays with sufficient sensitivity and specificity to direct clinical management have yet to be clearly defined, ADAMTS13 activity levels of <10% are more clearly associated with idiopathic TTP.

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FIGURE 140-4

Pathogenesis of thrombotic thrombocytopenic purpura (TTP). Normally the ultra-high-molecular-weight multimers of von Willebrand factor (VWF) produced by the endothelial cells are processed into smaller multimers by a plasma metalloproteinase called ADAMTS13. In TTP, the activity of the protease is inhibited, and the ultra-high-molecular-weight multimers of VWF initiate platelet aggregation and thrombosis.

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Idiopathic TTP appears to be more common in women than in men. No geographic or racial distribution has been defined. TTP is more common in patients with HIV infection and in pregnant women. TTP in pregnancy is not clearly related to ADAMTS13. Medication-related microangiopathic hemolytic anemia may be secondary to antibody formation (ticlopidine and possibly clopidogrel) or direct endothelial toxicity (cyclosporine, mitomycin C, tacrolimus, quinine), although this is not always so clear, and fear of withholding treatment, as well as lack of other treatment alternatives, results in broad application of plasma exchange. However, withdrawal, or reduction in dose, of endothelial toxic agents usually decreases the microangiopathy.

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TREATMENT
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TREATMENT Thrombotic Thrombocytopenic Purpura

TTP is a devastating disease if not diagnosed and treated promptly. In patients presenting with new thrombocytopenia, with or without evidence of renal insufficiency and other elements of classic TTP, laboratory data should be obtained to rule out DIC and to evaluate for evidence of microangiopathic hemolytic anemia. Findings to support the TTP diagnosis include an increased lactate dehydrogenase and indirect bilirubin, decreased haptoglobin, and increased reticulocyte count, with a negative direct antiglobulin test. The peripheral smear should be examined for evidence of schistocytes (Fig. 140-1D). Polychromasia is usually also present due to the increased number of young red blood cells, and nucleated RBCs are often present, which is thought to be due to infarction in the microcirculatory system of the bone marrow.

Plasma exchange remains the mainstay of treatment of TTP. ADAMTS13 antibody-mediated TTP (idiopathic TTP) appears to respond best to plasma exchange. Plasma exchange is continued until the platelet count is normal and signs of hemolysis are resolved for at least 2 days. Although never evaluated in clinical trials, the use of glucocorticoids seems a reasonable approach, but should only be used as an adjunct to plasma exchange. Additionally, other immunomodulatory therapies have been reported to be successful in refractory or relapsing TTP, including rituximab, vincristine, cyclophosphamide, and splenectomy. A significant relapse rate is noted; 25–45% of patients relapse within 30 days of initial “remission,” and 12–40% of patients have late relapses. Relapses are more frequent in patients with severe ADAMTS13 deficiency at presentation.

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Hemolytic-Uremic Syndrome
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HUS is a syndrome characterized by acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. It is seen predominantly in children and in most cases is preceded by an episode of diarrhea, often hemorrhagic in nature. Escherichia coli O157:H7 is the most frequent, although not only, etiologic serotype. HUS not associated with diarrhea is more heterogeneous in presentation and course. Atypical HUS (aHUS) due to genetic defects that result in chronic complement activation has been defined, and screening for mutations in complement regulatory genes is available.

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TREATMENT
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TREATMENT Hemolytic-Uremic Syndrome

Treatment of HUS is primarily supportive. In HUS associated with diarrhea, many (~40%) children require at least some period of support with dialysis; however, the overall mortality is <5%. In HUS not associated with diarrhea, the mortality is higher, approximately 26%. Plasma infusion or plasma exchange has not been shown to alter the overall course. ADAMTS13 levels are generally reported to be normal in HUS, although occasionally they have been reported to be decreased. In patients with atypical HUS, eculizumab therapy increases the platelet count and preserves renal function.

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THROMBOCYTOSIS

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Thrombocytosis is almost always due to (1) iron deficiency; (2) inflammation, cancer, or infection (reactive thrombocytosis); or (3) an underlying myeloproliferative process (essential thrombocythemia or polycythemia vera) (Chap. 131) or, rarely, the 5q– myelodysplastic process (Chap. 130). Patients presenting with an elevated platelet count should be evaluated for underlying inflammation or malignancy, and iron deficiency should be ruled out. Thrombocytosis in response to acute or chronic inflammation has not been clearly associated with an increased thrombotic risk. In fact, patients with markedly elevated platelet counts (>1.5 million), usually seen in the setting of a myeloproliferative disorder, have an increased risk of bleeding. This appears to be due, at least in part, to acquired von Willebrand disease (VWD) due to platelet-VWF binding and removal from the circulation.

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QUALITATIVE DISORDERS OF PLATELET FUNCTION

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Inherited Disorders of Platelet Function
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Inherited platelet function disorders are thought to be relatively rare, although the prevalence of mild disorders of platelet function is unclear, in part because our testing for such disorders is suboptimal. Rare qualitative disorders include the autosomal recessive disorders Glanzmann’s thrombasthenia (absence of the platelet Gp IIb/IIIa receptor) and Bernard-Soulier syndrome (absence of the platelet Gp Ib-IX-V receptor). Both are inherited in an autosomal recessive fashion and present with bleeding symptoms in childhood.

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Platelet storage pool disorder (SPD) is the classic autosomal dominant qualitative platelet disorder. This results from abnormalities of platelet granule formation. It is also seen as a part of inherited disorders of granule formation, such as Hermansky-Pudlak syndrome. Bleeding symptoms in SPD are variable, but often are mild. The most common inherited disorders of platelet function prevent normal secretion of granule content and are termed secretion defects. Few of these abnormalities have been dissected at the molecular level but they likely result from various mutations.

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TREATMENT
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TREATMENT Inherited Disorders of Platelet Dysfunction

Bleeding symptoms or prevention of bleeding in patients with severe platelet dysfunction frequently requires platelet transfusion. Care is taken to limit the risk of alloimmunization by limiting exposure, using HLA-matched leuko-depleted platelet concentrates for transfusion. Platelet disorders associated with milder bleeding symptoms frequently respond to desmopressin (1-deamino-8-d-arginine vasopressin [DDAVP]). DDAVP increases plasma VWF and factor VIII levels; it may also have a direct effect on platelet function. Particularly for mucosal bleeding symptoms, antifibrinolytic therapy (ε-aminocaproic acid or tranexamic acid) is used alone or in conjunction with DDAVP or platelet therapy.

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Acquired Disorders of Platelet Function
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Acquired platelet dysfunction is common, usually due to medications, either intentionally as with antiplatelet therapy or unintentionally as with high-dose penicillins. Acquired platelet dysfunction occurs in uremia. This is likely multifactorial, but the resultant effect is defective adhesion and activation. The platelet defect is improved most by dialysis but may also be improved by increasing the hematocrit to 27–32%, giving DDAVP (0.3 μg/kg), or use of conjugated estrogens. Platelet dysfunction also occurs with cardiopulmonary bypass due to the effect of the artificial circuit on platelets, and bleeding symptoms respond to platelet transfusion. Platelet dysfunction seen with underlying hematologic disorders can result from nonspecific interference by circulating paraproteins or intrinsic platelet defects in myeloproliferative and myelodysplastic syndromes.

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VON WILLEBRAND DISEASE

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VWD is the most common inherited bleeding disorder. Estimates from laboratory data suggest a prevalence of approximately 1%, but data based on symptomatic individuals suggest that it is closer to 0.1% of the population. VWF serves two roles: (1) as the major adhesion molecule that tethers the platelet to the exposed subendothelium; and (2) as the binding protein for factor VIII (FVIII), resulting in significant prolongation of the FVIII half-life in circulation. The platelet-adhesive function of VWF is critically dependent on the presence of large VWF multimers, whereas FVIII binding is not. Most of the symptoms of VWD are “platelet-like” except in more severe VWD when the FVIII is low enough to produce symptoms similar to those found in FVIII deficiency (hemophilia A).

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VWD has been classified into three major types, with four subtypes of type 2 (Table 140-2; Fig. 140-5). By far the most common type of VWD is type 1 disease, with a parallel decrease in VWF protein, VWF function, and FVIII levels, accounting for at least 80% of cases. Patients have predominantly mucosal bleeding symptoms, although postoperative bleeding can also be seen. Bleeding symptoms are very uncommon in infancy and usually manifest later in childhood with excessive bruising and epistaxis. Because these symptoms occur commonly in childhood, the clinician should particularly note bruising at sites unlikely to be traumatized and/or prolonged epistaxis requiring medical attention. Menorrhagia is a common manifestation of VWD. Menstrual bleeding resulting in anemia should warrant an evaluation for VWD and, if negative, functional platelet disorders. Frequently, mild type 1 VWD first manifests with dental extractions, particularly wisdom tooth extraction, or tonsillectomy.

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FIGURE 140-5

Pattern of inheritance and laboratory findings in von Willebrand disease (VWD). The assays of platelet function include a coagulation assay of factor VIII bound and carried by von Willebrand factor (VWF), abbreviated as VIII; immunoassay of total VWF protein (VWF:Ag); bioassay of the ability of patient plasma to support ristocetin-induced agglutination of normal platelets (VWF:RCoF); and ristocetin-induced aggregation of patient platelets, abbreviated RIPA. The multimer pattern illustrates the protein bands present when plasma is electrophoresed in a polyacrylamide gel. The II-1 and II-2 columns refer to the phenotypes of the second-generation offspring.

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Not all patients with low VWF levels have bleeding symptoms. Whether patients bleed or not will depend on the overall hemostatic balance they have inherited, along with environmental influences and the type of hemostatic challenges they experience. Although the inheritance of VWD is autosomal, many factors modulate both VWF levels and bleeding symptoms. These have not all been defined, but include blood type, thyroid hormone status, race, stress, exercise, and hormonal (both endogenous and exogenous) influences. Patients with type O blood have VWF protein levels of approximately one-half that of patients with AB blood type; and, in fact, the normal range for patients with type O blood overlaps that which has been considered diagnostic for VWD. A mildly decreased VWF level should be viewed more as a risk factor for bleeding than as an actual disease.

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TABLE 140-2Laboratory Diagnosis of Von Willebrand Disease (VWD)
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Patients with type 2 VWD have functional defects; thus, the VWF antigen measurement is significantly higher than the test of function. For types 2A, 2B, and 2M VWD, platelet-binding and/or collagen binding VWF activity is decreased. In type 2A VWD, the impaired function is due either to increased susceptibility to cleavage by ADAMTS13, resulting in loss of intermediate- and high-molecular-weight multimers, or to decreased secretion of these multimers by the cell. Type 2B VWD results from gain-of-function mutations that result in increased spontaneous binding of VWF to platelets in circulation, with subsequent clearance of this complex by the reticuloendothelial system. The resulting VWF in the patients’ plasma lacks the highest molecular-weight multimers, and the platelet count is usually modestly reduced. Type 2M occurs as a consequence of a group of mutations that cause dysfunction but do not affect multimer structure.

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Type 2N VWD is due to mutations in VWF that affect binding of FVIII. As FVIII is stabilized by binding to VWF, the FVIII in patients with type 2N VWD has a very short half-life, and the FVIII level is markedly decreased. This is sometimes termed autosomal hemophilia. Type 3 VWD, or severe VWD, describes patients with virtually no VWF protein and FVIII levels <10%. Patients experience mucosal and joint bleeding, surgery-related bleeding, and other bleeding symptoms. Some patients with type 3 VWD, particularly those with large VWF gene deletions, are at risk of developing antibodies to infused VWF.

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Acquired VWD is a rare disorder, most commonly seen in patients with underlying lymphoproliferative disorders, including monoclonal gammopathies of underdetermined significance (MGUS), multiple myeloma, and Waldenström’s macroglobulinemia. It is seen most commonly in the setting of MGUS and should be suspected in patients, particularly elderly patients, with a new onset of severe mucosal bleeding symptoms. Laboratory evidence of acquired VWD is found in some patients with aortic valvular disease. Heyde’s syndrome (aortic stenosis with gastrointestinal bleeding) is attributed to the presence of angiodysplasia of the gastrointestinal tract in patients with aortic stenosis. The shear stress on blood passing through the stenotic aortic valve appears to produce a change in VWF, making it susceptible to serum proteases. Consequently, large multimer forms are lost, leading to an acquired type 2 VWD, but return when the stenotic valve is replaced.

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TREATMENT

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TREATMENT Von Willebrand Disease

The mainstay of treatment for type 1 VWD is DDAVP (desmopressin), which results in release of VWF and FVIII from endothelial stores. DDAVP can be given intravenously or by a high-concentration intranasal spray (1.5 mg/mL). The peak activity when given intravenously is approximately 30 min, whereas it is 2 h when given intranasally. The usual dose is 0.3 μg/kg intravenously or two squirts (one in each nostril) for patients >50 kg (one squirt for those <50 kg). It is recommended that patients with VWD be tested with DDAVP to assess their response before using it. In patients who respond well (increase in laboratory values of two- to fourfold), it can be used for procedures with minor to moderate risk of bleeding. Depending on the procedure, additional doses may be needed; it is usually given every 12–24 h. Less frequent dosing may result in less tachyphylaxis, which occurs when synthesis cannot compensate for the released stores. The major side effect of DDAVP is hyponatremia due to decreased free water clearance. This occurs most commonly in the very young and the very old, but fluid restriction should be advised for all patients for the 24 h following each dose.

Some patients with types 2A and 2M VWD respond to DDAVP such that it can be used for minor procedures. For the other subtypes, for type 3 disease, and for major procedures requiring longer periods of normal hemostasis, VWF replacement can be given. Virally inactivated VWF-containing factor concentrates are safer than cryoprecipitate as the replacement product.

Antifibrinolytic therapy using either ε-aminocaproic acid or tranexamic acid is an important therapy, either alone or in an adjunctive capacity, particularly for the prevention or treatment of mucosal bleeding. These agents are particularly useful in prophylaxis for dental procedures, with DDAVP for dental extractions and tonsillectomy, menorrhagia, and prostate procedures. It is contraindicated in the setting of upper urinary tract bleeding, due to the risk of ureteral obstruction.

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DISORDERS OF THE VESSEL WALL

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The vessel wall is an integral part of hemostasis, and separation of a fluid phase is artificial, particularly in disorders such as TTP or HIT that clearly involve the endothelium as well. Inflammation localized to the vessel wall, such as vasculitis, and inherited connective tissue disorders are abnormalities inherent to the vessel wall.

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METABOLIC AND INFLAMMATORY DISORDERS

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Acute febrile illnesses may result in vascular damage. This can result from immune complexes containing viral antigens or the viruses themselves. Certain pathogens, such as the rickettsiae causing Rocky Mountain spotted fever, replicate in endothelial cells and damage them. Vascular purpura may occur in patients with polyclonal gammopathies but more commonly in those with monoclonal gammopathies, including Waldenström’s macroglobulinemia, multiple myeloma, and cryoglobulinemia. Patients with mixed cryoglobulinemia develop a more extensive maculopapular rash due to immune complex–mediated damage to the vessel wall.

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Patients with scurvy (vitamin C deficiency) develop painful episodes of perifollicular skin bleeding as well as more systemic bleeding symptoms. Vitamin C is needed to synthesize hydroxyproline, an essential constituent of collagen. Patients with Cushing’s syndrome or on chronic glucocorticoid therapy develop skin bleeding and easy bruising due to atrophy of supporting connective tissue. A similar phenomenon is seen with aging, where following minor trauma, blood spreads superficially under the epidermis. This has been termed senile purpura. It is most common on skin that has been previously damaged by sun exposure.

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Henoch-Schönlein, or anaphylactoid, purpura is a distinct, self-limited type of vasculitis that occurs in children and young adults. Patients have an acute inflammatory reaction with IgA and complement components in capillaries, mesangial tissues, and small arterioles leading to increased vascular permeability and localized hemorrhage. The syndrome is often preceded by an upper respiratory infection, commonly with streptococcal pharyngitis, or is triggered by drug or food allergies. Patients develop a purpuric rash on the extensor surfaces of the arms and legs, usually accompanied by polyarthralgias or arthritis, abdominal pain, and hematuria from focal glomerulonephritis. All coagulation tests are normal, but renal impairment may occur. Glucocorticoids can provide symptomatic relief but do not alter the course of the illness.

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INHERITED DISORDERS OF THE VESSEL WALL

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Patients with inherited disorders of the connective tissue matrix, such as Marfan’s syndrome, Ehlers-Danlos syndrome, and pseudoxanthoma elasticum, frequently report easy bruising. Inherited vascular abnormalities can result in increased bleeding. This is notably seen in hereditary hemorrhagic telangiectasia (HHT, or Osler-Weber-Rendu disease), a disorder where abnormal telangiectatic capillaries result in frequent bleeding episodes, primarily from the nose and gastrointestinal tract. Arteriovenous malformation (AVM) in the lung, brain, and liver may also occur in HHT. The telangiectasia can often be visualized on the oral and nasal mucosa. Signs and symptoms develop over time. Epistaxis begins, on average, at the age of 12 and occurs in >95% of affected individuals by middle age. Two genes involved in the pathogenesis are eng (endoglin) on chromosome 9q33-34 (so-called HHT type 1), associated with pulmonary AVM in 40% of cases, and alk1 (activin-receptor-like kinase 1) on chromosome 12q13, associated with a much lower risk of pulmonary AVM.

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Acknowledgment
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Robert Handin, MD, contributed this chapter in the 16th edition and some materials from his chapter are included here.

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