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. 19-1B) 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.
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.
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. 19-2). 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, as 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/μL 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 pin-point, 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 a thrombocytopenic patient. Excessive bruising is seen in disorders of both platelet number and function.
Algorithm for evaluating the thrombocytopenic patient. DIC, disseminated intravascular coagulation; RBC, red blood cell; TTP, thrombotic thrombocytopenic purpura.
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 (ITP) is less clear in adults.
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 is recommended when the diagnosis is needed urgently or when other, less invasive methods have been unsuccessful.
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. 28). Other, commonly used drugs that cause isolated thrombocytopenia are listed in Table 19-1, 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/index.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.
TABLE 19-1DRUGS REPORTED AS DEFINITELY OR PROBABLY CAUSING ISOLATED THROMBOCYTOPENIAa ||Download (.pdf) TABLE 19-1DRUGS REPORTED AS DEFINITELY OR PROBABLY CAUSING ISOLATED THROMBOCYTOPENIAa
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 GpIIbIIIa 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.
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 antiheparin/PF4 antibody can activate platelets through the FcγRIIa receptor and 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 (≤50%) will develop thrombosis (HITT).
HIT can occur after exposure to low-molecular-weight heparin (LMWH) as well as unfractionated heparin (UFH), although it is about 10 times more common with the latter. Most patients develop HIT after exposure to heparin for 5–14 days (Fig. 19-3). It occurs before 5 days in those who were exposed to heparin in the prior few weeks or months (<~100 days) and have circulating antiheparin/PF4 antibodies. Rarely, thrombocytopenia and thrombosis begin several days after all heparin has been stopped (termed delayed-onset HIT). The 4 Ts 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. A new scoring model based on broad expert opinion (the HIT Expert Probability [HEP] Score) has improved operating characteristics and should provide better utility as a scoring system.
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 an 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 heparin (UFH) or low-molecular-weight heparin (LMWH).
Laboratory testing for HIT
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. Since 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, in which 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, 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 ELISA. However, HIT remains a clinical diagnosis.
TREATMENT: Heparin-Induced Thrombocytopenia
Early recognition is key in treatment of HIT, with prompt discontinuation of heparin and use of alternative anticoagulants. 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 have a higher risk of thrombosis. In patients diagnosed with HIT, imaging studies to evaluate the patient for thrombosis (at least lower extremity duplex Dopplers) 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 glycosoaminoglycans 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 strongly 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 fonda parinux and started after resolution of the thrombocytopenia and lessening of the prothrombotic state.
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 usually runs a more chronic course. 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.
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.
Laboratory testing in ITP
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 older adults (usually >60 years) or 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.
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, and immunoglobulin levels to potentially detect hypogammaglobulinemia; selective testing for IgA deficiency or monoclonal gammopathies; and, if anemia is present, direct antiglobulin testing (Coombs test) to rule out combined autoimmune hemolytic anemia with ITP (Evans syndrome).
TREATMENT: Immune Thrombocytopenic Purpura
The treatment of ITP utilizes 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 greater than 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 as 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 postinfusion 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 2 g/kg total, given in divided doses over 2–5 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-Rh0D therapy, and, as needed, additional immunosuppressive agents. Rituximab, an anti-CD20 (B cell) antibody, has shown efficacy in the treatment of refractory ITP.
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 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.
Thrombopoietin 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), have shown response in many patients with refractory ITP. Roles for these agents in ITP treatment are not fully defined, but given the chronicity of treatment, they are generally reserved for patients with refractory disease
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. 19-1C). 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 GPIb-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.
THROMBOTIC THROMBOCYTOPENIC PURPURA AND HEMOLYTIC UREMIC SYNDROME
Thrombotic thrombocytopenic microangiopathies are a group of disorders characterized by thrombocytopenia, a microangiopathic hemolytic anemia evident by fragmented RBCs (Fig. 19-1D) and laboratory evidence of hemolysis, and microvascular thrombosis. They include thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (HUS), as well as syndromes complicating bone marrow transplantation, certain medications and infections, pregnancy, and vasculitis. In DIC, while 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.
Thrombotic thrombocytopenic purpura
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 the mortality rate from 85–100% to 10–30%.
The pathogenesis of inherited (Upshaw-Schulman syndrome) and idiopathic TTP is related to a deficiency of, or antibodies to, the metalloprotease ADAMTS13, that 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. 19-4). This defect alone, however, is not sufficient to result in TTP as 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. However, assays with sufficient sensitivity and specificity to direct clinical management have yet to be clearly defined.
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.
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.
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 result. The peripheral smear should be examined for evidence of schistocytes (Fig. 19-1D). 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. While never evaluated in clinical trial, 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. The role of rituximab in the treatment of this disorder needs to be defined. A significant relapse rate is noted, 25–45% within 30 days of initial "remission" and 12–40% with late relapses. Relapses may be more frequent in patients with severe ADAMTS13 deficiency at presentation.
Hemolytic uremic syndrome
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 (termed DHUS) is more heterogeneous in presentation and course. Some children who develop DHUS have been found to have mutations in genes encoding factor H, a soluble complement regulator, and membrane cofactor protein that is mainly expressed in the kidney.
TREATMENT: Hemolytic Uremic Syndrome
Treatment of HUS is primarily supportive. In D+HUS, many (~40%) children require at least some period of support with dialysis; however, the overall mortality rate is <5%. In D–HUS, the mortality rate 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. As ADAMTS13 assays improve, they may help in defining a subset that better fit a TTP diagnosis, and may respond to plasma exchange.
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. 13]) or, rarely, the 5q- myelodysplastic process (Chap. 11). 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 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 adhesion and removal.
QUALITATIVE DISORDERS OF PLATELET FUNCTION
Inherited disorders of platelet function
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 GpIIb–IIIa receptor) and Bernard Soulier syndrome (absence of the platelet GpIb-IX-V receptor). Both are inherited in an autosomal recessive fashion and present with bleeding symptoms in childhood.
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 are disorders that prevent normal secretion of granule content. Few of the abnormalities have been dissected at the molecular level, but these are likely due to multiple abnormalities. They are usually described as secretion defects. Bleeding symptoms are usually mild in nature.
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 apheresis leuko-depleted platelets 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 FVIII levels; it may also have a direct effect on platelet function. Particularly for mucosal bleeding symptoms, antifibrinolytic therapy (epsilon-aminocaproic acid or tranexamic acid) is used alone or in conjunction with DDAVP or platelet therapy.
Acquired disorders of platelet function
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.
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 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, while 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).
VWD has been classified into three major types, with four subtypes of type 2 (Table 19-2; Fig. 19-5). 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. Since 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 the result is negative, functional platelet disorders. Frequently, mild type 1 VWD first manifests with dental extractions, particularly wisdom tooth extraction, or tonsillectomy.
TABLE 19-2LABORATORY DIAGNOSIS OF VON WILLEBRAND DISEASE ||Download (.pdf) TABLE 19-2LABORATORY DIAGNOSIS OF VON WILLEBRAND DISEASE
|TYPE ||APTT ||VWF ANTIGEN ||VWF ACTIVITY ||FVIII ACTIVITY ||MULTIMER |
|1 ||Nl or ↑ ||↓ ||↓ ||↓ ||Normal distribution, decreased in quantity |
|2A ||Nl or ↑ ||↓ ||↓ ↓ ||↓ ||Loss of high- and intermediate-MW multimers |
|2Ba ||Nl or ↑ ||↓ ||↓ ↓ ||↓ ||Loss of high-MW multimers |
|2M ||Nl or ↑ ||↓ ||↓ ↓ ||↓ ||Normal distribution, decreased in quantity |
|2N ||↑↑ ||Nl or ↓b ||Nl or ↓b ||↓↓ ||Normal distribution |
|3 ||↑↑ ||↓↓ ||↓↓ ||↓↓ ||Absent |
Pattern of inheritance and laboratory findings in von Willebrand disease. The assays of platelet function include a coagulation assay of factor VIII bound and carried by von Willebrand factor (VWF), abbreviated 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.
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 half that of patients with AB blood type; 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 perhaps be viewed more as a risk factor for bleeding than as an actual disease.
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, vWF activity is decreased, measured as ristocetin cofactor or collagen-binding activity. 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 of the molecule but do not affect multimer structure.
Type 2N VWD is due to mutations in vWF that preclude 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 postoperative symptoms as well as 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.
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. However, 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.
TREATMENT: von Willebrand Disease
The mainstay of treatment for type 1 VWD is DDAVP, 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 minutes, while it is 2 h when given intranasally. The usual dose is 0.3 μg/kg intravenously or 2 squirts (1 in each nostril) for patients >50 kg (1 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 values of two- to fourfold), it can be used for procedures with a 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 thought to be 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.