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Figure 11–5 provides a classification of coagulation disorders. The major division in the classification is between disorders associated with bleeding and disorders associated with thrombosis. There are 2 major subdivisions of bleeding disorders—those associated with coagulation factor and fibrinolytic pathway factor deficiencies, and those associated with an abnormal platelet count or impaired platelet function. Isolated factor deficiencies are usually congenital, although occasionally an isolated acquired factor deficiency develops. An example of an acquired isolated coagulation factor deficiency is the Factor X deficiency associated with amyloidosis. The deficiency of antiplasmin is listed in this section because its absence permits increased plasmin activity and overactive clot dissolution, resulting in a bleeding tendency. Another major category of coagulation factor abnormalities is multiple coagulation factor deficiencies. There are several commonly encountered situations associated with multiple factor deficiencies. These include vitamin K deficiency or warfarin intake (which results in a reduced amount of functional Factors II, VII, IX, and X as well as protein C and protein S); disseminated intravascular coagulation (DIC), which results in the consumption of multiple coagulation factors; and liver disease that results in decreased synthesis of coagulation factors. Several activated coagulation factors are inhibited by heparin. Heparin administration results in inactivation of most of the activated coagulation factors.
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Quantitative platelet disorders include thrombocytopenia and thrombocytosis. Qualitative platelet disorders are characterized by abnormal platelet function in the presence of a normal platelet count.
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The group of disorders associated with platelets is divided first into quantitative platelet disorders and qualitative platelet disorders. Quantitative platelet disorders include thrombocytopenia and thrombocytosis. Thrombocytopenia can be produced as a result of increased platelet destruction, from a variety of immune or nonimmune causes, or decreased platelet production. Common causes of decreased platelet production include tumor infiltration of bone marrow from metastases or a hematologic malignancy, and drug-induced thrombocytopenia as occurs with chemotherapy. Thrombocytopenia can also occur as a result of increased sequestration of platelets in the spleen, usually in patients with splenomegaly. Thrombocytosis is much less common than thrombocytopenia. Thrombocytosis can be divided into reactive thrombocytosis, in which there is a transiently increased number of platelets from a stimulus to increase platelet production, or neoplastic thrombocytosis, as seen in myeloproliferative disease and, less commonly, myelodysplastic disorders.
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Qualitative platelet disorders are characterized by abnormal platelet function in the presence of a normal platelet count. vWD is a disorder in which there is defective platelet function, but from a defect originating outside the platelet, since vWF is generated primarily in endothelial cells. vWF coats the surface of the activated platelet to allow it to adhere to the cut vessel surface and initiate platelet plug formation.
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Other causes of defective platelet function result from abnormalities within the platelet. These disorders may be congenital or acquired. The congenital ones are extremely rare, and the acquired ones are very frequently encountered. Congenital platelet abnormalities associated with defective function include GT, Bernard–Soulier disease, and storage pool disease (SPD). The much more common acquired qualitative platelet disorders include drug-induced platelet dysfunction, such as produced by aspirin and clopidogrel (Plavix), and uremia-induced platelet dysfunction, which occurs in patients with impaired renal function.
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Fibrinogen Deficiencies
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Fibrinogen is produced in the liver by hepatocytes. Abnormalities of fibrinogen production may be congenital or acquired and, in general, involve either decreased production of a normal molecule (afibrinogenemia and hypofibrinogenemia) or production of an abnormal molecule (dysfibrinogenemia) (see Table 11–1).
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In congenital afibrinogenemia and hypofibrinogenemia, there is a reduced (hypofibrinogenemia) or absent (afibrinogenemia) production of a normal fibrinogen molecule. In general, the homozygous deficiency results in afibrinogenemia, and the heterozygous state results in hypofibrinogenemia. Both disorders are rare. Homozygotes suffer a mild-to-moderate spontaneous bleeding tendency. Manifestations include umbilical stump hemorrhage and bleeding from mucous membranes, among many other possible signs and symptoms related to blood loss. Severe bleeding may occur with trauma or surgery. Hypofibrinogenemic patients are usually asymptomatic, but may bleed significantly with surgery or trauma.
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Congenital dysfibrinogenemia is a result of inheritance of a gene for an abnormal fibrinogen molecule, which is produced in normal or near-normal quantities. All the fibrinogen produced by a homozygote for dysfibrinogenemia is abnormal, and approximately half of the fibrinogen in a heterozygote is abnormal. Hundreds of abnormal fibrinogens have been described. The true incidence of dysfibrinogenemia is not known because many forms of the disorder are asymptomatic. Homozygotes may have a mild bleeding tendency, perhaps because the fibrinogen molecule is cleaved too slowly to form fibrin monomers or because abnormal fibrin monomers polymerize too slowly. The bleeding tendency is characterized by easy or spontaneous bruising, menorrhagia, and prolonged or severe bleeding with surgery or trauma. Heterozygotes are usually asymptomatic, but may show excessive bleeding with surgery or trauma. Several types of dysfibrinogenemia (approximately 10%-15% of cases) are associated with an increased risk of thrombosis rather than bleeding. A few types of congenital dysfibrinogenemia are associated with both bleeding and thrombosis.
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Acquired hypofibrinogenemia is observed predominantly in patients with advanced liver disease, in patients with a consumptive coagulation disorder such as DIC, and in those treated with thrombolytic therapy.
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Acquired hypofibrinogenemia is observed predominantly in patients with advanced liver disease, in patients with a consumptive coagulation disorder such as DIC, and in those treated with thrombolytic therapy.
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Acquired dysfibrinogenemia represents the acquired production of an abnormal fibrinogen molecule in normal or near-normal quantities, most often in patients with acute or chronic liver disease, especially those with primary or metastatic hepatic malignancies. The patient may or may not be symptomatic, depending on 1) whether there is simultaneous production of normal fibrinogen in amounts sufficient to allow normal hemostasis and 2) whether the abnormal fibrinogen can polymerize like a normal fibrinogen molecule (see the section “Hemostatic Abnormalities in Liver Disease”).
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See Table 11–1 for the laboratory evaluation of the patient with a fibrinogen deficiency.
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Prothrombin (Factor II) Deficiency
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Prothrombin (Factor II) is the precursor to thrombin (Factor IIa), which converts fibrinogen into fibrin in the common pathway of the coagulation cascade. Deficiency of prothrombin, either inherited or acquired, may result in a hemorrhagic diathesis. Inherited abnormalities of prothrombin are rare. As with fibrinogen, abnormalities occur in 2 major forms. The first is reduced or absent production of a normal prothrombin molecule. The second is production of normal amounts of an abnormal prothrombin molecule with decreased activity (dysfunctional form or dysprothrombinemia). Heterozygotes usually have approximately 50% of normal activity and may be asymptomatic or have a bleeding tendency. In 1 study, 83% of a small cohort of heterozygotes had bleeding, with Factor II levels ranging from 21% to 35%. Homozygotes usually have 1% to 25% of normal activity and have a mild-to-severe hemorrhagic tendency. Acquired hypoprothrombinemia occurs most often along with deficiencies of Factors VII, IX, and X in vitamin K deficiency and with warfarin (Coumadin) therapy; with deficiencies of multiple coagulation factors in liver disease or DIC; as an isolated coagulation factor deficiency in some patients with lupus anticoagulant (LA); and in patients exposed to topical bovine thrombin who develop antibodies to prothrombin (and not uncommonly to Factor V also). Bleeding manifestations depend on the level of prothrombin activity; usually no bleeding occurs with a prothrombin level >50% of normal.
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Abnormalities occur in 2 major forms. The first is reduced or absent production of a normal prothrombin molecule. The second is production of normal amounts of an abnormal prothrombin molecule with decreased activity (dysfunctional form or dysprothrombinemia).
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See Table 11–2 for the laboratory evaluation of the patient with a prothrombin (Factor II) deficiency.
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Factor V is a high-molecular-weight protein (approximately 300,000 Da) that acts as an accelerating cofactor for the enzymatic conversion of prothrombin to thrombin by Factor Xa. When Factor V is cleaved to Factor Va by thrombin, its cofactor activity is significantly increased. Factors Va and VIIIa are degraded by activated protein C. An isolated deficiency of Factor V is a rare cause of bleeding.
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Apparent heterozygous and homozygous deficient states have been observed. Heterozygotes usually have levels of approximately 50% of normal and can experience bleeding or may be asymptomatic. In a cohort of 19 heterozygous patients, 50% had bleeding, with Factor V levels ranging from 21% to 55%. Homozygotes have variable levels below 50%; they are most likely to be symptomatic if the level is 10% or less.
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As with the other coagulation factors, 2 major forms of the inherited deficiency are described: reduced or absent production of a normal Factor V molecule (absence form) and production of an abnormal molecule with reduced activity in normal amounts (dysfunctional form). A rare combined deficiency of Factors V and VIII is due to a genetic defect in intracellular transport of Factors V and VIII. Acquired deficiencies of Factor V occur with liver dysfunction or DIC.
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See Table 11–2 for the laboratory evaluation of the patient with a Factor V deficiency.
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Factor VII Deficiency
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Factor VII is a vitamin K-dependent coagulation factor precursor that, when activated by thrombin, Factor Xa, or Factor IXa, is converted to Factor VIIa. This activated factor then converts phospholipid-bound Factor X into Factor Xa in the presence of calcium and tissue factor. It also converts Factor IX to Factor IXa. Factor VII deficiency may occur as an inherited or acquired disorder.
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The inherited deficiency state, which is rare, may be present as reduced or absent production of a normal molecule (absence form) or production of an abnormal molecule with decreased activity in normal amounts (dysfunctional form). An inherited isolated deficiency of Factor VII in heterozygotes is usually associated with a Factor VII activity level of approximately 50%. In a cohort of 88 heterozygous patients, 36% had a bleeding tendency, with Factor VII levels ranging from 21% to 69%. In homozygotes, there are variable Factor VII activity levels below 50%. The bleeding risk is difficult to predict in these patients because the factor activity level correlates poorly with the patient's tendency to hemorrhage, but in general values <10% can be associated with major spontaneous bleeding. A large proportion of patients with less than 2% Factor VII do not bleed. Acquired Factor VII deficiency occurs in vitamin K deficiency and with warfarin therapy along with deficiencies of Factors II, IX, and X; and in DIC or liver disease along with multiple other coagulation factor deficiencies.
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The bleeding risk is difficult to predict because the factor VII activity level correlates poorly with the patient's tendency to hemorrhage. A large proportion of patients with less than 2% Factor VII do not bleed.
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Intracranial hemorrhage has been reported in Factor VII-deficient patients, most often occurring in infants <1 year of age. Elevated Factor VII levels have been associated with an increased risk of cardiovascular disease.
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See Table 11–2 for the laboratory evaluation of the patient with a Factor VII deficiency.
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Hemophilia A (Factor VIII Deficiency)
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Hemophilia A is a bleeding disorder resulting from a deficiency of Factor VIII procoagulant activity. Factor VIII circulates in the plasma bound to vWF. Approximately 90% of patients with hemophilia A synthesize low amounts of normal Factor VIII molecules, and 10% of patients with hemophilia A synthesize normal amounts of an abnormal (nonfunctional) Factor VIII. Hemophilia A is inherited as an X-linked trait, and 65% to 75% of patients have a positive family history. Disease prevalence in the United States is 1 in 10,000 males; the carrier state in females is rarely symptomatic. Hemophilia A and hemophilia B (Factor IX deficiency, see below) are clinically indistinguishable. The likelihood of hemorrhage depends on the amount of Factor VIII present; the majority of patients (approximately 50%-70% of hemophilia A patients) have severe disease. The severity of disease is categorized as follows:
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In mild disease: the VIII level is 6% to 20% of normal, with rare spontaneous bleeding.
In moderate disease: the VIII level is 1% to 5% of normal, with occasional spontaneous bleeding.
In severe disease: the VIII level is <1% of normal, with frequent spontaneous bleeding.
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Hemophilia A is a bleeding disorder resulting from a deficiency of Factor VIII procoagulant activity. Factor VIII inhibitors are antibodies, usually IgG, that bind to Factor VIII and inhibit its coagulant activity.
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All hemophilia patients (A and B) may experience severe hemorrhage following trauma or surgery if there is no prior treatment to elevate the factor level. Bleeding that is characteristic of hemophilia (A and B) includes intra-articular (joint), intracranial, and intramuscular hemorrhage. The latter can produce a compartment compression syndrome. Easy bruising and prolonged bleeding after minor cuts and abrasions are also characteristic. The onset of hemorrhage is typically delayed following injury, and pathologic bleeding may occur hours after injury. Primary hemostasis (dependent on platelet plug formation) is intact, but secondary hemostasis (dependent on the fibrin clot generated by the coagulation cascade) is defective. Up to 15% of hemophilia A patients develop an inhibitor to Factor VIII at some time during the course of their disease (ie, an antibody against Factor VIII). The inhibitor develops only in those transfused with Factor VIII-containing products, and most often in patients with <1% Factor VIII. Factor VIII inhibitors may also spontaneously occur rarely in nonhemophiliacs (see the section “Factor VIII Inhibitors”).
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See Table 11–2 for information regarding the laboratory evaluation for Factor VIII deficiency.
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Factor VIII Inhibitors
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Factor VIII inhibitors are antibodies, usually IgG, that bind to Factor VIII and inhibit its coagulant activity.
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Factor VIII inhibitors have been found in several clinical situations.
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Inhibitors are diagnosed most commonly in patients with hemophilia A. Inhibitors occur in 10% to 15% of these patients and make the treatment of hemorrhage much more difficult. The vast majority of cases of Factor VIII inhibitors in hemophilia A patients occur in those with severe hemophilia A (<1% Factor VIII activity). Inhibitor formation is related to transfusion of exogenous Factor VIII, and usually develops before 100 treatment days if it appears. Two immune response patterns have been observed in hemophilia A patients. The first is a high response pattern. Inhibitors rise to a high titer in response to exposure to Factor VIII. The titer may not decline for months to years, even without further exposure to Factor VIII. Rapid anamnestic responses are often seen within 3 to 7 days of reexposure in these patients. In the second pattern, there is a low response. In addition, inhibitors usually remain at a low titer despite reexposure. They may occasionally disappear and reappear spontaneously. Little, if any, anamnestic response is likely found in a low responder.
Spontaneous inhibitors to Factor VIII can occur in the postpartum patient. Usually they
are recognized 2 to 5 months after the birth of the first child and disappear spontaneously after 12 to 18 months. However, the course is variable, and there are reports of death from hemorrhage in some patients. Antigenic differences between mother and fetus do not sufficiently explain the development of a Factor VIII inhibitor, and its cause remains unknown.
Inhibitors may occur in those with allergic and enhanced immunologic reactions, including patients with:
(a) Rheumatoid arthritis
(b) Systemic lupus erythematosus
(c) Reactions to drugs, such as penicillin, chloramphenicol, sulfonamides, and phenytoin
(d) Malignancy
(e) Asthma
(f) Crohn disease
(g) Ulcerative colitis
(h) Pemphigus
(i) Multiple myeloma
Inhibitors may appear in patients without any obvious underlying disorder. These are usually older individuals, and the inhibitor may remit in several months, persist for years, or disappear with immunosuppressive therapy.
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In a hemophilia A patient, a poor response to treatment with Factor VIII concentrate may be the first indication that an inhibitor is present, or there may be an increased frequency of bleeding episodes. In nonhemophiliacs, development of a new hemorrhagic tendency is usually the presenting feature of a spontaneous Factor VIII inhibitor. The most favorable prognoses are for patients with low titer inhibitors, peripartum women, and patients without an underlying disorder.
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Hemophilia B is an inherited hemorrhagic disorder resulting from a lack of procoagulant activity of Factor IX.
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See Table 11–3 for information regarding the laboratory evaluation for a Factor VIII inhibitor.
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Hemophilia B (Factor IX Deficiency)
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Hemophilia B is an inherited hemorrhagic disorder resulting from a lack of procoagulant activity of Factor IX. Factor IX is a vitamin K-dependent factor that, in its active form (Factor IXa), is a serine protease of the intrinsic pathway of the coagulation cascade. Approximately 70% to 90% of hemophilia B patients have a deficiency of a normal coagulant protein, and 10% to 30% produce an abnormal Factor IX that is nonfunctional. Inheritance is sex-linked, with affected males, and female carriers. Of hemophilia B patients, 60% to 70% have a positive family history for bleeding. The prevalence of hemophilia B is much less than that of hemophilia A. Approximately 1 in 50,000 males in the United States has hemophilia B versus 1 in 10,000 males with hemophilia A. The hemophilia B carrier state in the female is usually asymptomatic, as is the case with hemophilia A. Acquired Factor IX deficiency may occur along with deficiencies of Factors II, VII, and X in patients with vitamin K deficiency or those receiving warfarin therapy, and with deficiencies of other coagulation factors in patients with liver disease, DIC, or nephrotic syndrome.
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As previously noted, hemophilia B is clinically indistinguishable from hemophilia A. The severity of hemorrhage depends on the amount of Factor IX activity present:
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In mild disease: 6% to 20% of normal IX activity is present, with rare spontaneous bleeding.
In moderate disease: 1% to 5% of normal IX activity is present, with occasional spontaneous bleeding.
In severe disease: <1% of normal activity is present, with frequent spontaneous bleeding.
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Profuse bleeding may occur in any hemophilia B patient with trauma or surgery if there is no prior treatment to elevate the factor level. Bleeding in hemophilia B resembles that found in hemophilia A and includes deep tissue bleeding, intra-articular bleeding (hemarthrosis), intracranial bleeding (which may be lethal), and intramuscular bleeding with potential compartment compression syndrome. Severe mucosal membrane bleeding can occur in hemophilia, particularly after dental surgery.
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Inhibitors develop to Factor IX in 1% to 5% of hemophilia B cases. These antibodies often occur in high titer and frequently present a major bleeding problem despite treatment.
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See Table 11–2 for information regarding the laboratory evaluation for patients with hemophilia B.
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An inherited isolated deficiency of Factor X is a rare disorder. Homozygotes and heterozygotes have been identified. Homozygotes usually possess <2% of normal activity. Heterozygotes usually possess 40% to 70% of normal activity. In a cohort of 15 heterozygous patients, 33% had a bleeding tendency, with Factor X levels ranging from 23% to 47%. Patients with Factor X values <10% can have a high risk of spontaneous major bleeding, and those with >40% are usually asymptomatic. Inherited Factor X deficiency, like the other factor deficiency states, occurs in 2 major forms: reduced or absent synthesis of a normal molecule (absence form) and synthesis of an abnormal molecule in normal amounts (dysfunctional form).
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Acquired Factor X deficiency may result from warfarin or vitamin K deficiency (in the presence of deficiencies of Factors II, VII, and IX), from liver disease (with deficiencies of other factors synthesized in the liver), with DIC, or as an isolated deficiency in cases of amyloidosis. In amyloidosis, Factor X becomes irreversibly bound to amyloid fibrils in the extracellular space, and is thereby removed from the circulation.
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See Table 11–2 for information regarding the laboratory evaluation of patients with Factor X deficiency.
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Factor XI deficiency is a commonly encountered disorder. Homozygotes typically have less than 20% of normal Factor XI activity. Heterozygotes have 20% to 70% of normal Factor XI activity. The deficiency in almost all cases appears to be a reduced or absent production of a normal molecule, rather than production of an abnormal or dysfunctional molecule.
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The vast majority of the cases of Factor XI deficiency are in people of Jewish descent, particularly those of Ashkenazi origin. The frequency of the homozygous deficient state is 0.2% to 0.3% in the Ashkenazi population, and the frequency of the heterozygous state is extremely high, at approximately 5.5% to 11.0%.
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The hemorrhagic tendency is variable for both heterozygotes and homozygotes. Patients with Factor XI levels <15% to 20% uncommonly have spontaneous bleeding but frequently have postoperative bleeding, and patients with levels between 20% and 65% tend to be asymptomatic or have low rates of postoperative bleeding. Bleeding does not correlate well with the level of Factor XI activity. Some homozygotes have an abnormal partial thromboplastin time (PTT), a very low Factor XI level of less than 10%, and no bleeding, even with surgery. The bleeding tendency of a particular individual is more closely related to the bleeding tendency of the patient's kindred than to the measured Factor XI level. The explanation, which is true for all mutations affecting coagulation factors, is that certain mutations produce a low level of Factor XI and a prolonged PTT but are not clinically significant in vivo. This is because they only affect the activity of the factor in the in vitro clotting factor assays, which are not exact replicas of clot formation in vivo. Acquired decreases in Factor XI can occur with pregnancy, proteinuria, liver dysfunction, and DIC.
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See Table 11–2 for information regarding the laboratory evaluation of patients with Factor XI deficiency.
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Deficiencies of the Contact Factors
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The contact coagulation factors (so named because they were originally thought to activate the coagulation cascade by contacting the cut surface of the vessel wall) include Factor XII, PK, and HMWK. A deficiency of any of the contact factors prolongs the PTT because the PTT assay is constructed to involve these factors, even though the coagulation cascade in vivo does not depend on these factors. Bleeding diatheses have not been reported in patients with deficiencies at any level of Factor XII, PK, or HMWK. Factor XII deficiency is fairly common, with many thousands affected, especially individuals of Asian descent and children with tonsillitis. HMWK deficiency and PK deficiency are rare.
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A deficiency of any of the contact factors prolongs the PTT because the PTT assay is constructed to involve these factors, even though the coagulation cascade in vivo does not depend on these factors. Bleeding diatheses have not been reported in patients with deficiencies at any level of Factor XII, PK, or HMWK.
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See Table 11–2 for information regarding the laboratory evaluation for contact factor abnormalities.
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Factor XIII Deficiency
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Factor XIII circulates in plasma as a zymogen and is converted to its active form (Factor XIIIa) by thrombin. Factor XIIIa catalyzes the formation of covalent bonds between chains of adjacent fibrin monomers. This stabilizes the fibrin clot, making it rigid and more resistant to the action of plasmin. Congenital deficiency of Factor XIII is rare. The bleeding tendency in homozygotes is characterized by umbilical stump bleeding in newborns (>90% of patients with clinically significant Factor XIII deficiency have this finding), intracranial hemorrhage, miscarriages, and posttraumatic hematomas, with bleeding often delayed hours to days after the trauma. Patients with mild or moderate deficiencies might have mucocutaneous bleeding or be asymptomatic. Patients with Factor XIII levels above 30% are usually always asymptomatic.
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See Table 11–2 for information regarding the laboratory evaluation for Factor XIII deficiency.
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Antiplasmin Deficiency
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Antiplasmin or plasmin inhibitor (formerly known as alpha-2 antiplasmin) is a glycoprotein (GP) that serves as a regulator of fibrinolysis in several ways (see Figure 11–4). It blocks the enzymatic activity of plasmin (the major fibrinolytic enzyme) and other serine proteases, some of which are coagulation factors, and it inhibits the binding of plasminogen to fibrin. A bleeding diathesis is associated with the congenital deficiency of plasmin inhibitor. It is an extremely rare disorder and only homozygotes with <10% of normal plasmin inhibitor activity appear to be clinically affected. Those who do bleed may experience mucosal membrane bleeding (particularly in the genitourinary tract), subcutaneous hematomas, spontaneous bruising, and severe bleeding with trauma. Most heterozygotes are asymptomatic, but those few who are symptomatic have only a mild bleeding tendency. Acquired deficiency of plasmin inhibitor can occur in liver disease, nephrotic syndrome, amyloidosis, DIC, and, most notably, following thrombolytic therapy. In thrombolytic therapy, plasminogen is purposefully converted to plasmin, which results in the formation of plasmin–antiplasmin complexes, thereby reducing the amount of available antiplasmin.
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See Table 11–4 for information on the laboratory evaluation of plasmin inhibitor deficiency.
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In adults, vitamin K deficiency most often occurs secondary to disease or drug therapy; it rarely occurs as a dietary deficiency. Causes of vitamin K deficiency include:
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Warfarin therapy (reduces the amount of active vitamin K)
Antibiotic therapy (capable of suppressing bowel flora that synthesize vitamin K)
Malabsorption syndromes: cystic fibrosis, sprue, ulcerative colitis, Crohn disease, parasitic infections, short bowel syndrome, and ileojejunostomy (for morbid obesity)
Dietary restriction with incidental decrease in vitamin K intake
Long-term total parenteral nutrition
Biliary obstruction
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In adults, vitamin K deficiency most often occurs secondary to disease or drug therapy; it rarely occurs as a dietary deficiency.
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Vitamin K depletion can occur in as little as 2 weeks if both intake (enteral and parenteral) and endogenous production of vitamin K are eliminated. In early deficiency, Factor VII only, or Factors VII and IX only, may be decreased due to their shorter half-lives. Vitamin K deficiency may present as an asymptomatic prolongation of the PT in mild cases or as a major spontaneous hemorrhage in severe deficiencies. The degree of prolongation of the PT does not accurately predict the risk of hemorrhage.
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Most antibiotics destroy bacterial flora and must be considered as a possible cause of vitamin K deficiency in the bleeding patient. However, certain cephalosporins produce vitamin K deficiency much more rapidly than other antibiotics. Cephalosporins with an N-methylthiotetrazole (MTT) group in position 3 directly inhibit the vitamin K-dependent carboxylase that is responsible for converting Factors II, VII, IX, and X to their active form. Cephalosporins in the MTT group include cefamandole, cefoperazone, cefotetan, moxalactam, cefmetazole, and cefmenoxime. Weekly prophylaxis with vitamin K has been recommended when MTT-cephalosporins are given to patients at high risk for vitamin K deficiency.
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See Table 11–5 for information on the laboratory evaluation for vitamin K deficiency.
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Disseminated Intravascular Coagulation
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DIC is a common acquired coagulation disorder that occurs secondary to a variety of underlying disorders. The most common cause is infection; 10% to 20% of patients with gram-negative sepsis develop DIC. Other causes of DIC include obstetrical complications (retained dead fetus, placental abruption, amniotic fluid embolism, hypertonic saline-induced abortion, and septic abortion), extensive tissue injury (including trauma, ischemia, infarction, and burns), liver disease, transfusion of ABO-incompatible blood, and adult respiratory distress syndrome. The clinical presentation varies from an asymptomatic condition, detectable only by laboratory abnormalities, to a severe coagulopathy with a mortality of up to 80%.
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The major events in acute DIC, independent of the cause, are microvascular thrombosis with consumption of platelets and coagulation factors, and then hemorrhage as a result of low levels of platelets and coagulation factors and overactivation of the fibrinolytic system to remove the thrombi. Hemorrhagic symptoms can include any of the following—petechiae, ecchymoses, mucosal oozing, hematuria, gastrointestinal tract bleeding, bleeding into surgical wounds, and prolonged bleeding at venous access sites. Severe bleeding may contribute to hypotensive shock.
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The major events in acute DIC, independent of the cause, are microvascular thrombosis with consumption of platelets and coagulation factors, and then hemorrhage as a result of low levels of platelets and coagulation factors and overactivation of the fibrinolytic system to remove the thrombi.
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DIC may present as a more chronic, low-grade condition in patients with malignancy. These patients are at risk for macrovascular (large vessel) thrombosis as well, most likely as a deep vein thrombosis.
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The prolongations of the PT and the PTT reflect a decrease in fibrinogen and other coagulation factors that are consumed by clotting. In addition, fibrinogen is degraded by excess plasmin activation in the fibrinolytic system. Platelets are also consumed, and, therefore, the platelet count is typically low. The presence of FDP, 1 of which is the D-dimer, indicates that fibrin clots have been formed and subsequently degraded. There is no single laboratory test that can diagnose or exclude DIC, and the diagnosis is made when the characteristic laboratory abnormalities are present along with a known stimulus for DIC. A practical approach to diagnosis of DIC is to perform the PT, the PTT, and a D-dimer assay, with serial measurements of fibrinogen and platelets. In severe acute DIC, most of the laboratory test results will be abnormal, although fibrinogen may be normal or even elevated. In chronic DIC, the laboratory abnormalities may be less pronounced or even absent because the liver and bone marrow can increase production of coagulation factors and platelets, respectively, to offset the losses from consumption.
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See Table 11–6 for information on the laboratory evaluation for DIC.
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Hemostatic Abnormalities in Liver Disease
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Patients with acute and chronic liver disease often have laboratory evidence of a hemostatic abnormality. These patients may be asymptomatic or have only mild bleeding problems, but those with advanced liver disease may experience a severe hemorrhage.
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Hemorrhage in patients with liver disease may be due to 1 or more of the following:
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Coagulation factor abnormalities: These are caused by decreased hepatic synthesis of vitamin K-dependent factors (II, VII, IX, and X) and non-vitamin K-dependent factors. Decreased fibrinogen is usually found only in patients with severe hepatic failure; in fact, patients with acute hepatitis without hepatic failure usually have an increased fibrinogen level.
Thrombocytopenia: This frequently occurs as a consequence of sequestration in the spleen, impaired platelet production, or increased platelet destruction. It is not usually a severe decrease in platelet number.
Platelet dysfunction: The dysfunction is usually mild and its clinical significance is uncertain; platelet dysfunction may be clinically important only in liver disease patients with severe thrombocytopenia or severe renal failure, which can result in uremia-induced platelet dysfunction.
DIC or a DIC-like syndrome: There is no general agreement as to whether the coagulation abnormalities that occur in patients with liver disease are due to DIC, liver disease alone, or a combination of these and other mechanisms. A DIC-like syndrome occurs frequently in patients with acute hepatic failure. Laboratory abnormalities in these cases include hypofibrinogenemia, thrombocytopenia, increased FDP such as D-dimer, and decreased levels of Factors V and VIII.
Acquired dysfibrinogenemia (in patients with selected liver diseases [see the section “Fibrinogen Deficiencies”]): Impaired fibrin polymerization may result and thereby predispose the patient to bleeding.
Increased fibrinolysis: Hemostatic abnormalities in patients with cirrhosis may be due to increased fibrinolysis. This may occur as a result of decreased hepatic clearance of plasminogen activators and decreased synthesis of inhibitors of fibrinolysis (see Figure 11–4).
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Patients with acute and chronic liver disease often have laboratory evidence of a hemostatic abnormality. These patients may be asymptomatic or have only mild bleeding problems, but those with advanced liver disease may experience a severe hemorrhage.
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The laboratory evaluation for hemostatic defects from liver disease is shown in Table 11–7.
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Immune Thrombocytopenic Purpura (ITP)
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ITP (where the I formerly stood for idiopathic) exists in both an acute and a chronic form. The disorder is one in which accelerated platelet destruction occurs in the absence of other causes such as DIC, thrombotic thrombocytopenic purpura (TTP), drug-induced thrombocytopenia, and neonatal thrombocytopenia. Platelet production is also often reduced.
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The destruction of platelets in ITP is antibody-mediated. The amount of platelet-associated IgG is increased in the majority of patients with acute and chronic ITP. Many patients with chronic ITP have increased levels of antiplatelet antibodies in the serum, as well as on the platelet surface. It should be noted that there are a host of disorders unrelated to immune thrombocytopenias, which are associated with increased IgG on the platelet surface. Helicobacter pylori infection has been associated with ITP.
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In acute ITP, the platelet may be an innocent target of an antipathogen antibody that cross-reacts with an epitope on the platelet membrane. Chronic ITP appears to be more of a classic autoimmune illness in which the target antigens for platelet autoantibodies are platelet GPs. Sequestration and destruction of antibody-coated platelets occur predominantly in the spleen.
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Acute ITP usually presents as a childhood illness with peak incidence between 2 and 9 years. It is heralded by a prodromal illness, such as a viral respiratory infection, in 60% to 80% of cases. The infection occurs 2 to 21 days prior to onset of thrombocytopenia. The risk of hemorrhage is greatest during the first 1 to 2 weeks after the onset of acute ITP. Intracranial hemorrhage is the most feared complication of ITP. The majority of patients experience a spontaneous resolution of acute ITP 3 weeks to 3 months after onset. A small percentage of patients do not recover fully after 12 months, and advance to a diagnosis of chronic ITP.
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Acute ITP usually presents as a childhood illness with peak incidence between 2 and 9 years. Chronic ITP occurs most commonly between the ages of 20 and 50 years, and in females more often than males.
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Chronic ITP occurs most commonly between the ages of 20 and 50 years, and in females more often than in males (ratio of 2:1 to 3:1). It is characterized by the absence of a prodromal illness and the presence of mild bleeding that may continue for months before medical attention is sought. Manifestations include scattered petechiae or purpura, mostly on distal extremities, mild mucosal bleeding, easy bruising, epistaxis, and menorrhagia. ITP is often discovered in an asymptomatic patient found to have a low platelet count as part of a complete blood count (CBC). The diagnosis of ITP is made only after ruling out other causes for an isolated thrombocytopenia by history, physical examination, and laboratory studies.
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See Table 11–8 for information on the laboratory evaluation for ITP.
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Drug-induced Immunologic Thrombocytopenia
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Many drugs have been implicated in drug-induced immune thrombocytopenia. However, most cases can be attributed to relatively few drugs, notably heparin, quinidine/quinine, gold salts, and sulfonamides. Exposure to most of these compounds is readily ascertained. However, when obtaining the patient's history, one should include inquiries regarding consumption of over-the-counter medications and topical medications, as well as soft drinks, mixers, and aperitifs to rule out exposure to quinine. The pathogenesis of thrombocytopenia for most drugs involves both the drug and IgG (as the predominant class of antibody involved). A plasma protein bound to the drug serves as the antigen; the antigen combines with a specific antibody, and this complex binds to the platelet membrane. This is known as an “innocent bystander” effect. The antibody-coated platelet is then sequestered and destroyed. Certain other drugs (eg, protamine, bleomycin, and ristocetin) can cause destruction of platelets by a direct toxic effect that is nonimmune. In heparin-induced thrombocytopenia (HIT), a complex of heparin and a circulating protein derived from the platelet, known as platelet factor 4 (PF4), acts as the antigen. The complex, along with bound antibody, binds to the platelet surface, causing platelet activation, and unlike other drug-induced thrombocytopenias, an increased risk for thrombosis.
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Many drugs have been implicated in drug-induced immune thrombocytopenia. However, most cases can be attributed to relatively few drugs, notably heparin, quinidine/quinine, gold salts, and sulfonamides.
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The true incidence of drug-induced immunologic thrombocytopenia is not known. The incidence varies with the drug in question and the clinical condition or treatment of the patient. It may be as high as 1% to 3% of people exposed to the drug, as is the case with unfractionated (standard) heparin. Of quinidine users, approximately 1 in 1000 develop symptomatic thrombocytopenia. Drug-induced immunologic thrombocytopenia occurs most commonly in patients more than 50 years old, but it also has been reported in infants less than 1 year old. It is not possible to predict that patients will develop thrombocytopenia from drug treatment.
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Ingestion of a drug that induces thrombocytopenia may produce flushing, fever, headache, and chills prior to onset of thrombocytopenia. The onset of thrombocytopenia may be abrupt following drug exposure or, if it requires antibody generation to lower the platelet count, it may be delayed for 4 to 15 days. Anamnestic responses may occur and if they arise, the delay is shorter. Bleeding may occur as early as 6 to 12 hours after exposure to the drug in highly responsive patients. Bleeding manifestations may include 1 or more of the following: petechiae, purpura (usually the first symptom), mucosal hemorrhagic bullae, gastrointestinal or genitourinary hemorrhage, intrapulmonary hemorrhage, and, lastly, intracranial hemorrhage, which is rare, but often lethal. HIT is unique in that bleeding is uncommon, and, as noted above, HIT patients are at risk for thrombosis rather than bleeding.
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Heparin-induced thrombocytopenia is unique in that bleeding is uncommon, and HIT patients are at risk for thrombosis rather than bleeding.
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See Table 11–9 for information on the laboratory evaluation for drug-induced immunologic thrombocytopenia. Laboratory tests for drug-induced thrombocytopenia are not routinely available, with the exception of testing for HIT. If HIT is considered, a platelet count should be performed first. If the platelet count decreases to 50% or less of its apparent baseline value, a test for antibodies to the heparin–PF4 complex or a functional test that shows platelet activation in the presence of heparin and the patient's plasma should be performed.
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Posttransfusion Purpura
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Posttransfusion purpura (PTP) is a rare syndrome characterized by the sudden onset of thrombocytopenia 7 to 10 days following transfusion of blood or blood products containing platelets or platelet material. The thrombocytopenia appears to be due to antibody-mediated destruction of autologous as well as transfused platelets. In over 90% of cases, the antibody that develops in the affected individuals is directed against the antigen HPA-1a, formerly known as P1A1, on platelet membrane GP IIIa. In these cases, the recipient's own platelets are HPA-1a negative. It is not known why there is destruction of the patient's own HPA-1a-negative platelets following platelet transfusion with HPA-1a-positive platelets. Only 2% to 3% of the population in the United States lacks this antigen. Antibodies against other platelet-specific antigens have been reported in PTP, but they are much less commonly encountered. In almost all cases, the development of anti-HPA-1a antibody is thought to be an anamnestic response, with prior sensitization occurring through previous transfusion or pregnancy.
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PTP occurs predominantly in females, perhaps due to the likelihood of sensitization through pregnancy. The interval between the first exposure to the HPA-1a antigen and the transfusion that incites the thrombocytopenia is greater than 3 years in most cases in which the information has been reported. The onset of thrombocytopenia is fulminant in most cases, with the platelet count decreasing to <10,000/μL. Hemorrhage usually begins with purpura and mucocutaneous bleeding, and may progress to gastrointestinal and genitourinary bleeding, epistaxis, oozing from intravenous access sites, and intracranial hemorrhage. In severely affected patients sustained with supportive therapy of red blood cells and/or platelets, the thrombocytopenia usually begins to resolve in 14 days (mean value with a range 1-35 days). Cases with less severe thrombocytopenia apparently require a longer recovery period (24 days average, range 6-70 days). The outcome is fatal in approximately 10% of cases, usually due to hemorrhage. The risk of fatal hemorrhage appears to be greatest at the onset of the disease. Recurrent PTP has been documented, with the recurrence appearing no sooner than 3 years after the first episode, even though antibody may persist in the patient's blood during the intervening time and there may be repeated challenges with exogenous platelets.
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See Table 11–10 for information on the laboratory evaluation for PTP.
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Neonatal Alloimmune Thrombocytopenia (NAIT)
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NAIT is a disorder in which there is destruction of platelets in the fetus and newborn. The destruction occurs following transplacental passage of maternal IgG antibodies directed against a platelet-specific antigen present on fetal platelets and absent from the mother's platelets. The antibody-coated platelets are removed from the circulation by the neonate's reticuloendothelial system around the time of birth. The estimated incidence ranges from 1 in 5000 to 1 in 2000 births, with an increasingly higher incidence in recent years attributed to improved surveillance and serologic testing for the disorder. The platelet-specific antigen implicated in 80% to 90% of all cases (and 95% of symptomatic cases) of NAIT is HPA-1a. As previously noted, this antigen is present on the platelets of 97% to 98% of the general population. In approximately 50% of cases, NAIT occurs during the first pregnancy; when it does occur, there is a 97% chance that the next pregnancy will be affected.
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Neonatal alloimmune thrombocytopenic purpura is a disorder in which there is destruction of platelets in the fetus and newborn. The destruction occurs following transplacental passage of maternal IgG antibodies directed against a platelet-specific antigen present on fetal platelets and absent from the mother's platelets.
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Affected newborns are usually the product of an otherwise uncomplicated pregnancy and delivery. Within hours after birth, petechiae and ecchymoses appear in a generalized distribution. Other clinical signs include neurologic abnormalities if intracranial hemorrhage occurs, and pallor from anemia, if the bleeding is severe. Intracranial hemorrhage is the leading cause of death in NAIT, with a 50% mortality. Overall mortality from NAIT is approximately 5% to 10%. Thrombocytopenia usually persists for approximately 2 weeks in untreated cases (range of 1 week to 2 months), and 1 week in treated cases.
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See Table 11–11 for information on the laboratory evaluation for NAIT.
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Discussions of TTP and hemolytic–uremic syndrome (HUS), which are thrombocytopenias associated with thrombosis, are presented among the thrombotic disorders.
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Essential Thrombocythemia
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Essential thrombocythemia is a chronic myeloproliferative disorder, characterized by thrombocytosis arising from the clonal proliferation of a neoplastic multipotent stem cell. Life expectancy can be essentially normal with a median survival of 10 to 15 years, but the disease course is frequently complicated by both hemorrhage and thrombosis. A small percentage (<5%) of patients progress to acute leukemia, predominantly those patients previously treated with radioactive phosphorus or alkylating agents to reduce their platelet counts. At the time of diagnosis using older criteria, mild splenomegaly occurs in 30% to 50% of patients, and hepatomegaly in 15% to 20%. Using 2008 WHO diagnostic criteria, splenomegaly is present in only a minority of patients at diagnosis. The incidence of the disorder is higher in older age groups.
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The principal diagnostic feature of essential thrombocythemia is a persistently elevated platelet count with bone marrow megakaryocyte hyperplasia. Patients with this disorder can progress to a “spent” phase, characterized by myelofibrosis and a low platelet count. The purpose of the laboratory testing is to eliminate other possible etiologies for the thrombocytosis. Other entities in the differential diagnosis of an elevated platelet count include reactive thrombocytosis and other myeloproliferative disorders—myelofibrosis, polycythemia vera, and chronic myelogenous leukemia.
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See Table 11–12 for information on the laboratory evaluation for essential thrombocythemia.
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von Willebrand Disease
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vWD is caused by a quantitative deficiency of normal vWF in the majority of cases and a qualitatively abnormal vWF in the remainder of cases. vWF normally polymerizes to form multimers, which are aggregates of a single vWF polypeptide; in normal plasma, the multimers have a range of sizes. vWF has 2 major roles:
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von Willebrand disease is caused by a quantitative deficiency of normal von Willebrand factor in the majority of cases and a qualitatively abnormal von Willebrand factor in the remainder of cases.
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Platelet adhesion: Large multimers of vWF (ie, those with many units of the single polypeptide) effectively promote platelet adhesion to the subendothelium in injured vessels; if only small multimers are present, platelet plugs form poorly.
Binding of Factor VIII: vWF circulates in the plasma with Factor VIII, the coagulant protein that is lacking in hemophilia A. vWF prolongs the half-life of Factor VIII by protecting it from rapid degradation. If vWF is reduced, Factor VIII coagulant activity is often reduced as well.
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vWD prevalence estimates vary, with reported values as high as 1% of the general population. Unlike hemophilia A and B, vWD affects both men and women. It is likely to be the most common inherited bleeding disorder. There are 3 major types of vWD. The types were reorganized and renumbered with Arabic numerals in the 1990s (see Table 11–13). The most common type (type 1) is usually a mild bleeding disorder; it accounts for the majority of all cases of vWD. Type 2 vWD includes patients with qualitative vWF defects. Type 3 is rare and inherited as an autosomal recessive trait. It is associated with severe bleeding and very low to absent vWF levels. The types are distinguished from each other by laboratory testing.
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vWD prevalence estimates vary, with reported values as high as 1% of the general population. Unlike hemophilia A and B, vWD affects both men and women.
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It should also be noted that the mean vWF levels vary with blood type as shown in the second portion of Table 11–14.
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More than 65% of patients with vWD have type O, presumably because patients with this blood type start from a lower baseline value for vWF.
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The severity of bleeding is highly variable among patients, even within the same subtype of vWD, and even within an individual patient over time. Typically, bleeding manifestations such as easy bruising or epistaxis begin in early childhood. Other manifestations include menorrhagia and mucous membrane bleeding (from the gingiva, oropharynx, and gastrointestinal and genitourinary tracts). Profuse hemorrhage may occur with a significant hemostatic challenge such as trauma or surgery.
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Laboratory test results vary with the type and subtype of vWD. Like the severity of bleeding, the laboratory values can also vary widely over time for an individual patient, and may sometimes be normal. Normal results from a single determination do not rule out the diagnosis. If the patient history strongly suggests vWD, and the test results are normal, the tests should be repeated at a later time because plasma levels for vWF are increased during pregnancy, stress, while receiving oral contraceptives, and during an acute illness or injury. Therefore, values obtained at these times may be unreliable for diagnosis. It is also not yet clear if the absolute level of vWF or the level relative to the mean vWF for the blood type of the patient is more important in establishing the diagnosis. Current guidelines note that the absolute level of vWF seems to be more important than the level relative to blood type.
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See Table 11–14 for information on the laboratory evaluation for vWD.
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If the patient history strongly suggests vWD, and the test results are normal, the tests should be repeated at a later time because plasma levels for vWF are increased during pregnancy, stress, while receiving oral contraceptives, and during an acute illness or injury.
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von Willebrand Disease Types, Subtypes, and Their Expected Test Results
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Type 1: vWF multimers of all sizes are decreased due to a defect in synthesis or release of vWF from the endothelium, the site of most vWF synthesis. Functional (ristocetin cofactor or vWF:RCo) and antigenic (vWF antigen or vWF:Ag) levels of vWF are usually proportionately decreased. Factor VIII activity might also be low. The vWF multimer pattern shows a normal distribution of multimers.
Type 2A: Absence of large and intermediate-size vWF multimers from the plasma and platelet surface, due to a defect in the synthesis or polymerization of multimers, or from increased proteolysis of multimers. Functional activity (vWF:RCo) is decreased compared with antigenic levels (vWF:Ag). Therefore, vWF:RCo < vWF:Ag < Factor VIII is the most commonly observed pattern in type 2A. The vWF multimer pattern shows an abnormal distribution of multimers, with the absence of large and intermediate-size multimers.
Type 2B: Marked deficiency of large vWF multimers from plasma. Intermediate-size and small multimers are present. Large multimers are present on the patient's platelets, due to increased affinity of the abnormal vWF molecule for the platelet surface. Functional and antigenic levels in plasma samples are similar to those in type 2A (vWF:RCo < vWF:Ag < Factor VIII). The vWF multimer pattern shows the absence of large multimers from plasma. The patient's platelets show increased aggregation at low concentrations of ristocetin that do not cause normal platelets to aggregate. The patient's platelets aggregate at low concentrations of ristocetin because they are coated with large vWF multimers.
Types 2M and 2N are uncommon and are briefly described in Table 11–13.
Type 3: Severe deficiency of all vWF multimers, due to a marked defect in synthesis. Factor VIII activity is less severely affected than vWF activity. Both functional and antigenic vWF levels are markedly reduced. The vWF multimer pattern shows a virtual absence of all-size multimers.
Platelet-type Willebrand disease: vWF is qualitatively normal, but abnormal platelets have an increased affinity for large multimers of vWF due to a defect in platelet GP Ib. The laboratory test values are similar to those in type 2B.
Acquired vWD: This disorder has been found in patients with systemic lupus erythematosus, multiple myeloma, Waldenström macroglobulinemia, lymphoproliferative disorders, and other diseases. Patients have no congenital or familial history of bleeding. Causes of the decrease in circulating vWF include adsorption of large multimers onto cells (eg, lymphocytes or tumor cells) or the presence of antibodies to vWF. Acquired vWD resolves when the underlying disorder is effectively treated.
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Bernard–Soulier Disease and Glanzmann Thrombasthenia
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Bernard–Soulier syndrome (BS) and GT are rare congenital hemorrhagic disorders that result from absent or defective specific platelet membrane GPs, impairing platelet function. BS is characterized by a decrease of functional GP Ib/IX/V, the platelet receptor for vWF. GT is characterized by a decrease of functional GP IIb/IIIa, the complex that mediates platelet aggregation by binding fibrinogen to the platelet surface when platelets are activated.
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Bernard–Soulier syndrome and Glanzmann thrombasthenia are rare congenital hemorrhagic disorders that result from absent or defective specific platelet membrane glycoproteins, impairing platelet function.
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GT often decreases in severity with age. Manifestations include easy bruising, epistaxis, mucous membrane bleeding—particularly in the gastrointestinal tract—and menorrhagia. The amount of hemorrhage is highly variable among affected patients.
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See Table 11–15 for information on the laboratory evaluation for BS and GT.
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Platelet Storage Pool Disease
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Platelet SPD represents a group of disorders in which there is a deficiency of platelet granules. Decreased secretion of platelet granular contents at the time of platelet activation makes the platelets less hemostatically effective. The congenital forms of SPD include:
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Delta SPD: platelets have a decreased number of delta (dense) granules; these secretory granules contain ADP, polyphosphate, serotonin, and calcium.
Alpha-delta or alpha-partial delta SPD: decreased number of delta granules with either a complete or partial deficiency of alpha granules; alpha granules contain many proteins including fibrinogen, PF4, platelet-derived growth factor, and beta-thromboglobulin.
Alpha SPD (“gray platelet syndrome”): decreased number of alpha granules, and a normal number of delta granules; platelets appear gray, large, and vacuolated on a peripheral blood smear.
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SPD also may occur as an acquired abnormality, acutely in patients who have been supported on a cardiopulmonary bypass device and chronically in some cases of acute leukemia and myeloproliferative disorders. The molecular basis of most types of congenital SPD is unknown. It may result from abnormal granule morphogenesis or abnormal granule maturation in megakaryocytes. SPD may be a manifestation of a global defect in granule formation as in the Hermansky–Pudlak syndrome (see below). Hereditary SPD is the most common congenital qualitative platelet disorder, but it is still quite rare.
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Most patients with storage pool disease have mild bleeding symptoms. Bleeding manifestations of SPD include mild mucous membrane bleeding, easy bruising, menorrhagia, and excessive bleeding following dental or general surgery.
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Most patients with SPD have mild bleeding symptoms. Bleeding manifestations of SPD include mild mucous membrane bleeding, easy bruising, menorrhagia, and excessive bleeding following dental or general surgery. SPD may also occur as a component of the following syndromes:
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Hermansky–Pudlak syndrome: Features include delta SPD, oculocutaneous albinism, pulmonary fibrosis, and the accumulation of ceroid-like material in cells of the reticuloendothelial system. One subtype is due to a defective gene (called HSP1) on chromosome 10.
Chediak–Higashi syndrome: Features include delta SPD with giant platelet granules, photophobia, nystagmus, pseudoalbinism, lymphadenopathy, splenomegaly, and increased susceptibility to infection. It is attributed to defects in a gene called CHS1 on chromosome 1, affecting protein trafficking.
Thrombocytopenia with absent radius: Features include alpha SPD and absence of the radius bone.
Wiskott–Aldrich syndrome: Features of this X-linked recessive disorder include delta SPD with other metabolic platelet defects, recurrent infections, eczema, lymphocytopenia, multiple cellular and humoral immunologic defects, and thrombocytopenia with microplatelets (small platelets); the thrombocytopenia may resolve following splenectomy. It is attributed to a genetic defect in a gene called WASP on the X chromosome, affecting signal transduction and other functions.
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See Table 11–16 for information on the laboratory evaluation for storage pool deficiency.
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Hemostatic Defects in Uremia
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The bleeding tendency in uremia-induced hemorrhage is attributed to platelet dysfunction and endothelial cell dysfunction.
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The bleeding tendency in uremia-induced hemorrhage is attributed to platelet dysfunction and endothelial cell dysfunction. Bleeding manifestations may be mild or severe and can include petechiae, ecchymoses, epistaxis, and purpura.
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Bleeding manifestations may be mild or severe and can include petechiae, ecchymoses, epistaxis, and purpura. Paradoxically, chronic renal failure is also associated with an increased incidence of arterial and venous thrombosis, and, therefore, can influence hemostasis toward bleeding or clotting.
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See Table 11–17 for information on the laboratory evaluation for hemostatic defects in uremia.
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Drug-induced Qualitative Platelet Dysfunction
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Platelet dysfunction may occur on ingestion of a wide variety of drugs, particularly aspirin and clopidogrel (Plavix). Due to the ubiquity of aspirin in over-the-counter medications, many medications are implicated in platelet dysfunction. Some patients consume multiple drugs, such as aspirin and clopidogrel, with different and additive antiplatelet effects and thereby inhibit platelet function by more than 1 mechanism. Drug-induced platelet dysfunction can present a high bleeding risk in patients with existing hemostatic defects, but typically does not result in clinically significant bleeding in normal individuals. When hemorrhage does occur, there is usually an underlying hemostatic disorder affecting either the platelets or coagulation factors, or an anatomic lesion, such as an ulcer, that predisposes the patient to bleeding.
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Commonly encountered coagulopathies that place patients at risk for bleeding when there is a superimposed drug-induced platelet defect include vWD, thrombocytopenia of any cause, and anticoagulation therapy. Hemorrhagic manifestations can include petechiae and purpura, ecchymoses, mucosal membrane bleeding, hematuria, epistaxis, and oozing from intravenous access sites and surgical incisions.
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Laboratory tests are of little value in predicting the clinical significance of drug-induced platelet defects. They can confirm the presence of abnormal platelet function, but cannot assess the risk of bleeding. Furthermore, laboratory abnormalities in platelet function are not specific for a particular drug. See Table 11–18 for information on the laboratory evaluation for drug-induced platelet defects.
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