Page 2071 - Hematology_ Basic Principles and Practice ( PDFDrive )

1840 Part XII Hemostasis and Thrombosis

destruction of platelets can occur via immune mechanisms, such as bleeding with minimal trauma. Those with factor levels between 1%
immune thrombocytopenic purpura (ITP), alloimmune thrombocy- and 5% have an intermediate phenotype, whereas patients with factor
topenia, posttransfusion purpura, and drug-induced thrombocytope- VIII or IX levels above 5% usually have mild disease and bleed only
nia (see Chapter 131), or nonimmune mechanisms, which include with trauma or surgery. The frequency of bleeding episodes in patients
microangiopathic disorders, such as thrombotic thrombocytopenic with severe hemophilia can be reduced with prophylactic administra-
purpura and hemolytic uremic syndrome (see Chapter 134), as well tion of the appropriate factor concentrate; such treatment is also
as consumption because of activation of coagulation, such as occurs administered to hemophiliacs with overt bleeding, or in preparation
with disseminated intravascular coagulation (see Chapter 139). for surgery or other major interventions. Long-lasting factor VIII and
Platelet function disorders include disorders of platelet (a) adhesion, IX molecules have been developed to reduce the frequency of factor
such as von Willebrand disease (see Chapter 138) and Bernard-Soulier replacement. The half-lives of these recombinant full-length or
syndrome (see Chapter 125); (b) thromboxane synthesis; (c) secretion, truncated proteins have been prolonged by conjugating them to
such as alpha or dense granule deficiency or aspirin-like secretion hydrophilic polymers such as polyethylene glycol or by fusing them
defects; (d) aggregation, such as Glanzmann thrombasthenia (see with albumin or the Fc fragment of IgG 1. Conjugation to polyethyl-
Chapter 125); or (e) procoagulant activity (Scott syndrome) where the ene glycol protects the proteins from proteolytic degradation, whereas
platelets fail to support clotting factor complex assembly (see Chapter fusion technology creates new recycling pathways that diminish
126). Acquired disorders of platelet function can occur in patients natural protein breakdown (see Chapter 136). Management of
taking drugs that impair platelet function, such as aspirin or nonste- hemophilia becomes more complicated if patients develop inhibitory
roidal antiinflammatory drugs, or in patients with uremia, paraproteins antibodies that attenuate or abolish the activity of the infused factor.
or myelodysplastic or myeloproliferative disorders (see Chapter 130). Congenital deficiencies of prothrombin (factor II), factors V, VII,
Bleeding can also occur with inflammation or malformations of X, or XI (hemophilia C), or fibrinogen are less common causes of
the blood vessels or abnormalities of the connective tissue supporting bleeding (see Chapter 137). In contrast, deficiencies of components of
the blood vessels. Inflammatory disorders include Henoch-Schonlein the contact pathway—factor XII, high-molecular-weight kininogen,
purpura (see Chapter 152) and the vasculitis that occurs with para- and prekallikrein—are not associated with bleeding. The clinical and
proteins or cryoglobulins or in patients with systemic lupus erythe- laboratory evaluation of such patients is detailed in Chapters 128 and
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matosis or other immune disorders. Hereditary hemorrhagic 129, respectively, whereas their treatment is outlined in Chapter 115.
telangiectasia is an inherited disorder associated with malformations Acquired deficiencies of coagulation factors can result from
of the capillaries. Telangiectatic vessels can often be seen in the oral decreased synthesis due to severe liver disease, vitamin K deficiency
and nasal cavities of patients with this disorder and bleeding episodes, or intake of drugs that interfere with vitamin K metabolism, con-
primarily from the nose and gastrointestinal tract, are common. sumption because of excessive activation of coagulation (e.g., dis-
Abnormalities of the connective tissue matrix supporting the blood seminated intravascular coagulation; see Chapter 139), or accelerated
vessels include Marfan syndrome, Ehlers-Danlos syndrome, and clearance due to adsorption by paraproteins or amyloid (see Chapters
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pseudoxanthoma elasticum. Patients with these disorders frequently 86 and 87) or to autoantibodies that shorten the half-life or attenuate
report easy bruising. or abolish clotting factor activity.
Congenital disorders of fibrinogen include absence or low levels
of fibrinogen (afibrinogenemia and hypofibrinogenemia, respectively)
Disorders of Secondary Hemostasis or synthesis of a dysfunctional protein (dysfibrinogenemia). Acquired
disorders of fibrinogen include decreased synthesis or production of
Secondary hemostasis depends on rapid generation of sufficient an abnormal fibrinogen, increased fibrinogen consumption or the
amounts of thrombin to generate a fibrin mesh that not only con- presence of inhibitors that interfere with fibrin polymerization, such
solidates the platelet aggregates that form at sites of vascular injury, as paraproteins, autoantibodies, particularly in patients with systemic
but also is stable enough to provide a barrier that prevents leakage of lupus erythematosis or other immune disorders or elevated levels of
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blood from the damaged blood vessel. Secondary hemostasis can be fibrin(ogen) degradation products.
compromised by (a) impaired thrombin generation because of con- Stabilization of fibrin requires cross-linking of the α and γ chains
genital or acquired deficiencies of coagulation factors or cofactors or of adjacent fibrin monomers to yield a polymer that is resistant to
intake of drugs that inhibit one or more steps in the coagulation premature breakdown. Factor XIIIa, a transglutaminase, performs
pathways, (b) congenital or acquired fibrinogen deficiency or dys- this function by catalyzing the condensation of lysine residues on one
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function, and/or (c) impaired cross-linking of fibrinogen because of chain with glutamic acid residues on another chain. Congenital or
congenital or acquired deficiency of factor XIII (Table 122.3). acquired deficiency of factor XIII can impair cross-linking, resulting
Examples of inherited deficiencies of coagulation factors include in bleeding. The hallmarks of severe factor XIII deficiency include
hemophilia A and B, deficiencies of factor VIII and factor IX, respec- umbilical stump bleeding in the neonatal period (see Chapter 150),
tively (see Chapter 135). Because of redundancy in the coagulation intracranial hemorrhage with little or no trauma, recurrent soft tissue
system, only patients with a factor VIII or factor IX level less than hemorrhages, and, in females, recurrent spontaneous miscarriages.
1% have severe disease characterized by spontaneous bleeding or

Disorders of Tertiary Hemostasis
TABLE Disorders of Secondary Hemostasis
122.3 Tertiary hemostasis depends on the generation of plasmin, which
Components Affected Causes degrades fibrin and restores blood flow in damaged vessels. Premature
lysis of fibrin in hemostatic plugs can lead to bleeding; this can occur
Coagulation factors Congenital deficiency, autoantibodies, systemically or can be localized (Table 122.4). Systemic fibrinolysis
increased consumption, or drugs that that occurs in the absence of activation of coagulation, so-called
attenuate thrombin generation or thrombin primary hyperfibrinolysis, is rare but can occur with inherited defi-
activity
ciency of PAI-1 or α 2-antiplasmin, the inhibitors of the plasminogen
Fibrinogen Decreased production; increased consumption activators and plasmin, respectively, advanced liver disease, and some
or synthesis of an abnormal protein snake bites. More commonly, systemic hyperfibrinolysis is secondary
Impaired fibrin polymerization because of to activation of coagulation by procoagulants such as tissue factor
fibrin(ogen) degradation products or (e.g., in patients with metastatic cancer) or artificial surfaces (e.g.,
paraproteins in cardiopulmonary bypass surgery or with cardiac assist devices).
Fibrin cross-linking Congenital or acquired factor XIII deficiency Examples of localized hyperfibrinolysis include menorrhagia or hema-
turia after prostatectomy triggered by excessive plasmin generation