Disorders of Hemostasis
DISORDERS OF THE PLATELET AND VESSEL WALL - Robert I. Handin
INTRODUCTION
Patients with platelet or vessel wall disorders usually bleed into superficial sites such as the skin, mucous membranes, or genitourinary or gastrointestinal tract. Bleeding begins immediately after trauma and either responds to simple measures, such as pressure and packing, or requires systemic therapy with glucocorticoids, desmopressin, plasma fractions, or platelet concentrates. The most common platelet/vessel wall disorders are (1) various forms of thrombocytopenia, (2) von Willebrand's disease (vWD), and (3) drug-induced platelet dysfunction. This chapter reviews the diagnosis and treatment of quantitative and qualitative platelet disorders as well as vessel wall defects that cause bleeding. For further discussion of the physiology of normal hemostasis and the cardinal manifestations of bleeding arising from hemostatic disorders, see Chap. 53.
PLATELET DISORDERS
Platelets arise from the fragmentation of megakaryocytes, which are very large, polyploid bone marrow cells produced by the process of endomitosis. They undergo from three to five cycles of chromosomal duplication without cytoplasmic division. After leaving the marrow space, about one-third of the platelets are sequestered in the spleen, while the other two-thirds circulate for 7 to 10 days. Normally, only a small fraction of the platelet mass is consumed in the process of hemostasis, so most platelets circulate until they become senescent and are removed by phagocytic cells. The normal blood platelet count is 150,000 to 450,000/uL. A decrease in platelet count stimulates an increase in the number, size, and ploidy of megakaryocytes, releasing additional platelets into the circulation. This process is regulated by thrombopoietin (TPO) binding to its megakaryocyte receptor, a proto-oncogene c-mpl. TPO (c-mpl ligand) is secreted continuously at a low level and binds tightly to circulating platelets. A reduction in platelet count increases the level of free TPO and thereby stimulates megakaryocyte and platelet production.
The platelet count varies during the menstrual cycle, rising following ovulation and falling at the onset of menses. It is also influenced by the patient's nutritional state and can be decreased in severe iron, folic acid, or vitamin B12 deficiency. Platelets are acute-phase reactants, and patients with systemic inflammation, tumors, bleeding, and mild iron deficiency may have an increased platelet count, a benign condition called secondary, or reactive, thrombocytosis. The cytokines interleukin (IL) 3, IL-6, and IL-11 may stimulate platelet production in acute inflammation. In these conditions, the platelet count is usually <>
THROMBOCYTOPENIA
Thrombocytopenia is caused by one of three mechanisms — decreased bone marrow production, increased splenic sequestration, or accelerated destruction of platelets. In order to determine the etiology of thrombocytopenia, each patient should have a careful examination of the peripheral blood film, an assessment of marrow morphology by examination of an aspirate or biopsy, and an estimate of splenic size by bedside palpation supplemented, if necessary, by ultrasonography or computed tomography (CT). Occasional patients have "pseudothrombocytopenia," a benign condition in which platelets agglutinate or adhere to leukocytes when blood is collected with EDTA as anticoagulant. This is a laboratory artifact, and the actual platelet count in vivo is normal. A scheme for classifying patients with thrombocytopenia based on these clinical observations and laboratory tests is outlined in Fig. 101-1.
Impaired Production Disorders that injure stem cells or prevent their proliferation frequently cause thrombocytopenia. They usually affect multiple hematopoietic cell lines so that thrombocytopenia is accompanied by varying degrees of anemia and leukopenia. Diagnosis of a platelet production defect is readily established by examination of a bone marrow aspirate or biopsy, which should show a reduced number of megakaryocytes. The most common causes of decreased platelet production are marrow aplasia, fibrosis, or infiltration with malignant cells, all of which produce highly characteristic marrow abnormalities. Occasionally, thrombocytopenia is the presenting laboratory abnormality in these disorders. Cytotoxic drugs impair megakaryocyte proliferation and maturation and frequently cause thrombocytopenia. Rare marrow disorders, such as congenital amegakaryocytic hypoplasia and thrombocytopenia with absent radii (TAR syndrome), produce a selective decrease in megakaryocyte production.
Splenic Sequestration Since one-third of the platelet mass is normally sequestered in the spleen, splenectomy will increase the platelet count by 30%. Postsplenectomy thrombocytosis is a benign self-limited condition that does not require specific therapy. In contrast, when the spleen enlarges, the fraction of sequestered platelets increases, lowering the platelet count. The most common causes of splenomegaly are portal hypertension secondary to liver disease and splenic infiltration with tumor cells in myeloproliferative or lymphoproliferative disorders (Chap. 54). Isolated splenomegaly is rare, and in most patients it is accompanied by other clinical manifestations of an underlying disease. Many patients with leukemia, lymphoma, or a myeloproliferative syndrome have both marrow infiltration and splenomegaly and develop thrombocytopenia from a combination of impaired marrow production and splenic sequestration of platelets.
Accelerated Destruction Abnormal vessels, fibrin thrombi, and intravascular prostheses can all shorten platelet survival and cause nonimmunologic thrombocytopenia. Thrombocytopenia is common in patients with vasculitis, the hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), or as a manifestation of disseminated intravascular coagulation (DIC). In addition, platelets coated with antibody, immune complexes, or complement are rapidly cleared by mononuclear phagocytes in the spleen or other tissues, inducing immunologic thrombocytopenia. The most common causes of immunologic thrombocytopenia are viral or bacterial infections, drugs (often heparin), and a chronic autoimmune disorder referred to as idiopathic thrombocytopenic purpura (ITP). Patients with immunologic thrombocytopenia do not usually have splenomegaly and have an increased number of bone marrow megakaryocytes.
DRUG-INDUCED THROMBOCYTOPENIA
Many common drugs can cause thrombocytopenia (Table 101-1). Cancer chemotherapeutic agents may depress megakaryocyte production. Ingestion of large quantities of alcohol has a marrow-depressing effect leading to transient thrombocytopenia, particularly in binge drinkers. Thiazide diuretics, used to treat hypertension or congestive heart failure, impair megakaryocyte production and can produce mild thrombocytopenia (50,000 to 100,000/uL), which may persist for several months after the drug is discontinued.
Most drugs induce thrombocytopenia by eliciting an immune response in which the platelet is an innocent bystander. The platelet is damaged by complement activation following the formation of drug-antibody complexes. Current laboratory tests can identify the causative agent in 10% of patients with clinical evidence of drug-induced thrombocytopenia. The best proof of a drug-induced etiology is a prompt rise in the platelet count when the suspected drug is discontinued. Patients with drug-induced platelet destruction may also have a secondary increase in megakaryocyte number without other marrow abnormalities.
Although most patients recover within 7 to 10 days and do not require therapy, occasional patients with platelet counts <10,000>
IDIOPATHIC THROMBOCYTOPENIC PURPURA
The immunologic thrombocytopenias can be classified on the basis of the pathologic mechanism, the inciting agent, or the duration of the illness. The explosive onset of severe thrombocytopenia following recovery from a viral exanthem or upper respiratory illness (acute ITP1) is common in children and accounts for 90% of the pediatric cases of immunologic thrombocytopenia. Of these patients, 60% recover in 4 to 6 weeks and >90% recover within 3 to 6 months. Transient immunologic thrombocytopenia also complicates some cases of infectious mononucleosis, acute toxoplasmosis, or cytomegalovirus infection and can be part of the prodromal phase of viral hepatitis and initial infection with HIV. Acute ITP is rare in adults and accounts for <10%>
TREATMENT
Treatment of patients with ITP1 must take into account the age of the patient, the severity of the illness, and the anticipated natural history. Although adults have a higher incidence of intracranial bleeding than children, specific therapy may not be necessary unless the platelet count is <20,000/ul>20,000/uL, consideration should be given to withholding therapy. Patients with severe chronic thrombocytopenia may live with their disease for two or three decades.
Rituximab, an anti-CD20 monoclonal antibody used to treat lymphoma, has also proven an effective approach to ITP1 and is probably preferable to long-term glucocorticoid therapy. Rituximab eliminates normal B cells, including those producing the antiplatelet antibody. This B cell depletion is transient (lasting 12 to 18 months, normally) and has surprisingly few side effects or toxicities.
FUNCTIONAL PLATELET DISORDERS
As described in Chap. 53, normal hemostasis requires three critical platelet reactions — adhesion, aggregation, and granule release. Clinical bleeding can result from a failure of any of these important functions. Table 101-2 lists the major functional platelet disorders. Table 101-3 lists methods to assess platelet function.
von Willebrand's Disease vWD4 is the most common inherited bleeding disorder, occurring in 1 in 100 to 500 individuals. The von Willebrand factor (vWF) is a heterogeneous multimeric plasma glycoprotein with two major functions: (1) It facilitates platelet adhesion under conditions of high shear stress by linking platelet membrane receptors to vascular subendothelium; and (2) it serves as the plasma carrier for factor VIII, the antihemophilic factor, a critical blood coagulation protein. Discrete domains in each vWF subunit mediate each of these important functions. The normal plasma vWF level is 10 mg/L. The vWF activity is distributed among a series of plasma multimers with estimated molecular weights ranging from 400,000 to >20 million. A single large vWF precursor subunit is synthesized in endothelial cells and megakaryocytes, where it is cleaved and assembled into the disulfide-linked multimers present in plasma, platelets, and vascular subendothelium. A modest reduction in plasma vWF concentration or a selective loss in the high-molecular-weight multimers decreases platelet adhesion and causes clinical bleeding.
Although vWD4 is heterogeneous, certain clinical features are common to all the syndromes. With one exception (type III disease), all forms are inherited as autosomal dominant traits, and affected patients are heterozygous with one normal and one abnormal vWF5 allele. In mild cases, bleeding occurs only after surgery or trauma. More severely affected patients have spontaneous epistaxis or oral mucosal, gastrointestinal, or genitourinary bleeding. The laboratory findings are variable. The most diagnostic pattern is the combination of (1) a prolonged bleeding time, (2) a reduction in plasma vWF concentration, (3) a parallel reduction in biologic activity as measured with the ristocetin cofactor assay, and (4) reduced factor VIII activity. The variability in laboratory tests is related to both the heterogeneous nature of the defects in vWD and the fact that plasma levels are influenced by ABO blood group type, central nervous system disorders, systemic inflammation, and pregnancy. Since vWD is an autosomal dominant disorder, some vWF is produced by the remaining normal allele. Thus patients with mild defects may have laboratory values that fluctuate over time and may occasionally be within the normal range.
There are three major types of vWD4. Their mode of inheritance and laboratory findings are shown in Fig. 101-2. Patients with type I disease, the most common abnormality, have a mild to moderate decrease in plasma vWF6. In the milder cases, although hemostasis is impaired, the vWF level is just below normal (50% activity, or 5 mg/L). In type I disease, vWF antigen, factor VIII activity, and ristocetin cofactor activity are decreased with a normal spectrum of multimers detected by sodium dodecyl sulfate (SDS)-agarose gel electrophoresis.
The variant forms of vWD4 (type II disease) are much less common and characterized by normal or near-normal levels of a dysfunctional protein. Patients with the type IIa variant of vWD have a deficiency in the high- and medium-molecular-weight forms of vWF7 multimer detected by SDS8-agarose electrophoresis. This is due either to an inability to secrete the high-molecular-weight vWF multimers or to proteolysis of the multimers soon after they leave the endothelial cell and enter the circulation. Mutations in a localized region of the vWF A-2 domain have been identified in families with type IIa vWD (Fig. 101-3). The quantity of vWF antigen and the amount of associated factor VIII are usually normal. In the type IIb variant, high-molecular-weight multimers are also decreased; however, the decrease is due to the inappropriate binding of vWF to platelets. Intravascular platelet aggregates form that are rapidly cleared from the circulation, causing mild, variable thrombocytopenia. Mutations in a disulfide-bonded loop in the A-1 domain that binds to Gp9 Ib/IX are the cause of the type IIb defect (Fig. 101-3). A few patients have a platelet membrane disorder that mimics type IIb vWD — platelet-type vWD. It is due to mutations in the portion of Gp Ib/IX that interacts with vWF. Levels of total vWF antigen and factor VIII are normal.
Approximately 1 in 1 million individuals has a very severe form of vWD4 that is phenotypically recessive (type III disease). Type III patients are usually the offspring of two parents (usually asymptomatic) with mild type I disease. Type III patients may inherit a different abnormality from each parent (a doubly heterozygous or compound heterozygous state) or be homozygous for a single defect. Type III patients have severe mucosal bleeding and no detectable vWF10 antigen or activity and, like patients with mild hemophilia, may have sufficiently low factor VIII that they have occasional hemarthroses. Major deletions in the vWF gene have been found in some type III families. Families with nonsense mutations and the combination of a deleted and nonsense mutant allele have also been described.
Type IIn disease is due to a defect in the factor VIII binding site of vWF11. Patients resemble those with mild hemophilia and have low levels of factor VIII. The presence of disease in both males and females in a family is a clue to the role of vWF in this disease.
TREATMENT
There are two therapeutic options. Factor VIII concentrates retain high-molecular-weight vWF12 multimers (Humate-P, Alfanate), are highly purified and heat-treated to destroy HIV2, and are appropriate treatments for all the inherited forms of vWD4. During surgery or after major trauma, patients should receive factor VIII concentrates twice daily for 2 to 3 days to assure optimal hemostasis. Minor bleeding episodes such as prolonged epistaxis or severe menorrhagia may respond to a single infusion. Recurrent menorrhagia, a major problem for women with severe vWD, can be treated effectively with oral contraceptive agents that suppress menses.
A second therapeutic option, which avoids the use of plasma, is the use of desmopressin, a vasopressin analogue that has minimal blood pressure-elevating and fluid-retaining properties and raises the plasma vWF13 level in both normal individuals and patients with mild vWD4. Patients with type I disease are the best candidates for desmopressin therapy. However, they must be tested for an adequate response before anticipated surgery, and vWF levels must be monitored closely during therapy, since the patient may develop tachyphylaxis when therapy is continued for >48 h. Desmopressin should not be given to patients with variant forms of vWD without prior testing, since it may not improve multimer pattern or hemostasis in type IIa patients and may actually worsen the defect by depleting high-molecular-weight multimers, inducing intravascular platelet aggregation, and lowering the platelet count in type IIb patients. It is ineffective therapy for the severe (type III) form of vWD.
ACQUIRED VWD Although most cases of vWD4 are inherited, acquired vWD may be caused by antibodies that inhibit vWF14 function or by lymphoid or other tumors that selectively adsorb vWF multimers onto their surfaces. Anti-vWF antibodies have developed in patients with severe vWD following multiple transfusions, as well as in patients with autoimmune and lymphoproliferative disorders. Adsorption of vWF to tumor surfaces has been documented in patients with Waldenstrom's macroglobulinemia and Wilms' tumor and inferred in other patients with lymphoma. Treatment of acquired vWD should focus on the underlying disease, since plasma derivatives and desmopressin are often not effective and the disorder can be fatal.
Platelet Membrane Defects Receptors that modulate platelet adhesion and aggregation are located on the two major platelet surface glycoproteins. vWF15 facilitates platelet adhesion by binding to Gp16 Ib/IX, while fibrinogen links platelets into aggregates via sites on the Gp IIb/IIIa complex. Two rare platelet defects are characterized by a loss of or a defect in these Gp receptors. Patients with the Bernard-Soulier syndrome have markedly reduced platelet adhesion and cannot bind vWF to their platelets due to deficiency or dysfunction of the Gp Ib/IX complex. They also have reduced levels of another membrane protein (GpV that associates with Gp Ib/II), mild thrombocytopenia, and extremely large, lymphocytoid platelets. Platelets from patients with Glanzmann's disease, or thrombasthenia, are deficient or defective in the Gp IIb/IIIa complex. Their platelets do not bind fibrinogen and cannot form aggregates, although the platelets undergo shape change and secretion and are of normal size.
Both these disorders are autosomal recessive traits and markedly impair hemostasis, leading to recurrent episodes of severe mucosal hemorrhage. Bernard-Soulier platelets react normally to all stimuli except ristocetin. In contrast, thrombasthenic platelets adhere normally and will agglutinate with ristocetin but will not aggregate with any of the agonists that require fibrinogen binding, such as adenosine diphosphate (ADP), thrombin, or epinephrine.
The only effective therapy for hemorrhagic episodes in these two disorders is transfusion with normal platelets. Alloimmunization will eventually limit the life span of infused platelets. In addition, a few patients have developed inhibitor antibodies with specificity for the missing protein. These antibodies bind to the protein that is expressed on the transfused normal platelets and impair their function.
Platelet Release Defects The most common mild bleeding disorders arise from the ingestion of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit platelet production of thromboxane A2, an important mediator of platelet secretion and aggregation (Figs. 53-3 and 53-4). These drugs inhibit cyclooxygenase (COX), which converts arachidonic acid to a labile endoperoxide intermediate that is critical for thromboxane formation. Aspirin is the most potent of these agents; it irreversibly acetylates the platelet enzyme so that a single dose impairs hemostasis for 5 to 7 days. The other agents are competitive and reversible inhibitors with more transient effects. Blocking thromboxane A2 synthesis partially inhibits platelet release and aggregation with weak agonists, such as ADP17 and epinephrine, and produces a mild hemostatic defect. Cyclooxygenase exists in two isoforms, COX-1, which is constitutively expressed and active in the normal platelet, and COX-2, which is induced, especially in inflamed tissue. The selective COX-2 inhibitors, such as celecoxib, are increasingly being used to control arthritis pain and in other settings where NSAIDs are clinically useful. The COX-2 inhibitors are long-acting reversible inhibitors that have no adverse effects on platelet function. Their chronic use may be associated with high blood pressure and risk of thrombosis. The administration of high doses of certain antibiotics, particularly penicillin, can coat the platelet surface, block platelet release, and impair hemostasis.
Patients with release defects generally have minimal symptoms such as easy bruising, and bleeding is usually confined to the skin. Occasional patients will have prolonged oozing after surgery, particularly with procedures involving mucous membranes such as periodontal, oral, or reconstructive plastic surgery. The antiplatelet effect of drugs such as aspirin is more dramatic when they are administered to patients with underlying defects such as vWD4 or hemophilia. Patients with drug-induced COX18 deficiency often have a mildly prolonged bleeding time, and their platelets fail to aggregate when incubated with arachidonic acid, epinephrine, or low doses of ADP19. Patients who have taken aspirin should be treated as if they have a mild hemostatic defect for the next 5 to 7 days. Platelet responses to collagen and thrombin are impaired at low doses but normal at higher doses. Symptomatic patients should be encouraged to use drugs such as acetaminophen that do not impair platelet function. Although most cases of COX deficiency are drug-induced, occasional patients have inherited disorders in platelet COX activity that impair thromboxane production or receptor level defects that prevent platelets from responding to thromboxane A2.
Of the metabolic disorders that can perturb hemostasis, uremic platelet dysfunction is clinically the most important. The mechanism by which uremia impairs platelet function is not well understood, and retention of phenolic and guanidinosuccinic acids, excess prostacyclin production, or impaired vWF20-platelet interactions have all been implicated. The degree of uremia correlates with bleeding symptoms and anemia. Bleeding can usually be reversed by dialysis and often improves after red cell transfusion or treatment with erythropoietin. In addition, factor VIII concentrate or desmopressin, both of which raise plasma vWF levels, can also improve hemostasis. Conjugated estrogens improve hemostasis and can be used as long-term therapy.
Storage Pool Defects Platelet granules have considerable amounts of adenine nucleotides, calcium, and adhesive glycoproteins such as thrombospondin, fibronectin, and vWF21, all of which promote platelet adhesion and aggregation. Patients with defective platelet granules have a mild bleeding disorder. Platelet storage pool defects may be inherited as an isolated disorder or be part of systemic granule packaging defects such as oculocutaneous albinism or the Hermansky-Pudlak or Chediak-Higashi syndromes. Clinically, these patients cannot be distinguished from those with other functional platelet disorders, since they all have easy bruising, mucosal bleeding, and a prolonged bleeding time. They can be differentiated from patients with the COX22 defects because their platelets will usually aggregate in response to arachidonic acid. In addition, their platelets have decreased levels of specific granule constituents such as ADP23 and serotonin and abnormalities in granule morphology that are best visualized by electron microscopy.
Occasionally, patients with acute or chronic leukemia or one of the myeloproliferative disorders develop an acquired storage pool disorder due to dysplastic megakaryocyte development. In addition, patients with liver disease and some patients with SLE24 or other immune complex-mediated disorders may have circulating platelets that have degranulated prematurely. Platelet degranulation and a transient storage pool disorder may occur after prolonged cardiopulmonary bypass. Fortunately, most patients with storage pool defects have only mildly impaired hemostasis. They can be treated with platelet transfusions. Occasional patients have responded to desmopressin.
VESSEL WALL DISORDERS
Bleeding from vascular disorders (nonthrombocytopenic purpura) is usually mild and confined to the skin and mucous membranes. The pathogenesis of bleeding is poorly defined in many of the syndromes, and classic tests of hemostasis, including the bleeding time and tests of platelet function, are usually normal. Vascular purpura arises from damage to capillary endothelium, abnormalities in the vascular subendothelial matrix or extravascular connective tissues that support blood vessels, or from the formation of abnormal blood vessels. Several idiopathic disorders involve the vessel wall and can cause more severe bleeding and organ dysfunction.
THROMBOTIC THROMBOCYTOPENIC PURPURA
TTP25 is a fulminant, often lethal disorder that may be initiated by endothelial injury and subsequent release of vWF26 and other procoagulant materials from the endothelial cell. Causes include pregnancy, metastatic cancer, mitomycin C, high-dose chemotherapy, HIV2 infection, and certain drugs, such as the antiplatelet agent ticlopidine. Characteristic findings include the microvascular deposition of hyaline fibrin thrombi, thrombocytopenia, microangiopathic hemolytic anemia, fever, renal failure, fluctuating levels of consciousness, and evanescent focal neurologic deficits. The presence of hyaline thrombi in arterioles, capillaries, and venules without any inflammatory changes in the vessel wall is diagnostic. The presence of a severe Coombs-negative hemolytic anemia with schistocytes or fragmented red blood cells in the peripheral blood smear, coupled with thrombocytopenia, and minimal activation of the coagulation system help to confirm the clinical suspicion of TTP. This disorder should be distinguished from vasculitis and SLE27, which can predispose patients to TTP. Platelet-associated IgG and complement levels are usually normal in TTP.
Clinical Manifestations The classic pentad of TTP28 consists of hemolytic anemia with fragmentation of erythrocytes and signs of intravascular hemolysis, thrombocytopenia, diffuse and nonfocal neurologic findings, decreased renal function, and fever. These signs and symptoms occur variably, depending on the number and sites of the arteriolar lesions. The anemia may be very mild to very severe, and the thrombocytopenia often parallels it. The neurologic and renal symptoms are usually seen only when the platelet count is markedly diminished (<20>90% of patients whose disease terminates in death. Initially, changes in mental status such as confusion, delirium, or altered states of consciousness may occur. Focal findings include seizures, hemiparesis, aphasia, and visual field defects. These neurologic symptoms may fluctuate and terminate in coma. Involvement of myocardial blood vessels may be a cause of sudden death. The severity of the disorder can be estimated from the degree of anemia and thrombocytopenia and the serum lactic dehydrogenase level. Prothrombin time, partial thromboplastin time, fibrinogen concentration, and the level of fibrin split products are usually normal or only mildly abnormal. If the coagulation tests indicate a major consumption of clotting factors, the diagnosis of TTP is doubtful. A positive antinuclear antibody (ANA) determination is obtained in ~20% of patients.
Pathogenesis TTP29 is due to a deficiency in the activity of a specific metalloproteinase called ADAMTS 13, a normal plasma constituent that cleaves the ultra-high-molecular-weight (UHMW) forms of vWF30 secreted by endothelial cells to yield the heterogeneous set of multimers normally present in plasma (Fig. 101-4). A small number of patients have recurrent episodes of a TTP-like illness (Upshaw-Schulman syndrome) and are deficient in ADAMTS 13; the syndrome is inherited as an autosomal recessive trait. The more common acquired form of TTP is due to an inhibitory antibody that blocks ADAMTS 13 activity. These findings have led to more reliable diagnostic tests based on ADAMTS 13 enzyme activity and may have implications beyond TTP. Studies are underway to see if asymptomatic carriers with 50% levels of ADAMTS 13 are at increased risk of thromboembolism.
TREATMENT
The treatment of acute TTP31 has focused on the use of exchange transfusion or intensive plasmapheresis coupled with infusion of fresh-frozen plasma. Therapy may remove abnormal forms of vWF32, lower the concentration of ADAMTS 13 inhibitor, and replenish the deficient enzyme. Overall mortality has been markedly reduced, and the majority of patients with TTP recover from this formerly fatal disorder. Most patients surviving the acute illness recover completely, with no residual renal or neurologic disease. Occasional patients with a chronic, relapsing form of TTP require maintenance plasmapheresis and plasma infusion, and a few patients are controlled only with glucocorticoids. They presumably have persistence of the ADAMTS 13 inhibitor. In the future, TTP patients may be treated with some combination of enzyme replacement and immunosuppression to block inhibitor production.
HEMOLYTIC-UREMIC SYNDROME
HUS33 is a disease of infancy and early childhood that closely resembles TTP34. Patients present with fever, thrombocytopenia, microangiopathic hemolytic anemia, hypertension, and varying degrees of acute renal failure. In many cases, onset is preceded by a minor febrile or viral illness, and an infectious or immune complex-mediated cause has been proposed. Epidemics related to infection with a specific strain of Escherichia coli (O157:H7) have been documented. The bacteria contain a Shigella-like toxin that damages endothelial cells. As in TTP, DIC35 is not found. In contrast to TTP, the disorder remains localized to the kidney, where hyaline thrombi are seen in the afferent arterioles and glomerular capillaries. Thrombi are not present in other vessels, and neurologic symptoms, other than those associated with uremia, are uncommon. No therapy is proven effective; however, with dialysis for acute renal failure, the initial mortality is only 5% in children but may be higher in adults. Between 10 and 50% of patients have some chronic renal impairment. ADAMTS 13 levels are normal, and no inhibitors of the enzyme are present in this disorder.
HENOCH-SCHONLEIN PURPURA
Henoch-Schonlein, or anaphylactoid, purpura is a distinct, self-limited type of vasculitis that occurs in children and young adults. Patients have an acute inflammatory reaction in capillaries, mesangial tissues, and small arterioles that leads to increased vascular permeability, exudation, and hemorrhage. Vessel lesions contain IgA and complement components. The syndrome may be preceded by an upper respiratory infection or streptococcal pharyngitis or be associated with food or drug allergies. Patients develop a purpuric or urticarial rash on the extensor surfaces of the arms and legs and on the buttocks as well as polyarthralgias or arthritis, colicky abdominal pain, and hematuria from focal glomerulonephritis. Despite the hemorrhagic features, all coagulation tests are normal. A small number of patients may develop fatal acute renal failure, and 5 to 10% develop chronic nephritis. Glucocorticoids provide symptomatic relief of the joint and abdominal pains but do not alter the course of the illness.
METABOLIC AND INFLAMMATORY DISORDERS
Acute febrile illnesses may cause capillary fragility and skin bleeding. Immune complexes containing viral antigens or the viruses themselves may damage endothelial cells. In addition, certain pathogens such as the rickettsiae that cause Rocky Mountain spotted fever replicate in endothelial cells and damage them. Thrombocytopenia is also a frequent finding in acute infectious disorders and may contribute to skin bleeding. In addition, whenever the platelet count is <10,000/ul,>
FURTHER READING
ALVING BM : How I treat heparin-induced thrombocytopenia and thrombosis. Blood 101:31, 2003
Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children, and pregnancy. Br J Haematol 120:574, 2003
HANDIN RI, EWENSTEIN BM : von Willebrand's disease, in Blood: Principles and Practice of Hematology, 2d ed, RI Handin et al (eds). Philadelphia, Lippincott Williams & Wilkins, 2003, pp 1103-1130
VESELY SK et al: ADAMTS 13 activity in thrombotic thrombocytopenic purpura — hemolytic uremic syndrome: Relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood 102:60, 2003
— — — : Management of adult patients with persistent idiopathic thrombocytopenic purpura following splenectomy: A systematic review. Ann Intern Med 140:112, 2004
BIBLIOGRAPHY
BOYCE TG et al: Current concepts: Escherichia coli O157:H7 and the hemolytic uremic syndrome. N Engl J Med 333:364, 1995
MARCHUK DA et al: Vascular morphogenesis: Tales of two syndromes. Hum Mol Genet 2 (Suppl): 12097, 2003
HARRISON'S PRINCIPLES OF INTERNAL MEDICINE - 16th Ed. (2005)
PART FIVE - ONCOLOGY AND HEMATOLOGY
Section 3 - Disorders of Hemostasis
101. DISORDERS OF THE PLATELET AND VESSEL WALL - Robert I. Handin
INTRODUCTION
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