Platelet and Blood Vessel Disorders

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Chapter 478 Platelet and Blood Vessel Disorders

J. Paul Scott, Robert R. Montgomery

Megakaryopoiesis

Platelets are non-nucleated cellular fragments produced by megakaryocytes within the bone marrow and other tissues. Megakaryocytes are large polyploid cells. When the megakaryocyte approaches maturity, budding of the cytoplasm occurs and large numbers of platelets are liberated. Platelets circulate with a life span of 10-14 days. Thrombopoietin (TPO) is the primary growth factor that controls platelet production (Fig. 478-1). Levels of TPO appear to correlate inversely with platelet number and megakaryocyte mass. Levels of TPO are highest in the thrombocytopenic states associated with decreased marrow megakaryopoiesis and may be variable in states of increased platelet production.

Figure 478-1 Scheme of megakaryocytopoiesis and platelet production in idiopathic thrombocytopenic purpura (ITP). Hematopoietic stem cells (HSC) are mobilized and megakaryocyte (MK) and erythroid progenitors (MEP) accumulate with MK-committed progenitors (MKP) giving rise to mature MKs under control of thrombopoietin (TPO) working with chemokines, cytokines, and growth factors, including stem cell factor (SCF) and interleukin (IL)-3, IL-6, and IL-11. Endoreplication results in ploidy changes in MKs and increased chromosome number (up to 64N). Mature MKs migrate to the endothelial cell barrier delimiting the vascular sinus and, under the influence of stromal-derived factor-1 (SDF-1), give rise to proplatelets that protrude into the circulation and produce large numbers of platelets under hemodynamic determinants. Therapeutically given romiplostim and eltrombopag enter the marrow and join with TPO to stimulate megakaryocytopoiesis and platelet production.

(From Nurden AT, Viallard JF, Nurden P: New-generation drugs that stimulate platelet production in chronic immune thrombocytopenic purpura, Lancet 373:1562–1568, 2009, p 1563.)

The platelet plays multiple hemostatic roles. The platelet surface possesses a number of important receptors for adhesive proteins, including von Willebrand factor (VWF) and fibrinogen, as well as receptors for agonists that trigger platelet aggregation, such as thrombin, collagen, and adenosine diphosphate (ADP). After injury to the blood vessel wall, subendothelial collagen binds VWF. VWF undergoes a conformational change that induces binding of the platelet glycoprotein Ib (GPIb) complex (the VWF receptor). This process is called platelet adhesion. Platelets then undergo activation. During the process of activation, the platelets generate thromboxane A₂ from arachidonic acid via the enzyme cyclo-oxygenase. After activation, platelets release agonists, such as ADP, adenosine triphosphate (ATP), Ca²⁺, serotonin, and coagulation factors, into the surrounding milieu. Binding of VWF to the GPIb complex triggers a complex signaling cascade that results in activation of the fibrinogen receptor, the major platelet integrin glycoprotein α_IIb-β₃ (GPIIb-IIIa). Circulating fibrinogen binds to its receptor on the activated platelets, complex linking platelets together in a process called aggregation. This series of events forms a hemostatic plug at the site of vascular injury. The serotonin and histamine that are liberated during activation increase local vasoconstriction. In addition to acting in concert with the vessel wall to form the platelet plug, the platelet provides the catalytic surface on which coagulation factors assemble and eventually generate thrombin through a sequential series of enzymatic cleavages. Last, the platelet contractile proteins and cytoskeleton mediate clot retraction.

Thrombocytopenia

The normal platelet count is 150-450 × 10⁹/L. Thrombocytopenia refers to a reduction in platelet count to <150 × 10⁹/L. Causes of thrombocytopenia include: (1) decreased production on either a congenital or an acquired basis; (2) sequestration of the platelets within an enlarged spleen or other organ; and (3) increased destruction of normally synthesized platelets on either an immune or a nonimmune basis (Chapter 469; Tables 478-1 and 478-2 and Fig. 478-2).

Table 478-1 DIFFERENTIAL DIAGNOSIS OF THROMBOCYTOPENIA IN CHILDREN AND ADOLESCENTS

DESTRUCTIVE THROMBOCYTOPENIAS

Primary Platelet Consumption Syndromes

Combined Platelet and Fibrinogen Consumption Syndromes

Disseminated intravascular coagulation

Kasabach-Merritt syndrome

Virus-associated hemophagocytic syndrome

IMPAIRED PLATELET PRODUCTION

Hereditary disorders

Acquired disorders

Aplastic anemia

Myelodysplastic syndrome

Marrow infiltrative process—neoplasia

Osteopetrosis

Nutritional deficiency states (iron, folate, vitamin B₁₂, anorexia nervosa)

Drug- or radiation-induced thrombocytopenia

Neonatal hypoxia or placental insufficiency

SEQUESTRATION

Hypersplenism

Hypothermia

Burns

HIV, human immunodeficiency virus; ITP, immune thrombocytopenic purpura; VWD, von Willebrand disease.

From Wilson DB: Acquired platelet defects. In Orkin SH, Nathan DG, Ginsburg D, et al, editors: Nathan and Oski’s hematology of infancy and childhood, ed 7, Philadelphia, 2009, WB Saunders, p 1555, Box 33-1.

Table 478-2 CLASSIFICATION OF FETAL AND NEONATAL THROMBOCYTOPENIAS *

	CONDITION
Fetal	Alloimmune thrombocytopenia
	Congenital infection (e.g., CMV, toxoplasma, rubella, HIV)
	Aneuploidy (e.g., trisomy 18, 13, or 21, or triploidy)
	Autoimmune condition (e.g., ITP, SLE)
	Severe Rh hemolytic disease
	Congenital/inherited (e.g., Wiskott-Aldrich syndrome)
Early-onset neonatal (<72 hr)	Placental insufficiency (e.g., PET, IUGR, diabetes)
	Perinatal asphyxia
	Perinatal infection (e.g., Escherichia coli, GBS, Haemophilus influenzae)
	DIC
	Alloimmune thrombocytopenia
	Autoimmune condition (e.g., ITP, SLE)
	Congenital infection (e.g., CMV, toxoplasma, rubella, HIV)
	Thrombosis (e.g., aortic, renal vein)
	Bone marrow replacement (e.g., congenital leukemia)
	Kasabach-Merritt syndrome
	Metabolic disease (e.g., proprionic and methylmalonic acidemia)
	Congenital/inherited (e.g., TAR, CAMT)
Late-onset neonatal (>72 hr)	Late-onset sepsis
	NEC
	Congenital infection (e.g., CMV, toxoplasma, rubella, HIV)
	Autoimmune
	Kasabach-Merritt syndrome
	Metabolic disease (e.g., proprionic and methylmalonic acidemia)
	Congenital/inherited (e.g., TAR, CAMT)

CAMT, congenital amegakaryocytic thrombocytopenia; CMV, cytomegalovirus; DIC, disseminated intravascular coagulation; GBS, group B streptococcus; ITP, idiopathic thrombocytopenic purpura; IUGR, intrauterine growth restriction; NEC, necrotizing enterocolitis; PET, preeclampsia; SLE, systemic lupus erythematosus; TAR, thrombocytopenia with absent radii.

* The most common conditions are shown in bold.

From Roberts I, Murray NA: Neonatal thrombocytopenia: causes and management, Arch Dis Child Fetal Neonatal Ed 88:F359–F364, 2003.

Figure 478-2 Differential diagnosis of childhood thrombocytopenic syndromes. The syndromes initially are separated by their clinical appearance. Clues leading to the diagnosis are shown in italics. The mechanisms and common disorders leading to these findings are shown in the lower part of the figure. Disorders that commonly affect neonates are listed in the shaded boxes. HSM, hepatosplenomegaly; ITP, idiopathic immune thrombocytopenic purpura; NATP, neonatal alloimmune thrombocytopenic purpura; SLE, systemic lupus erythematosus; TAR, thrombocytopenia-absent radius; TTP, thrombotic thrombocytopenic purpura; UAC, umbilical artery catheter; VWD, von Willebrand disease; WBC, white blood cell.

(From Scott JP: Bleeding and thrombosis. In Kliegman RM, editor: Practical strategies in pediatric diagnosis and therapy, Philadelphia, 1996, WB Saunders, p 849; Kliegman RM, Marcdante KJ, Jenson HB, et al, editors: Nelson essentials of pediatrics, ed 5, Philadelphia, 2006, Elsevier/Saunders, p 716.)

Bibliography

Nachman RL, Rafii S. Platelets, petechiae, and preservation of the vascular wall. N Engl J Med. 2008;359:1261-1270.

Newman PK, Newman DK. Platelets and the vessel wall. In: Orkin SH, Nathan DG, Ginsberg D, et al, editors. Nathan and Oski’s hematology of infancy and childhood. ed 7. Philadelphia: Saunders Elsevier; 2009:1379-1399.

478.1 Idiopathic (Autoimmune) Thrombocytopenic Purpura

J. Paul Scott, Robert R. Montgomery

The most common cause of acute onset of thrombocytopenia in an otherwise well child is (autoimmune) idiopathic thrombocytopenic purpura (ITP).

Epidemiology

In a small number of children, estimated about 1 in 20,000, 1-4 wk after exposure to a common viral infection, an autoantibody directed against the platelet surface develops with resultant sudden onset of thrombocytopenia. A recent history of viral illness is described in 50-65% of cases of childhood ITP. The peak age is 1-4 yr, although the age ranges from early in infancy to the elderly. In childhood, males and females are equally affected. ITP seems to occur more often in late winter and spring after the peak season of viral respiratory illness.

Pathogenesis

Why some children develop the acute presentation of an autoimmune disease is unknown. The exact antigenic target for most such antibodies in most cases of childhood acute ITP remains undetermined. although in chronic ITP most patients demonstrate antibodies against the platelet glycoprotein complexes, α11b-B3 and GPIb. After binding of the antibody to the platelet surface, circulating antibody-coated platelets are recognized by the Fc receptor on splenic macrophages, ingested, and destroyed. Most common viruses have been described in association with ITP, including Epstein-Barr virus (Chapter 246) and HIV (Chapter 268). Epstein-Barr virus-related ITP is usually of short duration and follows the course of infectious mononucleosis. HIV-associated ITP is usually chronic. In some patients ITP appears to arise in children infected with Helicobacter pylori or rarely following the measles, mumps, rubella vaccine.

Clinical Manifestations

The classic presentation of ITP is a previously healthy 1-4 yr old child who has sudden onset of generalized petechiae and purpura. The parents often state that the child was fine yesterday and now is covered with bruises and purple dots. Often there is bleeding from the gums and mucous membranes, particularly with profound thrombocytopenia (platelet count <10 × 10⁹/L). There is a history of a preceding viral infection 1-4 wk before the onset of thrombocytopenia. Findings on physical examination are normal, other than the finding of petechiae and purpura. Splenomegaly, lymphadenopathy, bone pain, and pallor are rare. An easy to use classification system has been proposed from the U.K. to characterize the severity of bleeding in ITP on the basis of symptoms and signs, but not platelet count:

1 No symptoms

2 Mild symptoms: bruising and petechiae, occasional minor epistaxis, very little interference with daily living

3 Moderate: more severe skin and mucosal lesions, more troublesome epistaxis and menorrhagia

4 Severe: bleeding episodes—menorrhagia, epistaxis, melena—requiring transfusion or hospitalization, symptoms interfering seriously with the quality of life

The presence of abnormal findings such as hepatosplenomegaly, bone or joint pain, or remarkable lymphadenopathy suggests other diagnoses (leukemia). When the onset is insidious, especially in an adolescent, chronic ITP or the possibility of a systemic illness, such as systemic lupus erythematosus (SLE), is more likely.

Outcome

Severe bleeding is rare (<3% of cases in 1 large international study). In 70-80% of children who present with acute ITP, spontaneous resolution occurs within 6 mo. Therapy does not appear to affect the natural history of the illness. Fewer than 1% of patients develop an intracranial hemorrhage. Those who favor interventional therapy argue that the objective of early therapy is to raise the platelet count to >20 × 10⁹/L and prevent the rare development of intracranial hemorrhage. There is no evidence that therapy prevents serious bleeding. Approximately 20% of children who present with acute ITP go on to have chronic ITP. The outcome/prognosis may be related more to age, as ITP in younger children is more likely to resolve whereas the development of chronic ITP in adolescents approaches 50%.

Laboratory Findings

Severe thrombocytopenia (platelet count <20 × 10⁹/L) is common, and platelet size is normal or increased, reflective of increased platelet turnover (Fig. 478-3). In acute ITP, the hemoglobin value, white blood cell (WBC) count, and differential count should be normal. Hemoglobin may be decreased if there have been profuse nosebleeds or menorrhagia. Bone marrow examination shows normal granulocytic and erythrocytic series, with characteristically normal or increased numbers of megakaryocytes. Some of the megakaryocytes may appear to be immature and are reflective of increased platelet turnover. Indications for bone marrow aspiration/biopsy include an abnormal WBC count or differential or unexplained anemia as well as findings on history and physical examination suggestive of a bone marrow failure syndrome or malignancy. Other laboratory tests should be performed as indicated by the history and physical examination. In adolescents with new-onset ITP, an antinuclear antibody test should be done to evaluate for SLE. HIV studies should be done in at-risk populations, especially sexually active teens. Platelet antibody testing is seldom useful in acute ITP. A direct antiglobulin test (Coombs) should be done if there is unexplained anemia to rule out Evans syndrome (autoimmune hemolytic anemia and thrombocytopenia) (Chapter 458) or before instituting therapy with IV anti-D.

Figure 478-3 Blood smear and bone marrow aspirate from a child who had ITP showing large platelets (blood smear [left]) and increased numbers of megakaryocytes, many of which appear immature (bone marrow aspirate [right]).

(From Blanchette V, Bolton-Maggs P: Childhood immune thrombocytopenic purpura: diagnosis and management, Pediatr Clin North Am 55:393–420, 2008, p 400, Fig 4.)

Diagnosis/Differential Diagnosis

The well-appearing child with moderate to severe thrombocytopenia, an otherwise normal complete blood cell count (CBC), and normal findings on physical examination has a limited differential diagnosis that includes exposure to medication that induces drug-dependent antibodies, splenic sequestration due to previously unappreciated portal hypertension, and rarely, early aplastic processes, such as Fanconi anemia (Chapter 462). Other than congenital thrombocytopenia syndromes (Chapter 478.8), such as thrombocytopenia-absent radius (TAR) syndrome and MYH9-related thrombocytopenia, most marrow processes that interfere with platelet production eventually cause abnormal synthesis of red blood cells (RBCs) and WBCs and therefore manifest diverse abnormalities on the CBC. Disorders that cause increased platelet destruction on a nonimmune basis are usually serious systemic illnesses with obvious clinical findings (e.g., hemolytic-uremic syndrome [HUS], disseminated intravascular coagulation [DIC]) [see Table 477-1 and Fig. 478-2]. Isolated enlargement of the spleen suggests the potential for hypersplenism owing to either liver disease or portal vein thrombosis. Autoimmune thrombocytopenia may be an initial manifestation of SLE, HIV infection, common variable immunodeficiency, or rarely lymphoma. Wiskott-Aldrich syndrome (WAS; Chapter 120.2) must be considered in young males found to have thrombocytopenia with small platelets, particularly if there is a history of eczema and recurrent infection.

Treatment

There are no data showing that treatment affects either short- or long-term clinical outcome of ITP. Many patients with new-onset ITP have mild symptoms, with findings limited to petechiae and purpura on the skin, despite severe thrombocytopenia. Compared with untreated control subjects, treatment appears to be capable of inducing a more rapid rise in platelet count to the theoretically safe level of >20 × 10⁹/L, although there are no data indicating that early therapy prevents intracranial hemorrhage. Antiplatelet antibodies bind to transfused platelets as well as they do to autologous platelets. Thus, platelet transfusion in ITP is usually contraindicated unless life-threatening bleeding is present. Initial approaches to the management of ITP include the following:

1 No therapy other than education and counseling of the family and patient for patients with minimal, mild, and moderate symptoms, as defined earlier. This approach emphasizes the usually benign nature of ITP and avoids the therapeutic roller coaster that ensues once interventional therapy is begun. This approach is far less costly, and side effects are minimal.

2 Intravenous immunoglobulin (IVIG). IVIG at a dose of 0.8-1.0 g/kg/day for 1-2 days induces a rapid rise in platelet count (usually >20 × 10⁹/L) in 95% of patients within 48 hr. IVIG appears to induce a response by downregulating Fc-mediated phagocytosis of antibody-coated platelets. IVIG therapy is both expensive and time-consuming to administer. Additionally, after infusion, there is a high frequency of headaches and vomiting, suggestive of IVIG-induced aseptic meningitis.

3 Intravenous anti-D therapy. For Rh positive patients, IV anti-D at a dose of 50-75 µg/kg causes a rise in platelet count to >20 × 10⁹/L in 80-90% of patients within 48-72 hr. When given to Rh positive individuals, IV anti-D induces mild hemolytic anemia. RBC-antibody complexes bind to macrophage Fc receptors and interfere with platelet destruction, thereby causing a rise in platelet count. IV anti-D is ineffective in Rh negative patients. Rare life-threatening episodes of intravascular hemolysis have occurred in children and adults following infusion of IV anti-D.

4 Prednisone. Corticosteroid therapy has been used for many years to treat acute and chronic ITP in adults and children. Doses of prednisone of 1-4 mg/kg/24 hr appear to induce a more rapid rise in platelet count than in untreated patients with ITP. Whether bone marrow examination should be performed to rule out other causes of thrombocytopenia, especially acute lymphoblastic leukemia, before institution of prednisone therapy in acute ITP is controversial. Corticosteroid therapy is usually continued for 2-3 wk or until a rise in platelet count to >20 × 10⁹/L has been achieved, with a rapid taper to avoid the long-term side effects of corticosteroid therapy, especially growth failure, diabetes mellitus, and osteoporosis.

Each of these medications may be used to treat ITP exacerbations, which commonly occur several weeks after an initial course of therapy. In the special case of intracranial hemorrhage, multiple modalities should be used, including platelet transfusion, IVIG, high-dose corticosteroids, and prompt consultation by neurosurgery and surgery.

There is no consensus regarding the management of acute childhood ITP, except that patients who are bleeding significantly should be treated, representing less than 5% of children with ITP. Intracranial hemorrhage remains rare, and there are no data showing that treatment actually reduces its incidence.

The role of splenectomy in ITP should be reserved for 1 of 2 circumstances. The older child (≥4 yr) with severe ITP that has lasted >1 yr (chronic ITP) and whose symptoms are not easily controlled with therapy is a candidate for splenectomy. Splenectomy must also be considered when life-threatening hemorrhage (intracranial hemorrhage) complicates acute ITP, if the platelet count cannot be corrected rapidly with transfusion of platelets and administration of IVIG and corticosteroids. Splenectomy is associated with a lifelong risk of overwhelming postsplenectomy infection caused by encapsulated organisms and the potential development of pulmonary hypertension in adulthood.

Chronic Idiopathic Thrombocytopenic Purpura

Approximately 20% of patients who present with acute ITP have persistent thrombocytopenia for >12 mo and are said to have chronic ITP. At that time, a careful re-evaluation for associated disorders should be performed, especially for autoimmune disease, such as SLE; chronic infectious disorders, such as HIV; and nonimmune causes of chronic thrombocytopenia, such as type 2B and platelet-type von Willebrand disease, X-linked thrombocytopenia, autoimmune lymphoproliferative syndrome, common variable immunodeficiency syndrome, autosomal macrothrombocytopenia, and WAS (also X-linked). The presence of co-existing H. pylori infection should be explored and, if found, treated. Therapy should be aimed at controlling symptoms and preventing serious bleeding. In ITP, the spleen is the primary site of both antiplatelet antibody synthesis and platelet destruction. Splenectomy is successful in inducing complete remission in 64-88% of children with chronic ITP. This effect must be balanced against the lifelong risk of overwhelming postsplenectomy infection. This decision is often affected by lifestyle issues as well as the ease with which the child can be managed using medical therapy, such as IVIG, corticosteroids, IV anti-D. Rituximab, a chimeric monoclonal anti–B cell antibody, effectively induces a remission in 30-50% of children with chronic ITP. Two new effective agents that act to stimulate thrombopoiesis, romiplastin and eltrombopag (see Fig. 478-1), have been approved by the Federal Drug Administration to treat adults with chronic ITP. There are no data regarding either drug’s safety or efficacy in children.

Bibliography

Blanchette V, Bolton-Maggs P. Childhood immune thrombocytopenic purpura: diagnosis and management. Pediatr Clin North Am. 2008;55:393-420. ix

Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011;377:393-402.

De Waele L, Freson K, Louwette S, et al. Severe gastrointestinal bleeding and thrombocytopenia in a child with an anti-GATA1 autoantibody. Pediatr Res. 2010;67:314-319.

Edmonson MB, Riedesel EL, Williams GP, et al. Generalized petechial rashes in children during a parvovirus B19 outbreak. Pediatrics. 2010;125:e787-e792.

Fogarty PF, Segal JB. The epidemiology of immune thrombocytopenic purpura. Curr Opin Hematol. 2007;14:515-519.

France EK, Glanz J, Xu S, et al. Risk of immune thrombocytopenic purpura after measles-mumps-rubella immunization in children. Pediatrics. 2008;121:e687-e692.

George JN. Management of immune thrombocytopenia—something old, something new. N Engl J Med. 2010;363(20):1959-1960.

Glanz J, France E, Xu S, et al. A population-based, multistate cohort study of the predictors of chronic idiopathic thrombocytopenic purpura in children. Pediatrics. 2008;121:e506-e512.

Heddle NM, Cook RJ, Tinmouth A, et al. A randomized controlled trial comparing standard- and low-dose strategies for transfusion of platelets (SToP) to patients with thrombocytopenia. Blood. 2009;113:1564-1573.

Kühne T, Blanchette V, Buchanan GR, et al. Splenectomy in children with idiopathic thrombocytopenic purpura: a prospective study of 134 children from the Intercontinental Childhood ITP Study Group. Pediatr Blood Cancer. 2007;49:829-834.

Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med. 2010;363:1889-1899.

Mantadakis E, Farmaki E, Buchanan GR. Thrombocytopenic purpura after measles-mumps-rubella vaccination: a systematic review of the literature and guidance for management. J Pediatr. 2010;156:623-628.

McMillan R. The pathogenesis of chronic immune thrombocytopenic purpura. Semin Hematol. 2007;44:S3-S11.

The Medical Letter. Desirudin (Iprivask) for DVT prevention. Med Lett. 2010;52(1350):85-86.

The Medical Letter. Two new drugs for chronic ITP. Med Lett. 2009;51:10-11.

Mueller BU, Bennett CM, Feldman HA, et al. One year follow-up of children and adolescents with chronic immune thrombocytopenic purpura (ITP) treated with rituximab. Pediatr Blood Cancer. 2009;52:259-262.

Neunert CE, Buchanan GR, Imbach P, et al. Severe hemorrhage in children with newly diagnosed immune thrombocytopenic purpura. Blood. 2008;112:4003-4008.

Nurden AT. Sustaining platelet counts in chronic ITP. Lancet. 2011;377:358-360.

Panzer S, Pabinger I. Eltrombopag in chronic idiopathic thrombocytopenic purpura. Lancet. 2009;373:607-608.

Psaila B, Petrovic A, Page LK, et al. Intracranial hemorrhage (ICH) in children with immune thrombocytopenic (ITP): study of 40 cases. Blood. 2009;114:4777-4783.

Slichter SJ, Kaufman RM, Assmann SF, et al. Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med. 2010;362:600-612.

Thachil J, Hall GW. Is this immune thrombocytopenic purpura? Arch Dis Child. 2008;93:76-81.

478.2 Drug-Induced Thrombocytopenia

J. Paul Scott, Robert R. Montgomery

A number of drugs are associated with immune thrombocytopenia as the result of either an immune process or megakaryocyte injury. Some common drugs used in pediatrics that cause thrombocytopenia include valproic acid, phenytoin, carbamazepine, sulfonamides, vancomycin, and trimethoprim-sulfamethoxazole. Heparin-induced thrombocytopenia (and rarely, thrombosis) is seldom seen in pediatrics, but it occurs when, after exposure to heparin, the patient has an antibody directed against the heparin–platelet factor 4 complex.

Bibliography

Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med. 2007;357:580-587.

478.3 Nonimmune Platelet Destruction

J. Paul Scott and Robert R. Montgomery

The syndromes of DIC (Chapter 477), HUS (Chapters 478.4 and 512), and thrombotic thrombocytopenic purpura (TTP) (Chapter 478.5) share the hematologic picture of a thrombotic microangiopathy in which there is RBC destruction and consumptive thrombocytopenia caused by platelet and fibrin deposition in the microvasculature. The microangiopathic hemolytic anemia is characterized by the presence of RBC fragments, including helmet cells, schistocytes, spherocytes, and burr cells.

478.4 Hemolytic-Uremic Syndrome

J. Paul Scott and Robert R. Montgomery

See also Chapter 512. Typical HUS is an acute disease of infancy and early childhood and usually follows an episode of acute gastroenteritis, often triggered by Escherichia coli 0157:H7. Shortly thereafter, signs and symptoms of hemolytic anemia, thrombocytopenia, and acute renal failure ensue. Sometimes neurologic symptoms are associated with these findings. E. coli 0157:H7 produces a specific toxin (verotoxin) that binds to and damages renal endothelial cells preferentially.

The hemolytic anemia is characterized by morphologically abnormal RBCs, with the presence of helmet cells, spherocytes, schistocytes, burr cells, and other distorted forms. Thrombocytopenia despite normal numbers of megakaryocytes in the marrow indicates excessive platelet destruction. Results of tests for DIC are usually normal, except for elevated levels of D-dimer. Evaluation of the urine shows protein, RBCs, and casts. Anuria and severe azotemia indicate grave renal damage. Treatment of most cases of HUS involves institution of careful fluid management and prompt appropriate dialysis. Treatment using plasmapheresis is usually reserved for patients with HUS associated with major neurologic complications. Atypical HUS, which is often recurrent and familial, results from hereditary deficiency of the VWF-cleaving metalloproteinase ADAMTS-13 or less often abnormalities of the complement regulatory proteins.

478.5 Thrombotic Thrombocytopenic Purpura

J. Paul Scott, Robert R. Montgomery

Thrombotic thrombocytopenic purpura (TTP) is a rare pentad of fever, microangiopathic hemolytic anemia, thrombocytopenia, abnormal renal function, and central nervous system changes that is clinically similar to HUS, although TTP usually presents in adults and occasionally in adolescents. Microvascular thrombi within the central nervous system cause subtle, shifting neurologic signs that vary from changes in affect and orientation to aphasia, blindness, and seizures. Initial manifestations are often nonspecific (weakness, pain, emesis); prompt recognition of this disorder is critical. Laboratory findings provide important clues to the diagnosis and show microangiopathic hemolytic anemia characterized by morphologically abnormal RBCs, with schistocytes, spherocytes, helmet cells, and an elevated reticulocyte count in association with thrombocytopenia. Coagulation studies are usually nondiagnostic. Blood urea nitrogen and creatinine are usually elevated. The treatment of TTP is plasmapheresis (plasma exchange), which is effective in 80-95% of cases. Corticosteroids and splenectomy are reserved for refractory cases.

The majority of cases of TTP are caused by an acquired deficiency of a metalloproteinase (ADAMTS-13) that is responsible for cleaving the high molecular weight multimers of VWF and appears to play a pivotal role in the evolution of the thrombotic microangiopathy. In contrast, levels of the metalloproteinase in HUS are usually normal. Congenital deficiency of the metalloproteinase causes rare familial cases of TTP/HUS, usually manifested as recurrent episodes of thrombocytopenia, hemolytic anemia and renal involvement, with or without neurologic changes that often present in infancy after an intercurrent illness. Abnormalities of the complement system have now also been implicated in rare cases of familial TTP. ADAMTS-13 deficiency can be treated by repeated infusions of fresh frozen plasma.

Bibliography

Loirat C, Veyradier A, Girma JP, et al. Thrombotic thrombocytopenic purpura associated with von Willebrand factor-cleaving protease (ADAMTS13) deficiency in children. Semin Thromb Hemost. 2006;32:90-97.

478.6 Kasabach-Merritt Syndrome

J. Paul Scott and Robert R. Montgomery

See also Chapter 642. The association of a giant hemangioma with localized intravascular coagulation causing thrombocytopenia and hypofibrinogenemia is called Kasabach-Merritt syndrome. In most patients, the site of the hemangioma is obvious, but retroperitoneal and intra-abdominal hemangiomas may require body imaging for detection. Inside the hemangioma there is platelet trapping and activation of coagulation, with fibrinogen consumption and generation of fibrin(ogen) degradation products. Arteriovenous malformation within the lesions can cause heart failure. Pathologically Kasabach-Merritt syndrome appears to develop more often as a result of a kaposiform hemangioendothelioma or tufted hemangioma rather than a simple hemangioma. The peripheral blood smear shows microangiopathic changes. Multiple modalities have been used to treat Kasabach-Merritt syndrome, including surgical excision (if possible), laser photocoagulation, high-dose corticosteroids, local radiation therapy, antiangiogenic agents, such as interferon-α₂_, and vincristine. Over time, most patients who present in infancy have regression of the hemangioma. Treatment of the associated coagulopathy may benefit from a trial of antifibrinolytic therapy with ε-aminocaproic acid (Amicar).

478.7 Sequestration

J. Paul Scott and Robert R. Montgomery

Thrombocytopenia develops in individuals with massive splenomegaly because the spleen acts as a sponge for platelets and sequesters large numbers. Most such patients also have mild leukopenia and anemia on CBC. Individuals who have thrombocytopenia caused by splenic sequestration should undergo a work-up to diagnose the etiology of splenomegaly, including infectious, inflammatory, infiltrative, neoplastic, obstructive, and hemolytic causes.

478.8 Congenital Thrombocytopenic Syndromes

J. Paul Scott, Robert R. Montgomery

See Table 478-2. Congenital amegakaryocytic thrombocytopenia (CAMT) usually manifests within the 1st few days to wk of life, when the child presents with petechiae and purpura caused by profound thrombocytopenia. CAMT is caused by a rare defect in hematopoiesis due to a mutation in the stem cell TPO receptor (MPL). Other than skin and mucous membrane abnormalities, findings on physical examination are normal. Examination of the bone marrow shows an absence of megakaryocytes. These patients often progress to marrow failure (aplasia) over time. Hematopoietic stem cell transplantation is curative.

Thrombocytopenia-absent radius (TAR) syndrome consists of thrombocytopenia (absence or hypoplasia of megakaryocytes) that presents in early infancy with bilateral radial anomalies of variable severity, ranging from mild changes to marked limb shortening (Fig. 478-4). Many such individuals also have other skeletal abnormalities of the ulna, radius, and lower extremities. Thumbs are present. Intolerance to cow’s milk formula (present in 50%) may complicate management by triggering gastrointestinal bleeding, increased thrombocytopenia, eosinophilia, and a leukemoid reaction. The thrombocytopenia of TAR syndrome frequently remits over the 1st few yr of life. The molecular basis of TAR syndrome remains to be defined. A few patients have been reported to have a syndrome of amegakaryocytic thrombocytopenia with radioulnar synostosis due to a mutation in the HOXA11 gene. Different from TAR syndrome, this mutation causes marrow aplasia.

Figure 478-4 A newborn, the 1st child of young, healthy parents, with fully expressed thrombocytopenia-absent radius syndrome, including thrombocytopenia, hypereosinophilia, and anemia. Hypoplasia of the distal humeri and the shoulder girdles, bilateral hip dysplasia, mild talipes calcaneus, and clinodactyly of both little fingers are seen. This patient had a pronounced allergy to cow’s milk, with exposure followed by diarrhea, vomiting, and decreased weight and platelet count, making a cow’s milk–free diet mandatory. A persistent depressed nasal bridge and development of pronounced bowed legs are seen.

(From Wiedemann H-R, Kunze J, Grosse F-R, editors: Clinical syndromes, ed 3, [English translation], London, 1997, Mosby-Wolfe, p 430.)

Wiskott-Aldrich syndrome (WAS) is characterized by thrombocytopenia, with tiny platelets, eczema, and recurrent infection due to immune deficiency (Chapter 120.2). WAS is inherited as an X-linked disorder, and the gene for WAS has been sequenced. The WAS protein appears to play an integral role in regulating the cytoskeletal architecture of both platelets and T lymphocytes in response to receptor-mediated cell signaling. The WAS protein is common to all cells of hematopoietic lineage. Molecular analysis of families with X-linked thrombocytopenia has shown that many affected members have a point mutation within the WAS gene, whereas individuals with the full manifestation of WAS have large gene deletions. Examination of the bone marrow in WAS shows the normal number of megakaryocytes, although they may have bizarre morphologic features. Transfused platelets have a normal life span. Splenectomy often corrects the thrombocytopenia, suggesting that the platelets formed in WAS have accelerated destruction. After splenectomy, these patients are at increased risk for overwhelming infection and require lifelong antibiotic prophylaxis against encapsulated organisms. Approximately 5-15% of patients with WAS develop lymphoreticular malignancies. Successful hematopoietic stem cell transplantation cures WAS. X-linked macrothrombocytopenia and dyserythropoiesis have been linked to mutations in the GATA-1 gene, an erythroid and megakaryocytic transcription factor.

Bibliography

Bolton-Maggs PH, Chalmers EA, Collins PW, et al. A review of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO. Br J Haematol. 2006;135:603-633.

478.9 Neonatal Thrombocytopenia

J. Paul Scott, Robert R. Montgomery

478.10 Thrombocytopenia Due to Acquired Disorders Causing Decreased Production

J. Paul Scott and Robert R. Montgomery

Disorders of the bone marrow that inhibit megakaryopoiesis usually affect RBC and WBC production. Infiltrative disorders, including malignancies, such as acute lymphocytic leukemia, histiocytosis, lymphomas, and storage disease, usually cause either abnormalities on physical examination (lymphadenopathy, hepatosplenomegaly, or masses) or abnormalities of the WBC count, or anemia. Aplastic processes may present as isolated thrombocytopenia, although there are usually clues on the CBC (leukopenia, neutropenia, anemia, or macrocytosis). Children with constitutional aplastic anemia (Fanconi anemia) often have abnormalities on examination, including radial anomalies, other skeletal anomalies, short stature, microcephaly, and hyperpigmentation. Bone marrow examination should be performed when thrombocytopenia is associated with abnormalities found on physical examination or on examination of the other blood cell lines.

478.11 Platelet Function Disorders

J. Paul Scott and Robert R. Montgomery

Bleeding time and the platelet function analyzer (PFA-100) are the only commonly available tests to screen for abnormal platelet function. Bleeding time measures the interaction of platelets with the blood vessel wall and thus is affected by both platelet count and platelet function. The predictive value of bleeding time is problematic because bleeding time is dependent on a number of other factors, including the skill of the technician and the cooperation of the patient, often a challenge in the infant or young child. A normal bleeding time does not rule out a mild platelet function defect in a clinically symptomatic individual. The PFA-100 measures platelet adhesion and aggregation in whole blood at high shear when the blood is exposed to either collagen-epinephrine or collagen-ADP. Results are reported as the closure time measured in sec. Many clinical laboratories have replaced bleeding time with the use of the PFA-100. Both the PFA-100 and bleeding time are sensitive to moderate/severe VWD and platelet dysfunction. Both are variably insensitive to mild platelet function abnormalities and mild VWD. The use of the PFA-100 as a screening test remains controversial and, like the bleeding time, lacks specificity. Bleeding time is the only commonly available test to assess platelet-vessel wall interaction. For patient with a positive history of bleeding suggestive of von Willebrand disease or platelet dysfunction, specific von Willebrand factor testing and platelet function studies should be done irrespective of the results of the bleeding time or PFA-100.

Platelet function in the clinical laboratory is currently measured using platelet aggregometry. In the aggregometer, agonists, such as collagen, ADP, ristocetin, epinephrine, arachidonic acid, and thrombin (or the thrombin receptor peptide), are added to platelet-rich plasma, and the clumping of platelets over time is measured by an automated machine. At the same time, other instruments measure the release of granular contents, such as ATP, from the platelets after activation. The ability of platelets to aggregate and their metabolic activity can be assessed simultaneously. When a patient is being evaluated for possible platelet dysfunction, it is critically important to exclude the presence of other exogenous agents and to study the patient, if possible, off all medications for 2 wk.

478.12 Acquired Disorders of Platelet Function

J. Paul Scott and Robert R. Montgomery

A number of systemic illnesses are associated with platelet dysfunction, most commonly, liver disease, kidney disease (uremia), and disorders that trigger increased amounts of fibrin degradation products. These disorders frequently cause prolonged bleeding time and are often associated with other abnormalities of the coagulation mechanism. The most important element of management is to treat the primary illness. If treatment of the primary process is not feasible, infusions of desmopressin have been helpful in augmenting hemostasis and correcting bleeding time. In some patients, transfusions of platelets and/or cryoprecipitate have also been helpful in improving hemostasis.

Many drugs alter platelet function. The most commonly used drug in adults that alters platelet function is acetylsalicylic acid (aspirin). Aspirin irreversibly acetylates the enzyme cyclo-oxygenase, which is critical in the formation of thromboxane A₂. Aspirin usually causes moderate platelet dysfunction that becomes more prominent if there is another abnormality of the hemostatic mechanism. In children, commonly used drugs that affect platelet function include other nonsteroidal anti-inflammatory drugs, valproic acid, and high-dose penicillin. Specific agents to inhibit platelet function therapeutically include those that block the platelet ADP receptor (clopidogrel), α11b-β3 receptor antagonists as well as aspirin.

478.13 Congenital Abnormalities of Platelet Function

J. Paul Scott, Robert R. Montgomery

Severe platelet function defects usually present with petechiae and purpura shortly after birth, especially after vaginal delivery. Defects in the platelet GPIb complex (the VWF receptor) or the αIIb-β3 complex (the fibrinogen receptor) cause severe congenital platelet dysfunction.

Bernard-Soulier syndrome, a severe congenital platelet function disorder, is caused by absence or severe deficiency of the VWF receptor (GPIb complex) on the platelet membrane. This syndrome is characterized by thrombocytopenia, with giant platelets and markedly prolonged bleeding time (>20 min) or PFA-100 closure time. Platelet aggregation tests show absent ristocetin-induced platelet aggregation, but normal aggregation to all other agonists. Ristocetin induces the binding of VWF to platelets and agglutinates platelets. Results of studies of VWF are normal. The GPIb complex interacts with the platelet cytoskeleton; a defect in this interaction is believed to be the cause of the large platelet size. Bernard-Soulier syndrome is inherited as an autosomal recessive disorder. Genetic mutations causing Bernard-Soulier syndrome are usually identified in the genes forming the GPIb complex of glycoproteins Ibα, Ibβ, V, and IX.

Glanzmann thrombasthenia is a congenital disorder associated with severe platelet dysfunction that yields prolonged bleeding time and a normal platelet count. Platelets have normal size and morphologic features on the peripheral blood smear, and closure times for PFA-100 or bleeding time are markedly abnormal. Aggregation studies show abnormal or absent aggregation with all agonists used except ristocetin, because ristocetin agglutinates platelets and does not require a metabolically active platelet. This disorder is caused by deficiency of the platelet fibrinogen receptor αIIb-β3, the major integrin complex on the platelet surface that undergoes conformational changes by inside out signaling when platelets are activated. Fibrinogen binds to this complex when the platelet is activated and causes platelets to aggregate. Caused by identifiable mutations in the genes for αIIb or β3, this disorder is inherited in an autosomal recessive manner. For both Bernard-Soulier syndrome and Glanzmann thrombasthenia, the diagnosis is confirmed by flow cytometric analysis of the patient’s platelet glycoproteins.

Hereditary deficiency of platelet storage granules occurs in 2 well-characterized but rare syndromes that involve deficiency of intracytoplasmic granules. Dense body deficiency is characterized by absence of the granules that contain ADP, ATP, Ca²⁺, and serotonin. This disorder is diagnosed by the finding that ATP is not released on platelet aggregation studies and ideally is characterized by electron microscopic studies. Gray platelet syndrome is caused by the absence of platelet α granules, resulting in platelets that appear gray on Wright stain of peripheral blood. In this rare syndrome, aggregation and release are absent with most agonists other than thrombin and ristocetin. Electron microscopic studies are diagnostic.

Other Hereditary Disorders of Platelet Function

Abnormalities in the pathways of platelet activation and release of granular contents cause a heterogeneous group of platelet function defects that are usually manifested as increased bruising, epistaxis, and/or menorrhagia. Symptoms may be subtle and are often made more obvious by high-risk surgery, such as tonsillectomy or adenoidectomy, or by administration of nonsteroidal anti-inflammatory drugs. In the laboratory, bleeding time is variable and closure time as measured by the PFA-100 is frequently, but not always, prolonged. Platelet aggregation studies show deficient aggregation with 1 or 2 agonists and/or abnormal release of granular contents.

The formation of thromboxane from arachidonic acid after the activation of phospholipase is critical to normal platelet function. Deficiency or dysfunction of enzymes, such as cyclo-oxygenase and thromboxane synthase, which metabolize arachidonic acid, causes abnormal platelet function. In the aggregometer, platelets from such patients do not aggregate in response to arachidonic acid.

The most common platelet function defects are those characterized by variable bleeding time/PFA closure times and abnormal aggregation with 1 or 2 agonists, usually ADP and/or collagen. These patients have normal aggregation with thrombin receptor peptide. Some of these individuals have only decreased release of ATP from intracytoplasmic granules; the significance of this finding is debated.

Treatment of Patients with Platelet Dysfunction

Successful treatment depends on the severity of both the diagnosis and the hemorrhagic event. In all but severe platelet function defects, desmopressin 0.3 µg/kg IV may be used for mild to moderate bleeding episodes. In addition to its effect on stimulating levels of VWF and factor VIII, desmopressin corrects bleeding time and augments hemostasis in many individuals with mild to moderate platelet function defects. For individuals with Bernard-Soulier syndrome or Glanzmann thrombasthenia, platelet transfusions of 1 U/5-10 kg corrects the defect in hemostasis and may be lifesaving. Rarely, antibodies develop to the deficient platelet protein, rendering the patient refractory to the transfused platelets. In such patients, the off-label use of recombinant factor VIIa has been effective, and this treatment is undergoing clinical trials. In both conditions, hematopoietic stem cell transplantation has been curative.

Bibliography

Lambert MP, Poncz M. Inherited platelet disorders. In: Orkin SH, Nathan DG, Ginsberg D, et al, editors. Nathan and Oski’s hematology of infancy and childhood. ed 7. Philadelphia: Saunders Elsevier; 2009:1463.

Neunert CE, Journeycake JM. Congenital platelet disorders. Hematol Oncol Clin North Am. 2007;21:663-684. vi

Nurden P, Nurden AT. Congenital disorders associated with platelet dysfunctions. Thromb Haemost. 2008;99:253-263.

478.14 Disorders of the Blood Vessels

J. Paul Scott, Robert R. Montgomery

Disorders of the vessel walls or supporting structures mimic the findings of a bleeding disorder although coagulation studies are usually normal. The findings of petechiae and purpuric lesions in such patients are often due to an underlying vasculitis/vasculopathy. Skin biopsy can be particularly helpful in elucidating the type of vascular pathology.

Henoch-Schönlein Purpura

Henoch-Schönlein purpura (HSP) is characterized by the sudden development of a purpuric rash, arthritis, abdominal pain, and renal involvement (Chapter 509). The characteristic rash, consisting of petechiae and often palpable purpura, usually involves the lower extremities and buttocks. Results of coagulation studies are normal. The pathologic lesions in the skin, intestines, and synovium are leukocytoclastic angiitis, inflammatory damage to the endothelium of the capillary and postcapillary venules mediated by WBCs and macrophages. The trigger for HSP is unknown. In the kidney, the lesion is focal glomerulonephritis with deposition of immunoglobulin A. Results of coagulation studies as well as platelet count are normal in HSP.

Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome is a common disorder of collagen structure that causes easy bruising and poor wound healing (Chapter 651). Suggestive findings on physical examination include soft, velvety skin that is hyperelastic; lax joints that are easily subluxed; and unusual scarring. More than 10 variants of Ehlers-Danlos syndrome have been described. The most serious forms have been associated with sudden rupture of visceral organs. Results of coagulation screening tests are usually normal, although bleeding time may be mildly prolonged. Results of platelet aggregation studies are either normal or mildly abnormal, with deficient aggregation to collagen.