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.