15.4 Bleeding & Platelet Disorders (ITP) & G6PD Deficiency

Immune Thrombocytopenic Purpura (ITP)

Immune thrombocytopenic purpura (ITP) is an acquired autoimmune condition in which antiplatelet antibodies cause accelerated splenic destruction of otherwise normal platelets. It is the most common cause of acute-onset isolated thrombocytopenia in childhood.

Presentation

The classic vignette is a previously healthy child, ages 2-6 years, who develops sudden-onset petechiae, purpura, and/or mucosal bleeding (epistaxis, gum bleeding) roughly 1-4 weeks after a viral illness or, less commonly, a live-virus vaccination (e.g., MMR). Critically, the child is otherwise well-appearing, with no fever, no hepatosplenomegaly, no lymphadenopathy, and no bone pain -- and the rest of the CBC (hemoglobin, white cell count and differential) and peripheral smear are normal except for isolated, often severe, thrombocytopenia (platelet counts frequently <20 x 10^9/L).

Exam trap: This is the pairing question the exam loves -- ITP versus leukemia. Both can present with petechiae/bruising in a young child. The discriminator is that ITP is an isolated cytopenia in a well child with a normal smear otherwise, while leukemia typically shows multiple cytopenias (anemia and/or neutropenia alongside thrombocytopenia), constitutional symptoms (fever, weight loss, bone pain), organomegaly/lymphadenopathy, and abnormal cells (blasts) on smear. If a vignette gives you any of these additional red flags, do not answer ITP -- pursue bone marrow evaluation for leukemia before starting ITP-directed treatment (corticosteroids can mask/partially treat leukemia and delay diagnosis, so steroids should not be given until leukemia is excluded when the picture is atypical).

Management

ITP is largely a clinical diagnosis in a classic presentation; bone marrow examination is not routinely required unless the presentation is atypical (as above) or the child fails to respond to first-line therapy as expected.

Most cases resolve within 3 months (acute ITP); ITP persisting beyond 12 months is termed chronic ITP and is more common in older children/adolescents.

Hemophilia A and B: Basics

Hemophilia A (factor VIII deficiency) and Hemophilia B (factor IX deficiency, "Christmas disease") are X-linked recessive disorders, so they present almost exclusively in males, with a maternal family history of affected male relatives (though up to a third of cases arise from de novo mutations with no family history). Hemophilia A is roughly 4-5 times more common than hemophilia B.

Laboratory Pattern

Both factor VIII and factor IX are part of the intrinsic coagulation pathway, so their deficiency prolongs the activated partial thromboplastin time (aPTT) while the prothrombin time (PT) -- which reflects the extrinsic/common pathway -- remains normal. Platelet count and bleeding time are also normal, because platelet plug formation is intact; the defect is in the secondary (fibrin-based) hemostatic phase.

Severity is classified by residual factor activity: severe (<1%), moderate (1-5%), mild (>5-40%), with severe disease causing spontaneous bleeding and mild disease often only manifesting after trauma or surgery.

Clinical Pattern

Hemophilia produces deep tissue bleeding rather than the mucocutaneous bleeding seen in platelet disorders: hemarthroses (bleeding into joints -- knees, elbows, ankles -- causing pain, swelling, and, if recurrent, chronic hemophilic arthropathy), intramuscular hematomas, prolonged bleeding after circumcision or minor procedures, and, in severe cases, life-threatening intracranial hemorrhage. This mucocutaneous-versus-deep-tissue distinction is a classic exam contrast: platelet disorders (ITP, von Willebrand disease) cause petechiae, mucosal bleeding, and immediate bleeding after minor cuts; coagulation factor disorders (hemophilia) cause delayed, deep bleeding into joints and muscles. Management is factor replacement (recombinant factor VIII or IX concentrate) for bleeding episodes or prophylactically in severe disease; desmopressin (DDAVP) can be used for mild hemophilia A (it raises endogenous factor VIII) but is not effective in hemophilia B.

Von Willebrand Disease

Von Willebrand disease (vWD) is the most common inherited bleeding disorder worldwide. Unlike hemophilia, most forms are autosomal (typically autosomal dominant in type 1) with variable severity. Von Willebrand factor (vWF) is required for platelet adhesion to subendothelium and also stabilizes factor VIII, so vWD can produce both a prolonged bleeding time or abnormal PFA-100 (platelet function defect) and, in types 2 and 3, a prolonged aPTT with low factor VIII -- overlapping with but distinct from the isolated aPTT prolongation with normal factor VIII seen in classic hemophilia A.

Clinical bleeding is typically mucocutaneous: epistaxis, menorrhagia (in adolescent females), easy bruising, and prolonged bleeding after dental extraction or minor surgery -- the same pattern as ITP but with a normal platelet count. Family history of easy bleeding is common. Desmopressin (DDAVP) releases stored vWF and factor VIII from endothelial stores and is effective first-line therapy for many type 1 vWD patients and for mild bleeding in type 2A; vWF/factor VIII concentrate is used for type 3 disease, DDAVP-unresponsive types, or major surgery/trauma.

Exam trap: A child with mucocutaneous bleeding, a normal platelet count, and a prolonged aPTT should prompt consideration of vWD (check vWF antigen/activity and factor VIII level) before defaulting to hemophilia -- hemophilia almost exclusively affects males and causes deep-tissue rather than mucosal bleeding.

G6PD Deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect worldwide and is particularly prevalent across Arab, Mediterranean, African, and Southeast Asian populations -- high relevance for the Arab Board exam. Inheritance is X-linked recessive, so hemizygous males are most severely affected, while heterozygous females have variable (mosaic) expression due to random X-inactivation and can range from unaffected to significantly deficient.

Pathophysiology

G6PD is the rate-limiting enzyme of the pentose phosphate pathway, generating NADPH, which is required to regenerate reduced glutathione -- the red cell's primary defense against oxidative stress. Without adequate G6PD activity, red cells cannot detoxify oxidative stressors, hemoglobin denatures and precipitates as Heinz bodies, and the spleen removes these Heinz bodies (forming "bite cells") or destroys the damaged cell entirely, causing acute hemolysis.

Triggers of Hemolysis

Clinical Presentation

Hemolytic episodes are episodic, occurring 1-3 days after exposure to a trigger, with pallor, jaundice, dark (tea-colored) urine (hemoglobinuria), and fatigue; severe episodes can cause significant anemia requiring transfusion. Laboratory findings during a hemolytic episode include an elevated reticulocyte count, elevated indirect bilirubin, elevated LDH, low haptoglobin, and Heinz bodies/bite cells on peripheral smear. Between episodes, the CBC and smear can be entirely normal.

Exam trap on testing timing: A G6PD enzyme activity assay obtained during or immediately after an acute hemolytic episode can be falsely normal, because the older, most severely G6PD-deficient red cells have already been destroyed, leaving a population of young reticulocytes with relatively higher (though still eventually deficient) enzyme activity. If clinical suspicion is high but the assay is normal during/soon after hemolysis, the test should be repeated 2-3 months later once the red cell population has re-equilibrated.

Neonatal Presentation

G6PD deficiency is a well-recognized and important cause of severe, sometimes exchange-transfusion-requiring neonatal hyperbilirubinemia and kernicterus in high-prevalence regions, including Arab populations. Unlike typical physiologic jaundice, G6PD-related jaundice can be severe, can appear without an obviously identified hemolytic trigger, and should be suspected in any neonate with unexplained significant jaundice, a family history of G6PD deficiency or neonatal jaundice, or a history of maternal fava bean ingestion while breastfeeding or household naphthalene (mothball) exposure. Many regional newborn screening programs include G6PD screening for exactly this reason, and the exam expects you to include G6PD deficiency in the differential of severe/atypical neonatal jaundice.