A Case of Chronic Thrombocytopenia in a 17-Year-Old Female

Roger Riley, MD, PhD; Asad Khan, MD; Shella Pai, MS, SH(ASCP); Laura Warmke, MD; Marcus Winkler, MD; William Gunning, PhD

Disclosures

Lab Med. 2019;50(4):406-420.

Abstract and Introduction

Abstract

Storage pool deficiency (SPD) is a group of rare platelet disorders that result from deficiencies in α-granules, δ-granules, or both. One type of α-SPD is gray platelet syndrome (GPS), caused by mutations in the neurobeachin-like 2 (NBEAL2) gene that results in a bleeding diathesis, thrombocytopenia, splenomegaly, and progressive myelofibrosis. Due to the lack of α-granules, platelets have a gray and degranulated appearance by light microscopy. However, definitive diagnosis of GPS requires confirmation of α-granule deficiency by electron microscopy. Treatment is nonspecific, with the conservative utilization of platelet transfusions being the most important form of therapy. We present a case of a 17-year-old female with a past medical history of thrombocytopenia, first identified at the age of five. Her clinical symptomatology included chronic fatigue, gingival bleeding, bruising, menorrhagia, and leg pain. This report will discuss both the clinical and the pathophysiologic aspects of this rare platelet disorder.

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Table 1. Laboratory Values for the Patient, a 17-Year-Old Adolescent Girl
Parameter	Result	Reference Range
WBC	3.5 × 10⁹/L^a	5.5–9.3 × 10⁹/L
RBC	4.66 × 10¹²/L^b	3.79–4.61 × 10¹²/L
Hemoglobin	12.0 g/dL	11.3–13.4 g/dL
Hematocrit	37.6%	32.1%–38.7%
MCV	80.8 fL	82.1–87.7 fL
MCH	25.7 pg^a	28.4–30.7 pg
MCHC	31.8 g/dL^a	33.9–35.4 g/dL
RDW	22.1%^b	12.8%–14.4%
PLT count	56 × 10⁹/L^a	192–307 × 10⁹/L
MPV	13.3 fL^b	7.5–8.3 fL
NEU	1.4 × 10⁹/L^a	3.0–6.1 × 10⁹/L
LYM	1.9 × 10⁹/L	1.2–2.3 × 10⁹/L
MONO	0.1 × 10⁹/L	0.4–0.9 × 10⁹/L
EOS	0 × 10⁹/L	0–0.2 × 10⁹/L
BASO	0 × 10⁹/L	0–0.1 × 10⁹/L

WBC, white blood count; RBC, red blood count; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; RDW, red cell distribution width; PLT, platelet; MPV, mean platelet volume; NEU, absolute neutrophil count; LYM, absolute lymphocyte count; MONO, absolute monocyte count; EOS, absolute eosinophil count; BASO, absolute basophil count.
^aDenotes low value.
^bDenotes high value.

Table 2. Disorders Involving the PLT-Membrane Receptors
Common Name	Gene(s) and Locus	Receptor(s) Affected	Inheritance	Mechanism of Disease	Laboratory Features	Clinical Features
ADP-receptor deficiency (P2RX1)	P2RX1 (17p13.2)	ADP (P₂X₁) receptor	Autosomal recessive	Altered modulation of aggregation by ATP	Impairment of ADP-induced PLT aggregation; normal PLT count and size	Severe mucocutaneous bleeding
ADP-receptor deficiency (P2RY12)	P2RY12 (3q25.1)	ADP (P₂RY₁₂) receptor	Autosomal recessive	Inability of ADP to induce PLT aggregation	Defective ADP-induced PLT aggregation	Mild to moderate mucocutaneous bleeding; increased posttraumatic and postsurgical bleeding
Bernard-Soulier syndrome	GPIBA (17p13.2), GPIBB (22q11.2), GP9 (3q21.3)	vWF receptor; GP_Ibα, GP_Ibβ	Autosomal recessive	Lack of PLT adhesion to vWF, abnormal response to thrombin	Prolonged PFA-100^a closure time, defective PLT aggregation to ristocetin, decreased CD42 (GP Ib/V/IX)	Thrombocytopenia with giant PLTs, easy bruising, mucocutaneous bleeding, menorrhagia, gastrointestinal bleeding
Glanzmann thrombasthenia	ITGA2B (17q21.31), ITGB3 (17q21.32)	Fibrinogen receptor; GPIIb/IIIa, GP_α11bβ₃	Autosomal recessive	Defective PLT aggregation	Prolonged PFA-100 closure time; defective PLT aggregation to ADP, epinephrine, and collagen; decreased CD41 (GP IIb/IIIa)	Easy bruising, mucocutaneous bleeding, menorrhagia, gastrointestinal bleeding
GP1a deficiency	ITGA2 (5q11.2)	GP1b; α₂β₁, x	Autosomal dominant	Defective PLT adhesion to subendothelium	Mild thrombocytopenia, normal PLT size, prolonged bleeding time, defective PLT adhesion to collagen, decreased GP1a expression	Mild mucocutaneous bleeding tendency
GPVI deficiency	GP6 (19q13.42)	Collagen receptor (GPVI)	Autosomal recessive	Defective collagen-induced PLT activation and aggregation	Prolonged bleeding time; defective collagen-induced PLT aggregation; defective thrombin generation; decreased GPVI expression; normal PLT response to ADP, arachidonic acid, and ristocetin	Mucocutaneous bleeding, postsurgical bleeding
PLT-type vWD; pseudo-vWD	GPIBA (17p13.2)	Alpha subunit of vWF receptor (GPIbα)	Autosomal dominant	Enhanced affinity of GPIbα for vWF	Mild thrombocytopenia with large PLTs and PLT aggregates; enhanced RIPA; normal to slightly decreased plasma vWF:Ag; reduced vWF activity with a low vWF:activity/vWF:Ag ratio	Mucocutaneous bleeding, increased bleeding after surgical procedure or trauma
Scott syndrome	TMEM16F (12q12)	TMEM16F	Autosomal recessive	Defective Ano6, defective PS exposure on plasma membrane with impaired thrombin formation	Normal coagulation factor levels, abnormal PCI	Mild postoperative or postpartum bleeding; none had spontaneous bleeding
Stormorken syndrome (York PLT syndrome)	STIM1 (11p15)	STIM1	Autosomal dominant	Increased calcium flux via the CRAC channel, increased PLT cytoplasmic Ca²⁺ levels, preactivation of PLTs, and reduced PLT cohesion	Anemia, thrombocytopenia, PLT dysfunction, tubular aggregate myopathy with increased serum creatine kinase	Mild bleeding diathesis, asplenia, muscle fatigue, migraine, dyslexia, congenital miosis, and ichthyosis
Thomboxane receptor deficiency	TBXA2R (19p13)	TBXA₂R	Autosomal dominant	Defective TBXA₂R	Defective PLT aggregation to epinephrine, ADP, and thromboxane; normal PLT count	Mild mucocutaneous bleeding
Thrombospondin receptor deficiency (PLT GPIV deficiency)	CD36 (7q21.11)	Thrombospondin receptor (GPIV, GPIIb)	Autosomal recessive	Complete deficiency of CD36 on PLTs and monocytes/macrophages (type I) or PLTs only (type II)	Macrothrombocytopenia, increased serum LDL cholesterol	Increased susceptibility to cerebral Plasmodium falciparum malaria; type II diabetes; no hemostatic problems

PLT, platelet; ARC, arthrogryposis, renal dysfunction, and cholestasis; ADP, ad Table 2. Disorders Involving the PLT-Membrane Receptors enosine diphosphate; ATP, adenosine triphosphate; vWF, von Willebrand factor; PFA, Platelet Function Analyzer; CD, cluster of differentiation; GP, glycoprotein; RIPA, ristocetin-induced platelet aggregation; Ag, antigen; Ano6, anoctamin 6; PS, phosphatidylserine; PCI, prothrombin consumption index; CRAC, Ca²⁺ release-activated Ca²⁺, TBXA₂R, thromboxane A2 receptor; LDL, low-density lipoprotein.
^aManufactured by Siemens AG.

Table 3. Disorders Involving the PLT Membrane Granules, Cytoskeletal Components, or Metabolic Pathways
Common Name	Gene(s) and Locus	Affected Component	Inheritance	Pathogenesis	Laboratory Features	Clinical Features
Diseases Affecting PLT Granules
ARC syndrome	VPS33B (15q26), VIPAS39 (14q34)	α-granule	Autosomal recessive	Impaired intracellular lysosomal sorting and trafficking	Abnormally large PLTs deficient in α-granules, defective PLT aggregation (ADP)	Bleeding, arthrogryposis, renal tubular dysfunction, cholestasis, facial dysmorphism, ichthyosis, cerebral malformations, sensorineural deafness, death in first years of life
GFI1B-related syndrome	GFI1B (9q34)	α-granule	Autosomal dominant	Defect in megakaryocyte development	Normal PLTs coexist with α-granule–deficient ones, decreased PLT aggregation with collagen	Bleeding
GATA1-related syndrome	GATA1 (Xp11)	α-granule	X-linked	Defect in α-granule production and/or distribution	Not all PLTs affected, can be linked with trisomy 21	Bleeding, dyserthropoiesis, β-thalassemia–like
Gray PLT syndrome	NBEAL2 (3p21)	α-granule	Autosomal recessive	Defect in formation of α-granules	Large PLTs deficient in α-granules	Bleeding, splenomegaly, myelofibrosis
Chédiak-Higashi syndrome	LYST (1q42.3)	Dense granule	Autosomal recessive	Defective lysosomal trafficking regulator protein with disordered intracellular trafficking	Giant inclusion bodies in leukocytes and PLT dense-granule deficiency	Bleeding, oculocutaneous albinism, pyogenic infections, peripheral neuropathy, accelerated terminal disease with malignant lymphoma
Hermansky-Pudlak syndrome	HPS1 (10q24.2), AP3B1 (5q14.1), HSP3 (3q24), HSP4 (22q12.1), HPS5 (11p15.1), HPS6 (10q24.32), DTNBP1 (6p22.3), BLOC1S3 (19q13.32), PLDN (15q21.1)	Lysosome-related organelle complexes including dense granule	Autosomal recessive	Abnormal biogenesis of lysosome-related organelle complexes	Absent dense PLT granules; prolonged bleeding time; impaired aggregation with collagen, thrombin, epinephrine, and adenosine diphosphate (ADP)	Multisystem disease with oculocutaneous albinism, bleeding diathesis, neutropenia, and abnormal lysosomal ceroid storage; pulmonary fibrosis, granulomatous colitis, and/or immunodeficiency may develop
Paris-Trousseau thrombocytopenia	Fli-1 (11q23)	α-granule	Unknown, isolated cases	Dysmegakaryopoiesis with formation of giant α-granules	Variable thrombocytopenia, increased mean PLT volume, giant α-granules, micromegakaryocytes	Mild bleeding tendency, dysmorphic facies, intellectual and developmental disabilities
Quebec PLT disorder	PLAU (10q22.2)	PLAU; α-granule	Autosomal dominant	Excessive PLAU causing intragranular plasmin generation and degradation of α-granule components on PLT secretion	Markedly increased PLT content of PLAU with normal or slightly increased plasma PLAU and normal urine PLAU; mild thrombocytopenia; normal closure time on PFA-100	Delayed-onset postsurgical bleeding, severe trauma-induced bleeding, muscle and joint bleeds, spontaneous hematuria, poor wound healing
Diseases Affecting PLT Cytoskeletal Components
MYH9-related disorders (May-Hegglin anomaly, Fechtner syndrome, Epstein syndrome, Sebastian syndrome)	MYH9 (22q12.3)	Nonmuscle MYH	Autosomal dominant	Defective PLT shape change, renal tubular dysfunction, cochlear dysfunction	Macrothromocytopenia; Döhle body–like inclusions in leukocytes; prolonged bleeding time; defective PLT aggregation in response to ADP, collagen, and epinephrine; proteinuria; microscopic hematuria	Variable phenotype with mucocutaneous bleeding, nephritis, sensorineural hearing loss, and cataracts
WAS	WAS (Xp11.23)	WASP	X-linked recessive	Abnormal signaling and movement of actin filaments	Thrombocytopenia, small PLTs, prolonged bleeding time, lymphopenia, increased IgA levels, elevated ESR and CRP	Mucocutaneous bleeding, eczema, recurrent infections, vasculitis, hemolytic anemia, iron-deficiency anemia, bloody diarrhea
Diseases Affecting PLT Metabolic and Signaling Pathways
PLA2 deficiency	PLA2G4A (1q31.1)	Cytosolic PLA2	Unknown	Defective PLT aggregation resulting from impaired synthesis of arachidonic acid from membrane phospholipids; decreased formation of prostaglandins, TXA₂, and prostacyclin	Impaired PLT aggregation and degranulation induced by ADP or collagen, normalized by arachidonic acid; markedly reduced plasma levels of thromboxane B2, 12-HETE, and leukotriene B4	Multifocal stenosis and ulceration of the small intestine
TXAS₁deficiency	TBXAS1 (7q34)	TXA₂ synthase	Autosomal dominant	Impaired conversion of prostaglandin H₂ to TBXA₂, resulting in defective PLT aggregation	Defective PLT aggregation with arachidonic acid; decreased plasma TBXB₂ and malondialdehyde; increased levels of prostaglandins, particularly prostaglandin D₂	Mucocutaneous bleeding, including petechiae, easy bruising, epistaxis, hematuria, and gastrointestinal bleeding; bleeding after dental extractions; symptoms can occur shortly after birth
PTGS1deficiency	PTGS1 (9q33.2)	PTGS1 (COX1, PGHS1)	Autosomal dominant	Decreased synthesis of PGG₂ and prostaglandin H₂ from arachidonic acid, impaired formation of TXA₂ and prostacyclin with defective PLT aggregation	Moderate thrombocytopenia, mildly prolonged bleeding time, defective second-wave PLT aggregation with release reaction restored with added PGG₂	Easy bruising, spontaneous hematomas, menorrhagia, epistaxis, hemarthroses, postsurgical bleeding, gastrointestinal bleeding
Albright hereditary osteodystrophy	GNAS (20q13.32)	Maternal loss of function of the Gsα isoform of the GNAS gene	Autosomal dominant	Reduced Gsα protein activity	Decreased cAMP formation on Gαs-receptor activation, hypocalcemia, hyperphosphatemia	Short stature, obesity, round face, mental disability, brachydactyly, ectopic ossification, pseudohypoparathyroidism
Leukocyte adhesion deficiency, type III	FERMT3 (11q13.1)	Integrin-activating proteins	Autosomal recessive	Defective in situ activation of leukocytes and PLT integrins with impaired PLT aggregation and leukocyte function	Leukocytosis; defective neutrophil chemotaxis, activation, and adhesion with normal expression of CD11/CD18; impaired PLT aggregation to all agonists; normal PLT count and morphology	Severe recurrent nonpurulent bacterial infections (skin infections, omphalitis, sepsis), moderate to severe bleeding diathesis beginning in infancy or early childhood, poor wound healing, anemia, hepatosplenomegaly, osteopetrosis-like radiologic signs

PLT, platelet; ARC, arthrogryposis, renal dysfunction, and cholestasis; ADP, adenosine diphosphate; Fli-1, Friend leukemia integration 1 transcription factor; PLAU, plasminogen activator, urokinase; MYH, myosin heavy chain; WAS, Wiskott-Aldrich syndrome; WASP, Wiskott-Aldrich syndrome protein; IgA, immunoglobulin A; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; PLA2, phospholipase; TXA2, thromboxane A2; 12-HETE, 12-hydroxyeicosatetraenoic acid; TBXB2, thromboxane B2; PTGS, prostaglandin-endoperoxide synthase; COX1, cyclooxygenase 1; PGHS1, prostaglandin endoperoxide H synthase; PGG2, prostaglandin G2; GNAS, guanine nucleotide binding protein (G protein), alpha stimulating activity polypeptide 1; cAMP, cyclic adenosine monophosphate; FERMT3, fermitin family member 3; CD, cluster of differentiation.