Hemorrhagic and Thrombotic Disorders

Neil A. Lachant , in Critical Care Medicine (Third Edition), 2008

Drug-Induced Thrombocytopenia

Although a large number of drugs have been associated with thrombocytopenia, a limited number have evidence-based data to support a causal role in the development of thrombocytopenia. 3,6,7 Medications commonly used in the ICU that can cause thrombocytopenia are shown in Box 79-2. Drug-induced thrombocytopenia most commonly occurs 7 to 21 days after exposure to the offending agent. Clinical manifestations can range from an asymptomatic decrease in platelets to life-threatening bleeding. The diagnosis is established by finding (1) a temporal relationship between starting the drug and the fall in the platelet count, (2) having no alternative diagnosis, and (3) having the platelet count recover after removal of the putative offending agent. Unfortunately, this is usually difficult to establish in the typical ICU patient. Treatment is based on removing the offending agent and initiating a drug of another class if possible. Though often used, steroids in general have not been shown to hasten the rate of platelet recovery. In severe thrombocytopenia with bleeding such as seen with quinine-induced thrombocytopenia, intravenous immunoglobulin (IVIG) (1 g/kg/d for 2 days) and platelet transfusion are beneficial.

Glycoprotein IIb/IIIa Inhibitors

All platelet glycoprotein (Gp) IIb/IIIa inhibitors have been associated with severe thrombocytopenia that can occur within hours of exposure, although the thrombocytopenia from abciximab may develop up to 2 weeks after exposure. 6 These patients are usually concomitantly exposed to heparin, thus making heparin-induced thrombocytopenia (HIT) the main differential diagnosis. Bleeding is very uncommon with HIT because of the strong prothrombotic state. Conversely, with Gp IIb/IIIa inhibitor–associated thrombocytopenia, bleeding or hematoma formation may occur, especially at the site of the sheath. A platelet count less than 20,000/μL and clinical bleeding are indications for platelet transfusion. The use of IVIG and corticosteroids is not evidence based.

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Antithrombotic Approaches in Cerebrovascular Disease

Gregory J. del Zoppo , in Vascular Medicine, 2006

Platelet-Fibrin Interaction Inhibitors

Platelet glycoprotein IIb/IIIa (integrin α IIbβ3) antagonists have been proposed as agents in stroke treatment; however, the target is unspecified. One phase II study of abciximab given within 24 hours of stroke onset did not produce significant improvement or intracerebral hemorrhage in 74 patients at the doses tested. 71 This is in contrast to published experimental studies with polypeptide or organic integrin αIIbβ3 inhibitors in acute middle cerebral artery occlusion. 43, 46

On the basis of its beneficial effects on outcome in patients with recent TIAs or completed stroke, ASA is the first choice for secondary prevention. ASA/extended release dipyridamole is superior to ASA alone (see Table 31-1). Ticlopidine was shown to produce a significant reduction in subsequent stroke, MI, or vascular-related death over ASA, but clopidogrel has been substituted by some physicians in practice. Supportive data are still pending. Current ACCP recommendations for secondary prevention in noncardioembolic ischemic stroke are management with ASA (50 to 325 mg/day), ASA/extended release dipyridamole, or clopidogrel (75 mg/day). 67

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HIGH-RISK PERCUTANEOUS CORONARY INTERVENTIONS

Oscar M. Aguilar , Glenn N. Levine , in Interventional Cardiac Catheterization Handbook (Second Edition), 2004

Antiplatelet Agents (Intravenous).

The platelet glycoprotein IIb/IIIa inhibitors block platelet aggregation and adhesion. Intravenous administration of these agents peri-procedure usually leads to between 80–95% inhibition of platelet aggregation. These agents reduce ischemic complications in patients undergoing PCI. The greatest absolute magnitude of risk reduction is in those with high-risk angiographic and/or clinical features. Therefore, these agents should be strongly considered during high-risk PCI. The characteristics of the three platelet IIb/IIIa inhibitors, and a suggested dosing regimen, for the three platelet IIb/IIIa inhibitors are given in Table 9-2.

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Cardiovascular Drugs and Hemostasis

Bahram Fariborz Farsad , Hanieh Salehi , in Practical Cardiology (Second Edition), 2022

Parenteral Antiplatelet Agents

The platelet glycoprotein (GP) IIb/IIIa receptor became a target for therapeutic intervention to prevent thrombosis. The monoclonal antibody ultimately named abciximab (ReoPro) was developed to irreversibly bind and inhibit the IIb/IIIa receptor. 37 The IIb/IIIa receptor is the final common pathway to platelet aggregation because it meditates cross-linking of activated platelets with fibrinogen and von Willebrand factor. Hence, IIb/IIIa agents remain the most potent available antiplatelet agents.

Reversible small molecule antagonists, including eptifibatide (Integrilin) and tirofiban (Aggrastat), were subsequently developed. All three agents have demonstrated efficacy in the reduction of ischemic complications, particularly postprocedural myonecrosis, in balloon angioplasty and stenting. Meta-analysis of the PCI trials not including STEMI patients demonstrates a 38% reduction in death and MI at 30   days. 38 The individual properties of these agents and several of the pivotal trials that influence their current use in PCI are listed in Table 39.2. 41

When (100   U/kg) doses of IV unfractionated heparin (UFH) were coadministered in the EPIC trial. 26 In the Evaluation of PTCA to Improve Long-term Outcome by c7E3 GP IIb/IIIa Receptor Blockade (EPILOG) trial, abciximab had equal efficacy to prevent ischemic complications with a lower dose of IV UFH (70   U/kg) compared with higher doses (100   U/kg). Major bleeding with abciximab and lower dose heparin (1.1%) was identical to high-dose heparin (1.1%) alone. 39 Heparin doses of 50–60   U/kg are generally recommended when administered with IIb/IIIa therapy for a target activated clotting time (ACT) of 200–250   s.

The ISAR-REACT trial demonstrated no benefit of abciximab in low-risk patients undergoing PCI (A Clinical Trial of Abciximab in Elective Percutaneous Coronary Intervention after Pretreatment with Clopidogrel) with a stent who had been pretreated with 600   mg of clopidogrel as well as aspirin at least 2   h before intervention. 40 The ISAR-REACT 2 trial, however, demonstrated benefit of abciximab in unstable angina and NSTEMI-ACS patients undergoing PCI (Table 39.3). 40

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Nonsteroidal Antiinflammatory Drugs, Antiplatelet Medications, and Spinal Axis Anesthesia

Lynn M. Broadman MD , Edmund H. Jooste MBChB , in Evidence-Based Practice of Anesthesiology (Second Edition), 2009

Platelet Glycoprotein IIb/IIIa Antagonists

The identification of the platelet glycoprotein IIb/IIIa receptor, a fibrinogen receptor important for platelet aggregation, has led to the development of platelet receptor antagonists. 35 Activated glycoprotein IIb/IIIa receptors become receptive to fibrinogen, and when fibrinogen binds to the glycoprotein IIb/IIIa receptors located on two different platelets it builds the cross-links for platelet-to-platelet aggregation. 36 The glycoprotein IIb/IIIa also mediates platelet adhesion and spreading. 35

Abciximab is a monoclonal antibody that binds nonspecifically to the glycoprotein IIb/IIIa receptor. 35 The binding of abciximab to the platelet IIb/IIIa receptor is a rapid high-affinity interaction, and all the receptors are blocked within 15 minutes following the parenteral administration of a bolus dose of 0.25 mg. The biologic half-life of abciximab is approximately 12 to 24 hours, but 24 hours after administration 50% to 60% of the platelet receptors are still blocked. 37 Abciximab can be detected on circulating platelets for more than 15 days, indicating platelet-to-platelet transfer. 35 Abciximab cannot be effectively reversed with the transfusion of platelets because the new platelets are inactivated by the free-circulating monoclonal antibody or platelet-to-platelet transfer of the drug. Platelet function recovers over the course of 48 hours due to platelet turnover. 35 Abciximab prolongs activated clotting time (ACT) by 30 to 80 seconds, and the activated partial thromboplastin time (aPTT) is also prolonged. 35 Comparative studies have shown that abciximab is superior to the other agents in preventing ischemic complications following percutaneous coronary interventions. 38 However, its potent inhibition of platelets also renders it likely to cause increased episodes of major bleeding. 39

Eptifibatide is a small cyclic heptapetide. 35 The drug sits in the binding pocket between the IIb and IIIa arms of glycoprotein IIb/IIIa and prevents the binding of fibrinogen and thrombus formation. 40 Eptifibatide has a plasma half-life of 2.5 hours, with a rapid onset of action and a rapid reversibility of platelet inhibition. 35 Four hours after the termination of an eptifibatide infusion platelet aggregation recovers to approximately 70% of normal and there is normal hemostasis. 41 The majority of the drug is eliminated by renal clearance. 35 Eptifibatide prolongs ACT by 40 to 50 seconds, but it has no effect on prothrombin time (PT) or aPTT. 35

Tirofiban is a tyrosine derivative. 35 Tirofiban occupies the binding pocket on the glycoprotein IIb/IIIa receptor and competitively inhibits platelet aggregation mediated by fibrinogen and von Willebrand factor. 41 It is given via an intravenous infusion and the plasma half-life is approximately 1.5 to 2.5 hours. 35 Greater than 70% of tirofiban is cleared by biliary elimination. 35 The remainder is eliminated by renal excretion and the drug may be removed by hemodialysis. 35 The ACT is prolonged by 40 to 50 seconds. 41

There are no known case reports of a spinal/epidural hematoma forming as the result of spinal axis blockade being performed in a patient who was simultaneously being treated with a glycoprotein IIb/IIIa antagonist. However, two studies show that patients who were using glycoprotein IIb/IIIa medications and required emergency cardiac surgery were at increased risk of having major bleeding compared with patients having elective surgery. 42,43 Eleven consecutive patients who were taking abciximab and required emergency cardiac surgery after failed angioplasty or stent placement were randomized into two groups. 43 Group-1 patients (n = 6) had taken the last dose of abciximab 12 or less hours before surgery, and group-2 patients (n = 5) had taken it more than 12 hours before their surgery. Group-1 patients required 20 packs of platelets to control bleeding, whereas group-2 patients did not require any platelets (p <0.02). Group-1 patients also required more packed erythrocyte transfusions (6 versus 0, p <0.02). The results of the Gammie study 43 are outlined in Table 50-2.

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Immune-Mediated Cytopenia in the Pediatric Setting

Hollie M. Reeves DO , in Immunologic Concepts in Transfusion Medicine, 2020

HPA incompatibility between the fetus and mother

To date, 35 HPAs located on platelet glycoproteins (GP) and GP complexes have been described ( http://www.ebi.ac.uk/ipd/hpa/table1.html last accessed 03/01/2019). These GPs coat the platelet membrane surface and are important for carrying out the platelet's biological functions, such as fibrinogen and von Willebrand factor binding sites. Single nucleotide polymorphisms (SNPs) in the genes that encode these platelet GPs lead to amino acid changes that can alter the GP structure, creating the HPA epitopes. 2 When an individual lacking an HPA antigen is homozygous for the opposite HPA, they can become alloimmunized when exposed to that missing antigen. The most commonly cited example of this is an individual who is HPA-1b/b (and therefore lacks HPA-1a) producing anti-HPA-1a antibodies.

Antibodies to platelet antigen HPA-1a (also known as PlA1) are the most commonly implicated antibodies in FNAIT in the Caucasian population, accounting for approximately 80%–85% of cases in this population. 2,8 Approximately 2%–2.5% of the Caucasian population lack the HPA-1a antigen putting them at risk for alloimmunization. 9 Furthermore, there is a well-documented association with HLA-DRB3∗0101, with over 90% of HPA-1a antibodies made by women who express this allele. 10–12 Much of our understanding of the pathogenesis of FNAIT comes from studies of HPA-1a.

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Antiplatelet Therapy

Ryan E. Wilson , Khaled M. Ziada , in Cardiac Intensive Care (Third Edition), 2019

Eptifibatide.

Eptifibatide is a cyclic heptapeptide competitive inhibitor of platelet GP IIb/IIIa. Eptifibatide binding to the IIb/IIIa receptor is reversible and the drug's efficacy is dependent on maintaining a high serum concentration that allows a steady state of IIb/IIIa receptor blockade. In ACS patients, eptifibatide is given as an IV bolus of 180 µg/kg followed by a continuous infusion of 2 µg/kg per minute. In patients with a creatinine clearance less than 50 ml/minute, the continuous infusion is given at 1 µg/kg per minute. High levels of platelet inhibition occur within 1 hour, with platelet function normalizing 4 to 8 hours after discontinuation. It is primarily secreted in the urine.

The benefit of eptifibatide in patients with acute coronary syndrome was established in the Inhibition of Platelet Glycoprotein IIb/IIIa with Eptifibatide in Patients with Acute Coronary Syndrome (PURSUIT) trial. This randomized, placebo-controlled trial included 10,948 NSTE-ACS patients. Most patients received aspirin and heparin, and were then randomized to receive placebo or eptifibatide (IV bolus of 180 µg/kg followed by an infusion at 1.3 or 2 µg/kg per minute). The duration of therapy extended to 72 hours (or 96 hours if PCI occurred later in the hospitalization) or until the patient left the hospital. The primary endpoint was a composite of death and nonfatal MI at 30 days. In the eptifibatide group, there was a 1.5% absolute reduction in the incidence of the primary endpoint (14.2 vs. 15.7%; P = .04), with this effect occurring in most major subgroups. 48,49 Further investigation of the PURSUIT cohort revealed that eptifibatide reduced the rates of death and MI in patients before and after PCI, in stented and nonstented patients and in those who did not undergo PCI, although the reduction in primary events appeared greater in patients who had an early PCI. 50

The Early Glycoprotein IIb/IIIa Inhibition in Patients With Non–ST Segment Elevation Acute Coronary Syndrome (EARLY-ACS) trial is an important experiment examining the role of eptifibatide and IIb/IIIa inhibitors in contemporary management of ACS in which P2Y12 inhibitor use is widespread. Patients were randomly assigned to either early, pre-PCI double-bolus eptifibatide or delayed, provisional eptifibatide at the time of PCI. Upstream preprocedure clopidogrel was administered in 75% of the population. Upstream eptifibatide therapy did not result in a significant reduction in the primary efficacy endpoint (a composite of death, MI, recurrent ischemia requiring urgent revascularization, or the occurrence of a thrombotic complication during PCI at 96 hours). However, the risk of major bleeding in the early eptifibatide group was 2.6% compared to 1.8% (P = .02) in the delayed provisional group (Fig. 36.5). 51 Thus the use of GP IIb/IIIa receptor antagonists has significantly shifted from an upstream drug to an adjunctive medication given at the time of PCI, usually in a bailout fashion.

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Hemostasis and Thrombosis

Heesun J. Rogers MD, PhD , ... Kandice Kottke-Marchant MD, PhD , in Hematopathology (Third Edition), 2018

Clinical Features

Bernard-Soulier syndrome is a rare congenital deficiency of the platelet GP Ibα/Ibβ/IX/V receptor, the surface receptor for VWF-mediated platelet aggregation. It is usually classified as a macrothrombocytopenia disorder, with clinical findings of early-onset bleeding symptoms, thrombocytopenia, decreased platelet adhesion, reduced platelet survival, and giant platelets. Most of the Bernard-Soulier genetic defects are caused by mutations of GPIBA, the GP Ibα gene, but they may also be caused by defects of GPIBB and GP9, the GP Ibβ and GP IX genes, respectively. The large platelets are thought to be caused by the loss of interaction between actin-binding proteins in the platelet cytoskeleton and the GP Ibα cytoplasmic domain.

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Biomechanics of Microcirculation

Stephanie Nix , ... Hiroki Kamada , in Integrated Nano-Biomechanics, 2018

2.4.4 Influence of Platelet Glycoprotein Receptors and SIPA

As described, platelet adhesion and aggregation result from interactions between platelet glycoprotein receptors and their ligands, although a thrombus is affected by multiple factors, such as blood flow, interactions with other platelets, and alteration of ligand characteristics (i.e., vWF). Therefore, a simulation model focusing on platelet glycoprotein receptors is necessary for better understanding of the differences in thrombogenesis between physiological conditions and pathological conditions caused by platelet dysfunction. In addition, a model is required for understanding pathological thrombus formation induced by SIPA, as exemplified by occlusion following the rupture of arteriosclerotic plaque. For these points, we proposed a platelet adhesion and aggregation model, focusing on the interactions between platelet glycoproteins and their ligands ( Kamada et al., 2013). The characteristics of the interactions of platelet glycoprotein receptors with their ligands were introduced to the spring model. The schematic of these models was shown in Fig. 2.4.4. GPIb/IX/V, GPIIb/IIIa (integrin α IIb β 3), and collagen receptors (GPVI and integrin α 2 β 1) were considered as platelet receptors. The SIPA model was also introduced for GPIb/IX/V and GPIIb/IIIa interactions mediated by vWF (Kamada et al., 2013). The potentiation of vWF interactions with the glycoprotein receptors was expressed as an increase in the number of springs depending blood flow shear. A critical shear rate threshold triggering SIPA (γ crit) was set to 5000   1/s based on experimental observations (Sutera et al., 1988; Schneider et al., 2007). Experimental studies suggest that the vWF conformational change is evoked by the continuous stimulus of a high shear rate (Sutera et al., 1988; Schneider et al., 2007). Therefore, shear rate, γ, was evaluated as the mean value over a particular period of time. Details of simulation conditions are described in our previous study (Kamada et al., 2013).

Fig. 2.4.4

Fig. 2.4.4. Schematic of the platelet adhesion and aggregation models (Kamada et al., 2013). (A) At low shear flow, platelet adhesion is assumed to be mediated by GPIb/IX/V and GPVI. VWF mediates the binding between GPIb/IX/V and the subendothelium. (B) At low shear, platelet aggregation is assumed to be mediated by bindings of GPIb/IX/V-vWF, GPIIb/IIIa-vWF, and GPIIb/IIIa-fibrinogen. (C and D) At high shear flow, bindings mediated by vWF (i.e., GPIb/IX/V-vWF and GPIIb/IIIa-vWF) are assumed to be multivalent depending on the magnitude of blood flow shear.

We conducted computer simulations of primary thrombogenesis under physiological conditions and pathological conditions of platelet glycoprotein receptor and secretion disorders. We also investigated thrombogenesis due to SIPA over a wide range of wall shear rates (γ w), 300–8900   1/s, in a straight vessel. Fig. 2.4.5 shows the maximum number of accumulated platelets. The volume of the thrombus showed a bimodal increase with the shear rate. The volume was larger at low shear (γ w  =   2600   1/s), was smaller at wall shear rate γ w 3500–5400   1/s, and became larger again at higher shear rate (γ w  >   6200   1/s). This tendency was observed in the experimental study by Ikeda et al. (1997). They measured platelet aggregation mediated by vWF over a wide range of shear flows (6–108   dyne/cm2) using a cone-plate viscometer and reported that platelet aggregation was bimodally prominent under shear stress of 6–12 and 81–108   dyne/cm2. The platelet accumulation as a function of shear rate shown by our simulation qualitatively agreed with the experimental observations; the prominence of aggregation was larger for high shear rates than for low shear rates, and little platelet aggregation was observed for a range of shear rates between the two prominences. In addition, a quantitative agreement with the experimental data was demonstrated in the sense that prominent aggregation occurred at high shear rates >   6200   1/s that corresponds to shear stress (=  μ·γ w) of 80.6   dyne/cm2. Ikeda et al. (1997) also suggested that platelet aggregation at high shear stress is irreversible through interactions among vWF, GPIb/IX/V, and GPIIb/IIIa. In our simulation, adhesion and aggregation of platelets were determined by the balance between receptor-ligand interactions and hemodynamics. At the shear rates >   6200   1/s, platelets became able to resist the fluid drag by the multiple and irreversible bindings between glycoprotein receptors and vWF, which resulted in the prominence of the accumulation of platelets. On the other hand, platelets were easily swept away at the shear rate of 3500–5400   1/s due to the lack of the mechanisms of SIPA. These results suggested that the mechanism of SIPA can contribute to the formation of thrombus that resist the blood flow in the physiological range of the shear rate, while it can cause abnormal thrombus formation in the high shear rate.

Fig. 2.4.5

Fig. 2.4.5. Relationship between wall shear rate, γ w, and maximum number of platelets accumulating on the injured wall (Kamada et al., 2013). The thrombus volume showed a bimodal increase with shear rate. The volume became larger at low shear (γ w  &lt;   2600   1/s), was smaller at wall shear rates γ w of 3500–5400   1/s), and became larger again at high shear (γ w  &gt;   6200   1/s).

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Platelet Disorders

Kandice Kottke-Marchant MD, PhD , in Hematopathology (Second Edition), 2012

Clinical Features

Bernard-Soulier syndrome is a rare congenital deficiency of the platelet GP Ibα/Ibβ/IX/V receptor, the surface receptor for VWF-mediated platelet aggregation. It is usually classified as a macrothrombocytopenia disorder, with clinical findings of early onset bleeding symptoms, thrombocytopenia, decreased platelet adhesion, reduced platelet survival, and giant platelets. Most of the Bernard-Soulier genetic defects are due to mutations of GPIBA the GP Ibα gene, but they may also be due to defects of GPIBB and GP9, the GP Ibβ and GP IX genes, respectively. GP Ib is expressed on the demarcation membrane system in the megakaryocytes that are responsible for platelet fragmentation. The large platelets are thought to be due to the loss of interaction between actin-binding proteins in the platelet cytoskeleton and the GPIbα cytoplasmic domain. The disorder is inherited as an incompletely autosomal recessive trait with severe, lifelong mucocutaneous bleeding that is often out of proportion to the mild thrombocytopenia.

Bernard-Soulier Syndrome—Fact Sheet

Definition

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Macrothrombocytopenia with a congenital deficiency of the platelet glycoprotein Iba/Ibb/IX/V receptor

Incidence

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Rare, less than 1 per 1 million

Morbidity and Mortality

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Moderate to severe bleeding disorder

Gender, Race, or Age Distribution

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Autosomal recessive congenital disorder; both males and females affected

Clinical Features

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Incompletely recessive autosomal trait

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Moderate to severe mucocutaneous bleeding

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May be associated with DiGeorge syndrome (deletion 22q11.2)

Prognosis and Therapy

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Routine therapy is not required.

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There is an increased bleeding risk during surgical procedures.

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Desmopressin platelet transfusions, or both, may help to prevent bleeding intraoperatively.

Defects in GPIBB, located on chromosome 22, are also associated with the more extensive genetic defects observed in the velocardiofacial or DiGeorge syndrome associated with a deletion in chromosome 22 (22q11.2). However, the GPIBB defect in these patients is usually heterozygous, and bleeding symptoms are uncommon. These patients may have associated velopharyngeal insufficiency, conotruncal heart disease, immunodeficiency, and learning disabilities.

Pathologic Features and Laboratory Studies

Individuals with Bernard-Soulier syndrome typically have moderately severe thrombocytopenia (30 to 200 × 103/µl), with uniformly large, granulated platelets. Platelets occasionally are the size of erythrocytes or lymphocytes, so automated platelet counts are often inaccurate. No neutrophil inclusions are present. This disorder has diagnostic surface GP abnormalities, so bone marrow analysis is not usually indicated.

Bernard-Soulier Syndrome—Pathologic Features

Complete Blood Cell Count and Peripheral Smear Morphology
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Thrombocytopenia (30 to 100 × 103/µL) with large, normally granulated platelets

Bone Marrow Findings
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Not indicated for diagnosis

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Normal megakaryocyte morphology

Platelet Screening Tests
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Markedly abnormal PFA-100

Platelet Aggregation
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Absent aggregation response to ristocetin and botrocetin

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Normal aggregation to ADP, epinephrine, collagen, and arachidonic acid

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Aggregation by α-thrombin may be abnormal

Ancillary Studies
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Abnormal shear-induced platelet adhesion

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Flow cytometry shows lack of platelet expression of GP Ib/IX

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Variant Bernard-Soulier syndrome may show partial expression

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Genetic mutations of GPIBA, GPIBB, and/or GP9

Differential Diagnosis
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The characteristic glycoprotein abnormalities are usually diagnostic

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Lack of neutrophil inclusions distinguishes Bernard-Soulier syndrome from MYH9 disorders

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Normal VWF studies exclude VWD

Normal platelet aggregation is noted with exposure to ADP, collagen, epinephrine, and arachidonic acid, but aggregation is characteristically absent with the addition of ristocetin or botrocetin (Figure 2-16; see Table 2-2). Adhesion of platelets to subendothelium or immobilized VWF is markedly reduced at all shear rates; this finding may have direct clinical consequences. Patients with Bernard-Soulier syndrome will also have abnormal PFA-100 results.

The genes GPIBA and GPIBB map to chromosomes 17 (17q12) and 22 (22q11.2), respectively. The genes GP9 and GP5 are both on chromosome 3, 3q21, and 3q29, respectively. More than 47 genetic defects in Bernard-Soulier syndrome have been described; most are due to mutations of GPIBA and GPIBB with truncation, frameshift, or nonsense mutations leading to loss of the extracellular protein domain. More rarely, mutations of GP9 have been described. Although the genetic defect usually affects only one protein, the entire GP Ib/IX/V complex is not expressed on the platelet surface if there is a deficiency of the GP Ibα, GP Ibβ, or GP IX chains. Variant Bernard-Soulier syndrome is due to genetic defects with a nonfunctional GP Ib/IX/V complex. The GP abnormality can be confirmed with flow cytometry or crossed immunoelectrophoresis in which a combined lack of GP Ibα, GP Ibβ, and GP IX is identified.

Differential Diagnosis

Bernard-Soulier syndrome, although rare, has characteristic surface GP abnormalities and is not usually confused with other platelet disorders. However, the thrombocytopenia in Bernard-Soulier syndrome presenting in childhood can often be mistaken for ITP, and patients with Bernard-Soulier syndrome have been known to undergo unnecessary splenectomy. The lack of neutrophil inclusions distinguishes Bernard-Soulier syndrome from the MYH9 disorders. Additional laboratory studies show normal VWF antigen and ristocetin cofactor activity, distinguishing Bernard-Soulier syndrome from VWD.

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