Bernard-Soulier Syndrome

Genetic disorder characterized by giant platelets, mild-to-moderate thrombocytopenia, abnormal platelet function, and bleeding disproportionate to the reduced number of platelets.

Giant Platelet Syndrome; Familial Macrothrombocytopenia; Deficiency of Platelet Glycoprotein Ib; Hemorrhagiparous Thrombocytic Dystrophy.

First described in 1948 by Jean Bernard and Jean-Pierre Soulier, French hematologists.

Probably less than 1:1,000,000 in the general population.

Autosomal recessive. Genetic research located the GP-1BA gene on 17pter-p12 for the classic Bernard-Soulier syndrome (type A) and the GP-1BB gene on 22q11.2 for type B.

The mutation results in a deficiency of platelet membrane glycoprotein (GP) Ib (GP-1BA), GP-Is (glycocalicin), GP-V, and GP-IX. (Glycocalicin results from proteolytic cleavage of GP-1BA.) These factors are responsible for the interaction between von Willebrand factor and the platelet membrane and are essential for normal platelet adhesion in the early phase of primary hemostasis. Furthermore, the giant platelets show altered binding of factors V and XI and do not develop regular coagulation activity upon contact with collagen.

Bleeding tendency noted during childhood. Clinical picture and morphologic features of the platelets on blood smear examination, which shows increased size (giant platelets may have a diameter up to 8 μm) with dense granulomeres, resulting in a pseudonucleated or lymphocytoid aspect.

Moderate-to-severe bleeding of purpuric type (bruising, epistaxis, menorrhagia). Bleeding time is prolonged, but clot retraction and platelet aggregation by adenosine diphosphate and collagen are normal. Heterozygous family members may show approximately half the normal levels of platelet GP Ib-IX-V expression; however, they suffer from only mild bleeding diatheses, if at all. Affected patients have a history of frequent episodes of epistaxis, gingival and cutaneous bleeding, and hemorrhage associated with trauma. Platelet counts may range from very low (<30,000/μL) to marginally low or normal (∼200,000/μL). In individual patients it may fluctuate considerably over a period of years. Skin bleeding time may range from only marginally prolonged (5-10 minutes) to more than 20 minutes. The severity of symptoms may progressively worsen or become alleviated throughout puberty and adult life. Splenectomy apparently has been beneficial in moderating thrombocytopenia and the severity of clinical symptoms.

Check platelet count and bleeding time. Bleeding tendency is variable (some patients remain asymptomatic until later adulthood), but can be severe during surgery, trauma, or pregnancy. Evaluate hematologic status (complete blood count, bleeding time, platelet function tests, prothrombin time, partial thromboplastin time). Activated recombinant factor VII (rFVIIa) and fresh plasma concentrate should be immediately available in the event they are required.

Avoid central neuraxial blocks. Direct laryngoscopy and tracheal intubation must be atraumatic. General supportive measures and specific treatment of bleeding episodes. Severe hemorrhagic shock occurs spontaneously or secondary to surgery. High-dose recombinant factor VIIa has been used to correct bleeding and was postulated to act on platelets in the absence of tissue factor to activate factors IX and X and thus enhance thrombin generation. Transfusion of platelet-rich plasma is another technique that has been used successfully to stop severe hemorrhage.

Consider use of desmopressin acetate (DDAVP) and antifibrinolytics. Avoid drugs or products adversely affecting platelet function, such as nonsteroidal antiinflammatory drugs and hydroethyl starch. Halothane and sevoflurane (and dibucaine) may affect platelet function. Antifibrinolytics may or may not be beneficial.

Thrombopathic Thrombocytopenia: Although this disorder is similar to the Bernard-Soulier syndrome, the inheritance is autosomal dominant.

Glanzmann Thrombasthenia: This autosomal recessive transmitted bleeding disorder is characterized by prolonged bleeding time, absence of platelet aggregation, and impaired clot retraction as a consequence of a dysfunction or deficiency of platelet membrane glycoprotein complex IIb-IIIa.

Gray Platelet Syndrome: Rare platelet disorder characterized by a marked decrease or absence of platelet-specific α-granules. These are the most abundant cell organelles in platelets containing more than 20 different proteins, of which platelet factor-4, thromboglobulin, platelet-derived growth factor, thrombospondin, and homologues of von Willebrand factor are the most important. The term gray platelet is derived from the gray microscopic appearance of these platelets, which is a result of their increased size in combination with the reduced number of granules. Inheritance most likely is autosomal dominant. Initially, the defect seemed to be limited to the megakaryocytic cell line, but new research in an affected family showed also a secretory disorder in the neutrophil blood cell line (alkaline phosphatase and others), resulting in gray neutrophils.

Montreal Platelet Syndrome: Resembles Bernard-Soulier syndrome in many aspects. Platelet gigantism is caused by superabundant platelet membranes and an abnormal change in shape. However, in contrast to Bernard-Soulier syndrome, GP I levels seem to be normal.

The following syndromes (May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, Epstein syndrome) called platelet storage pool defects or platelet-type von Willebrand disease all are caused by a mutation on gene map locus 22q11.2, which has been found to be the nonmuscle myosin heavy-chain-9 (MYH9) gene.

May-Hegglin Anomaly (Macrothrombocytopenia with Leukocyte Inclusions; Dohle Leukocyte Inclusions with Giant Platelets): Autosomal dominant inherited bleeding disorder characterized by the triad of giant platelets, thrombocytopenia, and large leukocyte inclusion bodies. Gene map locus is 22q11.2-q13. The pathophysiology is poorly understood but seems to be related to a defect in the microtubular system, which results in abnormal maturation and fragmentation of megakaryocytes. The lifespan of platelets appears to be normal. The inclusion bodies are called Dohle bodies, are often spindle shaped, and consist of cytoplasmic RNA. They may represent paracrystalline arrays of depolymerized ribosomes. Although thrombocytopenia occurs in half of these patients, severe bleeding is rare and many patients are asymptomatic. Successful craniotomy with DDAVP (desmopressin) therapy has been reported.

Sebastian Syndrome: The presence of macrothrombocytopenia with neutrophil inclusion bodies is reminiscent of May-Hegglin anomaly, but ultrastructural analysis of the inclusion bodies reveals their similarity with the ones found in Fechtner syndrome (see below). In fact, Sebastian and Fechtner syndrome differ from each other only by the features of Alport syndrome (deafness and nephritis). Inheritance is autosomal dominant. The defect is also located on the long arm of chromosome 22 (22q11.2).

Fechtner Syndrome (Macrothrombocytopathy, Nephritis, Deafness, and Leukocyte Inclusion Syndrome; Alport Syndrome with Leukocyte Inclusions and Macrothrombocytopenia): The name of this autosomal dominant transmitted syndrome is derived from the surname of the family first described with this disorder. Like May-Hegglin anomaly and Sebastian syndrome, the defect of this syndrome is located on the long arm of chromosome 22 (22q11.2). Clinically, it is characterized by a combination of nephritis (with symptoms ranging from microhematuria to end-stage renal failure), high-frequency sensorineural deafness, congenital cataracts, macrothrombocytopenia, and inclusion bodies in neutrophils and eosinophils. Although the aspect of the inclusion bodies under the light microscope is similar to the inclusion bodies seen in May-Hegglin Anomaly, ultrastructurally they are different. The abnormal size of the platelets seems to be a result of an abnormality in the cytoskeleton of megakaryocytes interfering with the demarcation membrane system and the normal expulsion of platelets.

Epstein Syndrome: The gene map locus of this autosomal dominant transmitted syndrome is also on the long arm of chromosome 22 (22q11.2). High-tone sensorineural deafness and renal disease are similar to that found in Alport syndrome. Macrothrombocytopenia results in prolonged bleeding time and impaired platelet aggregation in response to collagen. The giant platelet formation seems to be the result of a degenerative process in megakaryocytes, which leads to nuclear regression and cytoplasmic fragmentation.