Thrombasthenia 

Updated: Oct 25, 2018
Author: Vivian Y Chang, MD, MS; Chief Editor: Robert J Arceci, MD, PhD 

Overview

Background

Glanzmann, a Swiss pediatrician, initially described thrombasthenia in 1918 when he noted purpuric bleeding in patients with normal platelet counts.[1] The term thrombasthenia means weak platelets. Glanzmann thrombasthenia (GT) is one of several inherited disorders of platelet function, which also include Bernard-Soulier syndrome, as well as deficiencies of platelet adhesion, aggregation, and secretion.[2] Each of these disorders is characterized by a lifelong bleeding tendency.

As in most individuals with hereditary hematologic disorders, thrombasthenia is typically diagnosed at an early age. Pediatricians must be aware of its existence and, when confronted with a complicating coagulopathy, consider thrombasthenia in the differential diagnosis.

Pathophysiology

GT is a rare autosomal recessive disorder whereby the quantity or quality of platelet membrane glycoprotein (GP) IIb-IIIa is abnormal, preventing the aggregation of platelets and subsequent clot formation.

Review of platelet function

Platelets adhere to sites of endothelial injury and then activate, aggregate, and secrete various chemicals designed to promote further platelet recruitment and aggregation. von Willebrand factor (vWF) binds the exposed collagen and binds GP Ib-IX-V complex on the surface of the platelet. This binding adheres platelets to the site of injury. Fibrinogen and vWF bind to the GP IIb-IIIa complex exposed on the activated platelet's surface. This allows crosslinking of platelets and formation of a clot.

Specific deficiency

The platelet integrin GP IIb-IIIa (also referred to as α IIb-β) is a calcium-dependent heterodimer complex that can bind fibronectin, fibrinogen, vWF, and vitronectin. Approximately 80,000 GP IIb-IIIa receptors are present on the surface of each platelet. GP IIb and GP IIIa have their own separate genes on the long arm of chromosome 17. Abnormalities in either gene or in the assembly of the complex result in an abnormal or deficient receptor and, consequently, in disease. Specific genetic abnormalities of each GP include missense mutations, nonsense mutations, splice site mutations, deletions, and point mutations.[3, 4] More than 70 mutations have been described.

These mutations are widely distributed over the 2 genes that encode GP IIb and IIIa present at chromosome band 17q.21-23.[5] Small deletions, insertions, splicing defects, and nonsense and missense mutations are common. A database of these mutations can be reviewed at the Samuel Bronfman Department of Medicine's Glanzmann Thrombasthenia Database.

GT is an autosomal recessive disorder and heterozygous individuals are asymptomatic. Typically, one of the GPs is not properly formed, leaving the other unpaired in the endoplasmic reticulum, where it is degraded. Platelet aggregation, which requires the entire complex, is therefore deficient or completely absent. Binding sites for thrombin are preserved in thrombasthenic platelets, allowing the platelets to be activated for aggregation.[6] Although granule release still occurs, crosslinking as described is disabled.

The deficiency is uniformly present throughout the platelet population and is present in endothelial cells and precursor megakaryocytes. Patients with GT are classified as having type 1, type 2, or variant type based on the degree of GP IIb-IIIa deficiency, fibrinogen binding, and clot retraction.[6] Patients with type 1, the most severe form of the disease, have less than 5% of the normal amount of GP IIb-IIIa present on their platelets. Additionally, they have absent fibrinogen binding and clot retraction. Individuals with type 2 have 10-20% of GP IIb-IIIa, can bind fibrinogen, and have normal–to–moderately deficient clot retraction capability. Persons with the variant type of thrombasthenia have more than 50% of the normal amount of GPIIb-IIIa; however, fibrinogen binding and clot retraction widely vary.

Epidemiology

Frequency

United States

Over 500 cases of thrombasthenia have been reported in the international literature. Although GT predominates among certain ethnic groups, an estimate of worldwide incidence and prevalence has not been reported.

International

As stated above, international frequency data are unknown. However, particularly high carrier rates have been reported in certain ethnic groups, such as Arab populations, specifically Jordanian nomadic tribes, Iraqi Jews, French gypsies, and individuals from southern India. The incidence rate also appears to be increased in families with consanguinity.[7]

Mortality/Morbidity

The probability of death following bleeding is estimated at approximately 5-10%. Most of these cases are related to occurrence of severe unprovoked intracranial or GI hemorrhages.

Race

High carrier rates of GT mutations have been reported in Jordanian nomadic tribes, Iraqi Jews, French gypsies, and individuals from southern India. A report of 382 patients with GT in Iran may suggest that this hereditary hemorrhagic disorder may be more common than initially believed in the Arab population.[8]

Sex

The disease is inherited as an autosomal recessive disorder. No differences appear to occur based on sex. Men present more frequently with gingival bleeding, whereas women present more frequently with menorrhagia.

Age

Patients with GT are typically diagnosed in infancy or early childhood. However, age of diagnosis can range from birth to adulthood. Neonatal purpura typically suggests type 1 thrombasthenia. Epistaxis and GI bleeding are frequent presenting signs of GT and are more severe in children, especially those aged 4-10 years. Menorrhagia may be a presenting sign of GT in adolescent females and can be a critical problem. The severity and frequency of bleeding usually decrease with age.

 

Presentation

History

Initially, patients present with mucocutaneous bleeding in the neonatal period or with bleeding following circumcision.

Children with thrombasthenia may have purpura, epistaxis, gingival bleeding, GI bleeding, and menorrhagia.

The occurrence of most minor bleeding decreases with age.

Severe menorrhagia is a common problem that requires careful observation and treatment with oral contraceptive pills. It is usually associated with an excessively proliferative endometrium that reflects estrogen dominance.[7]

Additional presenting symptoms include GI bleeding and hematuria.

Excessive bleeding following parturition and postsurgical bleeding represent a significant risk.

Although uncommon, hemarthrosis and deep hematomas more characteristic of hemophilias can occur.

Posttraumatic bleeding may be severe in patients not prepared with normal platelets.

Clinical bleeding does not always correlate with the amount of GP IIb-IIIa present.

Interestingly, reports have described thrombosis in patients with congenital thrombocytopenic disorders. Patients with Glanzmann thrombasthenia (GT) have been reported to have venous and arterial thrombosis.[9]

Because the GT trait is recessive, the absence of a family history should not delay a workup for thrombasthenia.

Physical

Most patients with thrombasthenia present with signs of purpura or bleeding.

The initial physical examination should focus on assessing hemodynamic stability.

The diagnosis is made in patients with refractory hemorrhage and appropriate findings on the diagnostic laboratory studies (see Laboratory Studies).

Other than identification of hemorrhage, physical examination findings are of limited use.

Causes

GT is typically inherited as an autosomal recessive disorder. Patients can have homozygous or compound heterozygous mutations in the genes of GPIIb and GPIIIa, leading to quantitative or qualitative abnormalities of the platelet receptor proteins.[10]

Almost 100 different mutations have been identified in GPIIb, which include missense mutations, nonsense mutations, deletions, and insertions, with most being missense mutations. Mutations identified in GPIIIa include missense mutations, nonsense mutations, deletions insertions, inversion/deletions, and rearrangements, with most being missense mutations as well.

About 20% of patients do not have identifiable mutations as a cause of GT. These patients may have mutations in genes involved in transcription of GPIIb and GPIIIa.[11]

Of note, patients with an acquired GT have been reported; they form autoantibodies secondary to lymphoproliferative disorders.[12, 13]

 

DDx

Diagnostic Considerations

Other Problems to be considered:

  • Disseminated intravascular coagulation

  • Idiopathic thrombocytopenic purpura

  • Gray platelet syndrome (α -granule deficiency)

  • Hermansky-Pudlak syndrome

  • Pseudo-von Willebrand disease (vWD)

  • Scott syndrome

  • Quebec platelet syndrome

  • Chédiak-Higashi syndrome

  • Medication-induced (aspirin) platelet inhibition

Differential Diagnoses

 

Workup

Laboratory Studies

A history of prolonged bleeding, a prolonged bleeding time, and failure of platelets to aggregate in response to L-epinephrine, adenosine 5'-diphosphate (ADP), collagen, and arachidonic acid are diagnostic of thrombasthenia. Note that response to ristocetin in platelet aggregation studies is normal.

The platelet function assay PFA-100 (Dade-Behring; Miami, Fla) can replace bleeding times and may aid in the diagnosis of Glanzmann thrombasthenia (GT). The PFA-100 measures the time to closure when blood is passed through a collagen filter. This time is prolonged in patients with GT.[14]

A CBC count and peripheral smear may also be helpful to suggest the degree of bleeding and rule out other potential causes. Patients who are thrombasthenic have platelet counts within the reference range and, on blood smear findings, normal platelet morphology.

Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are within reference ranges.

A urinalysis may reveal proteinuria and microscopic hematuria.

The diagnosis of GT should always be confirmed by documenting the deficiency of GP IIb-IIIa using flow cytometry or immunoblot analysis.

Various methods have been used for genetic testing and screening for mutations in GPIIb and GPIIIa, including single strand conformation analysis (SSCP), conformation sensitive gel electrophoresis (CSGE), and denaturing gradient gel electrophoresis (DGGE).

Imaging Studies

Perform head CT scanning in patients with a history of the disease and head trauma. Abdominal CT should be performed after abdominal trauma.

 

Treatment

Medical Care

Refractory bleeding in individuals with thrombasthenia requires the transfusion of normal platelets. Use human leukocyte antigen (HLA)–matched platelets whenever possible to prevent alloimmunization complications.

Epistaxis can be controlled with nasal packing or application of gel foam soaked in topical thrombin. Case reports have described nasal packing with cured salted pork in the form of a nasal tampon being an effective therapy for uncontrollable epistaxis in a patient with Glanzmann thrombasthenia (GT),[15] as well as use of the medicinal plant extract Ankaferd Blood Stopper for gingival bleeding.[16] E-aminocaproic acid may be used to control bleeding in patients with severe epistaxis or after dental extraction.

Menorrhagia can be severe in patients affected with GT. It usually results from excessive estrogen secretion, which causes a highly proliferative endometrium. Acute menorrhagia can be treated with high doses of progesterone followed by maintenance therapy with oral contraceptive pills.

Iron deficiency anemia can develop in patients with chronic gingival bleeding, GI bleeding, or menorrhagia and may require oral iron supplementation.

Recombinant factor VIIa (rFVIIa) has been successfully used to achieve hemostasis in patients with GT,[17] particularly in patients who have developed isoantibodies to the GP IIb-IIIa complex and who are thus refractory to platelet transfusions.[18] rFVIIa appears to enhance endothelial deposition of GP IIb-IIIa–deficient platelets. Combined with antifibrinolytic therapy, rFVIIa further stabilizes the newly formed clot.[7] rFVIIa has been approved by the European Union for use in patients with GT and platelet refractoriness due to antibodies.

The use of rFVIIa continues to be investigated in the setting of GT. It is currently not approved by the US Food and Drug Administration (FDA) for patients with GT, and its use in children with thrombasthenia remains controversial. It should be noted that off-label use of rFVIIa has not been shown to provide an overall mortality benefit and may increase the risk of thromboembolism.[19, 20, 21, 22] Optimal dosing has yet to be defined in both pediatric and adult patients with GT. A dose of 90 mcg/kg given every 2 hours for 3 or more doses has been used with success.[18]

Antihemophilic factor VIII/von Willebrand factor concentrate (Humate-P) has been used in active bleeding, refractory to rFVIIa.[23] The von Willebrand factor component may increase platelet plug formation. However, pre-Humate-P and post-Humate-P laboratory testing of platelet aggregation studies, as well as thrombin levels and activity, were not significantly affected.

HLA-matched sibling allogeneic stem cell transplantation (SCT) has been successfully performed in patients with GT and platelet isoantibodies that cause severe refractory bleeding. Although curative, this treatment is not recommended in routine cases of thrombasthenia because of the potential complications associated with SCT. The decision to pursue SCT as a potential treatment for GT should be made on a case-by-case basis. Reduced intensity conditioning regimens with SCT have been used in small series with excellent results.[24] This raises the possibility of curative therapy with reduced adverse late effects. Most recently, patients with GT who have undergone successful unrelated donor cord blood transplantations have been reported; this may be an option for patients without matched-sibling donors.[25, 26]

Surgical Care

Treatment with platelet transfusions is often necessary prior to surgical or dental procedures. Aminocaproic acid may also be used postsurgically to control bleeding. Recombinant factor VIIa has been used in invasive surgical procedures or high-risk surgical procedures such as cardiothoracic surgery and spinal/neurosurgery. For dental extractions, molded plastic splints can aid in achieving hemostasis.

Pregnancy and especially delivery can be a major challenge for patients with GT and their care providers. HLA-matched platelet transfusions should be given prior to delivery and are usually required for a week postpartum.[7] rFVIIa has been used successfully to treat severe bleeding at delivery.

Consultations

Consultation with a hematologist is strongly suggested.

Diet

No special diet is required. However, patients with GT should avoid consuming excessive quantities of foods and substances that further interfere with platelet function. This includes excessive quantities of garlic, onions, ginger, and ginseng, as well as food products with quinine and aspirin.

Activity

Any degree of trauma in a patient with thrombasthenia can be severe.

Advise persons with thrombasthenia to take appropriate limitations and precautions with sports and other activities.

 

Medication

Medication Summary

The goal of thrombasthenia therapy is to compensate (partly) for defective platelet function.

Antifibrinolytic agents

Class Summary

These agents inhibit fibrinolysis via inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. The thrombus that forms during treatment is not lysed as rapidly. Effectiveness is uncertain.

Aminocaproic acid (Amicar)

Synthetic competitive inhibitor of plasminogen activation. Preparations include 250 mg/mL PO syr, 500-mg and 1000-mg PO tab, and IV susp.

Vasopressin analogs

Class Summary

These agents act like antidiuretic hormone (ADH) to increase factor VIII levels (transiently). They also have direct and local effect on vessel walls that produces increase in platelet adhesion. In part, this local hemostatic action of desmopressin may account for the clinical observation that desmopressin shortens the bleeding time, bleeding episodes, or both.

Desmopressin (DDAVP, Stimate)

Synthetic vasopressin analog used to control severe bleeding.

Clotting factors

Class Summary

Hemostasis is the physiologic response to bleeding. Injury and factors released by platelets initiate the coagulation cascade, which is mediated by blood clotting factors. This results in formation of an insoluble fibrin clot, reinforcing the initial platelet plug.

Coagulation factor VIIa, recombinant (NovoSeven)

Vitamin K–dependent GP that promotes hemostasis by activating extrinsic pathway of coagulation cascade. Data for refractory severe bleeding in the setting of platelet allosensitization are limited. Reports of efficacy in refractory severe bleeding in pregnancy and in the perioperative period. Not approved by the FDA for treatment of GT associated bleeding.

Hemostatic agents, topical

Class Summary

These agents are used as an adjunct to achieve hemostasis.

Gelatin, topical absorbable (Gelfoam, Gelfilm)

Used to provide hemostasis in surgery. Can be used for PO and dental surgery and with topical thrombin to stop epistaxis. Available in sponges, dental packs, and sterile powder.

Thrombin (Thrombin-JMI, Reothrom)

Used as an adjunct to achieve hemostasis. Topical thrombin catalyzes the conversion of fibrinogen to fibrin. Available as powder and lyophilized powder for reconstitution.

 

Follow-up

Further Inpatient Care

Patients with thrombasthenia who receive platelet transfusion warrant admission for close observation.

Patients with significant blood loss may require close observation in a critical care setting.

Human leukocyte antigen (HLA)-matched platelets should be requested on standby for rebleeding episodes.

Avoid administering medications that interfere with platelet function (nonsteroidal anti-inflammatory drugs [NSAIDs]).

Deterrence/Prevention

Actions taken to prevent minor trauma are strongly suggested.

Complications

Alloimmunization is a possible complication of treating patients without matched blood.

Some patients have developed antibodies to the glycoprotein (GP) IIb-IIIa receptor.

Transfusion of HLA-matched platelets may prevent formation of anti-platelet antibodies, although even GT patients who have never been transfused have spontaneously developed anti-platelet antibodies.[27]

Prognosis

If patients receive timely platelet transfusions, the prognosis is very good.

Individuals with thrombasthenia and GI bleeding have the worst prognosis (see Mortality/Morbidity).

Patient Education

Advise patients with thrombasthenia to avoid contact sports or activities that may result in even minor trauma.

Encourage avoiding causes of GI bleeding (ie, alcohol, NSAIDs).