Blogger Widgets



5 April 2012

Disorders of Platelets and Focus on von Willebrand Disease

The hemostatic system consists of platelets, coagulation factors, and the endothelial cells lining the blood vessels. The platelets arise from the fragmentation of the cytoplasm megakaryocytes in the bone marrow and circulate in blood as disc-shaped anucleate particles. 
Under normal circumstances, the resistance of the endothelial cell lining to interactions with platelets and coagulation factors prevents thrombosis.
Platelets play a primary role in this process, interacting with subendothelium-bound von Willebrand factor (vWf) via the membrane glycoprotein (GP) Ib complex. This initial interaction (platelet adhesion) sets the stage for other adhesive reactions that allow the platelets to interact with each other to form an aggregate. 
he platelet GP IIb/IIIa complex mediates platelet-to-platelet interactions (platelet aggregation). On resting platelets, GP IIb/IIIa is unable to bind fibrinogen or vWf. Platelet activation allows binding of these proteins, which bridges adjacent platelets. Morphologically, the platelets change dramatically from discs to spiny spheres in a process called shape change.
Platelets contain 2 unique types of granules: the alpha granules and the dense granules. The alpha granules contain hemostatic proteins such as fibrinogen, vWf, and growth factors (eg, platelet-derived growth factor). The dense granules contain proaggregatory factors such as adenosine 5'-diphosphate (ADP), calcium, and 5-hydroxytryptamine (serotonin). During activation, the granules are centralized and their contents are discharged into the lumen of the open canalicular system, from which they are then released to the exterior 
when platelets are activated, negatively charged phospholipids move from the inner to the outer leaflet of the membrane bilayer. This negative surface provides binding sites for enzymes and cofactors of the coagulation system, resulting in the formation of a clot (secondary hemostasis).
Pathophysiology of Platelet Disorders
Platelet disorders lead to defects in primary hemostasis and produce signs and symptoms different from coagulation factor deficiencies (disorders of secondary hemostasis). The body's reaction to vessel wall injury is rapid adhesion of platelets to the subendothelium. The initial hemostatic plug, composed primarily of platelets, is stabilized further by a fibrin mesh generated in secondary hemostasis. The arrest of bleeding in a superficial wound, such as the bleeding time wound, almost exclusively results from the primary hemostatic plug.
Hence, primary hemostatic disorders are characterized by prolonged bleeding time, and the characteristic physical examination findings are petechiae and purpura. In comparison, defects in secondary hemostasis result in delayed deep bleeding (eg, into muscles and joints) and the characteristic physical examination finding is hemarthrosis. Hemarthrosis and muscle hematomas are not present in primary hemostatic disorders.
Disorders of Platelet Function
von Willebrand disease
von Willebrand disease (vWD) is the most common inherited bleeding disorder. It is autosomal dominant, and its prevalence is estimated to be as high as 1 case per 1000 population.
The hallmark of von Willebrand disease is defective platelet adhesion to subendothelial components caused by a deficiency of the plasma protein vWf. This factor is a large, multimeric protein that is synthesized, processed, and stored in the Weibel-Palade bodies of the endothelial cells, and secreted constitutively following stimulation.
vWf has a major role in primary hemostasis as mediator of the initial shear-stress–induced interaction of the platelet to the subendothelium via the GP Ib complex. In addition, von Willebrand protein acts as a carrier and stabilizer of coagulation factor VIII by forming a complex in the circulation.
In the absence of vWf, the factor VIII activity level is low. In classic hemophilia A, the factor VIII activity level is low because of a defect in factor VIII itself, whereas in von Willebrand disease, the factor VIII activity level is low because of a deficiency in its carrier protein.
von Willebrand disease is a relatively mild bleeding disorder, except in the occasional patient who is homozygous for the defect and who has severe bleeding often indistinguishable from classic hemophilia. The bleeding manifestations are predominantly skin-related and mucocutaneous (ie, easy bruising, epistaxis, GI hemorrhage).
Most bleeding episodes occur following trauma or surgery. In women, menorrhagia is common, often exacerbated by the concurrent administration of nonsteroidal anti-inflammatory drugs. Pregnant patients with this disease usually do not have problems.
Bleeding time is prolonged in persons with von Willebrand disease. Because the von Willebrand protein is phase-reactant (ie, increased synthesis in the presence of inflammation, infection, tissue injury, and pregnancy), a mild prolonged bleeding time may be normalized, resulting in difficulty in diagnosis.
In addition to the prolonged bleeding time, characteristic abnormalities in platelet aggregation tests occur. In patients with von Willebrand disease, platelets aggregate normally to all agonists except the antibiotic ristocetin, which induces binding of the von Willebrand protein to platelets, similar to what happens with platelets following vessel wall injury in vivo. Ristocetin-induced platelet aggregation correlates with the platelet-aggregating activity of the von Willebrand protein. levels of coagulation factor VIII are also low, resulting from a decrease in vWf.
Variants of von Willebrand disease
Although the common form of von Willebrand disease (type I) results from a quantitative deficiency of vWf, the variants result from abnormalities in the von Willebrand protein.
A common variant (type IIA) of von Willebrand disease results from functionally defective vWf that is unable to form multimers or be more susceptible to cleavage by ADAMTS13. Larger multimers are more active in mediating platelet vessel-wall interaction. In these variants, the factor VIII level may be normal.
In the type IIB variant, the von Willebrand protein has heightened interaction with platelets, even in the absence of stimulation. Platelets internalize these multimers, leading to a deficiency of von Willebrand protein in the plasma.
A disorder of platelet GP Ib has also been described. In this condition, increased affinity for von Willebrand protein in the resting stage leads to the deletion of plasma von Willebrand protein. This disease is called pseudo von Willebrand disease or platelet-type von Willebrand disease.
Type III von Willebrand disease is a severe form of von Willebrand disease that is characterized by very low levels of vWf and clinical features similar to hemophilia A, but with autosomal recessive inheritance. This condition results from a homozygous state or double heterozygosity.
Bernard-Soulier syndrome
Bernard-Soulier syndrome results from a deficiency of platelet glycoprotein protein Ib, which mediates the initial interaction of platelets with the subendothelial components via the von Willebrand protein. It is a rare but severe bleeding disorder. Platelets do not aggregate to ristocetin. The platelet count is low, but, characteristically, the platelets are large, often the size of red blood cells, and may be missed on complete blood counts because most automatic counters do not count them as platelets.
Glanzmann thrombasthenia
Glanzmann thrombasthenia results from a deficiency of the GP IIb/IIIa complex. Platelets do not aggregate to any agents except ristocetin. The more severe type I results from a complete absence of the GP IIb/IIIa complex, whereas in the milder type II, some of the GP IIb/IIIa complex is retained.
Both Bernard-Soulier syndrome and Glanzmann thrombasthenia are characterized by lifelong bleeding. Although platelet transfusions are effective, they should be used only for severe bleeding and emergencies, because alloantibodies often develop in these patients.
Etiology of Platelet Disorders
Platelet disorders can involve either a decreased number of platelets (thrombocytopenia) or defective platelet function. Functional disorders of platelets can be inherited (rare) or acquired (common). Platelet aggregation tests are useful in differentiating various disorders of platelet function. In all cases of thrombocytopenia, the peripheral blood smear must be reviewed to confirm the thrombocytopenia. This review is crucial.
Spurious thrombocytopenia can occur due to aggregates forming in the specimen. In addition, dilutional thrombocytopenia may occur in situations of fluid replacement or blood component replacement without platelet support.
Thrombocytopenia can be further divided into increased destruction or decreased production. Thrombocytopenia resulting from increased destruction occurs either by an immune mechanism or increased consumption.
Platelets are consumed intravascularly by the activation of the coagulation process (diffuse/disseminated intravascular coagulation [DIC]) or by deposition on damaged endothelial cells (microangiopathy). Production defects result from those diseases that cause bone marrow failure, such as aplastic anemia, infiltration by leukemia or another malignancy, fibrosis or granulomatous disorders, or tuberculosis.
Causes of thrombocytopenia related to increased destruction include 
(1) Immune thrombocytopenias (eg, autoimmune, alloimmune, drug-induced) and 
(2) Increased consumption (eg, DIC, TTP). Causes of thrombocytopenia related to decreased production include bone marrow depression.
Disorders of platelet function are as follows:
  • Disorders of platelet adhesion (von Willebrand disease, Bernard-Soulier syndrome)
  • Disorders of aggregation (Glanzmann thrombasthenia)
  • Disorders of secretion
  • Disorders of thromboxane synthesis
  • Acquired disorders of platelet function (drugs [eg, aspirin, NSAIDs, alcohol])
  • Uremia
  • Paraproteins
  • Fibrin degradation products
  • Myelodysplasia or a myeloproliferative syndrome
Treatment of von Willebrand Disease
Desmopressin (DDAVP) is a vasopressin analogue that releases vWf from endothelial cells.
Most patients with type I von Willebrand disease can be treated with DDAVP for minor surgeries and dental procedures. The usual dose is 0.3 μg/kg infused slowly approximately 30 minutes before an operative procedure. This dose can be repeated once a day for 2-3 days, after which it is ineffective because of tachyphylaxis. Other adverse effects occasionally include a hypertensive response and hyponatremia.
An intranasal preparation of DDAVP has been made available for individuals with von Willebrand disease and is administered at a dose of 150 μg or 300 μg (ie, 150 μg per nostril). The more diluted preparation is used in patients with diabetes insipidus and does not increase vWf levels.
DDAVP does not usually increase factor VIII levels in patients with type IIA and can induce thrombocytopenia in patients with type IIB or pseudo von Willebrand disease.
Replacement therapy is used for more extensive surgeries or trauma and for patients with type II and type III disease. The treatment of choice is vWf concentrates (Humate-P or Alphanate). These preparations are heat-treated, and the solvent is extracted; therefore, they are considered safe from viral contamination.
The dose is calculated based on ristocetin cofactor units (usual dose is 50-100 U/kg). The factor VIII level often rises following the infusion of von Willebrand protein concentrate, and it remains elevated for at least for 40 hours, reflecting the half-life of von Willebrand protein rather than that of factor VIII. The need for further doses is often assessed based on clinical criteria rather than blood test results.
Cryoprecipitate has approximately 100 U of factor VIII per bag and has all multimeric forms of vWf. Despite screening tests, patients have a small risk developing viral infections.
Highly purified preparations of factor VIII or recombinant factor VIII should not be administered to patients with von Willebrand disease, because these preparations have very little von Willebrand protein.
Source: Scopus
Pharm.D Resident
Hyderabad, India