GREY PLATELET SYNDROME

Rare, inherited disorder characterized by abnormalities of platelet alpha granules, thrombocytopenia, and fibrosis in the bone marrow; consanguinity is common.

Platelet alpha granules - include insulin-like growth factor 1, platelet-derived growth factor TGF, platelet factor 4 (which is a heparin-binding chemokine) and other clotting proteins (thrombospondin, fibronectin, and von Willebrand factor.)

This includes thrombocytopenia with hypogranular platelets. It is inherited as autosomal dominant andmay be associated with severe bleeding.

In GPS, the platelets do not function properly, which interferes with the process of clotting and may lead to prolonged bleeding time, excessive blood loss, and anemia. There is limited information regarding the prevalence of GPS. The condition appears to affect males, females, and individuals of all ethnic and racial groups in equal numbers. The life expectancy of patients with GPS is unknown.

Researchers believe that GPS is caused by a genetic mutation or defect, although the specific location of the mutation is currently unknown. Symptoms Prolonged bleeding time Skin hemorrhage Large platelets

Diagnosis

A lifelong history of mild to moderate mucocutaneous bleeding usually is present. The presence of the abnormality is often first recognized from the gray appearance (lack of azurophilic granules) of the patients platelets on the Wrights stained blood film; the platelets are also larger than normal.

Pathology The underlying problem concerning GPS is the inability of the body's megakaryocytes to properly pack protein into platelets, causing uncontrolled bleeding at the site of wounds. The proteins that should be distributed in the platelets are instead distributed in bone marrow, possibly causing myelofibrosis Giant Platelets HERMANSKY PUDLAK SYNDROME } rare autosomal recessive disorder } Results in: Oculocutaneous albinism Bleeding disorders due to platelet abnormality storage of an abnormal fat-protein compound Described in 1959 by Hermansky and Pudlak } HPS1 is extremely prevalent in Puerto Rico.

} HPS3 is also common on the island, primarily in the central region. Prognosis } cause dysfunctions of the lungs, heart, kidney or intestines. } major complication of most forms of the disorder is pulmonary fibrosis. } it is the usual cause of death from the disorder. Pathogenesis } Due to the mutation on several genes: HPS1 HPS3 HPS4 HPS5 HPS6 HPS7 Symptoms } There are three main disorders caused by HermanskyPudlak syndrome: Albinism and eye problems Bleeding disorders Cellular storage disorders Diagnosis } hypopigmentation of the skin and hair, } characteristic eye findings } demonstration of absent dense bodies in platelets Treatment } While there is no cure for HPS, treatment for chronic hemorrhages associated with the disorder includes therapy with vitamin E and the antidiuretic dDAVP.

GROUP 3 ESSENTIAL ATHROMBIA ETIOLOGY: It is described during 1955 and 1962 in which it confirms the existence of a type of primary functional platelet disorder characterized solely by an aggregation defect, called "Essential Athrombia". This disorder appears to be transmitted as a dominant trait, either autosomal or sex-linked. PLATELET CHARACTERISTICS: > Normal platelet count > Normal platelet factor 3 activity > impaired platelet aggregation *Platelet aggregation, studied turbidimetrically, was absent in the presence of usual doses of ADP (1-4MUM) although a small wave of primary aggregation was obtained by very large ADP concentrations (25-50MUM) > Platelets unresponsive to epinephrine, thrombin and diluted collagen suspensions. *Normal aggregation response occurred with strong collagen suspensions. > Platelets responded to Ristocetin. > Release of platelet ADP is normal in collagen and thrombin but impaired in kaolin. > Platelet fibrinogen is normal CLINICAL DESCRIPTION: > Autosomal recessive > Petechiae and purpura > Easy and spontaneous bruising > Mucosal membrane bleeding > Large hematomata > Intraarticular bleeding (rare) > Decreasing severity with age LABORATORY FINDINGS: > Prolonged template bleeding time > Abnormal/Absent primary aggregation with ADP, EPINEPHRINE, THROMBIN and COLLAGEN > Abnormal platelet factor-3 release

> Clot retraction- NORMAL > Absence of platelet membrane glycoprotein (PGMP) IIb/IIa complex DIAGNOSIS AND THERAPY: > THERAPY: Infusion of platelet concentrates

May-Hegglin Anomaly History

MHA is after German physician Richard May and Swiss physician Robert Hegglin. The disorder was first described by Richard May in 1909, and was subsequently described by Robert Hegglin in 1945. Etiology

May-Hegglin anomaly is one of a family of macrothrombocytopenias characterized by mutations in the MYH9 gene. The protein is involved in several important functions, including cytokinesis, cell motility and maintenance of cell shape. An autosomal dominant disorder

Pathophysiology Patients have a mutation of the MYH9 gene present in chromosomal region 22q12-13. The mutation results in disordered production of nonmuscle myosin heavy-chain type IIA, which leads to invariable macrothrombocytopenia secondary to defective megakaryocyte maturation. Platelet function in patients with May-Hegglin anomaly has been reported as normal. Leukocyte Dhlelike inclusion bodies are visualized on standard Wright stain and appear bright blue and spindle shaped. Ultrastructural studies reveal that these bodies consist of clusters of ribosomes oriented along parallel myosin heavy-chain filaments 710 nm in diameter. Neutrophil function is considered to be normal, and patients have no increased susceptibility to infections. Clinical Features Thrombocytopenia that may be associated with purpura and bleeding Giant platelets containing few granules Large (2-5 m), well-defined, basophilic, cytoplasmic inclusion bodies in granulocytes that resemble Dhle bodies. Symptoms of May-Hegglin Anomaly Minor hemorrhages Mild leukopenia Mild reduction in level of blood platelets Skin hemorrhage Nosebleed Excessive oral bleeding during dental procedures Headache Muscle weakness on one side of body Intracranial bleeding Large blood platelets Mild reduction of level of blood platelets Prolonged bleeding time Bleeding inside the brain Excessive menstrual bleeding Easy bruising Gums that bleed easily Excessive bleeding after operations Treatment of May-Hegglin Anomaly

In mild cases, treatment for May-Hegglin Anomaly is not usually necessary. In more severe cases, transfusions of blood platelets may be necessary.

WISKOTT-ALDRICH SYNDROME

named after Dr Robert Anderson Aldrich an American pediatrician who described the disease in a family of Dutch-Americans in 1954 it is a rare hereditary immune deficiency with recessive inheritance linked to the X chromosome (Xp11.22-p11.23) linked to polymorphic markers Characterized by the association of thrombocytopenia with small-sized platelets that do not function properly, eczema and repeated infections Occurs early in the childhood (during the 1st decade & usually before the age of 3)

CLINICAL DESCRIPTIONS

Young boy with : hemorrhagic signs Purpura Petechiae Ecchymoses Epistaxis Bloody diarrhea Recurrent infections Bronchial Pulmonary ENT Eczema Sometimes, sign of autoimmunity

Isolated thrombocytopenia linked to the X chromosome presents the same hematological characteristics as WAS but IT is the sole symptom with no particular susceptibility to infections.

METHODS OF BIOLOGICAL DIAGNOSIS:

CBC shows severe thrombocytopenia, often fewer than 50,000 platelets Analysis of platelet size shows them to be small (4-5 microns) low immunoglobulin levels IgM levels are low, IgA levels are elevated, and IgE levels may be elevated paraproteins are occasionally observed Skin immunologic testing Decreased levels of Wiskott-Aldrich syndrome protein and/or confirmation of a causative mutation provides the most definitive diagnosis TREATMENT:

When thrombocytopenia is very severe, splenectomy may be beneficial Only a bone marrow transplant can cure this pathology Good management of infections lower the risk of the disease evolving towards the development of lymphoma or tumor

NEONATAL ALLOIMMUNE THROMBOCYTOPENIA Thrombocytopenia is defined as a platelet count less than 150,000 per microliter of blood

 Platelet count less than 100,000/uL is considered as definitely abnormal at any gestational age and deserves further evaluation Is the most common cause of severe isolated thrombocytopenia in the fetus and newborn. ETIOLOGY It results from the destruction of the fetal platelets by maternal IgG antibodies elicited during pregnancy and directed against fetal specific platelet antigens that are inherited from the father and are different from those present in the mother (Shulman N. R. et al, 1964). First pregnancy can have affected child (unlike neonatal Rh disease) Human platelet antigen 1 (HPA-1 or PLA-1) incompatibility accounts for 80% to 90% of cases of NAIT. Incidence of NAIT is 0.05% to 0.1% Severe thrombocytopenia, < 50,000 in 87% of cases Petechiae in 80% of cases Intracranial hemorrhage in 11% of cases EPIDEMIOLOGY Studies of a large number of women have shown that about one in every 1000 women who are HPA-1 negative have antibodies. About 10% of HPA-1 negative women who have previously given birth to a HPA-1 positive child, have antibodies. Neonatal Alloimmune Thrombocytopenia occurs in about one out of every 5000 deliveries. CLINICAL MANIFESTATIONS severe, generalized petechiae rash or purpura can be normal at birth and may develop symptoms and signs during 2-3 day post-partum. severe complication is intracranial hemorrhage which is seen in approximately 10-15% cases and half of these occurs in utero with neuro-developmental sequele DIAGNOSIS There is no routine blood test that is performed in pregnancy to see if a mother has antibodies to platelets. Most mothers do not even know they have this disease unless they give birth to a baby with a low platelet count or if their sister gives birth to an affected baby. Physicians take several steps to diagnose this disease. They can: Check the mother's platelet type Check the fathers platelet type Check the mother's blood for antibodies Perform an amniocentesis (the process of getting a fluid sample from the amniotic sac) to check the babys platelet type Perform several ultrasounds If necessary, conduct a cordocentesis (the process of getting a blood sample from the unborn babys umbilical cord) for more information. TREATMENT DURING PREGNANCY In an effort to prevent a low platelet count in the baby, a medication called intravenous immune globulin is often prescribed. This medication is made from antibodies from many people. The exact way that intravenous immune globulin prevents thrombocytopenia in the baby is unknown. It may cause the mother to make less anti-platelet antibodies, it may block her antibodies from crossing the placenta (afterbirth) to get to the fetus or it may prevent the platelets in the fetus that have antibodies attached to them from being destroyed. END OF PREGNANCY COMPLICATION Medications will be continued throughout the pregnancy. Most physicians will deliver a pregnancy complicated by Neonatal Alloimmune Thrombocytopenia by 38 weeks (two weeks before the usual due date). One of two approaches can be taken: Cordocentesis Elective cesarean section AFTER BIRTH Your baby will be watched very closely and his or her blood will be checked several times to measure the platelet count. If the count is low, the baby will receive platelets that were collected earlier, or will receive platelets from a special antigen negative donor person. In addition, if the baby's first few platelet counts are low, he or she may need treatment with intravenous immune globulin or steroids (much like you received during pregnancy). Also, your baby may undergo a special ultrasound or MRI of the head to be sure that there was no bleeding into the brain. Typically, a baby at risk for Neonatal Alloimmune Thrombocytopenia will remain in the hospital a little longer than usual. Idiopathic Thrombocytopenic Purpura (ITP) Definition

A bleeding disorder in which the immune system destroys platelets, which are necessary for normal blood clotting. Persons with the disease have too few platelets in the blood sometimes called immune thrombocytopenic purpura

Etiology The exact cause of ITP isn't known. That's why it's referred to as idiopathic, which means "of unknown cause." It is known, however, that in people with idiopathic thrombocytopenic purpura, the immune system malfunctions and begins attacking platelets as if they were foreign substances. Antibodies produced by your immune system attach themselves to the platelets, marking the platelets for destruction. The spleen, which helps your body fight infection, recognizes the antibodies and removes the platelets from your system. The result of this case of mistaken identity is a lower number of circulating platelets than normal. Symptoms

Easy or excessive bruising (purpura) your skin naturally bruises and bleeds more easily as you age, but this shouldn't be confused with ITP Superficial bleeding into your skin that appears as a rash of pinpoint-sized reddish-purple spots (petechiae), usually on your lower legs Prolonged bleeding from cuts Spontaneous bleeding from your gums or nose Blood in urine or stools Unusually heavy menstrual flows Profuse bleeding during surgery

Exams and Tests Laboratory tests will be done to see how well your blood clots and to check your platelet count.

A complete blood count (CBC) shows a low number of platelets. Blood clotting tests (PTT and PT) are normal. Bleeding time is prolonged. Platelet associated antibodies may be detected. A bone marrow aspiration or biopsy appears normal or may show a greater than normal number of cells called megakaryocytes. These cells are an early form of platelets. Treatment In children, the disease usually goes away without treatment. Some children, however, may need treatment. Adults are usually started on an anti-inflammatory steroid medicine called prednisone. In some cases, surgery to remove the spleen (splenectomy) is recommended. This will increase the platelet count in about half of all patients. However, other drug treatments are usually recommended instead. If the disease does not get better with prednisone, other treatments may include:

A medicine called danazol (Danocrine) taken by mouth Injections of high-dose gamma globulin (an immune factor) Drugs that suppress the immune system Filtering antibodies out of the blood stream Anti-RhD therapy for people with certain blood types

Types of Immune Thrombocytopenia The two types of ITP are acute (temporary or short-term) and chronic (long-lasting). 1. 2. Acute ITP generally lasts less than 6 months. It mainly occurs in childrenboth boys and girlsand is the most common type of ITP. Acute ITP often occurs after a viral infection. Chronic ITP lasts 6 months or longer and mostly affects adults. However, some teenagers and children do get this type of ITP. Chronic ITP affects women two to three times more often than men.

Treatment depends on the severity of bleeding and the platelet count. In mild cases, treatment may not be needed. Sex

In chronic ITP (adults), the female-to-male ratio is 2.6:1. More than 72% of patients older than 10 years are female. In acute ITP (children), distribution is equal between males (52%) and females (48%).

Age

Peak prevalence occurs in adults aged 20-50 years. Peak prevalence occurs in children aged 2-4 years. Approximately 40% of all patients are younger than 10 years. Acquired Platelet Dysfunction in relation to Uremia Platelet: Function

Thrombus formation Cytokine Signaling Clinical Features

Gastrointestinal bleeding Peptic Ulcer Disease Clinical Features Telangiectasias in the stomach, duodenum, jejunum and colon Duodenitis Esophagitis Intracerebral hemorrhage Clinical Features Ecchymoses Purpura Epistaxis Uremia

urea and other waste products, which are normally excreted into the urine, are retained in the blood. levels of urea and other nitrogenous waste products are increased in the blood. Factors in Hemostasis

INCREASED: Prostacyclin Nitric Oxide Guanidine Succinate cAMP Urea Prostacyclin

Inhibits platelet activation Promotes vasodilation

Nitric Oxide

Vasorelaxant Guanidine Succinate

Inhibits platelet factor 3 *Platelet Factor 3 aids on the activation of Factor VIII Factors in Hemostasis DECREASED:

ADP Serotonin Integrin IIB3 vWF ADP

For platelet activation Recruits other platelets to the hemostatic plug Serotonin

Promotes vasoconstriction Integrin IIB3

Receptor for fibrinogen Anemia

RBCs release ADP & Thromboxane A2 Reduced hematocrit Reduced hemoglobin (Hb has high affinity for Nitric Oxide) Complications: Medications

Anticoagulants: Aspirin IIB3 antagonists Heparin Warfarin Diagnosis

Bleeding Time Management

Hemodialysis Peritoneal Dialysis Renal Taansplant RBC Transfusion Administration of EPO

Cryoprecipitate (factor VIII, vWF, fibrinogen) Estrogen (L-arg) THROMBOTIC THROMBOCYTOPENIC PURPURA is a rare disorder of the blood-coagulation system, causing extensive microscopic clots to form in the small blood vessels throughout the body. These small blood clots, called thromboses, can damage many organs including the kidneys, heart and brain. Etiology TTP is caused by spontaneous aggregation of platelets and activation of coagulation in the small blood vessels. Platelets are consumed in the coagulation process, and bind fibrin, the end product of the coagulation pathway. These platelet-fibrin complexes form microthrombi which circulate in the vasculature and cause shearing of red blood cells, resulting in hemolysis. Pathophysiology The pathophysiology of TTP is still poorly understood. The current view includes endothelial cell damage and the presence of abnormally large molecular weight von Willebrand factor (vWF) multimers. In TTP, endothelial cell damage causes the release of ultra-large vWF multimers in the blood stream. These multimers increase platelets' adhesiveness and clumping. Normally these vWF multimers undergo proteolysis in the high-shear environment of the arterial circulation by the enzyme vWF metalloproteinase. Proteolysis reduces the size of polymers and inhibits their binding to platelet glycoprotein (GP) Ib/IX/V and GP IIb/IIIa receptors. SIGNS AND SYMPTOMS

Thrombocytopenia Microangiopathic hemolytic anemia Neurologic symptoms Kidney failure Fever Malaise Diarrhea Heart rate over 100 beats per minute Pallor Shortness of breath EPIDEMIOLOGY Incidence In the U.S.: 0.30.6 cases per 100,000 persons per year Age Can occur at any age More common from 1040 years Median age at diagnosis: 35 years Sex Women: 67% Men: 33% Mortality/Morbidity TTP has a mortality rate of as high as 90%. With plasma exchange, the mortality rate is reduced to 10-20%. RISK FACTORS Pregnancy and use of oral contraceptives Metastatic cancer HIV infection Vasculitis Systemic lupus erythematosus Chemotherapy Hormone replacement therapy and estrogens Many commonly used medications (including ticlopidine, clopidogrel, and cyclosporine A) Diagnostic Tests In TTP, there will be a lower than normal number of platelets and red blood cells . In TTP, the red blood cells are torn and broken.

Complete Blood Count Blood Smear

Coombs Test

This blood test is used to find out whether TTP is the cause of hemolytic anemia. When TTP is the cause of hemolytic anemia, the Coombs test is negative. The test is positive if antibodies (proteins) are destroying the red blood cells.

Lactate Dehydrogenase Test

This blood test measures a protein called lactate dehydrogenase (LDH). LDH is released from tissues that are injured by blood clots as a result of TTP.

Bilirubin Test

In a patient with TTP, bilirubin levels may be high because the body is breaking down red blood cells faster than normal.

Kidney Function Tests and Urine Tests

If a person has TTP, his/her urine may contain protein or blood cells. Also, the blood creatinine level may be high.

ADAMTS13 Assay

A lack of activity in the ADAMTS13 enzyme causes TTP. For this test, a sample of blood is drawn from a vein, usually in your arm. The blood is sent to a special lab to test for the enzyme's activity.

Platelet Count

This test counts the number of platelets in a blood smear. People who have TTP have a lower than normal number of platelets in their blood. This test is used with the blood smear to help diagnose TTP. Treatment The therapy of choice is plasma exchange with fresh frozen plasma. When immediate plasma exchange is not available, simple plasma infusion can be performed until transfer to a facility that performs plasma exchange. Have surgery to remove the spleen Get drugs that suppress the immune system, such as Corticosteroids or Rituximab Prevention Because the cause is unknown, there is no known way to prevent this condition.