LEC11 Disorders of Primary Hemostasis Platelet Disorders 1 PDF

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Summary

Pathophysiologic Process that result in Thrombocytopenia o Decreased Platelet Production o Increased Platelet Destruction o Abnormal Platelet Distribution 2 Categories in Abnormal Platelet Production Megakaryocyte Hypoplasia Ineffective Thrombopoiesis MYH9-related Thrombocytopenia Syndromes Autosoma...

Description

Thrombocytopenia with Absent Radius (TAR)

Pathophysiologic Process that Thrombocytopenia o Decreased Platelet Production o Increased Platelet Destruction o Abnormal Platelet Distribution

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Autosomal Recessive Thrombocytopenia Associated with the mutation in the RBM8A – CH 1 Rare disease, first identified in 1959 Platelet count is, approximately 10-30 X 103 /uL o hypomegakaryocytic Serum TPO levels are normal, and marrow cellularity is normal or increased. Megakaryocytes are low in number, absent or appear immature. Can be managed by platelet transfusion. Commonly seen among infants and children. Treatment: Surgery

Congenital Amegakaryocytic Thrombocytopenia (CAMT) • • • • • • • 2 Categories in Abnormal Platelet Production Megakaryocyte Hypoplasia Ineffective Thrombopoiesis

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• • MYH9-related Thrombocytopenia Syndromes Autosomal Dominant Thrombocytopenia Caused by mutations in the MYH9 gene. These include May-Hegglin anomaly, Sebastian syndrome and its variant, Epstein syndrome and Fechtner syndrome. Affected patients have triad of thrombocytopenia, macrothrombocytes and Dohle body-like inclusions in the leukocytes except with Epstein syndrome which lacks the inclusion. Mild to moderate thrombocytopenia PBS revealed enlarged platelets with frequent giant platelets.

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X-Linked Thrombocytopenia 1.

Wiskott-Aldrich Syndrome • Originally described in 1937, is now known as Xlinked hereditary disorder associated with combined immunodeficiency thrombocytopenia, small platelets, eczema and an increased risk to autoimmune disorders and cancer • Microthrombocytopenia is the most consistent feature of WASP-associated disease.

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Neonatal Thrombocytopenia • Platelet count less than 150,000 /ul • Cause of Neonatal Thrombocytopenia o Infection with toxoplasma, rubella, cytomegalovirus, herpes • Thrombocytopenia may be severe plt count of 70, 000 /ul • CMV most common infectious agent

MYH9-related Thrombocytopenia Syndromes Syndrome

MayHegglin Sebastian Fechtner Epstein

Macrothr ombocyto penia Yes

Dohlelike bodies Yes

Nephritis

Deafness

Cataracts

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No

No

Yes Yes Yes

Yes Yes No

No Yes Yes

No Yes Yes

No Yes No

Autosomal Recessive Thrombocytopenia Mutation in the MPL gene –chromosome 1 – loss of TPO receptor. Presence of severe thrombocytopenia, absence of megakaryocytes in the bone marrow. Family history is negative, both parents having normal platelet counts and function. Markedly elevated serum thrombopoietin. Patients develop progressive marrow aplasia. Group CAMT I – More severe type of thrombocytopenia with constantly low platelet count and an early onset of pancytopenia. Group CAMT II – Transient increased in platelet counts during the first year of life and a later or no development of pancytopenia. Mutation on ANKRD26 –Ch 10- incomplete megakaryocyte differentiation Mild thrombocytopenia characterized by a normal platelet survival and normal number of bone megakaryocytes Thrombocytopenia (counts 20,000 to 100000/uL) or a history of increased bruisability is apparent on early life. PBS shows platelet macrocytosis Abnormal platelet aggregation, normal platelet membrane glycoproteins.

Immune Mechanism of Platelet Destruction • • • • • •

Acute and Chronic ITP Drug Induced immunologic Heparin Induced Thrombocytopenia Neonatal Alloimmune (isoimmune neonatal) thrombocytopenia Posttransfusion isoimmune thrombocytopenia Secondary autoimmune thrombocytopenia

Idiopathic Thrombocytopenic Purpura • • • • • 1.

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A.K.A immune thrombocytopenic purpura (ITP) One of the most common disorders causing severe isolated thrombocytopenia. Caused by an autoantibody to the patient’s platelet. No specific test to confirm presence of ITP rather diagnosis of exclusion. Can be present in children and adults. Acute / Childhood ITP • Young children may present with an immune thrombocytopenia that typically develops acute with a 1 to 3 weeks duration, usually with bruising or petechiae. • Present an initial platelet count of less than 20 X 109 /L. • Self-limiting, spontaneous remissions with or without therapy in majority of the patient. • Immunoglobulin and corticosteroids are often used to decrease the period of thrombocytopenia. Chronic / Adult ITP • Commonly presents in the 20-50-year old groups, chronic disease process with a greater predilection for women. • Occasionally, patients will have immune thrombocytopenia after a viral illness or exposure to drugs. • Platelet counts are typically less than 30 X 109 /L in patients who present with bleeding manifestations. • Patient present with mucosal bleeding typical of a primary hemostatic defect, such as menorrhagia, epistaxis, easy bruisability, or petechiae. • Does not usually remit spontaneously. • IVIG treatment of choice Common Clinical Findings o BM is characterized by an increased or normal numbers of megakaryocytes. o Platelet lifespan is shortened and circulating platelets are morphologically large on the smear o Bleeding time may not be as prolonged as the bleeding time in other disorders associated with the same degree of thrombocytopenia o Measurement of antibodies (IgG) specific for platelet surface GP IIb//IIIa and Ib/IX may provide greater specificity but still are not diagnostic. o Splenectomy and corticosteroids are the conventional therapies.

Clinical Picture of Acute and Chronic ITP Characteristic Acute Chronic Age at onset 2-6 yr 20-50 yr Sex predilection None Female Prior Infection Common Unusual Onset of Sudden Gradual Bleeding Platelet count < 20,000/ul 30,000-80,000 /ul 2-6 weeks Months - years Duration Spontaneous 90 % of pts Uncommon remission Therapy Steroids 70% response rate 30% response rate Splenectomy Rarely required < 45 y/o 90% response > 45 y /o 40 % response rate Drug-induced Immune Thrombocytopenia •

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Quinine has been recognized as one of the most frequent causes of drug-induced thrombocytopenia; where it acts as a hapten. Drug most frequently cited: quinine, quinidine, salicylates, thiazides and sulfa drugs. Appears more frequently in the elderly due to increased usage of medication. Purpura occurs approximately 7 days after initial use of the drug but may occur within 3-5 days owing to anamnestic response.

Neonatal alloimmune/Isoimmune Neonatal Thrombocytopenia •

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It results to from immunization of the mother by fetal platelet antigen and placental transfer of maternal antibody It is most often caused by maternal alloantibodies to the P1 A1 antigen. It is uncommon disorder, generally affecting the firstborn child. Infants who develop this disorder appear normal at birth but within a few hours develop scattered petechiae and purpuric hemorrhages, with platelet counts below 30 X 109 /L.

Neonatal Autoimmune Thrombocytopenia • •

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Passive transplacental transfer of abs from mother with ITP or SLE. Maternal disease severity and/or platelet count during pregnancy can be used to predict the neonatal platelet count in most cases, but the clinical manifestations are less severe than in NAITP. Affected newborns – normal – decreased platelet numbers at birth (1 week) dec. Neonatal Thrombocytopenia persist for 1-2 weeksmonths. Requires no treatment If severe Thrombocytopenic infants– IVIG tx Bleeding – Plt Transfusion, IVIG tx, and corticosteroid

Post Transfusion Purpura • • • • •

Rare disorder Develops after 1 week after transfusion of plt containing products. Manifested by rapid onset of severe thrombocytopenia – bleeding Plasmapheresis – effective in resolving bleeding IVIG – Tx of choice

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• Thrombocytopenia in Pregnancy and Preeclampsia •

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Incidental Thrombocytopenia of Pregnancy, Pregnancy Associated Thrombocytopenia, Gestational Thrombocytopenia Platelet count: 100,000 -150,000/ul Maternal Platelet returns to normal within several weeks Preeclampsia – Defined by hypertension and proteinuria; usually becomes evident during second trimester and is a major contributor to maternal and fetal morbidity and mortality Eclampsia – Defined by the occurrence of acute neurologic abnormalities in a preeclamptic woman during peripartum period. Connection with thrombocytopenia, in a manner that blood coagulation is activated and is detected by elevated FDG and thrombin-antithrombin process Low level of ADAMTS13 is detected.

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HELLPS Syndrome • Disorder related to preeclampsia/eclampsia and is seen in the peripartum period and defined by the presence of microangiopathic HA, elevated liver enzymes, and low platelet count • HELLP (hemolysis, elevated liver enzymes, low platelet count) • HELLP is difficult to differentiate from: o TTP o DIC o HUS

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Gestational Thrombocytopenia • Mild thrombocytopenia with platelet counts of 50- 80 X 109 /L • Commonly develops in the 3rd trimester of pregnancy and does not cause bleeding in the mother or infant. • Low platelet count returns to normal after deliver.

HIV Related Thrombocytopenia •

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Appears to be correlated between CD4+ T cell depletion, viral load in plasma and the occurrence of thrombocytopenia. Viral infection of hematopoietic cells, altered marrow microenvironment of dysfunction of the RES

contribute to ineffective thrombopoiesis in HIV-related thrombocytopenia. Development of marrow fibrosis and marrow involvement by AIDS-related lymphoma may also lead to thrombocytopenia. Antiretroviral therapy is often effective course of action. Intravenous IgG and anti-D globulin are found to be effective treatment. Corticosteroids may be effective but have the potential to increase the risk of infection in immunocompromised individuals Splenectomy may also be effective.

Thrombotic Thrombocytopenic Purpura •

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First described as a pentad of signs and symptoms that include: thrombocytopenia, microangiopathic hemolytic anemia, fever, neurologic abnormalities and renal dysfunction. Hyaline microthrombi are the characteristic pathologic feature and are found in multiple organs. Coagulation screening tests and D-Dimer assay are NORMAL in TTP, in contrast to DIC which they are abnormal Two types of TTP: acquired and hereditary Acquired Thrombotic Thrombocytopenic Purpura • Thrombi found most extensively in the heart, pancreas, spleen, kidney, adrenal gland and brain and are composed mainly of platelets and vWF. • Associated with ADAMTS13 deficiency (a disintegrin-like and matalloprotease with thrombospodin motifs) and is found in most cases. • ADAMTS13 is also decreased in sepsis, DIC, and liver disease. • Laboratory Findings: o Thrombocytopenia and hemolysis, with the blood smear showing polychromasia, basophilic stippling, nucleated cells, schistocytes. o Platelet counts below 20 X 109/L at first presentation. o Reticulocyte count increased o Bone marrow studies reveal erythroid hyperplasia, increased number of megakaryocytes and occasionally microvascular hyaline thrombi o Screening tests are usually normal and FDP may be slightly increased o Serum lactic dehydrogenase (LDH) and unconjugated concentrations are common but invariably increased. o Hemolysis is of the intravascular type: haptoglobin levels are reduced and hemoglobinuria and hemosiderinuria usually are present o LDH levels and platelet counts are sensitive indices of the response of the disorder to therapy;

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Proteinuria and microscopic hematuria are present in most cases Blood urea nitrogen (BUN) and creatinine are normal or slightly elevated Liver function tests are usually normal Analysis of the cerebrospinal fluid is rarely indicated but may reveal an increased protein concentration and xanthochromia ADAMTS13 binding IgG is detectable enzymelinked immunoabsorbent assay (ELISA) in 97-100% TTP cases

Hereditary Thrombotic Thrombocytopenic Purpura • Also known as Schulman-Upshaw syndrome or Chronic Relasping TTP • Rare disorder believed to < 1% of the TTP cases. • In the typical cases, the affected neonate is born with meconium stain or presents within a few hours after birth with neonatal distress, jaundice and thrombocytopenia. • Hemolysis with schistocytes on blood smears may be noted. • Hereditary TTP responds to 10-15 mL of FFP per kilogram of body weight administered every 2 to 3 weeks.

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Kasabach-Merritt Syndrome •

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DIC appears to be accelerated platelet destruction in combination with coagulation factors consumption. 2 Forms of DIC o Acute – rapid platelet consumption o Chronic – low grade consumptive coagulopathy Caused by many illnesses, sepsis, obstetric emergencies and severe trauma, and may cause bleeding. Chronic form may be seen in cancer and may result in thrombosis rather than bleeding. Thrombocytopenia is usually seen in acute DIC Platelet count may be normal or elevated in chronic DIC. DIC appears to be accelerated platelet destruction in combination with coagulation factors consumption.

Splenomegaly • • • •

May lead to thrombocytopenia by inducing a reversible pooling up to 90% of total body platelets. Platelet production is usually normal. Chronic liver disease with portal hypertension and congestive splenomegaly. Most common disorder causing thrombocytopenia.

Profound thrombocytopenia related to platelet trapping within a vascular tumour, either a Kaposilike hemangioendothelioma or a tufted angioma. Thrombocytopenia is usually severe and associated with DIC. Contributing factors include “platelet trapping” and platelet consumption associated with DIC. Platelet trapping demonstrated by immunohistochemical staining of the tumors with antiCD61 antibodies.

Hypothermia Loss of Platelets: Massive Blood Transfusion

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Characterized by an increase in the circulating platelet counts greater than 450,000/uL.

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Primary/ Essential Thrombocytosis • The result of primary bone marrow disorder. It is characterized by an increase number of platelets which is a result of clonal proliferation that affects all hematopoietic cells. Patients have bleeding tendencies because of platelet function abnormalities. It is most commonly seen in patients with the following disorders: o Hodgkin’s disease o Polycythemia vera o Myelofibrosis o CML o Thrombocythemia

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Reactive/ Secondary thrombocytosis • A secondary response most associated with the following disorders: o IDA associated with chronic blood loss o Chronic inflammatory disease may be associated with high platelet counts. o Splenectomy-associated thrombocytosis o Rebound thrombocytosis, which may occur after a platelet depletion through a massive blood loss. • TPO levels in plasma are decreased. • Promoted by different types of drug like epinephrine, recombinant IL11 (Oprevelkin).

Disseminated Intravascular Coagulation •

It is distinguished from uncomplicated splenomegaly in that pooling is accompanied by increased destruction of platelets, leukocytes and erythrocytes in association with increased marrow precursors of the deficient and correction of the cytopenia by splenectomy.

Glanzmann Thrombosthenia • Qualitative Abnormalities: Changes in Platelet Function (Thrombocytopathy) •

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Disorder of Platelet Aggregation o Glanzmann Thrombasthenia o Hereditary afibrinogenemia o Acquired defects of aggregation ▪ Acquired vWD ▪ Acquired uremia Disorder of Platelet Adhesion o BSS o VWD o Acquired defects of platelet adhesion ▪ Myeloproliferative, lymphoproliferative disorders, dysproteinemias ▪ Antiplatelet antibodies ▪ Cardiopulmonary bypass surgery ▪ Chronic liver disease ▪ Drug-induced membrane modification ▪ Multiple Myeloma ▪ Waldenstrom Macroglobulinemia ▪ Liver Disease ▪ Uremia Changes in Membrane Phospholipid Distribution o Scott syndrome o Stormorken syndrome Disorders of Platelet Secretion (release reactions) Storage pool diseases o Dense Granules Deficiency o Hermansky Pudlak Syndrome o Chediak Higashi Synnrome o Wiskott Adlrich syndrome o TAR syndrome o Alpha granule o Gray platelet syndrome

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Thromboxane pathway disorders

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Hereditary aspirin-like defects: o Cyclooxygenase or thromboxane synthetasedeficiency o Drug inhibition of the prostaglandin pathways o Drug inhibition of platelet phosphodiesterase activity

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Superficial bleeding – platelet defect o Petechiae o Epistaxis o Gingival bleeding Deep Tissue Bleeding – plasma coagulation o hematomas o hemarthrosis ▪ Sever type of hematoma

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Originally - bleeding disorder associated with abnormal in vitro clot retraction and normal platelet count. Hemorrhagic Manifestation: o petechiae, purpura, menorrhagia, GIT bleeding and hematuria. Rare autosomal-recessive disorder of platelet function. Deficiency or abnormality in GP IIb /IIIa. o GP IIb/IIIa – Capable of binding fibrinogen, vWF, and fibronectin Bleeding is most common from mucosal surfaces (easy bruisability, epistaxis, gingival bleeding, prolonged bleeding for minor cuts and menorrhagia). o Menorrhagia is treated with hormonal therapy. Facial petechiae and subconjunctiva hemorrhages seen in infants associated with crying. Deep hematoma formations and recurrent hemarthroses are not present. Laboratory features: o Normal: platelet count, platelet morphology o Lack of platelet aggregation in response to all platelet activating agent: ▪ ADP, collagen, thrombin, and epinephrine. o The PF 3 activity is diminished. Treatment: o Transfusion of platelet o Recombinant factor VIIa ▪ Treat the severe bleeding by enhancing thrombus formation at the site of lesion.

Bernard –Soulier syndrome (BSS) •

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An inherited disorder of the platelet GP Ib/IX/V complex characterized by thrombocytopenia, giant platelets, and a failure of the platelets to bind GPIb ligands (von Willebrand’s factor and thrombin). Rare autosomal –recessive disorder Bleeding time is prolonged clot retraction is normal. Usually manifested in infancy or childhood. Laboratory Features o BSS – normal responses to ADP, epinephrine, collagen and arachidonic acid o Do not respond to: Ristocetin and Thrombin ▪ Ristocetin – used to treat staphylococcal infection o 5 – 8 um size of platelet (large platelets) Treatment: o No specific treatment o Platelet transfusion –therapy of choice – (problem: production of alloantibody) o Recombinant factor VIIa o Desmopressin (DDAVP)

Glanzmann’s Thrombasthenia Platelet count Platelet morphology Bleeding Time Platelet aggregation • ADP • Thrombin • Collagen • Epineprhine • Ristocetin Clot Retraction Platelet GP defect

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BernardSoulier Syndrome Decreased Giant Platelets

Prolonged

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Abnormal Abnormal Abnormal Abnormal Normal

Normal Abnormal Normal Normal Abnormal

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Abnormal GPIIb/IIIa

Normal GPIb/IX

Hermansky-Pudlak Syndrome •

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An autosomal recessive disorder characterized by a severe deficiency of dense granules. Patients show albinism (oculocutaneous) and may have hemorrhagic events. Defective lysosomal function. The gene ...