Hema 2 Lec Module 9: Quantitative and Qualitative Disorders of Platelets

1. Decreased platelet production

2. Increased platelet destruction

What are the two major causes of Thrombocytopenia?

A

Identify the type of immune mediated thrombocytopenia: Primary immune

thrombocytopenic purpura

Choices:

a. Autoantibody-mediated platelet destruction by reticuloendothelial system (RES)

b. Alloantibody- mediated platelet destruction by RES

c. Drug-dependent, antibody-mediated platelet destruction by RES

d. Platelet activation by binding of immunoglobulin G (IgG) Fc of drug-dependent IgG to platelet Fcγlla receptors

A

Identify the type of immune mediated thrombocytopenia: Secondary immune thrombocytopenia associated with lymphoproliferative disease

Choices:

a. Autoantibody-mediated platelet destruction by reticuloendothelial system (RES)

b. Alloantibody- mediated platelet destruction by RES

c. Drug-dependent, antibody-mediated platelet destruction by RES

d. Platelet activation by binding of immunoglobulin G (IgG) Fc of drug-dependent IgG to platelet Fcγlla receptors

A

Identify the type of immune mediated thrombocytopenia: Collagen vascular disease

Choices:

a. Autoantibody-mediated platelet destruction by reticuloendothelial system (RES)

b. Alloantibody- mediated platelet destruction by RES

c. Drug-dependent, antibody-mediated platelet destruction by RES

d. Platelet activation by binding of immunoglobulin G (IgG) Fc of drug-dependent IgG to platelet Fcγlla receptors

A

Identify the type of immune mediated thrombocytopenia: Infections (infectious mononucleosis)

Choices:

a. Autoantibody-mediated platelet destruction by reticuloendothelial system (RES)

b. Alloantibody- mediated platelet destruction by RES

c. Drug-dependent, antibody-mediated platelet destruction by RES

d. Platelet activation by binding of immunoglobulin G (IgG) Fc of drug-dependent IgG to platelet Fcγlla receptors

A

Identify the type of immune mediated thrombocytopenia: HIV syndrome

Choices:

a. Autoantibody-mediated platelet destruction by reticuloendothelial system (RES)

b. Alloantibody- mediated platelet destruction by RES

c. Drug-dependent, antibody-mediated platelet destruction by RES

d. Platelet activation by binding of immunoglobulin G (IgG) Fc of drug-dependent IgG to platelet Fcγlla receptors

B

Identify the type of immune mediated thrombocytopenia: Neonatal alloimmune thrombocytopenia

Choices:

a. Autoantibody-mediated platelet destruction by reticuloendothelial system (RES)

b. Alloantibody- mediated platelet destruction by RES

c. Drug-dependent, antibody-mediated platelet destruction by RES

d. Platelet activation by binding of immunoglobulin G (IgG) Fc of drug-dependent IgG to platelet Fcγlla receptors

B

Identify the type of immune mediated thrombocytopenia: Post-transfusion purpura

Choices:

a. Autoantibody-mediated platelet destruction by reticuloendothelial system (RES)

b. Alloantibody- mediated platelet destruction by RES

c. Drug-dependent, antibody-mediated platelet destruction by RES

d. Platelet activation by binding of immunoglobulin G (IgG) Fc of drug-dependent IgG to platelet Fcγlla receptors

B

Identify the type of immune mediated thrombocytopenia: Passive alloimmune thrombocytopenia

Choices:

a. Autoantibody-mediated platelet destruction by reticuloendothelial system (RES)

b. Alloantibody- mediated platelet destruction by RES

c. Drug-dependent, antibody-mediated platelet destruction by RES

d. Platelet activation by binding of immunoglobulin G (IgG) Fc of drug-dependent IgG to platelet Fcγlla receptors

B

Identify the type of immune mediated thrombocytopenia: Alloimmune platelet transfusion refractoriness

Choices:

a. Autoantibody-mediated platelet destruction by reticuloendothelial system (RES)

b. Alloantibody- mediated platelet destruction by RES

c. Drug-dependent, antibody-mediated platelet destruction by RES

d. Platelet activation by binding of immunoglobulin G (IgG) Fc of drug-dependent IgG to platelet Fcγlla receptors

C

Identify the type of immune mediated thrombocytopenia: Drug-induced immune thrombocytopenic purpura

(ex. quinine)

Choices:

a. Autoantibody-mediated platelet destruction by reticuloendothelial system (RES)

b. Alloantibody- mediated platelet destruction by RES

c. Drug-dependent, antibody-mediated platelet destruction by RES

d. Platelet activation by binding of immunoglobulin G (IgG) Fc of drug-dependent IgG to platelet Fcγlla receptors

D

Identify the type of immune mediated thrombocytopenia: Heparin-induced

thrombocytopenia

Choices:

a. Autoantibody-mediated platelet destruction by reticuloendothelial system (RES)

b. Alloantibody- mediated platelet destruction by RES

c. Drug-dependent, antibody-mediated platelet destruction by RES

d. Platelet activation by binding of immunoglobulin G (IgG) Fc of drug-dependent IgG to platelet Fcγlla receptors

A

Identify the type of non-immune mediated thrombocytopenia: Disseminated intravascular

coagulation

Choices:

a. Platelet activation by thrombin or proinflammatory cytokines

b. Platelet destruction via ingestion by macrophages (hemaphagocytosis)

c. Platelet destruction through platelet interactions with altered von Willebrand factor

d. Platelet loss on artificial surfaces

e. Decreased platelet survival associated cardiovascular disease

A

Identify the type of non-immune mediated thrombocytopenia: Septicemia/systemic inflammatory response syndrome

Choices:

a. Platelet activation by thrombin or proinflammatory cytokines

b. Platelet destruction via ingestion by macrophages (hemaphagocytosis)

c. Platelet destruction through platelet interactions with altered von Willebrand factor

d. Platelet loss on artificial surfaces

e. Decreased platelet survival associated cardiovascular disease

B

Identify the type of non-immune mediated thrombocytopenia: Infections

Choices:

a. Platelet activation by thrombin or proinflammatory cytokines

b. Platelet destruction via ingestion by macrophages (hemaphagocytosis)

c. Platelet destruction through platelet interactions with altered von Willebrand factor

d. Platelet loss on artificial surfaces

e. Decreased platelet survival associated cardiovascular disease

B

Identify the type of non-immune mediated thrombocytopenia: Certain malignant lymphoproliferative disorders

Choices:

a. Platelet activation by thrombin or proinflammatory cytokines

b. Platelet destruction via ingestion by macrophages (hemaphagocytosis)

c. Platelet destruction through platelet interactions with altered von Willebrand factor

d. Platelet loss on artificial surfaces

e. Decreased platelet survival associated cardiovascular disease

C

Identify the type of non-immune mediated thrombocytopenia: Thrombotic thrombocytopenic

purpura

Choices:

a. Platelet activation by thrombin or proinflammatory cytokines

b. Platelet destruction via ingestion by macrophages (hemaphagocytosis)

c. Platelet destruction through platelet interactions with altered von Willebrand factor

d. Platelet loss on artificial surfaces

e. Decreased platelet survival associated cardiovascular disease

C

Identify the type of non-immune mediated thrombocytopenia: Hemolytic-uremic syndrome

Choices:

a. Platelet activation by thrombin or proinflammatory cytokines

b. Platelet destruction via ingestion by macrophages (hemaphagocytosis)

c. Platelet destruction through platelet interactions with altered von Willebrand factor

d. Platelet loss on artificial surfaces

e. Decreased platelet survival associated cardiovascular disease

C

Identify the type of non-immune mediated thrombocytopenia: Aortic stenosis

Choices:

a. Platelet activation by thrombin or proinflammatory cytokines

b. Platelet destruction via ingestion by macrophages (hemaphagocytosis)

c. Platelet destruction through platelet interactions with altered von Willebrand factor

d. Platelet loss on artificial surfaces

e. Decreased platelet survival associated cardiovascular disease

D

Identify the type of non-immune mediated thrombocytopenia: Cardiopulmonary bypass

surgery

Choices:

a. Platelet activation by thrombin or proinflammatory cytokines

b. Platelet destruction via ingestion by macrophages (hemaphagocytosis)

c. Platelet destruction through platelet interactions with altered von Willebrand factor

d. Platelet loss on artificial surfaces

e. Decreased platelet survival associated cardiovascular disease

D

Identify the type of non-immune mediated thrombocytopenia: Use of intravascular catheters

Choices:

a. Platelet activation by thrombin or proinflammatory cytokines

b. Platelet destruction via ingestion by macrophages (hemaphagocytosis)

c. Platelet destruction through platelet interactions with altered von Willebrand factor

d. Platelet loss on artificial surfaces

e. Decreased platelet survival associated cardiovascular disease

E

Identify the type of non-immune mediated thrombocytopenia: Congenital and acquired heart

disease

Choices:

a. Platelet activation by thrombin or proinflammatory cytokines

b. Platelet destruction via ingestion by macrophages (hemaphagocytosis)

c. Platelet destruction through platelet interactions with altered von Willebrand factor

d. Platelet loss on artificial surfaces

e. Decreased platelet survival associated cardiovascular disease

E

Identify the type of non-immune mediated thrombocytopenia: Cardiomyopathy

Choices:

a. Platelet activation by thrombin or proinflammatory cytokines

b. Platelet destruction via ingestion by macrophages (hemaphagocytosis)

c. Platelet destruction through platelet interactions with altered von Willebrand factor

d. Platelet loss on artificial surfaces

e. Decreased platelet survival associated cardiovascular disease

E

Identify the type of non-immune mediated thrombocytopenia: Pulmonary embolism

Choices:

a. Platelet activation by thrombin or proinflammatory cytokines

b. Platelet destruction via ingestion by macrophages (hemaphagocytosis)

c. Platelet destruction through platelet interactions with altered von Willebrand factor

d. Platelet loss on artificial surfaces

e. Decreased platelet survival associated cardiovascular disease

- Autosomal Dominant Thrombocytopenias

- Autosomal Recessive Thrombocytopenias

- Sex-linked Inherited Thrombocytopenias

What are the 3 types of congenital thrombocytopenias?

Congenital thrombocytopenias

- May present with isolated thrombocytopenia (thrombocytopenia alone) or in conjunction with characteristic syndromes.

- It is usually associated with mutations in genes.

- It may also be characterized based on the inheritance patterns or on platelet size or diameter.

A

Determine the classification of inherited thrombocytopenias by platelet size

Wiskott-Aldrich syndrome

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

A

Determine the classification of inherited thrombocytopenias by platelet size

X-linked thrombocytopenia

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

B

Determine the classification of inherited thrombocytopenias by platelet size

Congenital amegakaryocytic thrombocytopenia

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

B

Determine the classification of inherited thrombocytopenias by platelet size

Thrombocytopenia absent radius syndrome

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

B

Determine the classification of inherited thrombocytopenias by platelet size

Radioulnar synostosis with amegakaryocytic thrombocytopenia RUNX1 mutations (FPD/AML)

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

B

Determine the classification of inherited thrombocytopenias by platelet size

ANKRD26-related thrombocytopenia

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

B

Determine the classification of inherited thrombocytopenias by platelet size

CYCS-related thrombocytopenia

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

C

Determine the classification of inherited thrombocytopenias by platelet size

MYH9-related disorders

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

C

Determine the classification of inherited thrombocytopenias by platelet size

Bernard-Soulier syndrome

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

C

Determine the classification of inherited thrombocytopenias by platelet size

Gray platelet syndrome

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

C

Determine the classification of inherited thrombocytopenias by platelet size

Velocardiofacial syndrome

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

C

Determine the classification of inherited thrombocytopenias by platelet size

GATA-1 mutations

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

C

Determine the classification of inherited thrombocytopenias by platelet size

Type 2B von Willebrand Disease

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

C

Determine the classification of inherited thrombocytopenias by platelet size

Platelet-type von Willebrand disease

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

C

Determine the classification of inherited thrombocytopenias by platelet size

Paris-Trousseau (Jacobsen) syndrome

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

C

Determine the classification of inherited thrombocytopenias by platelet size

TUBB1-related macrothrombocytopenia

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

C

Determine the classification of inherited thrombocytopenias by platelet size

Thrombocytopenia associated with sitosterolemia

Choices:

a. Small Platelets (MPV <7 fL)

b. Normal-Sized Platelets (MPV 7-11 fL)

c. Large Platelets (MPV >11fL)

Myosin Heavy Chain 9 (MYH9)

encodes the non- muscle myosin heavy chain IIA, a contractile

cytoskeletal protein.

MYH9-Related Macrothrombocytopenias

The mutation of this gene results in disorder production of the non-muscle myosin heavy chain IIA, causing defective megakaryocyte maturation leading to invariable macrothrombocytopenia.

MYH9-Related Macrothrombocytopenias

It includes:

May-Hegglin anomal

Fechtner syndrome

Epstein syndrome

Sebastian syndrome

MYH9-Related Macrothrombocytopenias

All syndromes have macrothrombocytopenia (large

platelets)

MYH9-Related Macrothrombocytopenias

Shows cytoplasmic inclusions in leukocytes (Döhle bodies), and premature release of platelets

MYH9-Related Macrothrombocytopenias

Some may present with nephritis, sensorineural deafness, and cataracts

Familial Platelet Disorder with predisposition to acute myeloid leukemia (FPD/AML)

- Thrombocytopenia is secondary to mutations in the Runt-related transcription factor 1 (RUNX1) / Core-

binding Factor subunit Alpha-2 (CBFA2) / Acute Myeloid Leukemia 1 protein (AML1) gene (RUNX1/CBFA2/AML1 gene).

- This gene is a transcription factor that regulates the differentiation of hematopoietic stem cells into mature blood cells.

- Platelet size is normal and their function is abnormal.

Platelet-type vWD

Characterized by thrombocytopenia, gain-of-function mutations in Glycoprotein-IB-alpha (GPIBA), and enhanced responsiveness to ristocetin on platelet aggregation.

Velocardiofacial syndrome & DiGeorge syndrome

Arise due to deletions within chromosome 22q11

Velocardiofacial syndrome & DiGeorge syndrome

Associated with cardiac abnormalities, parathyroid and thymus insufficiencies, cognitive impairment, and facial dysmorphology (velocardiofacial only).

Paris-Trousseau/Jacobsen syndrome

Due to deletion of a portion of chromosome 11, 11q23- 24, which encompasses the transcription factor FLI-1 gene

Friend Leukemia Integration-1 (FLI-1) gene

A gene that helps in the regulation of the development of blood cells

Paris-Trousseau/Jacobsen syndrome

This is characterized by psychomotor retardation and facial and cardiac abnormalities

Paris-Trousseau/Jacobsen syndrome

Platelets are increased in size and have giant and defective α-granules.

Mediterranean macrothrombocytopenia, Bolzano variant

Has been associated with mutations in GP Ibα and considered a heterozygous form of Bernard-Soulier syndrome

Autosomal dominant Bernard-Soulier Syndrome

Resulting from a point mutation in a leucine tandem repeat of GP Ibα

Mutations in GP IIb or GP IIIa

Leads to constitutive activation of the GP IIb/IIIa integrin complex.

Classical Bernard-So

The macrothrombocytopenia results from biallelic mutations involving the GP Ib/IX/V complex.

Congenital amegakaryocytic thrombocytopenia (CAMT)

Associated with mutations in the thrombopoietin receptor MPL

Congenital amegakaryocytic thrombocytopenia (CAMT)

Characterized by severe thrombocytopenia and absence of megakaryocytes in the bone marrow

Gray Platelet Syndrome

Linked to mutations in the NBEAL2 gene, which encodes a BEACH protein involved in vesicular trafficking

ABSENT RADII (TAR) SYNDROME

Thrombocytopenia is associated with skeletal abnormalities.

Wiskott-Aldrich Syndrome (WAS) and the related X-linked thrombocytopenia

- Involves mutations in the WAS gene

- Characteristically have small platelets.

- Thrombocytopenia may occur in the absence of other immunologic features of the syndrome.

Mutations in transcription factor GATA-1/ Erythroid transcription factor

- This gene regulates the expression of genes that mediate the development of RBCs and platelets.

- It is also associated with:

Thrombocytopenia

Anemia

Alteration in red cell morphology

Immune Thrombocytopenias

Heterogeneous group of disorders characterized by auto-immune-mediated platelet destruction and impaired platelet production

Primary Immune Thrombocytopenic Purpura

Secondary Immune Thrombocytopenic Purpura Drug-Induced Immune Thrombocytopenia (DITP)

What are the 3 types of immune thrombocytopenias?

Primary Immune Thrombocytopenic Purpura

An autoimmune disorder characterized by isolated thrombocytopenia (peripheral platelet count <100 x 109 / L); a diagnosis of exclusion made in the absence of other causes or disorders that may be associated with thrombocytopenia.

Primary Immune Thrombocytopenic Purpura

The diagnosis remains one of exclusion: No robust clinical or laboratory parameters are currently available to establish this diagnosis with accuracy

Primary Immune Thrombocytopenic Purpura

Main clinical problem of this disease: An increased risk for bleeding, although bleeding symptoms may not always be present.

Secondary Immune Thrombocytopenic Purpura

Consists of all forms of immune-mediated thrombocytopenia except primary ITP (Secondary ITP is due to other diseases).

A

Disease happened within 3 months from diagnosis

Choices:

a. Newly diagnosed ITP

b. Persistent ITP

c. Chronic ITP

d. Severe ITP

B

Between 3 and 12 months from diagnosis

Choices:

a. Newly diagnosed ITP

b. Persistent ITP

c. Chronic ITP

d. Severe ITP

B

Includes:

Patients not reaching spontaneous remission

Patients not maintaining complete response of therapy

Choices:

a. Newly diagnosed ITP

b. Persistent ITP

c. Chronic ITP

d. Severe ITP

C

Lasting for longer than 12 months

Choices:

a. Newly diagnosed ITP

b. Persistent ITP

c. Chronic ITP

d. Severe ITP

D

Presence of bleeding symptoms at presentation sufficient to mandate treatment, or occurrence of new bleeding symptoms requiring additional therapeutic intervention with a different platelet-enhancing agent or an increased dose

Choices:

a. Newly diagnosed ITP

b. Persistent ITP

c. Chronic ITP

d. Severe ITP

Pediatric

Antecedent infectious diseases appear to be present in approximately 60% of _____________ (geriatric, pediatric) ITP patients

HIV and HCV infection

Molecular mimicry, in which immune responses initially directed against an infectious organism cross-react with platelet antigens in both children and adults.

H. pylori infection

Thrombocytopenia may be due to H. pylori organisms that trigger P-selectin-dependent platelet aggregation and increased PS expression.

T

T/F: There is no single laboratory test for the diagnosis of ITP. A variety of laboratory approaches were deemed to be either of potential utility or of unproven or uncertain benefit

Basic Evaluation

Tests of Potential Utility in the Management of an ITP Patient

Tests of Unproven or Uncertain Benefit

What are included in the recommendations for the diagnosis of ITP in children and adults?

Basic Evaluation

Which part of the diagnosis of ITP in children and adults include these?

Px history,Family history, Physical exam, CBC & Retic count, Peripheral blood film, Quantitative immunoglobulin measurement, DAT, H. pylori, HIV, HCV, Blood group (Rh), Bone marrow exam (in selected px)

Monoclonal Antibody Immobilization of Platelet Antigen (MAIPA) Technique

(SECONDARY IMMUNE THROMBOCYTOPENIC PURPURA)

Closest to what could be considered a reference methodology

Monoclonal Antibody Immobilization of Platelet Antigen (MAIPA) Technique

Through incubation of freshly obtained donor platelets with patient serum or with eluates from patient platelets

Monoclonal Antibody Immobilization of Platelet Antigen (MAIPA) Technique

It is a technique that optimally preserves the native conformations of the platelet membrane GP against which the patient antibodies are usually targeted

Drug-induced immune thrombocytopenia

An immune thrombocytopenia that is caused by platelet destruction through immunologic mechanisms

Drug-induced immune thrombocytopenia

May be induced by classic drug-dependent antibodies (e.g., quinine), haptens (e.g., penicillin), fiban-dependent antibodies (e.g., tirofiban, integrilin), monoclonal antibodies (abciximab), autoantibodies (e.g., gold), and immune-complex formation.

Drug-induced immune thrombocytopenia

Clinical features:

Platelet count less than 20,000/μL

Bleeding symptoms that typically begin 5-10 days after starting the drug.

Quinine

Quinidine

Trimethoprim-sulfamethoxazole

Vancomycin

Pipericillin/tazobactam

What are the most commonly implicated drugs in Drug-induced immune thrombocytopenia?

"FIBANS" (Eptifibatide and Tirofiban)

Are GP IIb/IIIa antagonist drugs

"FIBANS" (Eptifibatide and Tirofiban)

- Acute severe thrombocytopenia may occur, even following the first exposure to the drug

- Acute thrombocytopenia results from preexisting antibodies in the patients binding to novel epitopes exposed in the drug-bound GP IIb/IIIa complex.

ABCIXIMAB

- A chimeric human-mouse Fab fragment specific for GP IIIa

- Preexisting antibodies causing the DITP target structural elements in the abciximab molecule that are of murine origin

Quinine, Sulfonamides

Drug-dependent antibodies target epitopes on platelet: GP IIb/IIIa or GP Ib/IX

Gold and Procainamide

Autoantibodies are induced that have specificity for platelet GP

Heparins and Protamine

Induce thrombocytopenia by formation of immune complexes that bind and activate platelets

normal test platelets

(LABORATORY ASSESSMENT FOR DRUG-INDUCED IMMUNE THROMBOCYTOPENIA)

Employs ______________ as the target for antibody binding in the presence, but not the absence, of added drug.

acute episode

(LABORATORY ASSESSMENT FOR DRUG-INDUCED IMMUNE THROMBOCYTOPENIA)

Blood should be collected during the ______________episode of thrombocytopenia as soon as DITP is suspected.

blood group O/HPA-1a positive donors

(LABORATORY ASSESSMENT FOR DRUG-INDUCED IMMUNE THROMBOCYTOPENIA)

Test platelets obtained from ________________ donors can be studied either by flow cytometry or by enzyme immunoassay.