Objective 24

Describe the pathophysiology of vWF.

• megakaryocytes and endothelial cells synthesize vWF

• megakaryocyte derived vWF is stored in alpha granules of platelets in low molecular form so it can act as a carrier for FVIII

• vWF of endothelial is in high molecular form

• vWF acts as a bridge between platelet and vessel wall when injury occurs

What happens when there is a lack of vWF?

• results in impaired adhesion of platelets to exposed subendothelium

Why is vWF important?

• Platelet adhesion (binds platelet GpIb to subendothelium)

• Carrier for Factor VIII (stabilizes it)

What type of vWF disease is associated to low levels of vWF do to mutations affecting gene expression, and is autosomal dominant?

• Type 1 vWD

What clinical features are associated with Type 1 vWD?

• Epistaxis

• Menorrhagia

• Bleeding after dental work

What type of vWD disease is described as a partial quantitative deficiency, but the person lives a normal life?

• Type 1 VWD

What type of vWD is a qualitative defect that is autosomal dominant inherited and has mutations that affect multiple domains in the vWF molecule?

• Type 2 vWD

What vWD is associated with decreased vWF mediated platelet adhesion and mild to moderate mucocutaneous bleeds?

• Type 2A VWD

Describe the pathophysiology of Type 2A vWD?

• Loss of high-molecular-weight (HMW) multimers

• Increased cleavage by ADAMTS13

• ↓ ability to bind platelets

What lab findings would indicate Type 2A vWD?

• ↓ vWF activity

• ↓ HMW multimers

• ↓ platelet adhesion

What vWD is associated with decreased levels of large multimers in plasma and increased PLT clumping in the bloodstream, and Mucocutaneous bleeds?

• Type 2B vWD

Describe the pathophysiology of Type 2B vWD.

• Mutation increases vWF affinity for GpIb

• Causes spontaneous platelet binding → platelet clumping

What clinical findings are associated with Type 2B vWD?

• ↓ HMW multimers

• Thrombocytopenia (platelets consumed)

• Increased RIPA at low ristocetin levels

What vWD is a qualitative defect in which vWF dependent platelet adhesion is decreased without a deficiency of high molecular weight vWF multimers in plasma?

• Type 2M vWD

Describe the pathophysiology of Type 2M vWD?

• Decreased platelet binding

• NORMAL multimers

What vWD is associated with a mutation in A3 domain-P1824H?

• Type 2M vWD

What lab findings are associated with Type 2M vWD?

• ↓ vWF activity

• Normal multimer distribution

• ↓ collagen binding (vWF:CB)

What vWD is associated with an autosomal recessive missense mutation in Arg854Gln?

• Type 2N vWD

Describe the pathophysiology of Type 2N vWD.

• Defect in vWF binding to Factor VIII

• Leads to rapid degradation of Factor VIII

What clinical findings are associated with Type 2N vWD?

• Normal vWF antigen

• Normal vWF activity

• ↓ Factor VIII

• ↑ aPTT

What vWD is an autosomal recessive mutation that is the most severe and leads to a complete quantitative deficiency of vWF and also has impaired primary/secondary hemostasis?

• Type 3 vWD

What vWD has clinical bleeding that looks similar to hemophilia A, but vWF is the problem?

• Type 2N

Describe the pathophysiology of Type 3 vWD?

• Complete absence of vWF

• Autosomal recessive

What clinical features are associated with Type 3 vWD?

• Mucosal bleeding

• Hemarthrosis

• Deep bleeding

What lab findings indicate Type 3 vWD?

• Undetectable vWF

• ↓↓↓ Factor VIII

• Absent multimers

What vWD has a point mutation involving gpIb that results in increased binding to vWF?

• platelet type vWD

What lab findings are associated with platelet type vWD?

• ↓ HMW multimers

• Increased RIPA (like Type 2B)

What is the key feature of platelet type vWD?

• Looks like Type 2B, BUT:

  • Problem is in platelet receptor, not vWF

What vWD do patients develop antibodies to vWF that results in moderate to severe mucosal bleeds?

• acquired vWD

What conditions are associated with acquired vWD?

• Autoimmune diseases

• Lymphoproliferative disorders

What clinical features are associated with acquired vWD?

• Moderate–severe bleeding

• No family history

What is the key feature of Type 2A vWD?

• Defective multimer structure → poor adhesion

What is the key feature of Type 2B vWD?

• Hyperactive vWF → causes platelet clumping + low platelets

• increased affinity for PLT GPIb

What key feature is associated with Type 2M vWD?

• Function problem WITHOUT loss of multimers

• collagen binding deficient

How is Type 1 and Type 2A vWD treated?

• DDAVP

• TxA

How is Type 2B, 2M, and 2N vWD treated?

• FVIII

• vWF

(HumateP)

How is Type 3 vWD treated?

• FVIII

  • NovoEight

• vWF

• PLTs

How is PLT- vWD treated?

• PLTs

• vWF

  • (Vonvendi)

A lab result showing a loss of HMW multimers would indicate…

• PLT-vWD

A. lab result showing a complete absents of vWF multimers and increased APTT would indicate…

• Type 3 vWD

A lab result showing increased APTT and abnormal FVIII-vWF binding would indicate…

• Type 2N vWD

A lab result showing low vWF:RCo and abnormal vWF: CB would indicate…

• type 2M vWD

A lab result showing decreased PLTs, increased RIPA, and large forms absent of vWF multimers would indicate…

• Type 2B vWD

A lab result showing decreased RIPA, and large intermed forms absent of vWF multimers could indicate…

• Type 2A vWD

A lab result showing decreased RIPA and NORMAL vWF multimers with low vWF:RCo and vWF Ag would indicate…

• Type 2M vWD

What vFD have normal PLT amounts?

• Type 1

• Type 2A

• Type 2M

• Type 2N

• Type 3

What vFD have low PLT amounts?

• Type 2B

• PLT-vWD

What are normal values for blood test results?

RIPA% - 50-150%

vWF:Ag - 50 - 200 IU/dL

vWF: C0 - 50-150%

FVIII:C - 50-200%

What disease is a rare autosomal recessive bleeding disorder caused by a deficiency of the platelet GPIb receptor?

• Bernard Soulier Syndrome

What bleeding manifestations are associated with Bernard Soulier syndrome?

• gingival bleeds

• epistaxis

• purpura

• menorrhagia

• GI bleeds

Describe the pathophysiology of Bernard Soulier Syndrome.

• Defect in GpIb receptor

• Platelets cannot bind vWF → impaired adhesion

What is the treatment for Bernard Soulier Syndrome?

• Antifibrinolytics

• RBC transfusion

What lab findings are associated with Bernard Soulier Syndrome?

• reduced PLTs

• LARGE PLTS on peripheral blood smear

• prolonged Bleed time

• normal megakaryocytes in bone marrow

• RIPA absent

• normal FVIII levels

• reduced CD42a and CD42b

What are the main indications of Bernard Soiler Syndrome?

• ↓ Platelet count (mild thrombocytopenia)

• Large platelets (giant platelets)

• ↑ Bleeding time

• Abnormal ristocetin (does NOT correct with plasma)

What disease is a rare autosomal recessive disorder of platelet function caused by an absence of deficiency in GPIIb/IIa?

• Glanzmann’s Thrombocytopenia

Describe the pathophysiology of Glanzmann’s Thrombocytopenia?

• Defect in GpIIb/IIIa receptor

• Platelets cannot aggregate (bind fibrinogen)

What disease is a result of a gene deletion in chromosome 17 and is associated with consanguinity?

• Glanzmanns Thrombocytopenia

What clinical manifestations are associated with Glanzmann’s Trombocytopenia?

• minor brusing to severe and fatal hemorrhaging

• epistaxis

• gingival bleeds

• prolonged bleeding from minor cuts

What lab findings are associated with Glanzmann’s Thrombocytopenia?

• Normal platelet count

• ↑ Bleeding time

• abnormal clot retraction

• Abnormal aggregation with ADP, collagen, epinephrine

• Normal ristocetin test

What is the treatment used for Glanzmann’s Thrombocytopenia?

• PLT transfusions

• Antifibrinolytics

What disease is an X-linked recessive inheritance that is caused by a deficiency of FVIII?

• Hemophilia A

Describe the pathophysiology of Hemophilia A.

• Deficiency of Factor VIII

• NOT a platelet disorder (coagulation defect)

Mild hemophilia A would show what results?

• FVIII levels: 6-40

• bleeding with trauma

Moderate hemophilia A would show what results?

• FVIII levels: 1-5

• bleeding with trauma and a few spontaneous bleeds

Severe hemophilia A would show what results?

• FVIII levels: <1

• spontaneous bleeds into joints, muscles, or intracranial bleeds

What treatment is needed for severe hemophilia A?

• constant transfusion therapy

  • AHF

  • FVIII concentrates

  • FIX concentrates for people with FVIII inhibitors

  • cryoop-risk of hepatitis,HIV viral transmission

What lab findings are associated with Hemophilia A?

• Normal platelet count

• Normal bleeding time

• ↑ aPTT

• ↓ Factor VIII:C

What disease is a rare PLT disease characterized by mild to moderate thrombocytopenia, enlarged PLTs that exhibit a grey appearance on Giemsa stained blood smears.

• Gray-PLT syndrome

Describe the pathophysiology of Gray PLT syndrome

• mutation in 3p21 NBeal2

• alpha granule proteins are reduced

What bleeding manifestations are associated with Gray-PLT syndrome?

• Mild to moderate bleeding

• bruising

• epistaxis

What lab findings indicate Gray PLT syndrome?

• Large, pale platelets

• ↓ platelet granules

• Mild thrombocytopenia

• ↑ bleeding time

• reduced PAR-1 and PAR-2 expression

What is the treatment for Gray PLT syndrome?

• PLT transfusions

• DDAVP

• CRYO

What disease is an autosomal recessive condition with mutations that affect 9 possible genes leading to a deficiency of dense granules of PLTs?

• Hermansky-Pudlak Syndrome

Describe the pathophysiology of Hermansky-Pudlak Syndrome

• Defect in dense granules

• Also affects melanin → albinism

What is the treatment for Hermansky-Pudlak Syndrome

• DDAVP

What lab findings are associated with Hermansky-Pudlak Syndrome

• ↓ dense granules

• Prolonged bleeding time

• Normal platelet count

What clinical findings are associated with Hermansky-Pudlak Syndrome?

• decreased pigmentation

• easy bruising

• bleeding gums

• excessive bleeding after surgery

• lipid deposits in the lungs,colon,heart, and kidneys

What disease is a rare autosomal recessive disorder that affects multiple organs and is associated with PLT dense granule abnormality and OCA?

• Chediak-Higashi Syndrome

Describe the pathophysiology of Chediak-Higashi Syndrome

• Defect in lysosomal trafficking

• Leads to:

  • Platelet dysfunction

  • Immune deficiency

Describe the etiology of Chediak-Higashi Syndrome

• nonsense and frameshift mutations in gene for CHS protein

• abnormal cytoplasmic granule fusion

What is the main hallmark of Chediak-Higashi Syndrome?

• presence of cytoplasm of different cells

What is used to treat Chediak-Higashi Syndrome?

• bone marrow transplants

• antibiotics for bacterial infections

What disease is autosomal recessive, is associated with severe neonatal thrombocytopenia and a absence or hypoplasia of radial bones?

• TAR

What lab findings are associated with TAR?

• Thrombocytopenia

• Normal platelet function (but low number causes bleeding)

• No platelets seen on peripheral blood smear

Describe the pathophysiology of TAR.

• Decreased platelet production

• Congenital syndrome

What disease has elevated WBC and PLT counts between 10,000 - 30,000/ uL?

• TAR

If a lab result has abnormal Ristocetin that corrects, what is the disease?

• vWD

If lab result has abnormal Ristocetin that does not correct, what is the disease?

• BSS

What is the key feature for BSS disease?

• GpIb defect + giant platelets + absent ristocetin response

what is the key feature for GT disease?

• Aggregation defect with NORMAL ristocetin

What qualitative PLT disorders are disorders of adhesion?

• Von Willebrands Disease (vWD)

• Bernard Soulier Disease (BSS)