1111

• 5. Other Congenital Single-Factor Deficiencies: Factor

  XIII Deficiency

  •Due to deficiency of factor XIII, patients form

  weak (non-crosslinked) clots that dissolve within 2

  hours when suspended in 5M Urea

  solution (traditional factor XIII assay)

  • To be confirmed by chromogenic substrate assay
• 5. Other Congenital Single-Factor Deficiencies: Factor

  V Deficiency

  • Prolonged bleeding time

  • Prolonged PT and PTT

  • Platelet concentrate: an effective form of

  therapy
• Hemophilia C

  • Also called Rosenthal syndrome, Factor XI

  deficiency

  • More than half of the cases have been described

  in Ashkenazi Jews

  • The frequency and severity of bleeding episodes

  do not correlate with factor XI levels
• Hemophilia B

  • Also called Christmas disease

  • Sex-linked

  • Laboratory Diagnosis:

  oNormal PT, Fibrinogen, TT

  oProlonged PTT
• Hemophilia A (Factor VIII Deficiency)

  •Therapy:

  oHuman plasma-derived

  FVIII (pdFVIII) concentrates

  ▪Undergoes viral inactivation

  ▪None has transmitted lipid-envelope viruses

  ▪May transmit non—lipid envelope viruses
• Hemophilia A (Factor VIII Deficiency)

  • Laboratory Diagnosis:

  oNormal PT, TT, Fibrinogen

  oProlonged PTT

  • Ratio of FVIII activity to VWF:Ag concentration:

  used to detect female carriers of hemophilia A
• Hemophilia A (Factor VIII Deficiency)

  • Complications:

  oDebilitating and progressive musculoskeletal lesions

  and deformities and neurologic deficiencies

  subsequent to intracranial hemorrhage

  o70% of hemophilicstreated before 1984 are HIV

  positive or have died from AIDS
• Hemophilia A (Factor VIII Deficiency)

  • Causes anatomic bleeds with deep muscle and

  joint hemorrhages

  • The severity of hemophilia A symptoms is

  inversely proportional to FVIII activity

  • < 1 unit/dL: severe

  • 1-5 units/dL: moderate

  • 5-40 units/dL: mild
• Hemophilia A (Factor VIII Deficiency)

  • Factor VIII: translated from the X chromosome

  • Most mutations result in quantitative disorders. Rarely

  qualitative

  • Male hemizygotes, whose sole X chromosome

  contains FVIII gene mutation, experience anatomic

  bleeding, but female heterozygotes, who are carriers,

  do not
• Hemophilia A (Factor VIII Deficiency)

  •Hemophilias: are congenital single-factor

  deficiencies marked by anatomic soft tissue

  bleeding

  • 85% are factor VIII deficient

  • 14% are factor IX deficient

  • 1% are factor XI deficien
• Von Willebrand Disease Treatment

  • PRICE

  (protection, rest, ice,

  compression,

  elevation)
• Type 3 von Willebrand Disease

  • "Null allele" VWF gene translation or deletion

  mutations

  •Is the most rare form of VWD
• Type 2 von Willebrand Disease: Subtype 2N

  • Also known as Autosomal Hemophilia

  •It affects both men and women
• Type 2 von Willebrand Disease: Subtype 2N

  • Missense mutation in the D9 domain impairs the

  protein's factor VIII binding site

  • Factor VIII deficiency despite a normal VWF

  antigen concentration assay result, normal VWF

  activity, and a normal multimeric pattern
• Type 2 von Willebrand Disease: Subtype 2M

  • Possesses poor platelet receptor binding despite

  generating a normal multimeric distribution

  pattern in electrophoresis
• Type 2 von Willebrand Disease: Subtype 2B

  • Mutations within the A1 comain

  • Raised affinity to GP Ib/IX/V

  • "gain-of-function" mutation

  •HMW-VWF multimers spontaneously bind to

  resting platelets

  Platelet-type vWD (PT-VWD) or pseudo-VWD:

  A platelet mutation that raises GP Ib affinity for

  normal HMW-VWF multimers
• Type 2 von Willebrand Disease: Subtype 2A

  • Arises from an autosomal dominant point

  mutations in A2 and D1 structural domains of the

  vWF molecule

  • VWF is susceptible to ADAMTS-13

  • Predominance of small molecular weight plasma

  multimers
• Type 2 von Willebrand Disease

  •Encompasses four qualitative vWF

  abnormalities:

  oSubtype 2A

  oSubtype 2B

  oSubtype 2M

  oSubtype 2N
• Type 1 von Willebrand Disease

  • Caused by autosomal dominant frameshifts,

  nonsense mutations, or deletions

  • Comprises 40-70% of vWD cases

  •Quantitative vWF deficiency
• Von Willebrand

  Disease Types

  and Subtypes

  1. Type 1 vWD

  2. Type 2 vWD

  (2A, 2B, 2M, 2N)

  3. Type 3 vWD
• von Willebrand Disease

  • Pathophysiology:

  oVWF deficiency creates factor VIII deficiency

  oLeads to mucocutaneous hemorrhage

  • When factor VIII levels (<30 units/dL) decrease,

  anatomic bleeding accompanies mucocutaneous

  bleeding
• von Willebrand Disease

  • Primary function of vWF: mediate platelet

  adhesion to subendothelial collagen in areas of

  high flow rate and high shear force
• von Willebrand Disease

  •Domain A: supports the receptor site for collagen

  and GP Ib/IX/V

  •Domain C: provides a site that binds GP IIb/IIIA

  •Domain D: provides the carrier site for factor VIII

  oVWF protects factor VIII from proteolysis

  • VWF gene: oConsists of 52 exons spanning 178 kilobase pairs on chromosome 12 oIts monomer of 2813 amino acids composed of four structural domains (A to D)
• 1. von Willebrand Disease

  • VWF:

  oThe largest molecule in human plasma

  oIs synthesized in the ER of ECs and stored in WeibelPalade bodies

  oIs also synthesized in megakaryocytes and stored in

  the alpha granules of platelets

  • First described by Finnish professor Erik von Willebrand

  • The most prevalent inherited mucocutaneous bleeding

  disorder

  • Either quantitative (type 1) or qualitative (type 2)

  • Leads to decreased platelet adhesion to injure vessel

  walls
• Congenital

  Coagulopathies

  1. von Willebrand Disease

  2. Hemophilia A

  3. Hemophilia B

  4. Hemophilia C

  5. Other Congenital Single-Factor

  Deficiencies
• Acquired von Willebrand Disease

  • Treatment for bleeding:

  oDDAVP or plasma-derived factor VIII/VWF

  concentrate (Humate-P, Wilate, Alphanate)

  oCryoprecipitate: NO longer recommended for

  treatment

  • With symptoms similar to those of congenital vWD

  • Has been described in hypothyroidism, benign

  monoclonal gammopathies, Wilms tumor, intestinal

  angiodysplasia, congenital heart disease, pesticide

  exposure, uremia, lupus erythematosus, autoimmune,

  lymphoproliferative, and myeloproliferative disorders
• Factor Inhibitors other than Autoanti-factor VIII

  1. Antiprothrombin antibodies

  o Develop as lupus anticoagulant

  2. Autoanti-factor XIII

  o Documented in patients receiving isoniazid treatment for

  tuberculosis

  3. Autoantibodies to factor V

  oMay arise spontaneously in autoimmune disorders and

  after exposure to bovine thrombin in fibrin glue

  4. Autoanti-factor X

  oIn amyloidosis
• Autoanti-factor VIII inhibitor and

  Acquired Hemophilia

  •Is occasionally associated with:

  oRheumatoid arthritis

  oInflammatory bowel disease

  oSLE

  oLymphoproliferative disease

  oPregnancy

  Laboratory Diagnosis:

  o Clot-based mixing studies

  o Nijeman-Bethesda assay

  • Autoanti-factor VIII: the most common acquired

  autoantibodies

  • Patients who have acquire hemophilia are often:

  oOlder than 60

  oHave no apparent underlying disease
• Vitamin K Deficiency and Hemorrhage:

  Vitamin K Antagonists

  •Warfarin (Coumadin): disrupts the vitamin K

  epoxide reductase and vitamin K quinone

  reductase reactions

  • Coumadin overdose: the single most

  common reason for hemorrhage-associated

  emergency department visits

  • The liver releases PIVKA factors
• Vitamin K Deficiency and Hemorrhage:

  Hemorrhagic Disease of the Newborn

  •Newborns are constitutionally vitamin K deficient

  because:

  oOf their sterile intestines

  oMinimal concentration of vitamin K in human milk

  oBreastfeeding
• Vitamin K Deficiency

  Hemorrhagic

  Disease of

  the Newborn

  Vitamin K

  Antagonists
• Vitamin K Deficiency and Hemorrhage

  • Acquired by patients fed only with parenteral

  (intravenous) nutrition for an extended period or when

  people embark upon fad diets

  • Vitamin K is fat soluble and requires bile salts for

  absorption (biliary duct obstruction, fat

  malabsorption, chronic diarrhea)
• Nephrotic Syndrome and Hemorrhage

  •Nephrotic syndrome: is a state of increased

  glomerular permeability associated with a variety

  of conditions

  • Clotting factors II, VII, IX, X, XII, antithrombin,

  and protein C have been detected in the urine
• Chronic Renal Failure and Hemorrhage

  • Is often associated with platelet dysfunction and mild to

  moderate mucocutaneous bleeding (anemia and

  thrombocytopenia)

  • Fibrin deposits in renal microvasculature reduce glomerular

  function

  • Guanidinosuccinic acid or phenolic compounds coat the

  platelets

  • Corrected by: dialysis, RBC transfusions, and erythropoietin

  therapy
• Treatment to Resolve Liver Disease-Related

  Hemorrhage

  1. Oral or intravenous vitamin K therapy

  2. Plasma transfusion: provides a volume of 200-

  280 mL
• Liver Disease Coagulopathy:

  Disseminated Intravascular Coagulation

  • Chronic or compensated DIC: is a significant

  complication of liver disease

  • Caused by:

  oDecreased liver production of regulatory proteins

  oRelease of activated procoagulants from

  degenerating liver cells
• Liver Disease Coagulopathy:

  Platelet Abnormalities

  • Platelet count of <150,000/uL: may result from

  sequestration and shortened platelet survival

  •Acute alcohol toxicity also suppresses platelet

  production
• Liver Disease Coagulopathy:

  Procoagulant deficiency

  • Fibrinogen: becomes elevated in early or mild

  liver disease

  •Dysfibrinogenemia: fibrinogen is coated with

  excessive sialic acid (in moderately to severely

  diseased liver)

  • <100 mg/dL: fibrinogen may fall to this level in

  end-stage liver disease
• Liver Disease Coagulopathy:

  Procoagulant deficiency

  • Liver Disease alters the production of the Vitamin

  K-dependent factors (des-y-carboxyl forms)

  • Factor VII: serves as the sensitive early marker

  • Factor V: is a more specific marker of liver disease

  than deficient factors II, VII, IX, and X (used in

  conjunction with the factor VII assay)
• Liver Disease Coagulopathy:

  Procoagulant deficiency

  • Liver produces nearly all of the plasma

  coagulation factors and regulatory proteins

  •Hepatitis, cirrhosis, obstructive jaundice, cancer,

  poisoning, congenital disorders of bilirubin

  metabolism (may suppress the biosynthetic

  function of hepatocytes)