F3: DISORDERS OF SECONDARY HEMOSTASIS PLATELET DISORDERS

• Platelet Disorders


  Disorders related to the function or number of platelets
• Inherited disorders of Coagulation

  • Intrinsic Pathway Disorders
  • Extrinsic and Common Pathway Disorder
  • Acquired Disorders of Coagulation
• Hemorrhage


  Severe form of bleeding that requires immediate intervention and transfusion
• Inherited disorders of Coagulation: Intrinsic Pathway Disorder


  • Prekallikrein (Fletcher Factor) Deficiency
  • High Molecular Weight Kininogen (Fitzgerald Factor) Deficiency
  • Factor XI Deficiency (Hemophilia C Or Rosenthal Syndrome)
  • Factor VIII:C Deficiency (Hemophilia A Or Classic Hemophilia)
  • Factor IX Deficiency (Hemophilia B Christmas Disease)
  • Von Willebrand's Disease
  • Hereditary Coagulation Disorders
  • Factor VII (Proconvertin Stable Factor) Deficiency
  • Factor X (Stuart Prower Factor) Deficiency
• Prekallikrein (Fletcher Factor) Deficiency


  Believed to be transmitted as an autosomal recessive trait
• Prekallikrein (Fletcher Factor) Deficiency

  • Laboratory findings are similar to Factor XII deficiency except that APTT's result is shortened because if the plasma is incubated with a surface activating substance such as kaolin
• High Molecular Weight Kininogen (Fitzgerald Factor) Deficiency


  Absence of HMWK results in poor contact phase reactions, a deficiency of kinin formation (active forms derived from kininogen) and defective fibrinolysis reaction
• High Molecular Weight Kininogen (Fitzgerald Factor) Deficiency


  • APTT results typically are prolonged, other tests are within normal limits
• Factor XI Deficiency (Hemophilia C Or Rosenthal Syndrome)


  Originally described in 1953, an autosomal dominant hemophilia, presents mild to moderate bleeding, represents the first inherited disorder of the intrinsic cascade to which a clinical bleeding syndrome is attributed, prevalent in Jewish population
• CLINICAL FINDINGS: Factor 11 Deficiency (Hemophilia C Or Rosenthal Syndrome)

  • Patients present mild bleeding tendencies which usually respond to therapy, most patients are symptomatically silent until stressed by trauma or surgery, clinical syndromes may include episodes of epistaxis, hematuria and menorrhagia
• Factor XI Deficiency (Hemophilia C Or Rosenthal Syndrome)

  • Prolonged APTT which is corrected by aged serum and adsorbed plasma, one stage PT and bleeding time are not affected
• Factor VIII:C Deficiency (Hemophilia A Or Classic Hemophilia)


  First scientifically described in 1803, referred to as "royal disease", it is a sex-linked disorder transmitted on an X chromosome by carrier women to their sons
• Factor VIII:C Deficiency (Hemophilia A Or Classic Hemophilia)


  • Bleeding diathesis arises from decreased or defective factor VIII C, bleeding into soft tissues or joints, epistaxis, hematuria, GIT or intracranial hemorrhages and post operative bleeding constitute the majority of hemorrhagic events, joints of the knee, elbow, ankle and shoulder are the most vulnerable parts of the patient, repeated hemarthroses can cripple and deform the patient
• Factor IX Deficiency Hemophilia B Christmas Disease)


  • Three variants of the disease based on antigenic reactivity of factor IX: Cross reactive material positive (CRM+), Cross reactive material negative (CRM-), Cross reactive material reduced (CRM R)
• Factor IX Deficiency Hemophilia B Christmas Disease)

  • Prolonged APTT which is corrected with aged serum but not with adsorbed plasma, specific Factor IX assay - used for diagnosis and to assess activity levels during therapy
• Von Willebrand's Disease


  In 1926 Eric von Willebrand described this disorder as autosomal dominant disorder that produces a prolonged bleeding time and evidence of vascular fragility, caused by defects in both in factor VIII C and VIIIR Ag of factor VIII complex

  
  

  • 1971 Zimmerman demonstrated that the vWF portion of the VIII complex is reduced or absent in this disease, platelets in von Willebrand's plasma, in contrast to platelets in normal plasma, do not aggregate in the presence of ristocetin
• Von Willebrand's Disease


  • Patients demonstrate easy bruisability, epistaxis, menorrhagia and hemorrhage from tooth extraction, it is the most frequently inherited disorder
• Von Willebrand's Disease


  • Prolonged bleeding time, incomplete APTT results, decreased activity of VIII:C, abnormal ristocetin platelet factor VIII related activity VIIIR:RCo, decreased levels of large vWF multimers
• Factor X (Stuart Prower Factor) Deficiency


  An autosomal recessive disorder, inherited as autosomal trait that is incomplete recessive but shows high penetrance, immune variants also exist, the disorder is uncommon in the general population, symptoms of patients having the disorder are variable
• Factor X (Stuart Prower Factor) Deficiency

  • Prolonged APTT, PT and Stypven's Time, prothrombin utilization is abnormal, PT is corrected by aged serum but not with adsorbed plasma
• Inherited disorders of Coagulation: Extrinsic and Common Pathway Disorder


  • Factor V Deficiency Owren's Disease Labile Factor Deficiency
  • Factor II Prothrombin Deficiency
  • Fibrinogen (factor I) deficiency
  • Factor XIII (fibrin stabilizing factor) deficiency
• Factor V Deficiency Owren's Disease Labile Factor Deficiency


  Discovered in 1944 by Professor Owren, an autosomal recessive trait which is most commonly demonstrated by homozygotes and is mild to silent in heterozygotes, also described as deficient in conjunction with factor VIII deficiency, due to genetic defect trace to chromosome 18
• Factor V Laiden Mutation (R506Q)


  described as deficient in conjunction with factor VIII deficiency due to genetic defect trace to

  chromosome 18
• Factor II Prothrombin Deficiency


  May be inherited as a deficiency or a dysfunction, hemarthroses in patients are rare, medications of aspirin may cause serious bleeding
• Factor II Prothrombin Deficiency


  • APTT one stage PT will be prolonged, TCT (Thrombin clotting time) is normal, two stage prothrombin method and immune based factor assay using anti-prothrombin antisera are the diagnostic test procedures
• Factor V Leiden mutation (R506Q)


  A new and very common inherited thrombophilic syndrome described in 1993 as Activated protein C resistance (APCR)
• Screening for APCR


  Easily performed by clot assays utilizing modified APTT Russell's viper venom time methods
• Factor II prothrombin deficiency


  May be inherited as a deficiency or a dysfunction
• Hemarthroses in patients with factor II prothrombin deficiency are rare
• Medications of aspirin may cause serious bleeding in patients with factor II prothrombin deficiency
• Laboratory findings for factor II prothrombin deficiency


  • APTT one stage PT will be prolonged
  • TCT (Thrombin clotting time) is normal
  • Two stage prothrombin method and immune based factor assay using anti-prothrombin antisera are the diagnostic test procedures
• Therapy for factor II prothrombin deficiency

  • Infusion of FFP is the usual choice of treatment
  • Vitamin K concentrates may also be given to patients but there is a risk of thrombosis after administration
• Fibrinogen (factor I) deficiency

  Defect may result in afibrinogenemia (inherited lack of fibrinogen), hypofibrinogenemia (inherited deficiency of fibrinogen), or dysfibrinogenemia (inherited production of dysfunctional fibrinogen molecule)
• History and clinical features aid in the differentiation between inherited and acquired forms of fibrinogen (factor I) deficiency
• Afibrinogenemia


  • An autosomal recessive and severe condition where patients have nearly undetectable amounts of fibrinogen
  • Molecular structure of fibrinogen is normal
  • Patients' platelets appear affected in that prolonged bleeding time may be measured
• Laboratory findings for afibrinogenemia


  • Prolonged bleeding time, PT, APTT TT
  • Abnormal platelet adhesion and aggregation
• Therapy for afibrinogenemia


  • Treatment requires administration of cryoprecipitate
  • FFP may be used however, volume overload is a major concern
  • Whole blood transfusions may be required if significant bleeding has occurred
• Hypofibrinogenemia


  • Patients possess 20-100 mg/dL level of fibrinogen (normal range 200-400 mg/dL)
  • Inherited as heterozygous, autosomal recessive disorder
  • Molecular structure of fibrinogen is said to be normal
  • Bleeding episodes are usually mild and not spontaneous which may occur after severe trauma or surgery
• Therapy for hypofibrinogenemia

  Cryoprecipitate and FFP are the treatment of choice
• Dysfibrinogenemia


  • Inherited as an autosomal dominant trait
  • Patients demonstrate abnormal fibrinogen function but usually have normal levels in antigenic assay
  • Substitution of amino acids in fibrinogen's polypeptide chains is the striking feature, which may result in inability to submit proteolysis by thrombin, peculiar behaviour during polymerization stages, addition of inappropriate side groups, or persistence of fetal fibrinogen into adulthood