(Hemophilia A): factor VIII deficiency – occurs in 1-2/10K male births
Factor VIII
: heterodimer protein; very labile (t1/2 = 8-12 hrs); synthesized in the liver and endothelium
normally stabilized in the plasma by binding to vWF; consequently, vW disease Þ ß factor VIII
Genetics
: X-linked recessive; 45% result from inversion of intron 22 in factor VIII gene; 20% are new mutations
Classification
:
severe
(VIII < 1% of normal): 70% of cases recurrent spontaneous bleeding in all joints
moderate
(VIII 1-5% of normal): no spontaneous bleeding; may have problems with surgery/trauma
mild
(VIII 5-25% of normal: clinically undetectable; may show up on random bloodwork
Clinical aspects
:
hemarthrosis
: most common symptom; may be spontaneous or linked to trauma; very painful bleeding into joint or surrounding bone; leads to chronic inflam. (‘chronic joint’) and eventually ankylosis (hemophilic arthropathy)
soft tissue bleeding
: sub Q or IM; psoas is a common site
GI
, GU hemorrhage, epistaxis (nosebleed)
traumatic bleeding
: primary hemostasis only temporarily effective Þ delayed bleeding
bleeding after circumcision
: often first sign; I got circumcised at birth - I couldn’t walk for a year!
Diagnosis
: PT and bleeding times are normal (extrinsic path and primary hemostasis intact); PTT is elevated if factor
VIII is < 20% of normal; family history and factor VIII assay are main diagnostic tools
differential diagnosis includes deficiency of factors IX, XI, XII, vWF
(2) Christmas Disease
(Hemophilia B): factor IX deficiency
Factor IX
: small, single chain glycoprotein; t1/2 = 18-24 hrs; most cases involve nonfunctional protein
Genetics
: X-linked recessive (distant from VIII site); 1/25K males; less frequent new mutations than classic
Clinical aspects
: clinically indistinct from classic hemophilia
Treatment
: recombinant factor IX is now available
von Willebrand’s Disease (vWD)
– the most common hereditary bleeding disorder
vWF
: large, complex factor; synth in endothelium and megakaryocytes (Weibel-Palade bodies,
a -granules in platelets)
(1) stabilzes factor VIII in the plasma
(2) mediates platelet adhesion to endothelium by binding GPIb and inducing GPIIb/IIIa binding complex
ristocetin
(an antibiotic) can bind vWF and allow it to spontaneously agglutinate platelets without endothelial contact
Þ
risocetin-induced platelet aggregation (RIPA) and risocetin cofactor are tests for vWD
vWF
and factor VIII are elevated in young and old, pregnancy, estrogens; decreased in women with O blood group
vWD Types
:
Type I
: quantitative deficiency; 70% of patients; autosomal dominant inheritance with incomplete penetrance
because of stabilizing properties, there is a decrease in factor VIII with Type I vWD
results in mucocutaneous hemorrhage; prolonged bleeding time;
Ý PTT due to ß factor VIII
Type IIa
: unstable vWF; absence of high molecular weight vWF (HMW vWF); absolute level normal or reduced
Type IIb
: Ý affinity for GPIbÞ spontaneous bindingÞ thrombocytopenia; hyperaggregability to ristocetin on RIPA study
Type 2M
: ß platelet-dependant function but HMW multimers are NOT decreased as in Iia
Type 2N
: ß affinity for factor VIII Þ factor VIII is 10-20% of normal Þ looks like classic hemophilia
Type III
: complete absence of vWF and factor VIII Þ hemarthroses, muscle hematomas, GI bleeding, etc
Some Clotting Factor Other Deficiencies
Factor XI
: circulates with HMW Kallikrein; higher freq. in Ashkenazi Jews and Japanese; associated with mild bleeding disorder; FXI has a long T1/2 and in vivo hemostatic concentration is reletively low Þ easy replacement therapy
Factor XII
(Hageman factor): autosomal recessive; common cause of prolonged PTT; MI and thromophlebitis
Factor VII
: acts with tissue factor and Ca, vit K dependant; T1/2 = 4-6 hrs and VII is the first factor to decrease in vit K deficiency; inherited deficiency is autosomal recessive; can lead to spontaneous hematomas, GI, GU bleeding; hemarthrosis; thromboembolis; treatment is difficult because of the short half life no FVII concentrate is available
Factor V
(proaccelerin): deficiency is AKA pseudohemophilia; usually mild Þ epistaxis, bruising, menorrhagia, etc
Factor X
(Stuart factor): can be true deficiency or dysfunctional protein; clinical picuture like factor VII deficiency
Prothrombin
: rare autosomal recessive; bleeding from umbilical stump; spontaneous hemorrhage is uncommon
Fibrinogen
: afibrogenemia, hypofibrogenemia; dysfibrogenemia; inheritance pattern is variable as is clinical severity
Factor XIII
: activated by thrombin and serves to stabilize the clot; autosomal recessive; life-long bleeding, can be treated with cryoprecipitate because the T1/2 is 6-10 days and hemostatic levels are low
Plasminogen activator inhibitor,
a -2antiplasmin: inhibit plasmin; deficiency leads to severe bleeding in homozygotes
Platelet Disorders
– hereditary disorders are reletively rare
Glanzmann’s Thromboasthenia
: autosomal recessive deficiency of GP IIb and IIIa
Þ decreased platelet aggregation
Symptoms (in homozygotes): ecchymoses, epistaxis, menorrhagia, gingival bleeding; bleeding time prolonged (20-30 min)
Defective Platelet Release Reaction
: ADP and other aggregation substances have impaired synthesis or release
: deficiency in number and content of a -granules, moderate thrombocytopenia, enlarged platelet forms; prolonged bleeding time; ecchymoses, petechiae, epistaxis
Bernard-Soulier syndrome
: autosomal recessive deficiency of GPIb/IX complex (vWF binding site)
abnormal RIPA, normal response to ADP, collagen, epi