Hemophilia & Bleeding Disorders Flashcards
hemophilia - overview
*can be congenital or acquired
*inability to form adequate complete clots due to specific clotting factor deficiency:
-mechanism: impaired/dysfunctional thrombin burst
*most commonly an X-linked recessive disorder, so affects males predominantly (females are often symptomatic carriers)
types of hemophilia
*factor VIII deficiency = classic hemophilia = hemophilia A
*factor IX deficiency = Christmas disease = hemophilia B
*factor XI deficiency (occasionally called hemophilia C)
coagulation mnemonics
*the PT (extrinsic) and the PTT (intrinsic) pathways meet at factor X because “X” marks the spot
*factor V is a cofactor for factor X, and you can remember this because V fits into the notch of X
*factor Xa converts prothrombin into thrombin
*thrombin converts the soluble molecule fibrinogen into a fibrin clot
what clotting factor should we investigate if ONLY the PT is prolonged
factor VII deficiency
what clotting factor should we investigate if ONLY the PTT is prolonged
deficiencies of factors 12, 11, 9, or 8 (XII, XI, IX, or VIII)
what clotting factor should we investigate if BOTH the PT and PTT are prolonged
most likely, factor X deficiency
clotting factor deficiencies that are clinically significant
*deficiencies of factors XI, IX, VIII, VII, X, V, prothrombin, and fibrinogen are clinically significant
*inhibitors of these factors are clinically significant for bleeding
note - deficiency of factor XII, and the presence of the lupus anticoagulant, are not clinically significant
hemophilia inheritance pattern
*X-linked recessive
*affects males predominantly (can occur in females though)
*can skip generations
*30% spontaneous (de novo) mutations
hemophilia - genetics
*factor VIII (hemophilia A) and factor IX (hemophilia B) genes are located near the top of the long arm of the X chromosome
*point mutations are the most common, but different mutation known to have different clinical phenotypes
*result in either case is absence of or low level of FVIII or FIX activity
hemophilia - female carriers
*majority of symptomatic individuals are male
*heterozygote females can be “symptomatic carriers” with bleeding tendencies and pattern most centered around baseline levels
*lyonization effect or double heterozygote inheritance can result in lower residual activity and clinically relevant bleeding
hemophilia - clinical manifestations
*HEMARTHROSES: joint bleeds → target joints (most relevant)
*easy bruising/bleeding
*deep muscle bleeds
*hematomas
*post-surgery/post-trauma
*dental extractions
*intracranial hemorrhage
hemophilia - severity of disease
<1% clotting activity = severe; sx in early childhood & spontaneous bleeds
1-5% clotting activity = moderate; bleeding after minor trauma or surgery; may be spontaneous
5-30% clotting activity = mild; only bleed after trauma or surgery
hemophilic arthropathy
*recurrent bleeds in joints
-inflammation, bony destruction, acute pain
-chronic pain (arthritis)
*decreased range of motion
*long-term disability, psychosocial consequences
development of hemophilic arthropathy
repeated joint bleeds → hemophilic arthropathy → pain and functional impairment
*proliferation of capillaries; synovial cell hyperplasia
*inflammatory cells infiltrate joint space → destruction of cartilage → synovial proliferation into joint space, burrowing into bone and covering cartilage → destruction of joint!
hemophilia - intramuscular/soft tissue bleeding
areas of greatest concern:
*face, neck, mouth, eye
*palm of hand, wrist
*calf
*thigh or groin
*hip or shoulder
*hematuria, GI tract bleeding
note - bleeding of muscles or soft tissues occur less frequently than joint bleeds
hemophilia A - lab findings
*ELEVATED PTT (factor 8 is in intrinsic pathway)
*normal PT
*normal platelet count
*normal PFA-100
factor VIII assay:
severe = < 1%
moderate = 1-5%
mild = 6-30%
hemophilia B - overview
*factor IX deficiency
*less common than hemophilia A
*X-linked mutation/deletion in factor IX gene (first described in Christmas family)
hemophilia B - lab findings
*ELEVATED PTT
*normal PT
*normal platelet count
*normal PFA-100
treatment of hemophilia
*plasma-derived factor concentrates:
-start with a pool of carefully screened donor plasma
-viral inactivation procedures (pasteurization, solvent-detergent treatment, ultrafiltration) are effective against HIV and hepatitis viruses
*recombinant human factor concentrates:
-purified from transfected mammalian cell lines
-no further viral attenuation needed
note: PROPHYLAXIS is KEY!
complications of hemophilia treatment
*development of inhibitors (allo-antibodies) [more common in hemophilia A]
*infections: HBV, HBC, HIV, CMV, parvo B19
acquired hemophilia (AHA)
*development of anti-Factor VIII antibodies
*NO preexistent congenital FVIII deficiency
-uncommon, occurs in older adults, 50% with underlying autoimmune disease
*presentation: prolongation of aPPT, large ecchymotic lesions, usually muscle bleeds
emicizumab (hemophilia therapy)
*normally, FVIII acts as a bridge to bring FIX near FX
*emicizumab is an antibody that MIMICS the activity of FVIII and performs the function of bringing together FIX and FX!!
gene therapy for hemophilia
*bioengineered particle with factor VIII gene
*target organ = liver
*clinical outcome: patient begins making factor VIII
von Willebrand’s Disease - inheritance pattern
AUTOSOMAL DOMINANT (but clinical variability, sometimes autosomal recessive)
von Willebrand’s Disease - overview
*most common bleeding disorder
*heterogeneous group of inherited or acquired bleeding disorders
*different types, including both quantitative (amount) and qualitative (function) deficiencies
von Willebrand’s Disease - symptoms
*menorrhagia (heavy menstrual cycle)
*epistaxis
*gingival bleeding
*hemorrhage after dental extraction
note - mucous membranes are the most common bleeding sites in patients with von Willebrand’s Disease
von Willebrand’s Disease - lab findings
*normal PT
*prolonged or normal PTT
*vWF LOW
*factor VIII may be moderately reduced
*normal factor IX
how does vWF work
*factor VIII and vWF form a complex, where vWF protects FVIII from degradation
*platelets bind vWF via GpIb to subsequently bind collagen on injured endothelium
treatment of von Willebrand’s Disease
*DDAVP (desmopressin):
-synthetic analog of ADH L-vasopressin
-intranasal spray or intravenous
-releases stored vWF from endothelial cells
*humate-P and other products:
-factor VIII concentrate containing BOTH vWF and factor VIII
-2:1 concentrate of vWF to VIII
