HEMOPHILIA

Inherited deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B) Sex-linked inheritance; almost all patients male
Female carriers may have mild symptoms

Most bleeding into joints, muscles; mucosal and CNS bleeding uncommon Severity inversely proportional to factor level
< 1%: severe, bleeding after minimal injury 1-5%: moderate, bleeding after mild injury > 5%: mild, bleeding after significant trauma or surgery

GENETICS OF HEMOPHILIA
About half of cases of hemophilia A due to an inversion mutation in intron 1 or 22 Remainder genetically heterogeneous
Nonsense/stop mutations prevent factor production Missense mutations may affect factor activity rather than production

15-20% of cases due to new mutations

XI XIa VIII

IX TF VIIa X

Injury

IXa VIIIa

Initiation

V Xa Va

PT Xa

Propagation
Fibrinogen

Thrombi n Fibrin

Deficiency of factor VIII or IX affects the propagation phase of coagulation Most likely to cause bleeding in situations where tissue factor exposure is relatively low

ACUTE COMPLICATIONS OF HEMOPHILIA

Muscle hematoma (pseudotumor)

Hemarthrosis (joint bleeding)

LONG-TERM COMPLICATIONS OF HEMOPHILIA

Joint destruction

Nerve damage

Hemophilic arthropathy

Target joint = irreversibly damaged joint with vicious cycle of injury and repeated bleeding

Hemophilic arthropathy

J Thromb Hemost 2010;8:1895

Hemophilic arthropathy
Variable relationship between # of joint bleeds and severity
Green line: Evidence of early joint damage with relatively few bleeds Yellow line: Linear relationship between # of bleeds and joint damage

Red line: Joint damage occurs after threshold # bleeds

Blue line: Little joint damage despite many bleeds

J Thromb Hemost 2010;8:1895

Management of hemophilic arthropathy

Physical therapy Weight control COX-2 inhibitors safe and effective Judicious use of opioids Surgical or radionuclide synovectomy Joint replacement

OTHER COMPLICATIONS OF HEMOPHILIA

Pseudotumor: gradually enlarging cyst in soft tissue or bone (requires surgery) Retroperitoneal hemorrhage Bowel wall hematoma Hematuria renal colic (rule out structural lesion) Intracranial or intraspinal bleeding (rare but deadly) usually after trauma

HEMOPHILIA
Treatment of bleeding episodes
Unexplained pain in a hemophilia should be considered due to bleeding unless proven otherwise External signs of bleeding may be absent Treatment: factor replacement, pain control, rest or immobilize joint Test for inhibitor if unexpectedly low response to factor replacement

Dosing clotting factor concentrate

1 U/kg of factor VIII should increase plasma level by about 2% (vs 1% for factor IX) Half-life of factor VIII 8-12 hours, factor IX 18-24 hours Volume of distribution of factor IX about twice as high as for factor VIII Steady state dosing about the same for both factors initial dose of factor IX should be higher

Factor replacement in severe hemophilia A

Site of bleed
Joint Muscle Oral mucosa Epistaxis GI GU CNS Trauma or surgery

Desired factor lev el

40-50% 40-50% 50% initially

Dose
20-40 U /kg/day 20-40 U /kg/day 25 U /kg x 1

Other
R est, immobilization, PT R isk of compartment syndrome or neuro compromise Follow with antifibrinolytic therapy Pressure, packing, cautery Endoscopy to find lesion R /O stones, U TI

Initially 80-100%, then 30% 40-50 U /kg then 30-40 until healed U /kg daily Initially 100%, then 30% 40-50 U /kg then 30-40 until healed U /kg daily Initially100%, then 30% 40-50 U /kg then 30-40 until healed U /kg daily Initially100%, then 50% 50 U /kg then 25 U /kg q until healed 12h infusion

Initially100%, then 50% 50 U /kg then 25 U /kg qTest for inhibitor before until healed 12h infusion surgery!

Give factor q 12 hours for 2-3 days after major surgery, continue with daily infusions for 7-10 days Trough factor levels with q 12 h dosing after major surgery should be at least 50-75% Most joint and muscle bleeds can be treated with minor (50%) doses for 1-3 days without monitoring

FACTOR VIII CONCENTRATE

Recombinant
Virus-free, most expensive replacement Treatment of choice for younger/newly diagnosed hemophiliacs Somewhat lower plasma recovery than with plasmaderived concentrate

Highly purified
Solvent/detergent treated, no reports of HIV or hepatitis transmission

Intermediate purity (Humate-P)

Contains both factor VIII and von Willebrand factor Solvent/detergent treated, no reports of HIV or hepatitis transmission Mainly used to treat von Willebrand disease

FACTOR IX CONCENTRATE
Recombinant (slightly lower plasma recovery) Highly purified (solvent/detergent treated, no reports of virus transmission) Prothrombin complex concentrate Mixture of IX, X, II, VII Low risk of virus transmission Some risk of thrombosis

DDAVP
Releases vWF/fVIII from endothelial cells Factor VIII levels typically rise 2-4 fold after 30-60 min (IV form) or 60-90 min (intranasal) Enhanced platelet adhesion due to vWF Useful for mild hemophilia (VIII activity > 5%) prior to dental work, minor surgery etc Trial dose needed to ensure adequate response Cardiovascular complications possible in older patients

Bethesda Assay for Inhibitors

Serial dilutions of patient plasma in normal plasma Incubate 2 hours Assay residual factor activity 1 Bethesda Unit neutralizes 50% of factor in an equivalent volume of normal plasma Example: 1:100 dilution of patient plasma + normal plasma 50% residual factor activity, so inhibitor titer is 100 BU

Bethesda Assay
Residual factor activity

50%

100 BU 1:1 1:10 1:100 1:1000 dilution pt plasma

TREATMENT OF HEMOPHILIACS WITH INHIBITORS

Recombinant factor VIIa FEIBA (Factor Eight Inhibitor Bypassing Activity) Mixture of partially activated vitamin Kdependent clotting proteases including VIIa High dose factor VIII (if low titer inhibitor) Induction of tolerance with daily factor VIII infusions
Optimal dose not established Role for concomitant immunosuppression?

Liver disease in hemophilia

Hepatitis C still a problem, though incidence falling with safer factor concentrates Treatment for hepatitis C with interferon often causes thrombocytopenia Liver transplantation done occasionally (cures hemophilia) All newly diagnosed hemophiliacs should be vaccinated against hepatitis A and B

ACQUIRED FACTOR VIII DEFICIENCY

Due to antibody to factor VIII (most common autoimmune factor deficiency) Most patients elderly Often presents with severe soft tissue or mucosal bleeding (different bleeding pattern than inherited hemophilia) Laboratory: prolonged aPTT not corrected by mixing, very low factor VIII activity
Normal INR, thrombin time and platelet count

Treatment: rVIIa, FEIBA, immunosuppression

VON WILLEBRAND DISEASE

Common (most common?) inherited bleeding disorder Partial lack of VWF causes mild or moderate bleeding tendency
Menorrhagia, bleeding after surgery, bruising

Typically autosomal dominant with variable penetrance Laboratory:

Defective platelet adherence (PFA-100) or long bleeding time Subnormal levels of von Willebrand antigen and factor VIII in plasma Low Ristocetin cofactor activity or VWF activity

VON WILLEBRAND DISEASE

Type 1 decreased production of vWF
Levels 20-50%, antigen activity

Type 2 qualitative defect (missense mutation)

Several different types Usually a disproportionate decrease in vWF activity vs antigen

Type 3 severe deficiency

Antigen, activity and factor VIII levels < 10% Hemophilia-like phenotype Recessively inherited

Type 2 vWD
2A: Selective deficiency of large multimers
Defective assembly Increased susceptibility to proteolysis

2B: Increased affinity for platelet Gp Ib

Large multimers bind spontaneously to platelets and cleared from blood Rarely, a mutation in Gp Ib may have the same effect (platelet-type vWD)

2M: Decreased vWF function but no loss of large multimers 2N: Decreased binding of factor VIII to vWF (recessive)

Weibel-Palade body (arrows) in the cytoplasm of endothelial cell. N - nucleus. Scale = 100 nm. (Human, skin.)

Desmopressin (DDAVP) in vWD

DDAVP releases vWF from endothelial cells Can be given IV or intranasally
0.3 mcg/kg IV, or 150 mcg per nostril

Typically causes 2-4 fold increase in blood levels of vWF (in type 1 vWD), with half-life of 8+ hours Response to DDAVP varies considerably Administration of a trial dose necessary to ensure a given patient responds adequately
Peak response Duration of response

Indications for clotting factor concentrate administration in vWD

Type 2 or 3 vWD
Active bleeding Surgery or other invasive procedure

Type 1 vWD with inadequate response to DDAVP

Acquired von Willebrand disease

Monoclonal gammopathy: vWF neutralized by paraprotein (?) Autoimmune disorders: Autoantibody to vWF Myeloproliferative disorder: large multimers absorbed onto neoplastic cells (platelets?) Cardiovascular diseases (AS, VSD, etc): High shear stress causes unfolding/proteolysis of large multimers Hypothyroidism: Decreased release of vWF from endothelial cells Treatment varies depending on cause/mechanism

ACQUIRED VON WILLEBRAND DISEASE

NEJM 2009;361:1887