2. OUTLINE
•
How I approach bleeding disorders in adults
•
Laboratory Tests
•
Specific Disorders
•
Hemophilia A (Factor VIII Deficiency)
•
Hemophilia B (Factor IX Deficiency)
•
Hemophilia C (Factor XI Deficiency)
•
Rare Factor Deficiencies
• Factor I (Fibrinogen)
• Factor VII
• Factor X
• Factor XIII
•
Von Willebrand‟s Disease
3. NOTE
•
Disorders I am not speaking about:
• Fibrinolysis
• Platelet function
• Disorders of blood vessel structure / function or subcutaneous tissue structure /
function
4. GENERAL APPROACH
•
Determine if the bleeding is inherited or acquired
• Very few acquired bleeding disorders in adults (medications, factor inhibitors,
myeloproliferative neoplasms, organ dysfunction etc)
•
Mucocutaneous versus soft tissue / joint
•
Delayed versus immediate bleeding
•
Provoked versus unprovoked
• Surgical bleeding can be associated with bleeding disorders, but can also be
associated with anatomic bleeding
•
Try and isolate the likely cause of bleeding prior to work-up and only initiate a work-up in
patients with a reasonable bleeding history
5. LABORATORY WORK-UP
•
PT, PTT, CBC, and mixing studies
•
Factor levels (II, V, VII, VIII, IX, X, XI) – activity and antigen levels
•
Fibrinogen
•
•
Thrombin Time
•
•
Activity / antigen levels
Reptilase time
Factor XIII
•
•
•
Urea solubility
Factor XIII Antigen
Von Willebrand‟s disease
•
vWD antigen
•
vWD activity
•
vWD multimers
11. PT, PTT AND MIXING STUDIES
•
Clot based assays
•
Can help identify the cause of pathologic bleeding
•
These tests „correct‟ when mixed with normal plasma if abnormal due to a coagulation
factor deficiency
• In theory, about 50% of any factor is needed to make these tests normal
•
Few caveats
• Some tests are more sensitive to factor deficiencies, needing 60% of the factor
present to fall within the normal rage
• Sometimes the mixing study does not correct if there are multiple coagulation factor
deficiencies
12. FACTOR LEVELS
•
Conventionally activity based assays (based on the ptt)
•
Some hospitals measure, others send out
•
Factors II, V, VII, VIII, IX, X, XI.
•
Fibrinogen
•
•
Antigen assay a send-out
•
•
Activity assay standard in most hospitals
Reptilase time and thrombin time assess fibrinogen formation and can identify
abnormalities in fibrinogen function not assessed with fibrinogen activity assays
Factor XIII
•
Cross links fibrin and stabilizes thrombus
•
Traditional assay assess stability of clot when exposed to urea
•
Antigenic assays becoming more common
13. FEW GENERAL RULES ABOUT TREATMENT
•
Replace exactly what you need to replace
•
Know what your goal levels are
•
Know the dosing (usually doses as units / kg)
• Know the peak level you want
• Know the trough level you want
•
Know the half life and when repeat dosing may be necessary
14. FIBRINOGEN DEFICIENCY (FACTOR I)
•
Fibrinogen is the soluble precursor to fibrin which forms the matrix for clots
•
Defects
• Type 1: Quantitative
• Type 2: Qualitative – can be associated with thrombosis
•
Deficiency rare – about 1 per million
•
Symptoms
• In severe cases bleeding is mucocutaneous and deep tissue (muscle) with or without
trauma.
• Less severe cases have bleeding only with trauma.
• Poor pregnancy outcomes in women with fibrinogen deficiency
•
Laboratory work-up: pt, ptt prolonged. Clot based and antigen based fibrinogen assays to
determine whether there is a type I or type II deficiency
15. FIBRINOGEN DEFICIENCY (FACTOR I)
Concentrate available: Riastap
Pregnancy requires prophylaxis to prevent hemorrhage and miscarriage.
Peyvandi Thrombosis Research 2012
16. FACTOR II DEFICIENCY (PROTHROMBIN)
•
Extremely rare
•
PT and PTT elevated (but sometimes only minimally), factor II assay (activity) will be
reduced.
•
Phenotype depends on severity, from mild to severe spontaneous bleeding
•
Treatment
• FFP: 15-20ml/kg to get levels >20%
• Volume can be difficult in some patients
• PCC (profilnine, kcentra): 20-30 units/kg generally acceptable
• Dosed by factor IX units
• Levels of other coagulation factors may go extremely high with repeat dosing
• Repeat dosing every 12 – 24 hours based on patient‟s response
17. FACTOR V DEFICIENCY
•
Epidemiology: Rare, less than 1 per million.
•
Factor V is found in both plasma and platelets
•
Serves to catalyze the conversion of prothrombin to thrombin by Xa
•
Occasionally a deficiency for factor VIII is coinherited.
19. FACTOR V DEFICIENCY
•
Phenotype: usually mucocutaneous bleeding
•
Laboratory work-up: PT, PTT prolonged, factor V levels
•
Treatment
• Plasma (no concentrates available)
• Consider platelet transfusion for severe bleeding
20. FACTOR VII DEFICIENCY
•
Incidence around 1:500,000 for severe deficiency, mild deficiencies seen more often
•
Occasionally mutations in vitamin K metabolism result in combined deficiencies of II, VII,
IX, and X
•
Bleeding can be severe, with joint bleeds, mucocutaneous bleeds, and surgical bleeding.
•
Treatment:
• Recombinant factor VIIa (probably higher risk of thrombosis)
• 4-factor prothrombin complex concentrates
21. HEMOPHILIA A (FACTOR VIII DEFICIENCY)
•
Most common hemophilia, sex-linked
•
Laboratory work-up: Prolonged PTT, normal PT (PTT was designed to monitor hemophilia
A treatment), factor VIII levels, „Betheseda‟ units when monitoring for inhibitors
•
Classification
• Severe: factor VIII levels <1%
• Moderate: factor VIII levels 1%-5%
• Mild: factor VIII levels 5% - ?
•
Treatments: Recombinate factor VIII (preferred), human derived concentrates,
cryopreciptate, FFP
22. HEMOPHILIA A (FACTOR VIII DEFICIENCY)
•
Every unit/kg of factor infused increases levels by 2%
• I.E. 50 units/kg will increase factor VIII levels to 100%
•
Half-life varies by individual but is between 8-19 hours
•
If peak levels are less than anticipated or half life shorter
• Consumption from bleeding
• Inhibitor development
•
Goal levels depend on indication
• Severe bleeding: replace to 100%, keep trough above 80%
• Prophylaxis: Trough levels above 1% - 5% prevent spontaneous bleeds (some
patients can be treated 3 times / week, or prior to sports activities etc)
23. HEMOPHILIA B (FACTOR IX DEFICIENCY)
•
Relatively common hemophilia, sex linked
•
Laboratory work-up: PTT prolonged, PT not prolonged, factor IX levels
•
Treatments: recombinant factor IX, human derived factor IX, PCC, FFP
•
For every unit/kg of factor IX concentrate infused, factor IX levels increase by about 0.8%
- 1.2%
• I.e. 100 units/kg will result in an increase of factor IX levels by about 80% - 120%
• These numbers are different for human derived versus recombinant factor IX
•
Half life: About 18 hours
•
Goal levels depend on indication
24. FACTOR X DEFICIENCY
•
Epidemiology: 1:500,000 to 1:1,000,000
•
PT and PTT prolonged, factor X levels decreased
•
Phenotype
• Mild deficiency: mucocutaneous bleeding, bruising
• Severe: Muscle / joint bleeds, spontaneous CNS hemorrhage
•
Treatment
• FFP
• Prothrombin complex concentrates: 3 factor favored over 4 factor concentrates
25. HEMOPHILIA C (FACTOR XI DEFICIENCY)
•
Relatively common: 1:100,000
• Common in some populations: Israel almost 1:10
•
Lab: ptt prolonged, factor XI level low
•
Bleeding phenotype
• Variable – often no spontaneous bleeding even at very low levels (<1%)
• Severe provoked bleeding especially for procedures on mucus membranes or GI
tract.
• Aspirin and other antiplatelet agents can bring out bleeding
•
Treatment
• FFP – often need large quantities
• Factor concentrates available in Europe.
26. FACTOR XII DEFICIENCY
•
Not a bleeding disorder, prevalence about 1:1,000,000
•
Prolongs the PTT
•
No treatment is necessary
27. FACTOR XIII DEFICIENCY
•
Extremely rare: 1:5,000,000
•
Bleeding
• Severe bleeding: individuals cannot stabilize clots so often delayed bleeding.
• In severely deficient cases recurrent CNS hemorrhages
•
Diagnosis
• Urea solubility test
• Factor XIII assays
•
Treatment – only need 5% to stop pathologic bleeding
• FFP/cryoprecipitate have factor XIII
• Corifact (factor XIII concentrate): Can be infused prophylactically once per month to
prevent bleeding.
28. BLEEDING DISORDERS
Factor Deficiency
Coagulation Studies
Factor Replacement
Fibrinogen
Prolonged PT / PTT
Fibrinogen assay
Fibrinogen concentrate
Cryoprecipitate
Factor II
Prolonged PT / PTT
Factor II assay
FFP
PCC (3 or 4 factor)
Factor V
Prolonged PT / PTT
Factor V assay
FFP
Platelet transfusions
Factor VII
Prolonged PT
Factor VII assay
Novo 7
FFP
PCC (4 factor)
Factor VIII
Prolonged PTT
Factor VIII assay
FFP
Cryoprecipitate
Factor Concentrates (recombinant and
human)
Factor IX
Prolonged PTT
Factor IX assay
FFP
PCC (3 and 4 factor)
Factor Concentrates (recombinant and
human)
Factor X
Prolong PT / PTT
Factor X assay
FFP
Prothrombin Complex Concentrate
Factor XI
Prolonged PTT
Factor XI assay
FFP
Factor XIII
Urea solubility, factor XIII
Corifact
Cryoprecipitate
29. PCC‟S AVAILABLE AT FAHC
Factor II
Factor VII
Factor IX
Factor X
Profilnine
148
11
100
64
Kcentra
128
68
100
152
•
PCC are dosed based on factor IX units
•
The ratio to other factors is relatively stable but can vary greatly
•
Avoid factor IX levels >150%
Contains
Heparin,
Protein C
and S
30. VON WILLEBRANDS DISEASE
•
Type 1: Mild to moderate quantitative defect
•
Type 2: Qualitative defect
•
Type 3: Near Complete absence of von Willebrand Factor
36. EVALUATION OF VWD
• Von Willebrand antigen
• Von Willebrand activity
• Von Willebrand multimers
• Factor VIII
• Blood Type
37. TYPE 1
•
Partial quantitative defect
•
Bleeding phenotype variable, from mild to severe
•
Diagnosis
• Normal multimers
• Activity and antigen levels nearly the same
• Difficult in individuals with blood type O (lower levels)
38. TYPE 2A VWD
• 10-20% of vWD
• Autosomal dominant (usually)
• Moderate to moderately severe bleeding
• Mechanism: Decrease in active high and intermediate molecular
weight multimers
• Group 1: Abnormal intracellular assembly
• Group 2: Increased proteolysis by ADAMTS13 after secretion
• Acquired vWD from myeloproliferative disorders, AVMs, and cardiac
valve stenosis similar to type 2A vWD
39. TYPE 2B VWD
• Type 2B
• 5% of vWD
• Autosomal dominant
• Moderate to moderately severe bleeding
• Mutations occur in A1 domain (majority) – GP1b binding domain
• Gain of function mutation (more avid binding) – increases clearance
• Can cause severe thrombocytopenia
• “Platelet-type” vWD
• Mutations in the platelet GP1b causing binding and clearance of vWF
40. TYPE 2 VWD
• Type 2M
• Uncommon, autosomal dominant
• Decreased binding of vWF to platelet GPiB resulting in decreased platelet adhesion.
• Moderate to severe bleeding
• Type 2N
• Uncommon, autosomal recessive.
• Decreased factor VIII binding – increased clearance of factor VIII
• Behaves similar to hemophilia
41. TYPE 3 VWD
•
Absence of vWF
•
Severe bleeding disorder, behaves clinically like hemophilia (factor VIII also decreased)
•
Treatment with factor replacement
42. DIAGNOSIS
• Diagnosis is often difficult in the acute situation
• Patient issues and analytic issues can affect results
• Inflammation, acute illness can increase levels
• Estrogen, pregnancy can increase levels
• Patients with blood type O have lower levels
43. TREATMENT PEARLS
• DDAVP
• Appropriate in Type 1 – need to document response
• Appropriate in Type 2 – except for type 2B, need to document response
• In type 2B, can worsen bleeding
• Not likely to work with type 3
• Factor replacement (Humate P®, Alphanate®, and Willate®, others)
• Dosing – by Ristocetin cofactor activity units (NOT FACTOR VIII)
• “Loading” dose of 40-60 ristocetin units per Kg
• “Maintenance” dose of 20-40 ristocetin units per Kg every 12-24 hours
• Try and avoid high factor VIII levels
• Hemostatic agents (i.e. antifibrinolytic agents)
44. PATIENT 1
•
Case History
• 35 year-old female comes in with an active bleed 2 days after an EGD with biopsies.
Hemoglobin is 6g/dL down from 13g/dL 3 days ago and she is orthostatic
• She tells you that she has a history of von Willebrand‟s disease
46. PATIENT 1
2 months prior
Bleeding
After Humate P
2 weeks later
vWF antigen
91%
228%
39%
vWF activity
30%
186%
<14%
Factor VIII
84%
298%
36%
Platelets
122
Clumped
Clumped
237
Multimers: Presentation and 2 weeks later: Lacking high molecular weight multimers
Exon 28 sequencing: Heterozygous for 394G>A resulting in valine 1316 substituted
by methionine – known mutation for Type 2B vWD
47. PATIENT 2
•
Patient History
• 60 year old male referred to hematology due to an abnormal ptt prior to a renal
biopsy for worsening renal function.
• Otherwise healthy, no family history of bleeding.
•
Labs
• CBC normal
• PT: 10s
• PTT 45s
•
What evaluation do you do?
•
Is it safe for the renal biopsy?
49. PATIENT 2
•
PTT 50/50 mix normalizes
•
Factor levels (which ones)?
• VIII, IX, XI, XII
•
Factor VIII 15% - patient has undiagnosed mild hemophilia A
•
Recombinant factor VIII
• Each unit/kg will increase factor VIII levels by about 2%
• How much factor VIII should you give?
50. PATIENT 3
•
Patient history
• 65 year-old male with hemophilia B comes in needing a knee replacement due to
arthropathy
• Baseline factor levels 3%, 2-4 target joint bleeds / year
• No history of infectious complications
•
How do you proceed?
51. PATIENT 3
•
1. Hemophilia B.
A. Baseline Factor IX, 4%.
B. Factor infused approximately 2 to 4 times per year. He uses BeneFix (Factor IX
replacement).
i. Minor bleed 22 units per kilogram.
ii. Moderate bleed 44 to 66 units per kilogram.
iii. Major bleed 88 to 111 units per kilogram.
C. In general, patient increases factor IX levels 1% per unit per kg.
D. BeneFIX half life approximately 9 hours "done in April 2009."
E. Infectious complications.
i. Hepatitis A antibody positive
ii. Hepatitis B surface antibody and core antibody positive, surface
antigen negative.
iii. Hep C antibody negative.
iv. HIV negative.
52. PATIENT 3
•
Half life known to be 9 hours, known that he gets a 1% increase per unit/kg infused of
recombinant factor IX.
•
Goal for surgery 100%, keep trough above 50%
• What is your initial dose?
• When will you have to redose him?
•
What will you do for DVT prophylaxis?
•
What will you do for home dosing of Factor IX?
53. PATIENT 4
•
40 year-old male with established factor X deficiency (baseline levels 3%)
•
Has hepatitis C due to transfusions as a child
•
Needs liver biopsy to determine whether to treat or not, how would you proceed?
54. PATIENT 4
•
1. Factor X deficiency
•
A. Baseline levels around 2%, INR baseline 5.8-6.
•
•
i. Few spontaneous bleeds, but including occasional joint bleeds and moderate to severe nose bleeds.
B. Factor Replacement Profilnine (a PCC)
•
•
Ii. Half life approximately 20-24 hours for factor X.
•
iii. Factor 9 by ~1%
•
•
I. 1 unit/kg of Profilnine (a PCC) increases his Factor X levels by ~2% (In June 12, he received 3500 units prior
to procedure, and his Factor X level increased to 74% ).
Iv. Factor 2 by ~3%.
C. Bleeding plan:
•
i. Mild to moderate bleeding: Profilnine 1500 units, which should Increase his Factor X level above 30%.
•
ii: Severe bleeding: Infuse Profilnine 3000-3500 units, should increase factor X levels above 50% and
normalize INR.
•
iii. In an emergency (with no Profilnine available): Can give FFP 10-30 ml / kg.
•
Iv. Caution with factor 2 levels as these can go very high. When he received 3500 units his factor 2
levels were >200%.
