Neil A. Zakai, MD MSc

01/20/14

INHERITED BLEEDING DISORDERS

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

NOTE• Disorders I am not speaking about:

• Fibrinolysis

• Platelet function

• Disorders of blood vessel structure / function or subcutaneous tissue structure / function

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

LABORATORY WORK-UP• PT, PTT, CBC, and mixing studies

• Factor levels (II, V, VII, VIII, IX, X, XI) – activity and antigen levels

• Fibrinogen

• Activity / antigen levels

• Thrombin Time

• Reptilase time

• Factor XIII

• Urea solubility

• Factor XIII Antigen

• Von Willebrand’s disease

• vWD antigen

• vWD activity

• vWD multimers

COAGULATION ‘CASCADE’

X

II

Fibrinogen Fibrin

VIIa-TFIX

XI

VIII

V PC,PS

PC,PS

AT

AT

AT – antithrombin – inhibits Xa and IIa (thrombin)

PC, PS – protein C, protein S – inhibit factors Va and VIIIa, the cofactors

X

II

Fibrinogen Fibrin

VIIa-TFIX

XI

VIII

V PC,PS

PC,PS

AT

AT

COAGULATION ‘CASCADE’aPTT

X

II

Fibrinogen Fibrin

VIIa-TFIX

XI

VIII

V PC,PS

PC,PS

AT

AT

COAGULATION ‘CASCADE’

PT

X

II

Fibrinogen Fibrin

VIIa-TFIX

XI

VIII

V PC,PS

PC,PS

AT

AT

COAGULATION ‘CASCADE’

] Thrombin time

X

II

Fibrinogen Fibrin

VIIa-TFIX

XI

VIII

V PC,PS

PC,PS

AT

AT

COAGULATION ‘CASCADE’

] Reptilase time

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

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

• Activity assay standard in most hospitals

• Antigen assay a send-out

• 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

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

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

FIBRINOGEN DEFICIENCY (FACTOR I)

Concentrate available: Riastap

Pregnancy requires prophylaxis to prevent hemorrhage and miscarriage.

Peyvandi Thrombosis Research 2012

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

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.

X

II

Fibrinogen Fibrin

VIIa-TFIX

XI

VIII

V PC,PS

PC,PS

AT

AT

COAGULATION ‘CASCADE’

] Reptilase time

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

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

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

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)

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

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

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.

FACTOR XII DEFICIENCY• Not a bleeding disorder, prevalence about 1:1,000,000

• Prolongs the PTT

• No treatment is necessary

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.

BLEEDING DISORDERSFactor Deficiency Coagulation Studies Factor Replacement

Fibrinogen Prolonged PT / PTTFibrinogen assay

Fibrinogen concentrateCryoprecipitate

Factor II Prolonged PT / PTTFactor II assay

FFPPCC (3 or 4 factor)

Factor V Prolonged PT / PTTFactor V assay

FFPPlatelet transfusions

Factor VII Prolonged PTFactor VII assay

Novo 7FFPPCC (4 factor)

Factor VIII Prolonged PTTFactor VIII assay

FFPCryoprecipitateFactor Concentrates (recombinant and human)

Factor IX Prolonged PTTFactor IX assay

FFPPCC (3 and 4 factor)Factor Concentrates (recombinant and human)

Factor X Prolong PT / PTTFactor X assay

FFPProthrombin Complex Concentrate

Factor XI Prolonged PTTFactor XI assay

FFP

Factor XIII Urea solubility, factor XIII CorifactCryoprecipitate

PCC’S AVAILABLE AT FAHCFactor II Factor VII Factor IX Factor X

Profilnine 148 11 100 64

Kcentra 128 68 100 152 Contains Heparin, Protein C and S

• 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%

VON WILLEBRANDS DISEASE• Type 1: Mild to moderate quantitative defect

• Type 2: Qualitative defect

• Type 3: Near Complete absence of von Willebrand Factor

VWD

Mannucci NEJM 2004

VWD

Mannucci NEJM 2004

VWD

Mannucci NEJM 2004

VWD

Mannucci NEJM 2004

TYPES OF VWD

Mannucci NEJM 2004

EVALUATION OF VWD

• Von Willebrand antigen

• Von Willebrand activity

• Von Willebrand multimers

• Factor VIII

• Blood Type

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)

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

TYPE 2B VWD

• Type 2B

• 5% of vWD

• Autosomal dominant

• Moderate to moderately severe bleeding

• Mutations occur in A1 domain (majority) – GP1b a binding domain

• Gain of function mutation (more avid binding) – increases clearance

• Can cause severe thrombocytopenia

• “Platelet-type” vWD

• Mutations in the platelet GP1b a causing binding and clearance of vWF

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

TYPE 3 VWD• Absence of vWF

• Severe bleeding disorder, behaves clinically like hemophilia (factor VIII also decreased)

• Treatment with factor replacement

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

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)

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

PATIENT 1vWF antigen vWF activity Factor VIII Platelets

2 months prior - - - 122Bleeding 91% 30% 84% Clumped

PATIENT 1vWF antigen vWF activity Factor VIII Platelets

2 months prior - - - 122Bleeding 91% 30% 84% ClumpedAfter Humate P 228% 186% 298% Clumped2 weeks later 39% <14% 36% 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

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?

PATIENT 2• PTT 50/50 mix normalizes

• Factor levels (which ones)?

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?

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?

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.

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?

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?

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)

• 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% ).

• Ii. Half life approximately 20-24 hours for factor X.

• iii. Factor 9 by ~1%

• 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%.

QUESTIONS?