1. Curs an IV - limba engleza 2012-2013
HEMOPHILIA
Curs an IV - limba engleza

2. Coagulation factor disorders
Inherited bleeding disorders
Hemophilia A and B
vonWillebrands disease
Other factor deficiencies
Acquired bleeding disorders
Liver disease
Vitamin K deficiency/warfarin overdose
DIC

3. Factor Deficiencies (CONGENITAL)
HEMOPHILIAS
Caused by lack of coagulation factors
VON WILLEBRAND’S DISEASE
Caused by lack of von willebrand´s factor

4. History
First references are mentioned in Jewish texts in second century AD by Rabbi Ben Gamaliel who correctly deduced that sons of mother- that he did not know at that time- was an hemophilic carrier bled to death after circumcision. Hence he made a ruling that excepted newborn Jewish boys of this ritual if two previous brothers had had bleeding problems with it.
Then Rabbi and physician Maimonides in the XII century noted that the mothers were the carriers, hence the second ruling that if she married twice the newborns from the second marriage were also excepted.
In 1800 John Otto a physician in Philadelphia wrote a description of the disease where he clearly appreciated the cardinal features: an inherited tendency of males to bleed
In 1928 the word Hemophilia was defined.

5. Types of Hemophilia Hemophilia A Absence or deficiency of Factor VIII
Hemophilia B (Christmas Disease)
Absence or deficiency of Factor IX
Hemophilia C
Absence or deficiency of Factor XI
Very rare and mild

6. Background
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

7. Etiology - Genetics of Hemophilia
Hemophilia is due to mutation of the gene situated on X chromosome
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

8. Etiology - Hemophilia Inheritance
Hemophilia is an X-linked gene disease.
A father with the X-linked gene will pass it to all his daughters resulting in heterozygous carriers.
A mother who is a carrier of the mutant gene will pass the gene on to half her sons and half her daughters. All her sons will have hemophilia and all her daughters will be heterozygous carriers.
Females are carriers
Males have the disease

9. Etiology - Genetics Transmitted by females, suffered by males
The female carrier transmits the disorder to half their sons and the carrier state to half her dtrs
The affected male does not transmit the disease to his sons (Y is nl) but all his dtrs are all carriers (transmission of defected X)

10. Etiology - Genetics Hemophilia in females
If a carrier female mates with an affected male there’s the possibility that half their daughters are homozygous for the disease
Other possibility: Turner syndrome (45,X0) with a defective X

11. Epidemiology Hemophilia A & B
It is the second most common inherited clotting factor abnormality (after von Willebrand disease)
1 in live male births
No difference between racial groups
Hemophilia A is 90-80% of all Hemophiliacs
Hemophilia B is10-15% of all Hemophiliacs
Factor VIII …1:10,000 males
Both X-linked recessive
Rare females…, inherited from both parents.
One-third - spontaneous genetic mutation.

12. Clinic - Hemophilia A & B
Clinical manifestations are indistinguishable
Hemarthrosis (most common)
Fixed joints
Soft tissue hematomas (e.g., muscle)
Muscle atrophy
Shortened tendons
Other sites of bleeding
Urinary tract
CNS, neck (may be life-threatening)
Prolonged bleeding after surgery or dental extractions

13. Clinical manifestations
Frequency and severity of bleeding are related to F VIII levels
Severity
F VIII activity
Clinical manifestations
Severe
<1%
Spontaneous hemorrhage from early infancy
Freq sp hemarthrosis
Moderate
2-5%
Hemorrhage sec to trauma or surgery
Occ sp hemarthrosis
Mild
>5%
Rare sp bleeding
Coinheritance of prothrombotic mutations (i.e. Factor V Leiden) can decrease the risk of bleeding

14. Clinical Manifestations: Hemarthrosis
The most common, painful and most physically, economically and psychologically debilitating manifestation.
Clinically:
Aura: tingling warm sensation
Excruciating pain
Generally affects one joint at the time
Most commonly: knee; but there are others as elbows, wrists and ankles.
Edema, erythema, warmth and LOM
If treated early it can subside in 6 to 8 hs and disappear in 12 to 24 hs.
Complications: Chronic involvement with joint deformity complicated by muscle atrophy and soft tissue contractures

15. Clinical Manifestations: Hemarthrosis
Pathophysiology:
Bleeding probably starts from synovial vessels into the synovial space.
Reabsorption of this blood is often incomplete leading to chronic proliferative synovitis, where the synovium is more thickened and vascular, creating a “target joint” with recurrence of bleeding.
There is destruction of surrounding structures as well-bone necrosis and cyst formations, osteophytes
Terminal stage: Chronic Hemophiliac arthropathy: fibrous or bony ankilosing of the joint.

16. Hemophilia – Hemarthrosis

17. Hemophilia – Hemarthrosis

18. Hemophilia – Hemarthrosis

19. Hemophilia – Hemarthrosis

20. Clinical Manifestations Hematomas
Subcutaneous and muscular hematomas spread within fascial spaces, dissecting deeper structures
Subcutaneous bleeding spreads in characteristic manner- in the site of origin the tissue is indurated purplish black and when it extends the origin starts to fade
May compress vital structures: such as the airway if it is bleeding into the tongue throat or neck; it can compromise arteries causing gangrene and ischemic contractures are common sequelae, especially of calves and forearms

21. Clinical Manifestations Hematomas
Muscle hematomas:
1. calf,
2. thigh,
3. buttocks,
4. forearms
Psoas hematoma- if right sided may mimic acute appendicitis
Retroperitoneal hematoma: can dissect through the diaphragm into the chest compromising the airway. It can also compromise the renal function if it compresses the ureter

22. Clinical Manifestations Hematomas

23. Clinical Manifestations Hematomas

24. Clinical Manifestations Hematomas

25. Clinical Manifestations Hematomas

26. Clinical Manifestations Hematomas

27. Clinical Manifestations Hematomas
Leading cause of death of hemophiliacs
Spontaneous or following trauma
May be subdural, epidural or intracerebral
Suspect always in hemophilic patient that presents with unusual headache
If suspected- FIRST TREAT, then pursue diagnostic workup
LP only when fVIII has been replaced to more than 50%

28. Laboratory diagnosis Nomenclature:
FVIII protein that is lacking or aberrant
FVIIIc functional FVIII measured by clotting assays
FVIIIag Antigenic protein that can be detected with immunoassays
Deficit can be quantitative or qualitative
General Lab: prolonged aPTT, nl PT and BT
Mixing studies: aPTT corrects with normal plasma –if there are no factor VIII antibodies present
Clotting assays: F VIII activity, expressed in % of normal DecreasedQUANTITATIVE
Immunoassays: “Cross Reactive Material” Positive- there is an antigen similar to the F VIII protein- QUALITATIVE

29. Differential diagnosis - Clinical Features of Bleeding Disorders
Platelet Coagulation disorders factor disorders
Site of bleeding Skin Deep in soft tissues
Mucous membranes (joints, muscles)
(epistaxis, gum,
vaginal, GI tract)
Petechiae Yes No
Ecchymoses (“bruises”) Small, superficial Large (hematomas), deep
Hemarthrosis / muscle bleeding Extremely rare Common
Bleeding after cuts & scratches Yes No
Bleeding after surgery or trauma Immediate, Delayed (1-2 days),
usually mild often severe

30. Differential diagnosis - Clinical Features of Bleeding Disorders
Remember the basic differences between bleeding associated with coagulation factor deficiencies and bleeding associated with platelet problems.
Deep bleeding such as in joints and hematomas generally arise as the result of a coagulation deficiency.
Superficial bleeding such as petechiae, bruises, epistaxis, and hematuria generally reflect a quantitative or qualitative deficiency of platelets.

31. 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

32. Treatment Factor replacement
Choice of treatment: is based on
Purity of the factor (how concentrated or “purified” the factor is)
Safety
Cost
Nowadays most used therapies are believed to be effective and relatively safe

33. Treatment of hemophilia A
Intermediate purity plasma products
Virucidally treated
May contain von Willebrand factor
High purity (monoclonal) plasma products
No functional von Willebrand factor
Recombinant factor VIII
Virus free/No apparent risk

34. Treatment Factor replacement
Replacement of F VIII is the cardinal step to prevent or reverse acute bleeding episodes
Dosing: Replacement products can be given on the basis of body weight or plasma volume ( aprox 5% of body weight)
1 U/ml = 100% factor activity
Practically 1 unit of F VIII/kg increases F VIII about 0.02 U/ml
In a severe hemophiliac, to raise F VIII to 100% activity or 1 U/ml, we need 50 U/kg
Redosing is based on half life: 8-12 hs
Monitoring of Factor activity is crucial during therapy

35. 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 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

36. FACTOR VIII CONCENTRATE
Recombinant
Virus-free, most expensive replacement
Treatment of choice for younger/newly diagnosed hemophiliacs
Somewhat lower plasma recovery than with plasma-derived 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
Mainly used to treat von Willebrand disease

37. DDAVP Releases vWF/fVIII from endothelial cells
Factor VIII levels typically rise 2-4 fold after min (IV form) or 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

38. Dosing guidelines for hemophilia A
Mild bleeding
Target: 30% dosing q8-12h; 1-2 days (15U/kg)
Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria
Major bleeding
Target: % q8-12h; 7-14 days (50U/kg)
CNS trauma, hemorrhage, lumbar puncture
Surgery
Retroperitoneal hemorrhage
GI bleeding
Adjunctive therapy
alfa amino caproic acid (Amicar) or DDAVP (for mild disease only)

39. 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

40. Complications of therapy
Formation of inhibitors (antibodies)
10-15% of severe hemophilia A patients
1-2% of severe hemophilia B patients
Viral infections
Hepatitis B Human parvovirus
Hepatitis C Hepatitis A
HIV Other

41. Complications of therapy Development of Antibodies
Specific inhibitor antibodies that neutralize FVIII activity
Most frequently in severe affected patients- affecting 25%
Predisposing factors: severe disease, type of genetic mutation (inversion, nonsense mutation, deletions), family history of inhibitors development
Seen aprox 9-11 days post factor VIII exposure

42. Complications of therapy Development of Antibodies
Diagnosis: mixing study does not correct aPTT.
Bethesda assay: which consists of serial dilutions of plasma is pooled with normal plasma and incubated for 2 hs, then the activity level is measured by coagulation assays. The higher inhibitor titer, the greater the dilution required to demonstrate residual FVIII activity. It is expressed on Bethesda Units: High responders: >5 Bethesda units, low responders <5.
11/6/2018

43. Course and prognosis Development of Antibodies
Treatment: of active bleeding and inhibitor ablation via immune tolerance induction.
High purity FVIII: treatment of life threatening hemorrhages in pts that are low responders
Porcine FVIII: high responders with high inhibitors levels that have life threatening hemorrhages
Prothrombin complex concentrates and activated prothrombin complex concentrates: bypassing agents for thrombosis (prothrombin, fVII, fIX, f X and Prot S and C). Carries high risk of thrombosis and it is difficult to monitor.
rFVIIa: Effective response in 90% of patients. Gets activated by tissue factor, so thrombosis response is more modulated than that of APCCs, however there are no studies comparing them both

44. Treatment of hemophilia B
Agent
High purity factor IX
Recombinant human factor IX
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
Dose
Initial dose: 100U/kg
Subsequent: 50 U/kg every 24 hours

45. Treatment - Prophylaxis
Prophylactic treatment should be considered in all patients with severe hemophilia
In 1997 was recommended by the Medical and Scientific Advisory Council of the National Hemophilia Foundation.
Candidate should be reliable to manage a central venous catheter device
Administration is three times a week to make a severe hemophiliac a moderate phenotype
There is significant improvement in the clinical condition and quality of life.

46. Carrier detection and Antenatal diagnosis
Family history: if we follow the inheritance pattern a female is a carrier if she:
Has an hemophilic father
Has two hemophilic sons
Has one hemophilic son and has a family history
Has a son but no family history, there is a 67% chance that she is.

47. Carrier detection and Antenatal diagnosis
Coagulation based assays:
Generally heterozygous females have <50% f VIII levels but if normal it can’t be excluded
vWF is usually normal or elevated in female carriers, so F VIII:FvW ratio is low which adds sensitivity to these tests
DNA based assays:
Southern blot can detect the inversion in intron 22
If negative for that, there is the need for DNA sequencing
For prenatal diagnosis: DNA testing on choronic villi samples obtained by biopsy at week 12