This document provides an overview of hemophilia, including:
- Hemophilia is an inherited bleeding disorder caused by deficiencies in coagulation factor VIII or IX.
- It affects males more often than females and symptoms include prolonged bleeding from cuts or wounds.
- Diagnosis involves screening tests and measuring coagulation factor levels. Severity depends on factor level.
- Treatment involves replacing the missing clotting factor through infusions or using bypassing agents for those who develop inhibitors against factor VIII or IX.
- Bypassing agents work by activating the clotting process without using the deficient factor. The choice of agent depends on factors like the treatment phase and dosing considerations.
- Monitoring is needed to track
This would give an idea of the various bleeding disorders, associated clotting factors and more specifically management in the dental office of the patients with bleeding disorders
Thrombocytopenia is most frequently encountered Hematological problem in hospitalized patients. The most common causes and differential diagnosis of In-patient and Outpatient presentations of Thrombocytopenia is discussed here. Useful for Internal Medicine Boards . Archer Internal Medicine Board review lectures will be released soon.
chronic myeloid leukemia, CML, epidemiology, BCR ABL1 gene, philadelphia chromosome, t(9;22), CML incidence, etiology of CML, pathophysiology of CML, phases of CML, treatment of CML, Allogenic stem cell transplant, TKI therapy for CML, Sokal index for CML,
Bleeding disorders Causes, Types, and DiagnosisDr Medical
https://userupload.net/v3l4i8jsk7wq
Factor II, V, VII, X, or XII deficiencies are bleeding disorders related to blood clotting problems or abnormal bleeding problems. Von Willebrand's disease isthe most common inherited bleeding disorder. It develops when the blood lacks von Willebrand factor, which helps the blood to clot.
This would give an idea of the various bleeding disorders, associated clotting factors and more specifically management in the dental office of the patients with bleeding disorders
Thrombocytopenia is most frequently encountered Hematological problem in hospitalized patients. The most common causes and differential diagnosis of In-patient and Outpatient presentations of Thrombocytopenia is discussed here. Useful for Internal Medicine Boards . Archer Internal Medicine Board review lectures will be released soon.
chronic myeloid leukemia, CML, epidemiology, BCR ABL1 gene, philadelphia chromosome, t(9;22), CML incidence, etiology of CML, pathophysiology of CML, phases of CML, treatment of CML, Allogenic stem cell transplant, TKI therapy for CML, Sokal index for CML,
Bleeding disorders Causes, Types, and DiagnosisDr Medical
https://userupload.net/v3l4i8jsk7wq
Factor II, V, VII, X, or XII deficiencies are bleeding disorders related to blood clotting problems or abnormal bleeding problems. Von Willebrand's disease isthe most common inherited bleeding disorder. It develops when the blood lacks von Willebrand factor, which helps the blood to clot.
Disseminated intravascular coagulation (DIC) is a syndrome in which either the extrinsic or intrinsic or both pathways are activated to produce multiple fibrin clots in small blood vessels.
Aplastic anemia is one of the stem cell disorder which leads to pancytopenia in the peripheral blood and decrease production of all cell line in bone marrow. it require bone marrow transplantation to cure the patient.
Hemophilia is a common hereditary coagulation disorder due to deficiency or reduce activity of clotting factor VIII or clotting factor IX.
This disorder is a X- linked recessive disorder.
Types:
Hemophilia A- deficiency of clotting factors VIII
Hemophilia B- deficiency of clotting factors IX
Hemophilia C- deficiency of clotting factors XI
Parahaemophilia- deficiency of clotting factor V
Causes of hemophilia
Hemophilia has a sex-linked recessive inheritance.
In most cases Hemophilia caused by a mutation in a gene that encodes for one of the clotting factors .
Since the hemophilia gene is located on the X chromosome, Hemophilia usually occurs in males, and Female is the carrier of hemophilia.
Diagnosis
Complete blood cell count
Coagulation studies
FVIII assay
Normal values for FVIII assays are 50-150%. Values in hemophilia are as follows:
Mild: >5%
Moderate: 1-5%
Severe: <1%
Treatment of Hemophilia
Other Types of Treatment
Desmopressin (DDAVP)
Antifibrinolytic Medicines
Vaccinations- hepatitis A and B.
Gene Therapy
Gene Therapy
New Drugs for Hemophilia treatment
New Drugs for Hemophilia treatment
Bangladesh perspectives
Bangladesh would have 10800 hemophiliacs.
But, initially the patients does not concern about hemophilia.
Patients are usually diagnosed only after bleeding episode and sometimes the episode are causes serious consequences.
Conclusion
Primary diagnosis with the success of gene therapy and availability of the new bioengineered products the prospect of the hemophiliacs will be brighter in near future.
Disseminated intravascular coagulation (DIC) is a syndrome in which either the extrinsic or intrinsic or both pathways are activated to produce multiple fibrin clots in small blood vessels.
Aplastic anemia is one of the stem cell disorder which leads to pancytopenia in the peripheral blood and decrease production of all cell line in bone marrow. it require bone marrow transplantation to cure the patient.
Hemophilia is a common hereditary coagulation disorder due to deficiency or reduce activity of clotting factor VIII or clotting factor IX.
This disorder is a X- linked recessive disorder.
Types:
Hemophilia A- deficiency of clotting factors VIII
Hemophilia B- deficiency of clotting factors IX
Hemophilia C- deficiency of clotting factors XI
Parahaemophilia- deficiency of clotting factor V
Causes of hemophilia
Hemophilia has a sex-linked recessive inheritance.
In most cases Hemophilia caused by a mutation in a gene that encodes for one of the clotting factors .
Since the hemophilia gene is located on the X chromosome, Hemophilia usually occurs in males, and Female is the carrier of hemophilia.
Diagnosis
Complete blood cell count
Coagulation studies
FVIII assay
Normal values for FVIII assays are 50-150%. Values in hemophilia are as follows:
Mild: >5%
Moderate: 1-5%
Severe: <1%
Treatment of Hemophilia
Other Types of Treatment
Desmopressin (DDAVP)
Antifibrinolytic Medicines
Vaccinations- hepatitis A and B.
Gene Therapy
Gene Therapy
New Drugs for Hemophilia treatment
New Drugs for Hemophilia treatment
Bangladesh perspectives
Bangladesh would have 10800 hemophiliacs.
But, initially the patients does not concern about hemophilia.
Patients are usually diagnosed only after bleeding episode and sometimes the episode are causes serious consequences.
Conclusion
Primary diagnosis with the success of gene therapy and availability of the new bioengineered products the prospect of the hemophiliacs will be brighter in near future.
A brief presentation on the Management of Haemophilia with a focus on bypassing agents. The presentation covers the disease, its available treatment options, intro to bypassing agents, and clinical evidence.
Acquired hemophilia is a rare disorder and if missed can cost lives. This presentation has been prepared keeping in view the non hematologist health care workers to broaden their index of suspicion and increase their awareness. The target people are medical residents those who work in ER and ICUs.
Venous thromboembolism (VTE) is a disorder that includes deep vein thrombosis and pulmonary embolism. A deep vein thrombosis (DVT) occurs when a blood clot forms in a deep vein, usually in the lower leg, thigh, or pelvis.
The Health Innovation Network Polypharmacy programme is working with healthcare professionals to address problematic polypharmacy by supporting easier identification of patients at potential risk from harm from multiple medications.
Our evidence-based polypharmacy Action Learning Sets (ALS) are being rolled out across England to support GPs, pharmacists and other healthcare professionals who undertake prescribing or medication reviews to understand the complex issues around stopping inappropriate medicines safely.
To drive and accelerate changes in practice, delegates complete a quality improvement project to address problematic polypharmacy in their workplace. This poster summary, Identifying Orthostatic Hypotension caused by Medication, can be viewed here.
For more information about the polypharmacy programme, please visit https://thehealthinnovationnetwork.co.uk/programmes/medicines/polypharmacy/
ISI 2024: Application Form (Extended), Exam Date (Out), EligibilitySciAstra
The Indian Statistical Institute (ISI) has extended its application deadline for 2024 admissions to April 2. Known for its excellence in statistics and related fields, ISI offers a range of programs from Bachelor's to Junior Research Fellowships. The admission test is scheduled for May 12, 2024. Eligibility varies by program, generally requiring a background in Mathematics and English for undergraduate courses and specific degrees for postgraduate and research positions. Application fees are ₹1500 for male general category applicants and ₹1000 for females. Applications are open to Indian and OCI candidates.
The use of Nauplii and metanauplii artemia in aquaculture (brine shrimp).pptxMAGOTI ERNEST
Although Artemia has been known to man for centuries, its use as a food for the culture of larval organisms apparently began only in the 1930s, when several investigators found that it made an excellent food for newly hatched fish larvae (Litvinenko et al., 2023). As aquaculture developed in the 1960s and ‘70s, the use of Artemia also became more widespread, due both to its convenience and to its nutritional value for larval organisms (Arenas-Pardo et al., 2024). The fact that Artemia dormant cysts can be stored for long periods in cans, and then used as an off-the-shelf food requiring only 24 h of incubation makes them the most convenient, least labor-intensive, live food available for aquaculture (Sorgeloos & Roubach, 2021). The nutritional value of Artemia, especially for marine organisms, is not constant, but varies both geographically and temporally. During the last decade, however, both the causes of Artemia nutritional variability and methods to improve poorquality Artemia have been identified (Loufi et al., 2024).
Brine shrimp (Artemia spp.) are used in marine aquaculture worldwide. Annually, more than 2,000 metric tons of dry cysts are used for cultivation of fish, crustacean, and shellfish larva. Brine shrimp are important to aquaculture because newly hatched brine shrimp nauplii (larvae) provide a food source for many fish fry (Mozanzadeh et al., 2021). Culture and harvesting of brine shrimp eggs represents another aspect of the aquaculture industry. Nauplii and metanauplii of Artemia, commonly known as brine shrimp, play a crucial role in aquaculture due to their nutritional value and suitability as live feed for many aquatic species, particularly in larval stages (Sorgeloos & Roubach, 2021).
hematic appreciation test is a psychological assessment tool used to measure an individual's appreciation and understanding of specific themes or topics. This test helps to evaluate an individual's ability to connect different ideas and concepts within a given theme, as well as their overall comprehension and interpretation skills. The results of the test can provide valuable insights into an individual's cognitive abilities, creativity, and critical thinking skills
Seminar of U.V. Spectroscopy by SAMIR PANDASAMIR PANDA
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Ultraviolet-visible spectroscopy is an analytical method that can measure the amount of light received by the analyte.
Comparing Evolved Extractive Text Summary Scores of Bidirectional Encoder Rep...University of Maribor
Slides from:
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Track: Artificial Intelligence
https://www.etran.rs/2024/en/home-english/
What is greenhouse gasses and how many gasses are there to affect the Earth.moosaasad1975
What are greenhouse gasses how they affect the earth and its environment what is the future of the environment and earth how the weather and the climate effects.
DERIVATION OF MODIFIED BERNOULLI EQUATION WITH VISCOUS EFFECTS AND TERMINAL V...Wasswaderrick3
In this book, we use conservation of energy techniques on a fluid element to derive the Modified Bernoulli equation of flow with viscous or friction effects. We derive the general equation of flow/ velocity and then from this we derive the Pouiselle flow equation, the transition flow equation and the turbulent flow equation. In the situations where there are no viscous effects , the equation reduces to the Bernoulli equation. From experimental results, we are able to include other terms in the Bernoulli equation. We also look at cases where pressure gradients exist. We use the Modified Bernoulli equation to derive equations of flow rate for pipes of different cross sectional areas connected together. We also extend our techniques of energy conservation to a sphere falling in a viscous medium under the effect of gravity. We demonstrate Stokes equation of terminal velocity and turbulent flow equation. We look at a way of calculating the time taken for a body to fall in a viscous medium. We also look at the general equation of terminal velocity.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
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30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
2. Overview
• Facts
• Hemophilia defined
• Epidemiology
• Pathophysiology
• Etiology
• Diagnosis
• Relationship of bleeding severity
and clotting level
• Etiological classification
• Clinical manifestation and
complication
• Chronic complication
• Major advances in treatment and
their associated outcomes
• Treatment consideration and options
• Treatment of hemophilia A
• Treatment of Hemophilia B
• Factors contributing to inhibitor
development
• Inhibitor diagnosis
• Current treatment strategies of patients
who develop inhibitors
• How are inhibitors treated
• Mechanism of action of Bypassing agents
• BPA prophylaxis regimen
• Choosing a BPA
• When to discontinue BPA
• Comparison of available BPA agents
• Pros and cons of BPA
• Inhibitors under clinical trial
• Case study
• BPA in News
• Current outcomes and remaining
challenges in therapeutic strategies
• Novel therapies
• Gene therapy
• Guidelines in management of hemophilia
3. https://www.hemophilia.org/About-Us/Fast-Facts
Royal disease
Hemophilia B, 1
in 25,000 to
30,000 males
Worldwide
incidence
> 400000
Affects both
men and women
75% of patients
receive
inadequate
treatment
Currently no
cure for
hemophilia
von Willebrand
disease most
common bleeding
disorder.
Hemophilia A
occurs in 1 in
5,000 male births
4. Hemophilia is an X-linked congenital bleeding disorder caused by
a deficiency of coagulation factor VIII (FVIII) (in hemophilia A)
or factor IX (FIX) (in hemophilia B). The deficiency is the result
of mutations of the respective clotting factor genes.
Hemophilia defined
5. Carcao MD. The diagnosis and management of congenital hemophilia. Semin Thromb Hemost 2012; 38:727.
Shetty S. Haemophilia - diagnosis and management challenges. Mol Cytogenet 2014; 7:I44.
WHF estimates
43% hemophilia
population lives in
India, Bangladesh,
Indonesia, and
China
Hemophilia B
1 in 30,000 live
male
Hemophilia A
1 in 5000 live
male
Hemophilia occurs in all ethnic groups and throughout the
world.
8. Screening tests
Complete blood Count
Activated partial Prothrombin time (APTT)
Prothrombin test (PT)
Fibrinogen test
Clotting factor test
9. Relationship Of Bleeding Severity to
Clotting Factor Level
Severity Percent of
patients
affected
Percent normal factor
level
Bleeding
Episodes
Severe (50-70%) < 1 IU/dL
(< 0.01IU /mL)
< 1% of normal
Bleeding after
trivial injury or
spontaneous
Moderate (10%) 1-5 IU/dl (0.01-0.05 IU/ml)
or
1-5% of normal
Bleeding after
minor injury;
occasional
spontaneous
bleeds
Mild 30-40% 5-40 IU/dl (0.05-0.40
IU/ml) or
5-<40% of normal
Following major
trauma, surgical
or dental
procedure
Guidelines For The Management Of Hemophilia ‹. World Health federation 2012
10. Etiological Classification
Hemophilia A Hemophilia B Hemophilia C Acquired
factor
deficiencies
Inhibitors
Inherited
deficiency of
factor VIII; an
X-linked
recessive
disorder.
Inherited
deficiency of
factor IX also
called Christmas
disease; an X-
linked recessive
disorder.
Inherited
deficiency of
factor XI (factor
11); also called
Rosenthal
syndrome; an
autosomal
recessive disorder.
Acquired
coagulation
factor
deficiencies
caused by an
autoantibody
(often to
factor VIII)
are sometimes
referred to as
acquired
hemophilia..
In hemophilia,
inhibitor refers
to an
autoantibody
that typically
forms in
response to
infused factor.
Inhibitors are
most common
in individuals
with very low
baseline factor
levels.
11. Clinical Manifestation and Complication
Easy Bruising Nosebleeds Bleeding from the gums
Hematuria Prolonged bleeding with cuts Bleeding into joints or muscles
• Heavy or abnormal menstrual periods
• Bleeding into critical organs
12. Chronic Complications
I. Musculoskeletal complications:
Chronic hemophilic arthropathy; Chronic synovitis; Deforming arthropathy;
Contractures; Pseudo-tumour formation (soft tissue and bone); Fracture
II. Inhibitors against FVIII/FIX
III. Transfusion-related infections of concern in people with hemophilia:
Human immunodeficiency virus (HIV); Hepatitis B virus (HBV); Hepatitis
C virus (HCV); Hepatitis A virus (HAV); Parvovirus B19;
Others
13. Major advances in therapy for hemophilia
and their associated outcomes.
Pre- Replacement
Therapy
• Supportive care only
• Hospital or clinic based
care
• Recurrent Acute and
chronic Pain
• Debilitating joint disease
• High Mortality
• Definitive bleed
prevention
• Home based care
until curative
treatment
• Inhibitor risk
eliminated
• No further
morbidity from
joint disease
• No bleeding
related mortality
Replacement Therapy
Non-Replacement Therapy
Gene Therapy
• Effective Blood
treatment and prevention
• Home based care
(high to low intensity)
• Inhibitor risk emerges
• Reduced morbidity from
joint disease
• Low mortality
• Effective bread
treatment and
prevention
• Home based care
(Low intensity,
Liberation from IV
infusion)
• Inhibitor risk
ameliorated
• Reduced morbidity
from joint disease
• Low mortality
On
demand
Prophylaxis
Steven W. Pipe. New therapies for hemophilia. American Society of Hematology. 2016. 650-656
14. Considerations
Goal: Rapid and
effective replacement of
missing coagulation
factor
Approach: Comprehensive
hemophilia treatment center
staffed with multidisciplinary
expert team
Strategies: Episodic or on demand
factor replacement.
Prophylaxis
Options
Replacement of missing
clotting protein: factor
VIII and IX
DDAVP (IV,intranasal) in
mild FVIII deficiency
Adjunctive therapies:
Antifibrinolytic agents:
Amicar/lysteda
Supportive measures:
“RICE”-rest, ice, compression
and elevation
Immobilization
Hemophilia facts. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/ncbddd/hemophilia/facts.html. Accessed March 2018.
Types of Bleeding Disorders. National Hemophilia Foundation Web site. https://www.hemophilia.org/Bleeding‐Disorders/Types‐of‐Bleeding‐Disorders. Accessed March 2018.
15. Treatment of Hemophilia A
Treatment option Dosage
FVIII concentrates • Vials of factor concentrates are available in
dosages ranging from approximately 250 to 2000
units each.
• Each FVIII unit per kilogram of body weight
infused intravenously will raise the plasma FVIII
level approximately 2%.
• The half-life is approximately 8–12 hours.
Cryoprecipitate/fresh frozen
plasma
• Only use cryoprecipitate if factor concentrates are
not available.
• Cryoprecipitate is best prepared from repeatedly
tested and virus-negative donors.
• FVIII content per bag of cryoprecipitate is 60-
100 units (average - 80 units) in a volume of 30-
40 ml.
• One ml of fresh frozen plasma contains 1 unit of
factor activity
Desmopressin (DDAVP) • DDAVP is useful in the treatment of persons with
mild hemophilia who have a 5% or
• greater FVIII level and who have been shown to
be responsive in pre-tests.
Guidelines for the Management of Hemophilia
16. Treatment of Hemophilia B
Treatment option Dosage
FIX concentrates • Vials of FIX concentrates are available in doses
ranging from approximately 300 to 1200 units
each.
• Each FIX unit per kilogram of body weight
infused intravenously will raise the plasma
• FIX level approximately 1%. The half-life is
about 18-24 hours. Verify
Fresh frozen plasma (FFP) • FIX levels above 25% are difficult to achieve. An
acceptable starting dose is 15-20 ml/kg.
• Solvent/detergent-treated FFP is available in
some countries.
Antifibrinolytic agents • Due to increased risk for thromboses,
antifibrinolytic agents, either as primary or
adjunctive therapy, are not recommended for
treatment of patients with FIXdeficiency already
receiving large doses of prothrombin complex
concentrates.
Guidelines for the Management of Hemophilia
17. Factors contributing to inhibitor development in
hemophilic patients.
Multiple genetic and environmental factors interact during the first exposures to
factor concentrate replacement treatment. Most data have been obtained from
studies in hemophilia A patients, who develop inhibitors with higher frequency than
those with hemophilia B.
18. How are inhibitors diagnosed?
• Inhibitors are often suspected during a routine blood test called the
activated partial thromboplastin time (APTT).
• In order to confirm the diagnosis, a Bethesda assay, or a
modification thereof, the Nijmegen method, is performed. This test
can determine the strength (titer) of the inhibitor.
• Inhibitor levels vary from one individual to another and can also
vary within the same person over time.
• The amount of inhibitors in a person's blood is measured in
Bethesda Units (BU) and referred to as “high titer” (more than 5
BU) or “low titer” (less than 5 BU).
Inhibitors are also classified as “low responding” or “high responding”
according to how strongly the person's immune system reacts to factor
concentrates based on memory from a previous encounter - this is called the
anamnestic response.
20. How are inhibitors treated?
https://www.cdc.gov/ncbddd/hemophilia/documents/Inhibitor-Treatment.pdf
Strategies
Immune tolerance induction With the goal of getting rid of the inhibitor, factor
is given (infused into the bloodstream through a
vein) regularly over a period of time until the
body’s immune system is trained to accept the
factor without trying to destroy it. It is effective
in many, but not all patients.
Treating and preventing bleeding
events
High-dosage clotting factor
concentrates
If factor still works, but maybe not as well, the
dose or frequency of infusing the factor can be
increased to overcome the inhibitor..
Use of bypassing agents These medications help the blood form normal
clots in people with inhibitors, without increasing
the amount of inhibitor in the blood. Bypassing
agents do not replace the missing clotting factor.
Instead, they correct the clotting process by
going around (or bypassing) the factor that does
not work because of the inhibitor. Bypassing
agents can also be given on a routine schedule to
prevent bleeding.
21. Mechanism of action of bypassing
agents (BPA)
Hoffman M, Monroe DM. Platelet binding and activity of recombinant factor VIIa. Thromb Res 2010; 125 (Suppl. 1): S16–18.
22. Choosing a BPA
• Multiple factors, including the phase of Immune tolerance induction therapy,
bleeding frequency, patient convenience (ie, dosing frequency and infusion
volumes), and clinical efficacy for the patient.
• rVIIa is often chosen as the first-line BPA for patients with hemophilia A and
B with inhibitors before the start of ITI because of the potential risk for
anamnesis and allergic reaction with aPCC resulting from small amounts of
Fviii and the presence of fIX, respectively.
• There is a theoretical higher thrombotic risk with high doses of either agent,
although very few cases of thrombosis have been reported.
Leissinger C, Gringeri A, Antmen B, et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med. 2011; 365(18):1684-
1692.
Konkle BA, Ebbesen LS, Erhardtsen E, et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia
patients with inhibitors. J Thromb Haemost. 2007;5(9):1904-1913.
23. AmyD.ShapiroandUllaHedner.Advancesinbypassingagenttherapyforhemophiliapatientswithinhibitorstoclosecaregapsandimprove
outcomes..TherAdvDrugSaf.2011.2(5):213-225
Comparison of available bypass therapies in patients with
hemophilia and inhibitors
Parameter rFVIIa pd-aPCC
Source Recombinant produced protein Pooled Human Plasma
Composition Highly purified recombinant protein Mixture of coagulation proteins (FII,FIX, FX
inactivated, FVIII activated, trace amounts of FVII)
and other plasma components
MOA rFVIIa binds to platelet activated by small
amount of thrombin generated by initial TF-
FVIIa-FXa complex, further activation of FX
converts additional prothrombin to thrombin
forming tight fibrin hemostatic plug.
Prothrombin complex zymogens in pd-aPCC;
Small amounts of thrombin activate prothrombinase
complex consisting of prothrombin (FII) and
activated FX which generates excess thrombin that
triggers feedback mechanism involving FIX,
activated by FXIa and FVIIa and zymogen FX,
activated by FIXa and FVIIa, for coagulation
independent FVIII or FVIIIa
Storage Stable at room temperature; reconstituted
solution may be stored at room temperature or
refrigerated upto 3 h
Must be kept refrigerated.
Time to mix Rapid reconstitution to clear colourless solution Storage vial and diluent must be at room temperature
before reconstituent; once diluent added, must be
swirled gently until completely dissolved
Vol. of
administration
Dependent on dose upto 5.2 mL Dependent on dose Kg body weight up-to a few
hundred mL
Time to administer 2-5 min as a slow IV bolus, depending on dose
administered within 3 h after reconstitution
Max infusion rate not to exceed 2U/Kg/min; infusion
time dependent on number of units to be
administered.
Tmax Resolves joint bleeds in ≤ 5 h May involve multiple administration at 12 h interval
T1/2 2.3 h (range – 1.7-2.7 h) 4-7 h measured by thrombin generation (TG); peak
TG estimated after 15-30 min infusion
Dosing interval 90µg/Kg every 2 h until homeostasis achieved,
then post hemostasis every 3-6 h for severe
bleeds and surgery. One dose of 90-120 µg/Kg
or 270µg/Kg is recommended for mild to
A function of type and severity of bleeds; 50-100
U/kg every 6-12 h but limited to a total daily patient
exposure of no more than 200U/Kg.
24.
25. When to discontinue BPA prophylaxis
• Anti-fVIII inhibitor titer, as measured by the Bethesda assay and
fVIII levels, are monitored regularly in the clinic to trend the
inhibitor titer and assess for fVIII recovery.
• It is routinely seen some level of factor recovery as the titer drops
below 100 BU/mL and begin checking peak fVIII levels (fVIII
activity 15 minutes after an infusion) during routine inhibitor
monitoring visits.
• The majority of patients have measurable recovery before their
titers drop below 10 to 20 BU/mL, and we frequently observe not
only measurable fVIII levels but also high fVIII levels (.100%)
before achieving a negative inhibitor titer.
• Any measurable peak recovery higher than 10% is evaluated
further. The kinetics of fVIII inhibition are assessed both in the
laboratory and in the clinic with further pharmacokinetics to
evaluate whether a patient would be a good candidate to stop
BPAs,
Shannon L. Meeks and Glaivy Batsuli. Hemophilia and inhibitors: current treatment options and potential new therapeutic approaches.Hematology. 2016; 657-662
26. Case illustration
An 18-month-old with severe hemophilia A, who initially presented with
an inhibitor titer of 40 BU/mL after circumcision, was started on ITI at 200
U/kg/d, and rfVIIa was added shortly afterward secondary to bleeding at
his port site with access.
His titer peaked at ~1000 BU/mL in the first month, and 6 months later was
down to 75 BU/mL.
His father reported that he no longer seemed to have bleeding after port
access. After his dose of 200 IU/kg fVIII, a peak fVIII level in clinic
returned at 4%, and subsequent testing showed a persistent fVIII level of
4% 6 hours later. Subsequently, his BPA prophylaxis was stopped.
He has had no joint bleeds off BPA prophylaxis now for more than 1 year,
with titers ranging from 34 to 166BU/mL.
He has had multiple traumatic injuries/lacerations to his face, which have
required on-demand use of BPAs, but no joint bleeds.
Shannon L. Meeks and Glaivy Batsuli. Hemophilia and inhibitors: current treatment options and potential new therapeutic approaches.Hematology. 2016; 657-662
27. Inhibitors currently in clinical trial
Shannon L. Meeks and Glaivy Batsuli. Hemophilia and inhibitors: current treatment options and potential new therapeutic
approaches.Hematology. 2016; 657-662
28. This report, described the use of sequential BPA therapy to prevent surgical
bleeding in a patient with moderately severe hemophilia A (FVIII 5 0.03
IU/mL) and a high-titer inhibitor.
29. Methods
58-year-old male with severe hemophilia A and a high-titer
inhibitor underwent total knee arthroplasty for advanced
arthropathy.
The patient presented severe left knee pain, and diagnosed with
septic arthritis and bacteremia.
Antibiotic therapy initiated with cefazolin.
Orthopedic surgery recommended urgent left knee arthrotomy,
synovectomy, and excisional debridement of soft tissue to bone.
Craig D. Seaman and Margaret V. Ragni. Sequential bypassing agents during major orthopedic surgery:
a new approach to hemostasis.2017.1(17); 1309-1311
31. Observations
Perioperative sequential BPA therapy was effective in maintaining
hemostasis without adverse events
Intraoperatively minimal blood loss .
A Jackson Pratt drain was placed at the time of surgery and drainage
monitored postoperatively, which was removed at 8th day POD.
Serosanguinous drainage was present without any evidence of overt
bleeding.
Normal postoperative pain and swelling
No evidence of overt hemarthrosis
Hemoglobin remained stable
No evidence of deep venous thrombosis, pulmonary embolism, or other
thrombotic event.
No other adverse events were experienced
Craig D. Seaman and Margaret V. Ragni. Sequential bypassing agents during major orthopedic surgery: a new approach to hemostasis.2017.1(17); 1309-1311
32. Conclusion
The effectiveness of sequential BPA therapy is probably related to the
differing effect of each drug on the coagulation cascade.
Whether alternating BPA agents is hemostatically more effective than
single-agent BPA treatment will require a clinical trial; however, the
present study suggested the use of sequential BPA therapy should be
considered.
Given the prevalence of advanced arthropathy, pain, and disability in
inhibitor patients, this treatment option may provide an approach to
achieving hemostasis not previously possible in surgical settings and
thereby improve the quality of life of such patients.
Craig D. Seaman and Margaret V. Ragni. Sequential bypassing agents during major orthopedic surgery: a new approach to hemostasis.2017.1(17); 1309-1311
35. Current outcomes and remaining challenges in
therapeutic strategies
Outcomes Challenges
Widespread availability of safe and
efficacious factor VIII & IX
Remaining barrier to adoption/ adherence
of prophylaxis: Venous access, time, cost,
health system access
Primary prophylaxis in children
Prevent joint bleeding , overall bleeding
and joint disease
Impact of Inhibitors
Secondary prophylaxis in
adolescent/adults
Prevent joint bleeding , overall bleeding
and slows progression of joint disease ,
permits increased activity, improved
HRQoL
Adapting to phenotypic/pharmacokinetic
variability
Tertiary prophylaxis in adults
Reduces joint bleeding, maintain mobility,
reduces pain, improved HRQoL
Long term follow up data with current
therapeutic approaches limited to 25-30
yrs
Annualized bleed rates are not zero
Joint disease still occurs in young adults
What happens in life time?
36. Novel Therapies
Valder R. Arruda, Bhavya S. Doshi, Benjamin J. Samelson-Jones. Novel approaches to hemophilia therapy: successes and challenges. Blood First Edition Paper,
prepublished online October 10, 2017
Hemophilia is an X-linked congenital bleeding disorder with a frequency of about one in 10,000 births.
Hemophilia is caused by a deficiency of coagulation factor VIII (FVIII) (hemophilia A) or factor IX (FIX) (hemophilia B) related to mutations of the clotting factor gene.
The number of affected persons worldwide is estimated to be about 400,000.
Hemophilia A is more common than hemophilia B, representing 80-85% of the total.
The life expectancy of persons born with hemophilia, who have access to adequate treatment, should approach normal with currently available treatment.
Calculate the dosage by multiplying the patient’s weight in kilograms by the factor
level desired multiplied by 0.5. This will indicate the number of factor units required.
Example: (50 kg x 40 (% level desired) x 0.5 = 1,000 units of FVIII).
Refer to Table 1 on page 45 for suggested factor level and duration of replacement
required based on type of hemorrhage.
• Infuse FVIII by slow IV push at a rate not to exceed 3 ml per minute in adults and 100 units
per minute in young children.
• It is best to use the entire vial of FVIII once reconstituted, though many products
have been shown to have extended stability after reconstitution.
• Continuous infusion will help avoid peaks and troughs and is considered by many to
be safer and more cost-effective. This will reduce significantly the total amount of
factor concentrates used to treat bleeding or during prophylaxis after surgery. Dosage
is adjusted based on frequent factor assays and calculation of clearance. Since FVIII
concentrates of very high purity are stable in IV solutions for at least 24-48 hours at
room temperature with less than 10% loss of potency, continuous infusion for a
similar number of hours is possible. The concentrates may be prepared by the pharmacy
or blood bank under sterile conditions, and administered without concern for
proteolytic inactivation, degradation, or bacterial contamination.
(A) Normal hemostasis – factor IXa binds FVIIIa (tenase complex) on the activated platelet surface to
activate FX (FXa), which binds FVa (prothrombinase complex) to generate thrombin (FIIa) from prothrombin (FII).
(B) Severe FVIII or FIX deficiency precludes formation of the platelet surface tenase complex. The inability to activate FX on the platelet surface leads to a failure of platelet surface thrombin generation, and therefore a failure to form stable fibrin clots.
(C) On the platelet surface, recombinant activated FVII (rFVIIa) directly activates small amounts of FX in the absence of the tenase complex (FVIIIa–FIXa). This FXa is incorporated into prothrombinase complexes, and restores platelet surface thrombin generation to a level sufficient for fibrin clot formation. (D) An important contributor to the hemostatic effects of Factor Eight Inhibitor
Bypassing Agent (FEIBA) is the presence of complexes of FXa with FII (prothrombin). This complex protects the FXa from inhibition, and facilitates assembly of prothrombinase complexes on the platelet surface. FEIBA also contains a high level of prothrombin, which increases the rate of thrombin generation by prothrombinase complexes. (Adapted from Ref. [30], 2010 with permission from Elsevier.)
APCC converts prothrombin in the prothrombinase complex to thrombin, and rFVIIa binds to and directly activates factor X on activated platelet surfaces, which then converts prothrombin t thrombin. These distinct actions probably have a synergistic effect on hemostasis.