Potpourri of bleeding
disorders
Kimo C. Stine, MD
Professor of Pediatrics UAMS
Medical Director of the Arkansas Center
for Bleeding Disorders and Thrombosis
The Cascade
• http://pharmacologycorner.com/coagulationcascade/
The Cascade
VWF facilitates
the adhesion of
activated
platelets to the
injured vessel
wall (primary
hemostasis)
initiation
amplification
FVIII and FIX
are vital in the
thrombin
generation
process
(secondary
hemostasis)
propagation
stabilization
Hemophilia
• Inheritance is X-linked
• Symptomatic carriers
– Women with symptoms related to low factor levels
• Spontaneous mutations do occur
• Mandatory carriers versus possible carriers
• Genotyping
Symptoms of bleeding disorders
Hemophilia
easy bruising, joint swelling due to bleeds,
easy or prolonged bleeding with dental procedures,
excessive bleeding with minor procedures
VWD
easy bruising, epistaxis, prolonged oral
bleeding, excessive bleeding with minor procedures,
GI bleeding, lack of joint involvement except in Type
3 patients.
Dysmenorrhagia
• Definition is patient or family dependent
– In other words what is a normal period or normal
amount of blood loss with menses
– Severe enough to cause some women to undergo
hysterectomies
VWD types?
• VWD can be caused by a quantitative or qualitative defect of
VWF1
Quantitative defects
• Type 1
– Any degree of reduced levels of VWF (most common and
usually the mildest form)
• Type 3
– Virtual absence of VWF (the most severe form, only
occurring in 1 to 3 persons
per million)1
Qualitative defects
• Type 2
– Divided into 4 subgroups (2A, 2B, 2M, and 2N)1
• Assessment process for VWD requires a
thorough personal and family history
• The importance of family and personal bleeding
history when evaluating patients with suspected
VWD:
– Probe patient regarding personal and family history
of bleeding that required medical attention
during/after surgery, during dental procedures, with
trauma, or during childbirth
or heavy menses
– Focus on personal history of excessive bleeding
including spontaneity, severity,
duration, and site of the bleed; ease with which it
could be stopped; type of injury associated with the
episode; and concurrent medications at time of the
bleed
(eg, NSAIDs, Plavix®, warfarin, or heparin)
• Additional probes:
– Spontaneous nosebleed that persisted for 10 minutes
or needed medical attention
– Prolonged bleeding (duration of 15 minutes or
spontaneous recurrence within 7 days)
from minor wounds
– Easy bruising with minimal trauma, with a lump under
the bruise
– Anemia requiring treatment or blood transfusion
• There is currently no standardized questionnaire
for the assessment of VWD, making the diagnosis
process of this complex disorder even more
difficult
• VWF has different functions in the hemostatic
process, requiring multiple lab tests
for diagnosis
• Specialized testing required, involving:
– Measuring a person’s level and activity of VWF and
factor VIII
– Further evaluations to determine if the disorder is
due to a deficiency, an abnormality of the protein
affecting function, or both
Women typically experience several obstetric and
gynecological complications as a result
of bleeding disorders
Women of childbearing age with VWD may be affected
by1,2:
Menorrhagia
Bleeding complications during and after pregnancy
Increased risk of miscarriage
Hemorrhagic cysts
Postpartum hemorrhage
Endometriosis
Hysterectomy at an early age
• Most common manifestation of a bleeding
disorder in women1
• Studies over the past decade indicate that 5%–
32% of menorrhagia sufferers have a
bleeding disorder1,2
• Bleeding disorders tend to be overlooked as an
underlying cause of menorrhagia3
• Defined as loss of >80 cc of blood per cycle1
• May result in iron deficiency anemia
– 1 mg iron lost per cc of blood
• Patient recall/report
– Menorrhagia since menarche in 65% of women with
VWD1
• Pictorial blood assessment chart (PBAC)
– PBAC score greater than 100 in 74% of women with
VWD2
Pictorial Blood Assessment Chart (PBAC)
for Assessment of Menstrual Blood Loss
Name:
Day Start:
DAY
TOWEL
CLOTS/FLOODING
TAMPON
CLOTS/FLOODING
Score:
1
2
3
4
5
6
7
8
• Menorrhagia may indicate a bleeding disorder,
especially in these circumstances1:
– For acute adolescent menorrhagia requiring
hospitalization
– When pelvic pathology has been excluded
– If hormonal treatment has failed
• Contraceptives or hormone therapy may be
ineffective in treating some cases of menorrhagia
• A history of endometriosis was reported in 30% of the
VWD patients compared with 13% in the control group
• Endometriosis
– May result from retrograde menstruation
• Possible explanations for the increased prevalence of
endometriosis in VWD patients include:
– Heavier menses resulting in more retrograde
menstruation,
– A greater likelihood of symptomatic bleeding from
extra-uterine endometrial implants, and,
– Because VWD patients are more likely to experience
intra-peritoneal bleeding, a greater likelihood of a
misdiagnosis of endometriosis
Antepartum management:
• VWF and FVIII levels increase significantly beginning at the
end of the first trimester, but often drop to below baseline after
delivery1
– It is recommended that levels be obtained in the third
trimester to prepare for delivery2
Postpartum management:
• VWF and FVIII levels rapidly fall after delivery, putting women
with VWD at increased risk of primary (first 24 hours) and
secondary (24 hours to 6 weeks) postpartum hemorrhage3
– Monitoring of VWF and FVIII levels post-delivery is
recommended
– Current studies are underway evaluating VWF levels
postpartum
• The mainstay of treatment is replacing the missing VWF1
• Non-replacement therapy
– Use of desmopressin to increase plasma concentration of
VWF by stimulating the
release of the protein stored in endothelial cells2
– Oral contraceptives and the levonorgestrel-releasing
intrauterine system2
• Replacement therapy
– Plasma-derived, virus-inactivated VWF concentrates to
replace the missing factor2
• Supplemental therapies
– Antifibrinolytics such as aminocaproic acid and tranexamic
acid to help stabilize clots
that have formed2
A Public Health Concern—
• Bleeding disorder prevalence in the US
population
– von Willebrand disease (VWD), the most common
bleeding disorder, is found in 1%–2%
of the population affecting men and women equally1
– Hemophilia, another well-known bleeding disorder,
affects about one in every 5,000 males1,2
• An estimated 2.5 million women in the US may
unknowingly have a bleeding disorder3
References: 1. Centers for Disease Control and Prevention. Bleeding disorders. Available at: http://www.cdc.gov/ncbddd/hbd/hemophilia.htm. Accessed July 15, 2008.
2. National Hemophilia Foundation. Hemophilia A (factor VIII deficiency). Available at: http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=179&contentid
=45&rptname=bleeding. Accessed July 9, 2008. 3. The National Women’s Health Information Center. US Department of Health and Human Services. womenshealth.gov:
bleeding disorders. Available at: http://www.womenshealth.gov/faq/bleed.htm. Accessed July 16, 2008
The Diagnosis, Evaluation, and Management
of von Willebrand disease—February 20081
• The National Heart, Lung, and Blood Institute has
developed extensive guidelines that will help
healthcare professionals learn more about VWD
– Because of the complexity in diagnosing and treating
this disorder, the NHLBI was urged by Congress to
develop a set of treatment guidelines
– An expert panel of scientists and physicians
(hematology, family medicine, OB/GYN) helped
develop these guidelines
Reference: 1. National Heart, Lung, and Blood Institute. Full report: The diagnosis,
evaluation, and management of von Willebrand disease. December 2007. Available at:
http://www.nhlbi.nih.gov.
Your Vital Role in Bleeding Disorder
Diagnosis
• Women with bleeding disorders appear to be more severely
affected by obstetric and gynecologic conditions associated
with bleeding1
• Bleeding disorders can be especially difficult to diagnose in
women, as symptoms may be attributed to other causes or go
unexplained2,3
• Undiagnosed bleeding disorders can lead to
– Unnecessary medical procedures, prolonged bleeding,
joint damage, and anemia4
– Reduced quality of life and days away from school or
work5
• Consultation with an HTC may be a patient’s best opportunity
to obtain proper diagnosis
and treatment
•
References: 1. James AH. More than menorrhagia: a review of the obstetric
and gynaecological manifestations of bleeding disorders. Haemophilia.
2005;11:295–307.
2. The National Women’s Health Information Center. US Department of
Health and Human Services. womenshealth.gov: bleeding disorders.
Available at: http://www.womenshealth.gov/faq/bleed.htm. Accessed July 16,
2008. 3. National Hemophilia Foundation. Bleeding disorders and women.
Available at:
http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=192&c
ontentid=20&rptname=bleeding. Accessed July 9, 2008. 4. National
Hemophilia Foundation.
What is a bleeding disorder. Available at:
http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=26&co
ntentid=5&rptname=bleeding. Accessed July 9, 2008.
5. James AH, Kouides PA, Abdul-Kadir R, et al. von Willebrand disease and
other bleeding disorders in women: Consensus on diagnosis and
management from an international expert panel. Am J Obstet Gynecol.
2009;201:12.e1-8.
Other deficiencies of clotting factors
•
•
•
•
•
Factor X
Factor V
Factor XI
Factor XII
Factor XIII
Factor V deficiency
•
•
•
•
•
•
•
•
Parahemophilia
Mild to moderate bleeding disorder
Autosomal
Mucocutaneous bleeding and hematomas
Rare hemarthrosis
Menorrhagia may occur
Both PT and APTT prolonged
Combined deficiency with Factor VIII:due to
abnormal chaperone protein from ER to Golgi
apparatus
Factor X deficiency
•
•
•
•
Rare autosomal
Mucocutaneous and post-traumatic bleeding
Prolonged PT and APTT
Associated with amyloidosis in adult patients due
to absorption of Factor X
Factor VII
•
•
•
•
•
1 in 500,000
Autosomal recessive
Severe deficiency may result in hemarthrosis
Neonates may have ICH
Prolonged PT and normal APTT
Factor XI deficiency
• Autosomal recessive
• Prolonged PTT and norma PT
• More common in Ashkenazi (1-3 per 1000
Ashkenazi in Israel)
• Hemophilia C: bleeding usually associated with
surgery or trauma
• Mucocutaneous bleeding or menorrhagia
Factor XII or contact factor deficiencies
• Very prolonged APTT with normal PTT
• NO BLEEDING
Factor XIII deficiency
•
•
•
•
•
•
Clot stabilization by cross-linking of fibrin
Deficiency associated with reduced clot stability
Autosomal recessive
Delayed hemorrhage
Delayed separation of the umbilical stump
Intracranial hemorrhage with little or no ttrauma,
poor wound healing , recurrent spontaneous
abortions
• Normal PT, aPTT, TT
• Increased solubility of clot
Hemophilia Treatment Center (HTC)—
Overview
• Specialty clinic that provides comprehensive
healthcare to those with bleeding disorders
• Approximately 140 government-funded centers
are part of the Centers for Disease Control
and Prevention (CDC) network1
• Team of hematologists, nurses, and other
healthcare professionals from several disciplines
HTC Role in Patient Care
• Diagnosis
• Treatment plan development and follow-up (in
conjunction with other outside healthcare
professionals and primary care providers)
• Emotional support
• Community outreach and education
• Clinical research
• Data surveillance and collection for the Universal
Data Collection project, a system established by
the CDC to monitor blood safety and research
healthcare outcomes1
Reference: 1. Centers for Disease Control and Prevention. Bleeding and clotting disorders in
women. Available at: http://www.cdc.gov/ncbddd/hbd/women.htm. Accessed July 9, 2008
• Healthcare professionals
– www.nhlbi.nih.gov
– www.cdc.gov
– www.signsofbleeding.com
• Patients
– www.projectredflag.org
– www.AllAboutBleeding-us.com
– www.hemophilia.org