DIAGNOSIS OF
HEMOPHILIA
Nairobi, Kenya
June 24, 2013
JIM MUNN, R.N., M.S.
Program Nurse Coordinator
University of Michigan HTC
Ann Arbor, MI, USA
Chair – WFH Nursing Committee
Acknowledgement:
Slides 20,21, 23-28 reproduced with permission from
Partners in Bleeding Disorders Education Program
www.partnersprn.org
OBJECTIVES
• Discuss the history of hemophilia
• Illustrate the clotting cascade and how bleeding occurs
• Describe the two main types of hemophilia
• Classify the severities of hemophilia
• List common presenting symptoms in patients with hemophilia
• Examine the process of diagnosing hemophilia
• Identify common labs used to diagnose hemophilia
EARLY OBSERVATIONS
Twelfth Century Physician and Talmudist Maimonides states
in the Mishneh Torah1
“If a woman had her first son
circumcised and he died as a result of
the circumcision, which enfeebled his
strength, and she similarly had her
second [son] circumcised and he died
as a result of the circumcision whether [the latter child] was from her
first husband or her second husband the third son may not be circumcised
at the proper time [on the eighth day
of life]…”2
1. Rosner F. “Moses Maimonides.” Ann Intern Med. 1965;372:1135-1204.
2. Mishneh Torah, Hilkhot Milah. 1:18.
EARLY OBSERVATIONS
1803: John Conrad Otto
• Provided first accurate account of
hemophilia in the modern medical
literature
• His investigation of “bleeders”
was published in a New York
journal under the title, “An
Account of an Hemorrhagic
Disposition Existing in Certain
Families”
• Traced to woman who settled in
Plymouth, New Hampshire in
1720
Otto JC. The Medical Repository. 1803;Vol VI (No 1):1-4.
EARLY OBSERVATIONS
1820: Nasse of Bonn
• German physician 1778-1851
• Formulated observations on inheritance of
hemophilia
• “Nasse’s Law”: Transmitted by unaffected females
to their sons
Nasse CF. Arch Med Erfahr. 1(1820):385.
EARLY OBSERVATIONS
1828: The word “hemophilia” first appears in a description of
inherited bleeding disorders by Physician Frederick Hopff at the
University of Zurich
1840: First recorded case of hemophilia treatment by
transfusion written by Samuel Lane in The Lancet 1
1893: First documentation of abnormal prolongation of
coagulation in capillary tube in hemophilics2
1. Farr AD. J Royal Soc Med. April 1981;74(4):301-305.
2. Wright AE. Br Med J. 1893;2:223-225.
THE ROYAL DISEASE: QUEEN VICTORIA FAMILY TREE
THE COAGULATION SYSTEM
Procoagulants
Platelet
Endothelial
Cell
Fibrinolysis
Coagulation inhibitors
THE CLOTTING CASCADE
Intrinsic pathway (I.P.)
Extrinsic pathway (E.P.)
XII
XI
IX
VII
VIII
X
V
Prothrombin (II)
Fibrinogen
Thrombin
Fibrin
CLOT FORMATION
XIII
HOW DOES CLOTTING OCCUR?
WHAT IS HEMOPHILIA?
• Rare, genetic condition
• Gene located on the X chromosome
• Results in bleeding manifestations in affected individuals
• Present at birth and continues throughout life
• Decreased amount or impaired functioning of one of the
plasma proteins
• Usually factor VIII (eight) or IX (nine)
• Factor levels usually do not change over time
WHY DO PEOPLE WITH HEMOPHILIA BLEED LONGER?
• In hemophilia, one clotting
factor is missing, or the level
of that factor is low.
• It is difficult for the blood to
form a clot, so bleeding
continues longer than usual
(not faster).
TYPES OF HEMOPHILIA
Types
Prevalence
% of Cases
Hem A/Factor VIII
1:5,000 males
80-85%
Hem B/Factor IX
1:25,000 males
15-20%
Hem C/Factor XI
All types:
• Affect all races
• Worldwide distribution
SEVERITY OF HEMOPHILIA
• Low levels of factor VIII (eight)
= hemophilia A.
• Low levels of factor IX (nine)
= hemophilia B.
• Hemophilia A and B can be
mild, moderate, or severe,
depending on the level of
clotting factor.
Severity of symptoms often
corresponds to factor level
COMMON PRESENTING SYMPTOMS IN HEMOPHILIA
• Bleeding at circumcision
• Mouth bleeds in young children
• Excessive bruising, hematomas – especially in
areas not subjected to bumps and scrapes
• Head bleeding related to birth trauma
• Joint bleeding
• Muscle bleeding
• Bleeding after surgery, dental work, or trauma
• In severe hemophilia, bleeding can be spontaneous
DIAGNOSING HEMOPHILIA: HISTORY AND PHYSICAL
• Accurate and detailed history with assessment of bleeding
episodes and trauma in individuals with bleeding disorders
is essential for determining appropriate care
• Use age-appropriate approach
• Get a patient and family history
• Start general (ROS), get specific
• History and assessment may be as, or more, important as
labs/imaging
• Listen to the patient and family
• The process is continuous from first notification of event to
follow-up
THE 7 HISTORY AND ASSESSMENT QUESTIONS
1.
What are the symptoms?
2.
How long have the symptoms been present?
3.
What treatment was given, and when?
4.
Did an injury happen before the symptoms
started?
5.
Did a similar problem occur in the past?
6.
How was that problem treated?
7.
Did that treatment resolve the issue?
LABORATORY EVALUATION
• Laboratory evaluation is guided by thorough history &
physical examination
• Clinical impression is critical to determine:
- Extent of evaluation
- Phase of coagulation most likely abnormal
- Need for repeated evaluations
LABORATORY EVALUATION: GUIDED BY SYMPTOMS
• Petechiae
• Abnormal bruising
• Mucocutaneous bleeding
 Abnormal platelet number or function
• Deep tissue, muscle, joint bleeding
• Abnormal bruising
• Bleeding with injury, surgery
→ Abnormal procoagulants
• Delayed bleeding
→ Abnormal fibrinolysis
THE CLOTTING CASCADE: PT AND APTT
Intrinsic pathway (I.P.)
Extrinsic pathway (E.P.)
XII
XI
IX
VII
VIII
X
APTT
PT
V
Prothrombin (II)
Fibrinogen
Thrombin
Fibrin
CLOT FORMATION
XIII
LABORATORY EVALUATION: APTT
• Activated partial thromboplastin time (aPTT)
• Non-specific test of “intrinsic system”
• aPTT screens for abnormality in factors VIII, IX, XI, XII
Activated Partial Thromboplastin Time. Virginia Commonwealth University, 2005.
http://www.pathology.vcu.edu/clinical/coag/aPTT.pdf.
Laboratory Evaluation of Hemostasis. Virginia Commonwealth University, no
date. http://www.pathology.vcu.edu/clinical/coag/Lab%20Hemostasis.pdf.
LABORATORY EVALUATION: PT
• Prothrombin time (PT)
• Tests efficiency of “extrinsic system”
• PT sole abnormality  factor VII
• Abnormality of PT may be due to deficiency in factors VII, X, V
• Somewhat useful for detecting changes in factors II
(prothrombin) and I (fibrinogen)
Laboratory Evaluation of Hemostasis. Virginia Commonwealth University, no
date. http://www.pathology.vcu.edu/clinical/coag/Lab%20Hemostasis.pdf
LABORATORY EVALUATION: PROLONGED PT AND APTT
Common pathway
• Both PT & aPTT prolonged
• May be due to deficiency in factors X, V, II, I (fibrinogen)
• May also indicate vitamin K deficiency: factors II, VII, IX, X
Laboratory Evaluation of Hemostasis. Virginia Commonwealth University, no
date. http://www.pathology.vcu.edu/clinical/coag/Lab%20Hemostasis.pdf
MIXING STUDY
• Prolonged coagulation screening tests such as PT & aPTT
should first be followed by a mixing study
• Mixing study consists of mixing equal parts the patient’s
plasma with a known normal plasma
• Coagulation test is then repeated
• Correction of the test to the normal range = Factor
deficiency
• Lack of correction of the test to the normal range =
Inhibitor
Partial Thromboplastin Time Mixing Study. University of Alabama at
Birmingham Coagulation Service, no date.
http://peir.path.uab.edu/coag/article_101.shtm
Patient with
prolonged
aPTT
+
aPTT corrects
=
Factor
deficiency
Mixed with
normal
plasma
Patient with
prolonged
aPTT
+
aPTT does not
correct or
re-prolongs with
incubation =
Inhibitor
Mixed with
normal
plasma
SPECIFIC FACTOR ASSAYS
• Factor VIII level
• Factor IX level
• May need repeat testing as factor IX levels are typically
low at birth due to immature liver (vitamin K-dependent
protein)
• Cord blood sampling can be done
• Exposure to blood products for treatment can falsely
elevate factor levels
SUMMARY
• Hemophilia has been around as long as people have been
around.
• Hemophilia is not a “Royal Disease”.
• Symptoms typically appear earlier in life in severe disease.
• Clotting involves a complex series of reactions between a
number of components.
• The diagnosis of hemophilia requires a coordinated
approach.
• Careful history and physical should precede any laboratory
investigations.
• Labs may need to be repeated.
ADDITIONAL WFH RESOURCES
• Diagnosis of Hemophilia and Other Bleeding
Disorders: A Laboratory Manual
• Guidelines for the Management of Hemophilia, 2nd
edition, Section 3.
Visit the Publications Library at
www.wfh.org/publications for free copies