Facilitator Version
Module # X – Bleeding Diatheses
Objectives:
By the end of this module, you should be able to:
1. Identify common causes of bleeding diatheses.
2. Explain the normal coagulation cascade and platelet function.
3. Identify and understand the typical laboratory tests used in working up bleeding
diatheses.
Case1:
A 35-year-old woman undergoes follow-up evaluation for recently diagnosed anemia and heavy
menstrual flow present since her menarche began at age 13 years. Her menstrual flow is heavy 6
of the 7 days of her period, requiring use of a new pad and tampon every hour. She has a history
of bleeding with tooth extractions and experienced postpartum hemorrhage with her two
children. She also has a history of iron deficiency. Her sister and mother had hysterectomies in
their late 20s for dysfunctional uterine bleeding, and her maternal grandfather died of
hemorrhagic stroke in his late 50s. Her only medication is a multivation.
Question 1. What factors of the history are helpful in determining the cause of bleeding?
Table 4. Diagnostic clues obtainable by means of proper evaluation of type or site of bleeding.
Conjunctival ecchymosis
Hypertension, thrombocytopenia, anticoagulants
Petechiae (skin or mucosae) Thrombocytopenia
Papular lesions in legs Cryoglobulinaemia, SH, other purpuras
Mucosal
Rendu-Osler, VWD, platelet disorders
Haematomas Single factor congenital deficiency, circulating anticoagulants, traumas
Haemarthrosis Haemophilia A and B, and less frequently, in FII, FVII or FX deficiency
Easy bruising Thrombocytopenia, Cushing’s disease
Table 5. Clinical clues for an acquired bleeding disorder.
Negative family history
Presence of associated diseases
Variable in time
Variable in aspect and type
Onset usually in middle age or later
Table 6. Clinical clues for congenital bleeding disorders.
More than one patient in the family is affected
Hereditary pattern
Onset at early age
Positive history for blood transfusion
Rather fixed pattern of bleeding
Source: Girolami et al 2005.
Question 2. What is in the differential diagnosis of bleeding disorders?
Source: Hunt 2014.
Question 3. Describe the pathophysiology of hemostasis.
Hemostasis is defined in Stedman’s Medical Dictionary as “the arrest of bleeding.” The steps
involved in hemostasis are:
1. Vasoconstriction (vasospasm).
2. Primary hemostasis. Formation of a platelet plug.
a. Platelet adhesion
b. Platelet activation
c. Platelet aggregation
3. Secondary hemostasis. Activation of the clotting cascade and formation of a blood clot.
4. Recanalization. Clot retraction and clot dissolution.
Source: Rote and McCance 2011, Marcucci et al.
Question X. What physical examination findings are you looking for in patients with bleeding
diathesis?
Although findings from the physical examination in bleeding disorders are often normal, it is
important to look for signs of active or recent bleeding, including the following:
1. Petechiae, perifollicular hemorrhages (typical of scurvy)
2. Oral blood blisters, particularly if the patient has thrombocytopenia
3. Ecchymoses, hematomas, and skin pigmentation changes due to recurrent bleeds
4. Signs of active bleeding from a site of trauma or an incision, including excessive blood loss
into drains
5. Sequelae of previous bleeds in individuals known or suspected to have a severe bleeding
disorder, such as muscle wasting and arthropathy, neurologic abnormalities from prior
intracranial or compartment syndrome bleeds
6. Pallor due to anemia: the palms are usually notably pale when the hemoglobin is less than 10
g/dL
7. Signs of an underlying hematologic disorder, such as lymphadenopathy and/or splenomegaly
8. Signs of acute or chronic liver disease, such as jaundice, hepatomegaly, spider nevi, palmar
erythema, or Dupuytren contractures
9. Signs of an endocrine disorder, such as hypothyroidism or Cushing syndrome
10. Vascular lesions such as telangiectasia on the face or buccal mucosa, which can suggest
hereditary hemorrhagic telangiectasia
11. Hyperextensibility if the bleeding history suggests Ehlers-Danlos syndrome as a potential
diagnosis
12. Signs that suggest a syndromic bleeding disorder (albinism, hearing impairment, absent radii)
Source: Hayward 2010.
Petechia
Discrete, pinhead-like, <2 mm in diameter, which do not coalesce but often
cluster in peculiar sites
Purpuric spots or lesions
3–4 mm in diameter, resulting often from confluence of many
petechiae in a particular area or spot
Ecchymosis Irregular, variable, patch-like hemorrhagic skin lesions, larger than 1 cm with
tendency to coalesce.
No modification of profile of skin
Hematomas Musculocutaneous hemorrhage forming a mass that modifies profile of the skin
surface and is also palpable and hot
Haemarthrosis Bleeding in joints
Easy bruising Susceptibility to several skin hemorrhagic contusions even after minor traumas
Source: Girolami et al 2005
Source: Hayward 2005.
Case Continued1:
On physical examination, blood pressure is 130/85 mm Hg, and pulse rate is 100/min. The
complete blood count indicates a hemoglobin level of 7.8 g/dL (78 g/L) and a mean corpuscular
volume of 78 fL. The platelet count is normal.
Question 2.Does the above physical exam and lab values help in narrowing the differential
diagnosis?
Case Continued1:
Question 3. Which of the following tests is most likely to establish the diagnosis?
(A) Activated partial thromboplastin time
(B) Platelet Function Analyzer (PFA-100®)
(C) Prothrombin time
(D) von Willebrand factor antigen and activity assays
Question 4. Elucidate a strategy for the laboratory workup of bleeding diatheses.
Source: 5.
Case Continued1:
Item 44. Answer D.
Educational Objective: Evaluate a patient with von Willebrand disease.
The next step in the diagnostic evaluation is von Willebrand factor (vWF) antigen and activity
assays. This patient has a personal and family history of mucocutaneous bleeding with a pattern
that appears to be autosomal dominant. The most common inherited bleeding disorder is von
Willebrand disease (vWD). Patients with vWD typically have low levels of vWF antigen and
activity. Because levels of vWF fluctuate in response to estrogen, stress, exercise, inflammation,
and bleeding, repeated assays may be required to establish the diagnosis.
Factor VIII levels in vWD may be low enough to prolong the activated partial thromboplastin
time (aPTT), but a prolonged aPTT is not diagnostic of vWD, and prothrombin time (PT) and a
aPTT prolongations are more often found in patients with deficiencies of humoral clotting
factors who typically have joint or muscle bleeding rather than mucocutaneous bleeding. The
exception is factor Xi deficiency, which can produce mucocutaneous bleeding and a prolonged
aPTT, found most commonly in persons of Ashkenazi Jewish descent. The most common causes
of a prolonged PT include warfarin use, vitamin K deficiency, and chronic liver disease. Rare
causes include acquired or inherited factor VII deficiency. As with other coagulation factor
deficiencies, patients with factor VII deficiency are most likely to present with mucosal, joint,
and muscle bleeding. None of these conditions is compatible with this patient’s long history of
bleeding, the nature of her bleeding, and family history. Consequently, neither the PT nor aPTT
is the appropriate next diagnostic test.
Results of the Platelet Function Analyzer-100 (PFA-100®) are expected to be prolonged in
patients with hemoglobin values below 10 g/dL (100 g/L); therefore, this test would provide no
additional information and is not indicated
Key Point
Patients with suspected von Willebrand disease should undergo von Willebrand factor and
activity assays to confirm the diagnosis.
Short Answers and Fill in the blank.
1. Most common inherited bleeding disorder
Answers to Short Answers and Fill in the blank:
1. von Willebrand disease (vWD)
Questions
Item 11.
A 34-year-old man is evaluated in the emergency department for severe bleeding following
surgical arthroscopy of the right knee 24 hours ago. The patient sustained a penetrating knee
injury 1 year ago as a result of a nail gun injury. Over the past year, he has had at least eight
recurrent episodes of hemarthroses at the site of the injury, requiring aspiration. As a child, he
experienced compartment syndrome in the left forearm after sustaining an injury. He is one of
eight siblings, and two of his four brothers have a history of epistaxis and posttraumatic
hematomas. His only medication is naproxen.
On physical examination, the temperature is normal, blood pressure is 100/55 mm Hg, pulse rate
is 120/min, and respiration rate is 22/min. His wound dressing is saturated, with fresh blood
welling from the arthroscopy sites.
Laboratory studies:
Hemoglobin
8.4 g/dL (84 g/L) (compared with 15.6 g/dL [156 g/L] preoperatively)
Platelet count
Normal
Prothrombin time
11.0 s
Activated partial thromboplastin time (aPTT)
23 s (Normal range: 25-35 s)
Which of the following is the most likely diagnosis?
(A) Acquired factor VIII inhibitor
(B) Factor V deficiency
(C) Factor IX deficiency
(D) Factor XII deficiency
Item 11
Answer: C
Educational Objective: Diagnose factor IX deficiency (hemophilia)
This patient most likely has a factor IX deficiency (hemophilia B). His bleeding history is
suggestive of a congenital X-linked bleeding disorder, most likely hemophilia B because of the
presentation in adulthood; however, it could be hemophilia A or B because the laboratory studies
for the two conditions are indistinguishable. Also suggestive of this disorder are the patient’s
normal prothrombin time (PT) and prolonged activated partial thromboplastin time (aPTT) that
fully corrects on mixing with a 1:1 ratio of normal plasma. Milder cases of hemophilia B may
remain undiagnosed until adulthood, but postoperative and traumatic bleeding may be severe.
This patient’s history of compartment syndrome is a manifestation of a bleeding diathesis.
Hemophilia A (factor VIII deficiency) and hemophilia B are X-linked hemorrhagic disorders,
with most bleeding episodes occurring in the articular spaces. Soft tissue bleding is also
common. Replacement of the deficient factor is the treatment of choice. Severe hemophilia A
and B are characterized by recurrent hemarthroses that result in chronic, crippling degenerative
joint disease unless treated prophylatically with factor replacement. Central nervous system
hemorrhage is especially hazardous, remaining one of the leading causes of death. Aspirin and
NSAIDs are contraindicated in patients with hemophilia.
Patients with an acquired factor VIII inhibitor have a normal PT and a prolonged aPTT, but the
mixing study fails to completely correct.
Factor V deficiency would be expected to produce prolongation of both the PT and the aPTT, not
just the aPTT.
Factor XII deficiency also produces a normal PT and prolonged aPTT but is not associated with
bleeding manifestations.
Key Point
Factor IX deficiency (hemophilia B) is an X-linked hemorrhagic disorder characterized by a
normal prothrombin time and prolonged activated partial thromboplastin time that fully corrects
with the mixing study.
Item 21
An 18-year-old woman is evaluated for severe menometrorrhagia of 5 years’ duration. She has
taken multiple varieties of oral contraceptive pills for 4 years to reduce the severity of her
bleeding. She also has a history of anemia and takes iron supplementation. Her mother and 16year-old sister also have menorrhagia, for which her mother had a hysterectomy at age 34 years,
and her sister takes oral contraceptive pills.
On physical examination, the blood pressure is 135/88 mm Hg, pulse rate is 90/min, and
respiration rate is 18/min. BMI is 22.
Coagulation studies are performed.
Laboratory studies following blood transfusion and estrogen therapy:
Hemoglobin
11 g/dL (110 g/L)
Activated partial thromboplastin time
29 s
von Willebrand factor (vWF) antigen assay 52% (Normal range: 50-150%)
vWF activity assay 58% (Normal range: 55-180%)
Factor VIII activity assay
80% (Normal range: 60-140%)
Which of the following is the most likely cause of her menorrhagia?
(A) Anovulatory cycles
(B) Factor XI deficiency
(C) Hemophilia A
(D) Uterine fibroids
(E) von Willebrand disease
Item 21
Answer: E
Educational Objective: Diagnose probable von Willebrand disease.
This patient’s personal and family history of mucocutaneous bleeding is suggestive of von
Willebrand disease (vWD). Although the patient’s von Willebrand factor (vWF) levels are
technically in the normal range, a diagnosis of vWD cannot be excluded because she is taking
estrogen-containing oral contraceptive pills (OCPs). Levels of vWF fluctuate, increasing in
response to estrogens, stress, exercise, inflammation, and bleeding, and diagnosis is often
difficult to establish, particularly in patients with mild disease. A patient such as this one, with a
personal and faily history of mucocutaneous bleeding who has borderline levels of vWF while
taking OCPs, can be considered to have “possible vWD.” Making a definitive diagnosis of vWD
may require testing of affected family members or requesting the patient discontinue OCPs and
remeasuring vWF levels 4 to 6 weeks later.
Anovulatory cycles are a common cause of menorrhagia in girls just past menarche but would
not be associated with borderline-low levels of vWF, nor would they be found in the patient’s
mother.
Factor XI deficiency can be associated with a personal and family history of mucocutaneous
bleeding, but the activated partial thromboplastin time (aPTT) would be expected to be
prolonged.
Hemophilia A is an X-linked disorder. Women can be affected under rare circumstances (for
example, in homozygotes, usually in cases of consanguineous parents; in women with Turner
syndrome; and in lionized carriers of factor VIII deficiency). However, in these cases, the factor
VIII level would be expected to be low and the aPTT prolonged.
Uterine fibroid tumors are rare in this age group and would be even less likely to affect the
patient’s 16-year-old sister.
Key Point
Patients with a personal and family history of mucocutaneous bleeding who have borderline-low
levels of von Willebrand factor while taking oral contraceptive pills have possible von
Willebrand disease.
Item 22
A 22-year-old woman is evaluated in the hospital for severe vaginal bleeding that developed 24
hours after an uncomplicated, normal spontaneous vaginal delivery. The patient has no personal
or family history of a bleeding disorder or menorrhagia. She underwent an uncomplicated
tonsillectomy at age 5 years. Her only medication has been a prenatal vitamin.
On physical examination, temperature is normal, blood pressure is 89/55 mm Hg, pulse rate is
120/min, and respiration rate is 24/min. She has bleeding from venipuncture sites. Pelvic
examination shows bleeding from the episiotomy suture and brisk cervical bleeding. Dilation and
curettage, packing, and resuturing are unsuccessful in stopping the bleeding.
Laboratory studies:
Hemoglobin
7.2 g/dL (72 g/L)
Leukocyte count
12,000/µL (12 x 109/L) with a normal differential
Platelet count
350,000/ µL (350 x 109/L)
Prothrombin time
11s
Activated partial thromboplastin time (aPTT)
75 s
aPTT mixing study 55 s (Normal range: 25-35 s)
Fibrinogen
345 mg/dL (3.5 g/L)
D-dimer
0.5 µg/mL (500 mg/L)
The remaining laboratory studies are normal.
Which of the following is the most appropriate treatment?
(A) Cryoprecipitate
(B) Desmopressin
(C) Fresh frozen plasma
(D) Recombinant activated factor VIIa
Item 22
Answer: D
Educational Objective: Manage acquired hemophilia.
This patient requires recombinant activated factor VIIa (rVIIa). She had an uncomplicated
vaginal delivery 24hours ago and has no bleeding history and a prolonged activated parital
thromboplastin time (aPTT) that failed to fully correct on 1:1 mixing with normal plasma. This
suggests the presence of an acquired inhibitor, most likely to factor VIII, which can develop in
the post-partum setting. rVIIa is approved for treating bleeding episodes in patients with acquired
factor VIII inhibitors. rVIIa acts to bypass the need for factor VIII by binding to the surface of
activated platelets, where it can generate factor Xa, leading to the production of a burst of
thrombin and the formation of fibrin.
Disseminated intravascular coagulation (DIC) is characterized by a microangiopathic hemolytic
anemia, low platelet counts, a prolonged prothrombin time, a low or decreasing fibrinogen level,
and an elevated D-dimer level. This patient’s normal prothrombin time, platelet count, and
fibrinogen level make DIC less likely. Consequently, fresh frozen plasma and cryoprecipitate are
not indicated.
Desmopressin is indicated in patients with von Willebrand disease (vWD), which can cause
postpartum hemorrhage. However, this patient’s lack of history of menorrhagia and absence of
bleeding with tonsillectomy make vWD less likely; therefore, desmoprssin is unlikely to be of
benefit. Additionally, although desmopressin may be helpful in patients with acquired
hemophilia who have low-titer inhibitor levels and mild mucocutaneous bleeding, it would be
unlikely to provide significant benefit in patients with this degree of hemorrhage and aPTT
prolongation.
Key Point
Recombinant activated factor VIIa is approved for treating bleeding episodes in patients with
acquired factor VIII inhibitors.
References:
1.
MKSAP 16 ISBN: 978-1-938245-00-8. (Hematology and Oncology) ISBN: 978-1938245-04-6. Item 44.
2.
Ibid. pp. 42-46.
3.
Rydz N, James PD. Why is my patient bleeding or bruising? Hematol Oncol Clin North
Am. 2012;26(2):321-344, viii. doi:10.1016/j.hoc.2012.01.002.
4.
Girolami A, Luzzatto G, Varvarikis C, Pellati D, Sartori R, Girolami B. Main clinical
manifestations of a bleeding diathesis: an often disregarded aspect of medical and surgical
history taking. Haemophilia. 2005;11(3):193-202. doi:10.1111/j.1365-2516.2005.01100.x.
5.
Hayward CPM. Chapter 130 – Clinical Approach to the Patient With Bleeding or
Bruising. In Hematology: Basic Principles and Practice, Sixth Edition by Ronald Hoffman MD,
Edward J. Benz Jr. MD, Leslie E. Silberstein MD and Helen Heslop MD . 2012.
6.
Stedman’s Medical Dictionary for the Health Professions and Nursing at a
Glance.Illustrated Seventh Edition. 2012.
7.
Hayward CPM. Diagnosis and management of mild bleeding disorders. Hematology Am
Soc Hematol Educ Program. 2005:423-428. doi:10.1182/asheducation-2005.1.423.
8.
Marcucci C, Chassot P-G, Asmis LM, Spahn DR. Hematological Risk Assessment. In
Perioperative medicine : managing for outcomes / [edited by] Mark F. Newman, Lee A. Fleisher,
Mitchell P. Fink.
9. Rote NS, McCance KL. Structure and function of the hematologic system. In Understanding
Pathophysiology, Fithh Edition, bySue E. Huether RN PhD (Author), Kathryn L. McCance RN
PhD (Author). 2011.
10. Hunt BJ. Bleeding and coagulopathies in critical care. N Engl J Med. 2014;370(9):847-859.
doi:10.1056/NEJMra1208626.
11. Girolami A, Luzzatto G, Varvarikis C, Pellati D, Sartori R, Girolami B. Main clinical
manifestations of a bleeding diathesis: an often disregarded aspect of medical and surgical
history taking. Haemophilia. 2005;11(3):193-202. doi:10.1111/j.1365-2516.2005.01100.x.