Download Bleeding Disorders Case

Bleeding Disorders Case
This 4 year old female is referred to the hematology department with a chief complaint of
acute onset of easy bruising and "rash" for 3 days. She has not had epistaxis, oral
bleeding, and gross blood in urine or stools. She has never had palpable bruises,
hemarthroses or deep muscle bleeds in the past. She has no history of fever or appetite
changes. She had upper respiratory infection symptoms approximately 2 weeks ago.
There is no travel history. She has 2 older brothers, neither of whom have had bleeding
symptoms. Family history is negative for frequent nosebleeds, oral bleeding, menorrhagia
or excessive bleeding with surgery or trauma. There is no history of malignancies, or
autoimmune disorders.
Exam: VS are normal. Height and weight are at the 50th percentile. She is a healthy
appearing, cooperative girl in no acute distress. HEENT exam demonstrates no signs of
bleeding or bruising. Heart and lung exams are normal. Her abdomen demonstrates no
hepatosplenomegaly. A diffuse petechial rash is noted on her neck, trunk, extremities and
groin. Nonpalpable ecchymoses of varying ages are present on shins and arms. Her
neurologic examination demonstrates no deficits.
CBC shows Hgb 12.8, Hct 38.5, WBC 6,000 with a normal differential. Platelet count is
low at 5,000. PT and PTT 12.0 and 32 seconds, respectively. Review of the peripheral
smear shows normal morphology of red and white blood cell lines. The platelets are
reduced in number and the majority of them are increased in size. A bone marrow
aspirate is not performed.
Bleeding Disorders(reading)
Bleeding disorders can either be inherited or acquired and are due to defects in either
primary or secondary hemostasis. While evaluating a child with a bleeding tendency, the
history and physical examination should be directed at differentiating between these. An
appropriate history can be more helpful in evaluating these children than any laboratory
test. Bruising with or without preceding trauma can be due to a defect in either primary or
secondary hemostasis although deep palpable bruises are usually due to a clotting factor
defect. Petechiae are usually due to a platelet or blood vessel defect. One should ask
about a history of mucosal bleeding (including epistaxis, oral bleeding, gastrointestinal,
genitourinary and menstrual bleeding), bleeding from injury or following procedures
such as circumcision and tonsillectomy, and deep tissue or musculoskeletal bleeding. Age
of onset, frequency and severity of each bleeding complaint should be determined and an
extensive family history and medication history should be obtained.
The child should be examined for signs of bleeding, such as petechiae, bruising, mucosal
bleeding, and oozing from venipuncture sites. Differentiate between superficial bruises
and deep palpable ecchymoses, making note of their location. Special attention should be
made to the joints and large muscle areas, looking for deep tissue bleeding.
Laboratory studies assist in confirming suspicions raised from the history and physical.
Routine screening laboratory studies should include complete blood count (CBC) with a
platelet count, prothrombin time (PT) and activated partial thromboplastin time (PTT).
Further specific testing should be performed based on the working diagnosis. These
include a PTT mixing study (which helps differentiate a factor deficiency from an
acquired inhibitor), bleeding time, factor assays, von Willebrand studies, and platelet
aggregation tests. The bleeding time is an uncommonly ordered test during which a
standardized small laceration is created on the patient's forearm and the time for the
bleeding to stop is measured and compared to standard times. This test is prolonged in
conditions of thrombocytopenia and platelet dysfunction. Platelet aggregation studies are
special studies that can be done to test the aggregation of platelets in response to several
known agents which induce platelet aggregation in vitro such as adenosine diphosphate
(ADP), epinephrine and collagen.
I. Primary Hemostasis (platelets)
. . . . A. Quantitative (thrombocytopenia)
. . . . . . . . 1. ITP
. . . . . . . . 2. Hemolytic uremic syndrome (HUS)
. . . . . . . . 3. Thrombotic thrombocytopenic purpura (TTP)
. . . . . . . . 4. Medications
. . . . . . . . 5. Marrow failure (leukemia, aplastic anemia)
. . . . . . . . 6. Platelet sequestration, consumption and dilution
. . . . B. Qualitative (poor platelet function)
. . . . . . . . 1. Inherited platelet aggregation defect
. . . . . . . . 2. Drug effect
II. Secondary Hemostasis (coagulation)
. . . . A. Congenital factor deficiency
. . . . . . . . 1. Hemophilia A and B
. . . . . . . . 2. von Willebrand disease
. . . . . . . . 3. Other factor deficiencies (rare)
. . . . B. Acquired factor deficiency
. . . . . . . . 1. Vitamin K deficiency
. . . . . . . . 2. Liver failure
. . . . C. Antiphospholipid antibody
Defects in Primary Hemostasis
Quantitative platelet disorders result in thrombocytopenia, either due to decreased bone
marrow production or increased platelet destruction.
Immune Thrombocytopenic Purpura
Immune or idiopathic thrombocytopenic purpura (ITP) is one of the most common
acquired bleeding disorders of childhood. Usually, it is a benign, self-limited disease that
occurs in previously healthy children. The typical course in an untreated child is
resolution of bleeding symptoms 3 to 10 days after diagnosis, regardless of the platelet
count and an increase in the platelet count within 1 to 3 weeks. The platelet count returns
to normal in 4 to 8 weeks in approximately half of patients and two thirds of children
have resolution by 3 months after diagnosis. By 6 months, platelet counts have returned
to normal (>150,000 per cubic mm) in 80% of patients. The remainder are defined as
having chronic ITP (1,2). Most children follow a course consistent with acute ITP, in
which the platelet counts are very low, but they recover as noted above. Adults more
commonly follow a course consistent with chronic ITP, in which the platelet counts are
usually moderately low, but the thrombocytopenia persists for long periods of time and
often for life. If patients with chronic ITP sustain significant consequences from recurrent
bleeding, a splenectomy is sometimes necessary to raise their platelet count.
ITP is an immune-mediated disorder in which circulating antiplatelet antibodies target
epitopes on the platelet membrane (1). The antibody-coated platelets are subsequently
destroyed by macrophages in the reticuloendothelial system. Children with ITP present
with sudden onset of bruising, petechiae and occasionally epistaxis. There may be a
history of a preceding viral infection or a recent live-virus immunization (1). There
should be no evidence of other disorders causing thrombocytopenia, such as systemic
lupus erythematosus or HIV infection. These children appear well except for bruises and
petechiae. A minority of patients have mucous membrane hemorrhage, such as
menorrhagia, gastrointestinal bleeding or oral blood blisters. They do not have jaundice,
pallor, or hepatosplenomegaly.
The most important laboratory assessment in the evaluation of ITP is the CBC and
peripheral blood smear. The platelet count is typically very low (<20,000 per cubic mm)
and unless there is appreciable bleeding, the hemoglobin concentration is normal as is the
leukocyte count. The peripheral smear shows normal morphology of all cell lines except
the platelets are reduced in number and tend to be large. PT and PTT are normal and do
not need to be performed. The bleeding time is predictably prolonged and unnecessary in
the evaluation of a child with ITP. When indicated by the medical history and physical
examination, evaluation for HIV, systemic lupus erythematosus, or Evan's syndrome
should be considered. Bone marrow aspiration should be considered in patients with
lymphadenopathy, hepatosplenomegaly, or other abnormalities on the CBC.
Management of ITP in a child includes education and reassurance of the child's parents.
The child's activities should be limited, and aspirin and NSAID containing medications
should not be used. Children without significant clinical bleeding may be closely
observed with CBCs once or twice weekly. Once the platelet count begins to increase, it
may be measured every 2 to 3 weeks until it returns to normal (>150,000). Once the
platelet count has normalized, recurrence is rare and follow-up platelet counts are
unnecessary (1,2). A few children with ITP have bleeding significant enough to warrant
medical management. Standard therapy options include oral or IV corticosteroids (which
block the reticuloendothelial system's destruction of antibody-coated platelets and reduce
synthesis of antiplatelet antibodies), IVIG (IV gamma globulin which inhibits Fc
receptors on phagocytes, allowing antibody-coated platelets to circulate and alters Tlymphocyte subsets and B-cell function and reduces autoantibody production), and AntiD (which is the anti-serum against the Rh(D) antigen on erythrocytes and by coating
Rh(D) positive erythrocytes, it decreases platelet destruction).
Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP)
HUS and TTP are closely related disorders caused by microvascular occlusion of
arterioles and capillaries producing ischemia of multiple organs. HUS is a combination of
thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure (4). It
occurs mostly in children and has a fairly good prognosis. TTP is characterized by a
pentad of features which include: thrombocytopenia, microangiopathic hemolytic anemia,
neurologic disturbances, renal dysfunction and fever (4). It occurs in young adults and
teenagers and carries a high mortality if unrecognized and not treated. Table 1 compares
both disorders.
Table 1: Comparison of HUS and TTP
Feature
HUS
TTP
Age
usually <3 yr
usually 3rd decade
Gender
M=F
F>M
Prodrome
infection, diarrhea
less common
Recurrence
rare
common
Diagnosis
Triad: Acute renal failure,
Pentad: CNS disturbance,
thrombocytopenia,
microangiopathic anemia.
thrombocytopenia, microangiopathic
anemia, renal dysfunction, fever.
Etiologic
factors
E. coli, Shigella gastroenteritis,
pneumococcus
Pregnancy, autoimmune disease,
malignancy, drugs.
Treatment
Renal dialysis, corticosteroids
do not help, transfuse only if
necessary.
Plasma exchange, corticosteroids,
avoid transfusions.
Prognosis
Good
Poor
A variety of drugs have been reported to cause thrombocytopenia either by drug-induced
platelet destruction or bone marrow suppression. Heparin merits special emphasis
because it is so commonly used. Heparin does not inhibit platelet function but it may
sometimes cause thrombocytopenia. There are two types of heparin-induced
thrombocytopenia (HIT). The first occurs 2 to 5 days after initiation of heparin. Platelet
counts rarely fall below 100,000 per cubic mm and normalize within 1 to 5 days. This
type is thought to result from platelet aggregation secondary to a direct heparin effect (4).
The second type of HIT occurs 3 to 15 days after the initiation of heparin (4). Platelet
counts fall below 40,000. Arterial thrombosis may occur. The mechanism is immune
mediated. Treatment involves discontinuation of heparin.
Decreased numbers of platelets result from impaired platelet production due to leukemia,
aplastic anemia or bone marrow suppression due to viral infection or drugs. These are
discussed in separate chapters. May-Hegglin anomaly is characterized by mild to
moderate thrombocytopenia and the presence of Dohle bodies in the leukocytes.
Kasabach-Merritt (giant hemangioma) syndrome is due to localized intravascular
coagulation from low blood flow through the abnormal vascular tissue and is associated
with thrombocytopenia (4). Foreign bodies in the circulation (central venous catheters
and prosthetic valves) are sites for platelet consumption. Platelet loss also results from
extracorporeal circulation and exchange transfusions. Massive plasma and blood
transfusions lead to a dilutional thrombocytopenia. Finally, platelet counts may be low as
a result of sequestration when the spleen is enlarged.
Qualitative platelet disorders (defects in platelet aggregation) are very rare. Most are
inherited as autosomal recessive traits. Patients present with bleeding similar to that seen
with thrombocytopenia. They complain of skin and mucous membrane bleeding,
recurrent epistaxis, gastrointestinal bleeding, menorrhagia, and prolonged bleeding with
injury or surgery (5). Aspirin (ASA) and non-steroidal anti-inflammatory drugs
(NSAIDs) are common causes of temporary platelet dysfunction. Laboratory evaluation
usually demonstrates a normal platelet count, prolonged bleeding time and abnormal
platelet aggregation studies. Coagulation studies (PT, PTT) are usually normal. The most
common platelet aggregation defects are described in table 2 below.
Table 2: Platelet aggregation defects
Condition
Platelet aggregation
studies
Platelet
count
Glanzmann
thrombasthenia
Abnormal to all
agonists
Normal
Bernard-Soulier
syndrome
Abnormal to
ristocetin
Decreased
Giant platelets.
Storage pool defect
(Dense body
deficiency, Gray
platelet syndrome)
Abnormal 2nd phase
of aggregation
Normal
Abnormal platelet
granules on electron
microscopy
ASA/NSAID
Abnormal to
arachidonic acid and
abnormal secondary
aggregation to ADP
and epinephrine
Normal
Drug induced enzyme
effect inhibiting platelet
granule release. This is
the most common cause
of platelet dysfunction.
Other
Defects in Secondary Hemostasis
Hemophilia
Hemophilia is an X-linked inherited bleeding disorder transmitted from female carriers to
their male children. It is due to a deficiency of factor VIII (Hemophilia A or "Classic
hemophilia") or factor IX (Hemophilia B or "Christmas disease"). Hemophilia A is more
common, occurring in 1/5000 male births while hemophilia B occurs in 1/15,000 (6).
Signs and symptoms vary depending on the severity of the hemophilia. Severity is
defined by baseline factor levels: severe <1%, moderate 1-5%, mild >5% (6,7). Children
with severe hemophilia usually present in the first year of life with a history of extensive
deep palpable ecchymoses. There may be a history of bleeding from the circumcision.
After the age of 2 years, they begin to develop spontaneous hemarthroses or deep muscle
bleeds. They can have mucosal bleeds, such as oral bleeding with procedures and
hematuria. The bleeding is usually not catastrophic. Instead, it is prolonged and
continuous without therapy. A head injury is considered an emergency since it is
potentially life threatening if not treated appropriately. Children with milder forms of
hemophilia may present later in life with a history of easy bruising or prolonged bleeding
following injury. They usually do not have spontaneous bleeding. Laboratory findings
include a markedly prolonged PTT (>100 seconds) and a decreased factor VIII or IX
activity. Other screening tests (PT, platelet count and bleeding time) should be normal.
The mainstay of therapy is replacing the deficient clotting factor with factor VIII or IX
concentrate (6,7). Both human derived and recombinant factor concentrates are available.
In the past, factor replacement carried a risk of transmission of viral infections, especially
hepatitis B and C, and HIV. This risk has been reduced with current viral inactivation
techniques and with the availability of recombinant factor. Each unit of factor VIII will
increase the factor VIII level by 2% and has an 8 to 12 hour half-life. Each unit of factor
IX will increase the factor IX level by 1% and has an 18 to 24 hour half-life (6,7). Dosing
depends on the location and severity of the bleed. In addition to factor replacement, males
with hemophilia benefit from supportive measures, physical therapy and often require
orthopedic intervention. Aminocaproic acid is an oral antifibrinolytic and can be used
adjunctively to treat mucous membrane bleeding. Mild factor VIII deficient patients may
be treated with intravenous or highly concentrated intranasal desmopressin (DDAVP)
which causes a release in endogenous factor VIII stores. These boys need to be cautioned
to avoid contact sports such as tackle football, boxing or wrestling. It is nationally
recognized that hemophilia treatment centers have improved the prognosis of patients
with hemophilia. Patients and their families have a home supply of factor and infuse
themselves promptly at the earliest sign of a bleed. Prophylaxis has been instituted in
most severely affected individuals where they infuse themselves regularly two to three
times a week and/or prior to a sports activity in order to prevent spontaneous bleeds. This
has reduced much of the chronic arthropathy in this population. Today, young people
with hemophilia can lead independent and nearly normal lives.
von Willebrand Disease
von Willebrand disease (vWD) is the most common inherited bleeding disorder. It affects
1% to 2% of the population. von Willebrand factor is a cofactor for platelet adhesion and
a carrier protein for factor VIII (8,9). The most common form is transmitted as an
autosomal dominant trait. Severity of bleeding symptoms depends on the type and
subtype. Types 1 and 3 result in quantitative defects of the von Willebrand protein (i.e.,
deficiency) while Type 2 is due to a qualitative defect in the von Willebrand protein. The
vWD types are listed in table 3.
Table 3 - von Willebrand disease subtypes
Type
Defect
Bleeding symptoms
Type 1 (common)
Quantitative: Decreased vWF
Mild
Type 2 (uncommon)
Qualitative: Normal vWF levels
2A
vWF not "sticky" enough
Variable
2B
vWF too "sticky"
Potentially severe
2N
Lacking receptor for factor VIII binding Similar to hemophilia
2M
Lacking receptor for platelet binding
Fairly mild
Type 3 (rare)
Quantitative: Absent vWF
Severe
Patients with vWD often have a positive family history of bleeding and easy bruisability
in addition to the personal bleeding history. The bleeding symptoms can be similar to that
seen with thrombocytopenia or platelet dysfunction and usually involve the mucous
membranes and patients present with complaints of recurrent epistaxis, oral bleeding with
dental care, and menorrhagia. In addition, they often have a history of easy or
spontaneous bruising and post-operative bleeding. More rarely, one may elicit a history
of gastrointestinal or genitourinary bleeding. Types 2N and 3 may also have deep tissue
bleeding, similar to the bleeding seen in moderate or severe hemophiliacs.
The most useful screening tests in patients with suspected vWD are bleeding time, PTT
and von Willebrand factor activity (ristocetin cofactor). Ristocetin cofactor is a functional
assay of the von Willebrand protein. At least one of these screening tests will be
abnormal in 97% of patients with vWD (10). Other useful studies include platelet count,
von Willebrand factor (vWF) antigen and factor VIII activity. Once the diagnosis of
vWD is made, the vWF multimeric assay and platelet aggregation studies will determine
the type of vWD. With deficient or defective von Willebrand factor, there will be
abnormal platelet aggregation to ristocetin. Other platelet aggregation studies should be
normal.
It is important to keep in mind that vWF is an acute phase reactant and therefore, studies
for vWD can be affected by cigarette smoking, stress, exercise, pregnancy,
corticosteroids, birth control pills, etc. In addition, people who are blood group O have a
lower normal range for vWF antigen and ristocetin cofactor activity. When there is a
strong suspicion that a patient has vWD, the laboratory evaluation may need to be
repeated up to 3 times.
In most cases of vWD the bleeding symptoms are quite mild, and therapy includes
education and measures for local control of bleeding. Aminocaproic acid is useful in
treating mucous membrane bleeding. Desmopressin (DDAVP) causes a release of factor
VIII and vWF from storage sites and is useful in treating bleeding symptoms in patients
with mild (type 1) vWD. Patient with severe forms of vWD (type 3) or a qualitative
defect of the vWF (types 2A, 2B, 2N) may need replacement with Humate-P (a factor
VIII product containing vWF) (8,9). Once diagnosed and followed and treated in a
comprehensive hemophilia treatment center, people with vWD can lead normal lives.
Other Factor Deficiencies
Deficiencies in other fluid factors are much more rare than deficiencies in factors VIII,
IX or vWF. Factor XI deficiency presents with variable bleeding and a prolonged PTT.
Bleeding symptoms do not correlate with the factor level (11). It is more common in the
Ashkenazi Jewish population. Deficiencies of the contact factors (factor XII-Hageman
factor, high molecular weight kininogen, and prekallikrein) are associated with a
significantly prolonged PTT without bleeding symptoms (11). Deficiencies of factors II,
V, VII, X and XIII are very rare. For most of these, bleeding symptoms occur in those
whose factor levels are <5% to 10% (11). Factor VII deficiency should be considered
with isolated prolongation of the PT. Factors II, V, and X are common pathway factors
and present with prolongation of both PT and PTT. Factor XIII deficiency is associated
with bleeding from the umbilical stump and intracranial hemorrhage with a normal PT
and PTT. It is only symptomatic in patients whose level is <1%. Treatment consists of
replacement of the deficient factor with fresh frozen plasma or, if available, specific
factor concentrate (11).
Acquired Defects of Secondary Hemostasis
Vitamin K is needed for the synthesis of factors II, VII, IX and X. Vitamin K is vital to
the carboxylation of glutamic acid residues which is needed for the calcium and
phospholipid-dependent activation of these factors (1). The most common circumstance
in which vitamin K deficiency leads to bleeding is hemorrhagic disease of the newborn.
Without vitamin K supplementation, significant GI and cutaneous hemorrhage may
develop within a few days (1). After the newborn period, vitamin K is absorbed from the
GI tract. Deficiency may then result from nutritional deficits, malabsorption, or alteration
in intestinal flora. Treatment must be directed at the underlying disorder and vitamin K
supplementation.
Decreased synthesis of coagulation proteins occurs in severe liver disease. Abnormalities
in the liver's capacity to synthesize one or more clotting factors may result in problems
with hemostasis. Treatment involves replacement of the decreased factor(s) with fresh
frozen plasma. Liver disease may also lead to portal hypertension and platelet
sequestration in the spleen.
Disseminated intravascular coagulation (DIC) occurs in patients who are critically ill and
therefore, rapid diagnosis is essential. Fever, hypotension, acidosis, oliguria, or hypoxia
may be present. In addition, petechiae, purpura, and oozing from wounds and
venipuncture sites may develop. Although not always clinically evident, microvascular
and large vessel thrombosis may occur. The platelet count is typically decreased due to
consumption and platelet destruction. The PT and PTT are prolonged from depletion of
factors V, VIII, IX, and XI. Fibrinogen is decreased. Fibrin degradation products and the
D-dimer assay are increased. The mainstay of therapy is to treat the underlying disease.
However, this may not always be enough to correct serious bleeding or thrombosis.
Additional therapy consists of replacing clotting factors and platelets and possibly the use
of heparin and antifibrinolytic agents .
Circulating inhibitors such as heparin and the lupus anticoagulant (antiphospholipid
antibody) often lead to abnormalities in screening coagulation laboratory values. These
cause a prolonged PTT which is not corrected with 1:1 dilution with normal plasma (the
PTT mixing study). If the patient has a factor deficiency such as hemophilia, adding
normal plasma to the patient's plasma, will partially correct the factor deficiency and the
PTT will normalize. If the PTT does not normalize by adding normal plasma, this implies
that an anticoagulant is present in the patient's plasma. The term “lupus anticoagulant” is
misleading because it can occur in many clinical settings other than in SLE and the
anticoagulant effects are only observed in vitro with prolongation of the PTT, but not
with excessive bleeding. Instead, when it occurs in adults, it may be associated with
spontaneous abortion, and thromboembolism. In the pediatric population, it usually
occurs in otherwise healthy children, often following a viral illness and is transient with
rare clinical sequelae (1).
A summary of laboratory studies for bleeding disorders is listed below. Routine tests are
commonly ordered by non-hematologists. Special tests are not ordered routinely and are
only ordered (most commonly by hematologists and other subspecialists) when a
bleeding disorder is highly suspected.
Tests for:
Abnormal in:
Platelet count
Disorders of platelet
quantity
ITP, HUS, TTP, thrombocytopenia due to
bone marrow suppression, platelet
consumption.
PT
Extrinsic and common
coagulation pathway
(factors I, II, V, VII, X)
Factor deficiency (I, II, V, VII, X), liver
failure, vitamin K deficiency, coumadin,
warfarins.
PTT
Intrinsic and common
pathway (factors I, II, V,
X, VIII, IX, XI, XII)
Factor deficiency (I, II, V, X, VIII, IX, XI,
XII), heparinization, circulating
anticoagulants, vWD
PTT mixing
study
Circulating anticoagulants
PTT corrects with factor deficiency, but it
does not normalize with circulating
antibodies/anticoagulants
Bleeding time
Platelet function
ASA, NSAIDs, platelet function disorders
(see table 2), vWD
Platelet
aggregation
Platelet function
ASA, NSAIDs, platelet function disorders
(see table 2), vWD
Ristocetin
cofactor
vWF function
vWD
vWF antigen
vWF quantity
vWD
vWF
multimeric
assay
Defines type of vWD
vWD
Routine
tests:
Special tests: