Assessing and Treating Disorders of Primary Hemostasis - The Clinical Advisor

Assessing and treating disorders of primary hemostasis - The Clinical Advisor
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Danielle Kruger, PA-C, MS Ed SIGN UP FOR FREE E-NEWSLETTERS

November 10, 2017
Assessing and treating disorders ✔

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of primary hemostasis ✔
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Red blood cells in a fibrin clot.
Each month, The Clinical Advisor makes one

new clinical feature available ahead of print. Don't forget to take
the poll. The results will be published in the next month's issue.
Disorders of primary hemostasis have a vast differential

diagnosis and may present in a variety of medical, obstetric,
surgical, and critical care settings. When evaluating patients with
thrombocytopenia or evidence of qualitative platelet dysfunction,
clinicians must determine the significance of the platelet count
as well as the risk for bleeding, thrombosis, and other potential
complications. In one study, thrombocytopenia was observed in
approximately 1% of adult inpatients in acute care hospitals.1
Surgical bleeding is of concern when platelet counts are
<50,000/µL, or <100,000/µL in patients undergoing some high-
risk cardiac, orthopedic, or neurosurgical procedures.2 In
intensive care units (ICUs), thrombocytopenia develops in 13%
to 44% of patients during their admission.2 Clinicians must be
https://www.clinicaladvisor.com/features/treating-disorders-primary-hemostasis/article/706749/[2018-04-13 08:11:13]
familiar with the conditions leading to disorders of primary

hemostasis because swift, accurate identification of the
underlying cause is crucial for appropriate management. This
article reviews disorders of primary hemostasis that range in
severity from benign to life-threatening, focusing on
pathophysiology, distinguishing features, diagnostic assessment,
and treatment.
Physiology of primary hemostasis
Megakaryocytes, which are derived from hematopoietic stem cell

precursors in bone marrow, form and release platelets; these
circulate in the blood for 8 to 10 days before they are removed
by hepatic or splenic macrophages. The concentration of
circulating platelets is normally 150,000 to 450,000/µL. A platelet
count <150,000/µL traditionally defines thrombocytopenia;
however, 2.5% of the population has a baseline concentration
<150,000/µL.2 Clinicians should repeat the platelet count for
trending; if the count is stable for 6 months, it is usually a normal
variant.1 Normal vascular endothelium opposes thrombosis by
resisting interactions with platelets and coagulation factors.
Damage to vessels exposes collagen fibrils that trigger a series
of adhesive reactions, allowing platelets to bind to the
subendothelium and to other platelets to form a temporary
hemostatic plug. A large protein, von Willebrand factor (vWF), is
synthesized, stored in, and secreted by vascular endothelial
cells following stimulation. Plasma vWF binds platelets to the
subendothelial collagen via its platelet glycoprotein Ib complex.
Platelets also have receptors that bind directly to collagen.
Normal engagement of these receptors enhances platelet
activation and signals extension of the plug. Activated platelets
release pro-aggregatory granules containing adenosine 5'-
diphosphate (ADP) and thromboxane A2 to amplify recruitment
and aggregation. Fibrinogen and vWF also bind activated
platelets together via the platelet glycoprotein IIb/IIIa complex.
The hemostatic plug stops bleeding in a superficial wound.
Initiation of the clotting cascade triggers secondary hemostasis,
which culminates in the formation of a fibrin mesh that cross-
links, reinforces, and further stabilizes the platelet plug. As a
carrier protein for clotting factor VIII, vWF also functions in
secondary hemostasis by protecting this factor from
degradation.
Manifestations
of disorders of Which of the following bleeding disorders
primary and do you encounter most frequently?

secondary
hemostasis Von Willebrand disease
Platelets play an Idiopathic thrombocytopenic

essential role in purpura
preserving
Thrombotic thrombocytopenic
vessel wall
purpura
integrity.
Deficiency or
dysfunction of
VOTE
platelets cause
defects in View Results
primary
hemostasis,
characterized by superficial mucocutaneous bleeding and a
prolonged bleeding time. Petechiae result from capillary bleeding
and are likely to develop on dependent body regions.
Confluence of petechiae results in the formation of purpura,
which is “dry” when located on the skin and “wet” when located
on mucous membranes. Wet purpura signifies potentially more
serious hemorrhage.2 The common bleeding manifestations of
primary hemostasis disorders (Table 1) occur frequently in many
of the disorders discussed in this review. Because the normal
values for platelets are >150,000/µL, the blood has a large
protective reservoir. Mild thrombocytopenia is defined by platelet
levels of 100,000 to 150,000/µL, moderate thrombocytopenia by
levels of 50,000 to 100,000/µL, and severe thrombocytopenia by
levels <50,000/µL. Significant spontaneous bleeding usually
does not occur until platelet counts are <10,000 to 20,000/µL.1
Severe thrombocytopenia confers a greater risk for bleeding, but
correlation between the platelet count and risk for bleeding
varies with the underlying condition. Comparatively, clotting
factor deficiency or dysfunction results in disorders of secondary
hemostasis and may cause delayed, deep, or prolonged
bleeding. Bleeding into the central nervous system (CNS),
hemarthrosis (bleeding into the fingers, wrists, knees, feet, and
spine), deep muscle hematomas, or retroperitoneal bleeding
usually indicates a clotting factor disorder. Clinically, no specific
type, location, or quantity of bleeding is certain to differentiate a
primary from a secondary disorder of hemostasis, and both can
be severe, even life-threatening. Laboratory testing will reveal a
prolonged bleeding time with or without thrombocytopenia in a
disorder of primary hemostasis; disorders of secondary
hemostasis are characterized by prolongation of the partial
thromboplastin time (PTT) with or without prolongation of the
prothrombin time (PT), depending on the clotting factors

affected. In disorders of secondary hemostasis, the bleeding
time and platelet count will be normal. Disorders of secondary
hemostasis are outside the scope of this article but may be
discussed in the differential diagnoses as appropriate.
Click to enlarge
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History and physical examination
The history and physical examination are imperative to guide the

differential diagnosis and focus the laboratory assessment.
Conduct a full mucocutaneous survey to search for signs of
platelet dysfunction, and carefully assess the patient for
hepatosplenomegaly, lymphadenopathy, and/or signs of
thrombosis because the presence of these abnormalities
influences the workup. Inquire about easy bruising or excessive
bleeding, determine the location and duration of bleeding and
whether it occurs spontaneously or after trauma (immediate vs
delayed), and assess for evidence of volume loss or anemia.
Extensive bruising or bruising in unusual locations where trauma
is less likely (trunk, inner arms, thighs) is suspect. Obtain
previous platelet counts if possible to determine if the level is
stable or decreasing. An acute drop in the platelet count of
>50%, even if the count is still within normal range, may herald a
https://www.clinicaladvisor.com/features/treating-disorders-primary-hemostasis/article/706749/2/[2018-04-13 08:11:52]
severe disorder and requires close follow-up.2 Lifelong bleeding

or a family history of a bleeding disorder may indicate a familial
or congenital disorder. Congenital platelet defects are strongly
associated with consanguinity. Bleeding should not be
overlooked in the elderly because age-related changes in
hemostasis parameters (shortened bleeding time and PTT;
increased levels of factors II, VIII, and X; and decreased levels
of antithrombin III) favor thrombosis, not bleeding. Aspirin,
nonsteroidal anti-inflammatory drugs (NSAIDs), and
anticoagulants are common causes of bleeding or factors that
exacerbate bleeding in the elderly. Clinicians may use a
validated, objective bleeding score, such as the one derived
from the Condensed MCMDM-1 VWD Bleeding Questionnaire,3
which grades the worst episode for each of the following:
epistaxis; cutaneous manifestations; bleeding from minor
wounds or the oral cavity; gastrointestinal bleeding; bleeding
following tooth extraction or surgery; menorrhagia; postpartum
hemorrhage; muscle hematoma; hemarthrosis; and CNS
bleeding.4,5 The higher the bleeding score, the greater the
likelihood of a bleeding disorder. In von Willebrand disease
(vWD), the most common bleeding disorder, a score >4 has a
sensitivity of 100% and a specificity of 87%, with a positive
predictive value of 0.2.5 Uneventful molar tooth extraction is
unlikely in a patient with a severe bleeding disorder.6
Assess for past medical history and for underlying diseases or

their risk factors, particularly the following:
Autoimmune and connective tissue disorders: systemic lupus

erythematosus, rheumatoid arthritis, antiphospholipid syndrome
Blood disorders and/or malignancy: leukemia, lymphoma,

myeloproliferative disorders
Infections: human immunodeficiency virus (HIV) infection; hepatitis

A, B, or C; disease caused by cytomegalovirus; other viral or
rickettsial disease
Recent vaccinations; medication use (prescribed, over-the-counter,

and alternative medications)
Pregnancy status, recent transfusion, surgery or organ transplant
Recent travel (malaria, rickettsial infection, leptospirosis, dengue or

viral hemorrhagic fever)
Alcohol and drug use, liver or kidney disease
A variety of infections may induce thrombocytopenia via

immune-mediated platelet destruction, bone marrow
suppression, or platelet consumption. In many viral infections
(eg, rubella; mumps; varicella; infection with parvovirus, Epstein-
Barr virus, or cytomegalovirus), thrombocytopenia is an
incidental finding and spontaneously resolves with recovery. In
some chronic infections, however, such as those caused by
Helicobacter pylori, HIV, or hepatitis C virus (HCV), the
thrombocytopenia may persist.2 Adults with the new onset of
isolated thrombocytopenia should be screened for these chronic
conditions. In many vector-borne diseases (eg, malaria,
babesiosis, brucellosis, and anaplasmosis), thrombocytopenia is
part of the clinical constellation, and parasites may be seen on
peripheral blood smear.
Clinicians should know the mechanism and duration of action of

common medications that affect platelet function. Aspirin
irreversibly inactivates cyclooxygenase in platelets, and the
effect lasts for the lifetime of the platelets. Bleeding time
generally normalizes within 3 days after the discontinuation of
aspirin. NSAIDs competitively inhibit cyclooxygenase, and the
effect is related to the drug half-life, usually 1 day. Clopidogrel
irreversibly inhibits the P2Y12 ADP receptor on platelets,
impairing the activation of platelets and cross-linking of fibrin.
The bleeding time gradually returns to baseline within about 5
days after the discontinuation of clopidogrel. Anticoagulants
(heparin, warfarin, dabigatran, apixaban, rivoraxaban) and
antiplatelet agents increase the tendency for bleeding and impair
hemostasis at sites of hemorrhage. This is particularly important
in the management of victims of head trauma. A strong index of
suspicion is required in managing mild head trauma in patients
treated with anticoagulants to minimize the risk for missed
intracranial bleeding.
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Alcohol abuse may cause thrombocytopenia through direct bone

marrow toxicity, nutrient deficiencies, or hypersplenism. Binge
drinking may precipitate severe thrombocytopenia, particularly in
those with alcoholic liver disease.6 Deficiency of the nutrients
required for hematopoiesis (folate, vitamin B12, copper)
secondary to malnutrition, veganism, or bariatric or
gastrointestinal surgeries usually induces pancytopenia, but
isolated thrombocytopenia may be seen.2 Similarly, clinicians
will see thrombocytopenia in bone marrow disorders
(myelodysplastic syndromes, infections, sepsis, or infiltrative
disease) in which pancytopenia is expected. Classification of
thrombocytopenia as an isolated blood cell deficiency or as part
of a constellation of pancytopenia is imperative in guiding the
differential diagnosis. Uremia is a common cause of qualitative
platelet dysfunction and is related to several dialyzable platelet-
inhibitory factors that cause the bleeding time to be very
prolonged. Gastrointestinal bleeding is the most frequent
bleeding symptom, and vigorous dialysis is used to treat the

manifestations.
Clinicians may also generate a differential diagnosis for platelet

disorders by categorizing the mechanism of platelet loss or
dysfunction (Table 2).
Click to enlarge
Diagnostic testing
The first step in the assessment of primary hemostasis disorders

is a review of the platelet count, bleeding time, PT, and PTT, in
addition to a careful examination of the peripheral blood smear.
Some authors suggest that the basic laboratory evaluation
should also include liver and renal function tests, a coagulation
panel with D-dimer, and measurement of the lactate
dehydrogenase (LDH) level. Historically, bleeding time was
quantified by measuring the hemostasis time in a fresh,
superficial cut to the volar forearm. This test is unreliable and its
use discouraged; it has largely been replaced by objective
closure time assays such as the PFA-100 (Platelet Function
Analyzer). Prolonged bleeding time indicates a disorder of
primary hemostasis. The platelet count will then determine if the
disorder is a qualitative dysfunction (the patient has normal
platelet counts) or a quantitative dysfunction (thrombocytopenia
is present). The bleeding time is generally prolonged with
6
platelet counts <75,000/µL. Platelet aggregation tests can

distinguish disorders of platelet function and are discussed
below together with the relevant diseases. In disorders of
secondary hemostasis, such as hemophilia, the bleeding time is
usually normal.
The PT and PTT may be prolonged in patients with a clotting

factor deficiency or dysfunction. The PT evaluates the activity of
the extrinsic and common pathway factors of the clotting
cascade and is prolonged in patients with a deficiency of these
factors, most notably factor VII. The PTT evaluates the activity of
the intrinsic and common pathway clotting factors; hemophilia,
for example, will cause prolongation of the PTT, but the PT will
be normal. In some coagulopathies, multiple clotting factors are
consumed, prolonging both the PT and PTT.
The peripheral blood smear may show morphologic

abnormalities relevant to an underlying diagnosis. If
thrombocytopenia is due to platelet destruction, large or giant
platelets may be seen in addition to platelets of normal size.
Fragmented red blood cells (schistocytes) suggest thrombotic
microangiopathy, and teardrop-shaped cells (dacryocytes)
suggest myelofibrosis. Blast cells are seen in acute leukemia,
atypical lymphocytes in various viral infections, and rouleau
formation in multiple myeloma. Clinicians should consider that
conditions such as bone marrow failure and acute leukemia
rarely present with isolated thrombocytopenia. Bone marrow
analysis is reserved for patients with thrombocytopenia of
unclear etiology, an atypical or a prolonged course, suspected
malignancy, or a worrisome abnormality (hepatosplenomegaly,
lymphadenopathy, or pancytopenia). A normal or increased
number of megakaryocytes on bone marrow analysis
accompanied by large platelets in the peripheral blood suggests
that thrombocytopenia is due to peripheral platelet destruction
and that marrow activity is normal or compensatory. A
decreased number of megakaryocytes and decreased bone
marrow cellularity suggest bone marrow failure or aplastic
anemia.
How swiftly a subsequent evaluation should take place depends

on the patient's presentation and platelet count. If the patient is
symptomatic with acute bleeding or the level of
thrombocytopenia confers a high risk for bleeding, an
assessment should be performed immediately. Otherwise,
outpatient testing can occur over 1 to 2 weeks, with the patient
counseled that he or she should return immediately or report to

an emergency department if any changes in clinical status or
bleeding occur. Patient education is imperative in the
management of congenital platelet disorders or moderate to
severe thrombocytopenia. Mucocutaneous bleeding is common,
but serious hemorrhage requires immediate treatment, and
clinicians should review a plan of action with patients. Patients
should avoid medications that interfere with platelet function
(aspirin, NSAIDs, ginko biloba) and should not engage in
extreme athletics (football, boxing, rugby, martial arts). Women
with severe menorrhagia may benefit from hormonal
suppression of the menses.
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Differential diagnosis of disorders of primary hemostasis
Von Willebrand Disease. vWD, the most common inherited

bleeding disorder, is caused by a deficiency or qualitative
abnormality of vWF. vWD affects about 1 in 1000 persons6 or
0.5% to 1.6% of the population in Western countries.7 It has an
autosomal-dominant or autosomal-recessive inheritance and is
equally distributed between the sexes. vWD results in defective
platelet adhesion to the vascular subendothelium and may lead
to the degradation of coagulation factor VIII in the circulation.
Manifestations vary, with bleeding that ranges from mild to life-
threatening. Patients have bleeding manifestations (Table 1)
with normal platelet counts and a prolonged bleeding time.
vWD is classified as follows: partial quantitative deficiency (type

1: 60%-80% of cases per Western data distribution), qualitative
dysfunction (type 2: 7%-30% of cases), and total deficiency (type

3: 5%-20% of cases).7 Patients should be at optimal baseline for
laboratory testing because stressors (illness, anxiety, recent
exercise, acute inflammation) and estrogen (pregnancy and oral
contraceptives) may transiently elevate vWF and factor VIII
levels.5 Accurate subtyping of vWD requires laboratory
investigations including, but not limited to, quantitative vWF
antigen (vWF:Ag) level, vWF ristocetin cofactor activity
(vWF:RCo), and factor VIII levels. The vWF:RCo measures the
ability of plasma to agglutinate platelets in the presence of
ristocetin, which is proportional to the hemostatic activity of vWF.
Defective aggregation with ristocetin is the characteristic
abnormality in vWD. Levels of vWF:RCo <30 IU/dL are
designated as definitive for vWD, although some patients with
type 2 vWD have higher levels.5 A very simplified analysis of the
variables used to determine the type of vWD appears in Table 3.
In type 1 vWD, the plasma vWF level (vWF:Ag) is low but
sufficient to mediate some platelet adhesion (vWF:RCo) and
stabilize factor VIII levels. Type 1 vWD is asymptomatic and may
result in relatively mild bleeding symptoms. Type 3 vWD is
characterized by undetectable vWF:Ag and vWF:RCo and factor
VIII levels usually <10 IU/dL7 with prolonged PTT and risk for
bleeding indistinguishable from that of hemophilia A. Type 2
vWD is subdivided into four variants (2A, 2B, 2M, 2N) on the
basis of specific defects that impair platelet adhesion or factor
VIII binding. In-depth factor ratios, collagen binding studies,
mutation analysis, and inhibitor assays are required to
distinguish the type 2 vWD subtypes.
Click to enlarge
For patients with type 1 vWD, the preferred prophylaxis in

anticipation of minor surgery or dental procedures is intravenous
or intranasal desmopressin (DDAVP), which stimulates the
release of vWF from endothelial cells. A trial dose of DDAVP is

given before anticipated use to determine responsiveness.
Therapy should achieve a vWF:RCo level >30 IU/dL, preferably
>50 IU/dL, and DDAVP should be discontinued 2 to 3 days after
the procedure to prevent tachyphylaxis.5,6 Most patients with
type 1 vWD respond to DDAVP, but if the response is
inadequate, vWF concentrates should be used. For severe
bleeding or prophylaxis before major surgery, patients receive
vWF concentrates or cryoprecipitate. The target VWF:RCo level
is >100 IU/dL; levels >50 IU/dL should be maintained for at least
7 to 10 days.5 Factor VIII levels often rise following the infusion
of vWF concentrate and remain elevated for about 40 hours,
reflecting the half-life of vWF.6
Bernard-Soulier syndrome and Glanzmann thrombasthenia. If

vWD is ruled out, additional aggregation tests can define the
platelet defect in qualitative platelet disorders. Bernard-Soulier
syndrome (BSS) and Glanzmann thrombasthenia are rare,
autosomal-recessive congenital disorders associated with a
history of familial consanguinity and may cause lifelong bleeding
manifestations (Table 1). In BSS, a molecular defect alters the
platelet glycoprotein complex Ib/IX/V, preventing the normal
adhesion of platelets to vWF and to ristocetin, although the
platelets aggregate normally in response to other agonists (ADP,
collagen, epinephrine). Patients have a prolonged bleeding time
and more severe bleeding than expected for the mild
thrombocytopenia associated with the condition. Giant
circulating platelets are seen on peripheral smear. The severity
of bleeding in BSS varies; the prognosis is related to the severity
of the disease, which may change over time in response to
hormones and aging.8 Glanzmann thrombasthenia results from
deficiency or dysfunction of the platelet glycoprotein IIb/IIIa
complex. Platelets can adhere to exposed subendothelium and
aggregate with ristocetin but have a limited ability to form platelet
microthrombi without the ability of this receptor to bind vWF and
fibrinogen. Typically, aggregation tests show poor aggregation to
ADP, epinephrine, collagen, and thrombin. Absent or severely
reduced platelet aggregation leads to a prolonged bleeding time
and severe mucocutaneous bleeding despite the normal
numbers and size of platelets. In cases of severe bleeding,
platelet transfusions are usually effective, but the benefit-to-risk
ratio should be evaluated. Repeated exposure to normal
platelets in conditions in which platelet glycoprotein is absent
(BSS or Glanzmann thrombasthenia) can result in the
development of autoantibodies to the missing proteins. This
renders subsequent transfusions of normal platelets ineffective.
To minimize sensitization, blood products should have few or no

leukocytes.8 Bone marrow transplant has been used in rare
cases of serious, repetitive bleeding.
Idiopathic thrombocytopenic purpura. The two most common

causes of isolated thrombocytopenia are idiopathic
thrombocytopenic purpura (ITP) and drug-induced
thrombocytopenia (DIT).1 In ITP, platelet autoantibodies
(immunoglobulin G, or IgG) to the target of the platelet
glycoprotein IIb/IIIa complex are produced. Once tagged, the
platelets are damaged, trapped in the spleen, and removed from
the circulation. Additionally, antibodies may interact with
megakaryocytes in bone marrow, suppressing thrombopoiesis.
ITP commonly occurs in persons with other autoimmune
disorders and in patients with chronic HIV or HCV infection. All
adult patients with newly diagnosed ITP should undergo
screening for HIV and HCV infection.9 The acute, self-limited
form of ITP has no gender predilection, is usually observed in
healthy children (5/100,000 persons6) 3 to 5 years of age, and
may follow a viral upper respiratory infection. The chronic form of
ITP occurs in adults 20 to 50 years of age (3/100,000-5/100,000
persons6), has an insidious onset, often persists for longer than
6 months, and has a female predilection. Bleeding
manifestations (Table 1) vary depending on the platelet count.
ITP usually causes no constitutional symptoms (weight loss,
bone pain, night sweats), lymphadenopathy, or
hepatosplenomegaly. The presence of splenomegaly or these
other findings suggests another condition. Abdominal ultrasound
may support ITP by ruling out chronic liver disease with
hypersplenism and the presence of organomegaly or abdominal
lymphadenopathy.1 Peripheral blood smear will show giant
platelets reflective of thrombopoietin-induced bone marrow
stimulation, and antiplatelet IgG assays are about 90% specific
for ITP.1 The American Society of Hematology (ASH) guidelines
consider bone marrow studies unnecessary regardless of age in
patients with typical features of ITP.
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Overall, >80% of untreated children exhibit spontaneous

remission within 2 to 8 weeks.10 The rest have a course similar
to that of individuals with adult-onset, chronic ITP. In children,
factors associated with the development of chronic ITP include
the following: female gender, age >11 years at onset, lack of
precedent infection/vaccination, insidious onset, presence of
antinuclear antibodies, and treatment with intravenous
immunoglobulin (IVIG) plus steroids vs IVIG alone.10 The ASH
guidelines specify that children with mild mucocutaneous
bleeding require only observation, regardless of the platelet
count. In children who require therapy, a single dose of IVIG or a
short course of corticosteroids is first-line treatment. There is no
evidence supporting the benefit of a prolonged course of
steroids rather than very brief courses in children.9 IVIG is
preferred over steroids if a rapid increase in the platelet count is
desired, although the combination of IVIG with high-dose
dexamethasone is synergistic in cases of imminent
hemorrhage.6 The risk for intracranial hemorrhage in children

with ITP is minimal (<0.1%), and intracranial hemorrhage
generally occurs with platelet counts <20,000/µL.6 Platelet
transfusions are used supportively if the platelet counts are
<20,000/µL. Anti-D immunoglobulin (anti-D) is first-line treatment
in Rh-positive children with an intact spleen, but the Food and
Drug Administration (FDA) cautions about risk for severe
hemolysis, and anti-D should not be used if post-hemorrhagic
anemia or autoimmune hemolysis is present. Children with
refractory ITP and significant or persistent bleeding may be
candidates for rituximab, high-dose dexamethasone, or
splenectomy. Because spontaneous remission is so common,
splenectomy should be avoided in children younger than 6 years
of age because of future risk of severe sepsis.6 The ASH
guidelines recommend splenectomy only if a child has had ITP
for longer than 1 year with bleeding and platelet counts <30,000/
µL.
Only 2% of adults with ITP have a spontaneous remission, but

60% to 90% respond to first-line therapy.10 Adults should be
treated when the platelet counts are <30,000/µL, or higher in
those with active bleeding or a risk for bleeding (eg, peptic ulcer
disease, hypertension). In adults, longer courses of steroids are
preferred over shorter courses or IVIG.9 IVIG may be paired with
steroids if a rapid rise in platelets is required. Anti-D is as
effective as IVIG in Rh-positive adults with an intact spleen, and
either may be used as first-line therapy in adults if steroids are
contraindicated. Second-line therapies for adults include
splenectomy, rituximab, thrombopoeitin receptor agonists, or
more potent immunosuppression. The platelet response to
thrombopoeitin receptor agonists (eltrombopag) averages 10 to
15 days; thus, they are unlikely to replace steroids or IVIG.
Severe ITP with platelet counts <5000/µL is associated with fatal
hemorrhages in the brain and internal organs. Elderly patients,
those with refractory disease or a previous history of
hemorrhage, and patients with concomitant bleeding disorders
(hemophilia, uremia) are at higher risk for life-threatening
hemorrhage.6
Drug-induced thrombocytopenia. In DIT, drug-dependent

antibodies against platelet glycoprotein epitopes form, induce
the immune-mediated destruction of platelets, and impair
thrombopoiesis. DIT is a misnomer because the “drug” may be a
prescribed or over-the-counter medication, herb, food, beverage,
or other substance (eg, walnuts, cow's milk, cranberry juice,
1,11
tonic water). This exposure variability can make it difficult to

distinguish DIT from ITP. A database of DIT associations can be
found at http://www.ouhsc.edu/platelets/ditp.html. Patients
usually present with moderate to severe thrombocytopenia
(<50,000/μL) and associated bleeding manifestations (Table 1).
DIT usually occurs within 2 to 3 days (sometimes within hours)
after a previously taken drug has been taken or within 1 to 2
weeks of daily exposure to a new drug. Once the drug is
discontinued, thrombocytopenia resolves in 5 to 10 days. In
patients exposed to a single drug and with no other explanation
for thrombocytopenia, recovery after drug discontinuation
provides empiric evidence of DIT; recurrent thrombocytopenia
following re-exposure to the drug is confirmatory. Recurrent,
symptomatic thrombocytopenia with recovery within days, even
in the absence of specific treatment, should prompt investigation
of DIT.1 Many laboratory methods can detect the presence of
drug-dependent antiplatelet antibodies.
Heparin-induced thrombocytopenia (HIT), a special case of DIT,

is a clinical emergency that occurs in 0.5% to 5% of heparin-
treated patients and approximately 1 in 5000 hospitalized
patients. HIT accounts for <1% of cases of thrombocytopenia in
the ICU.1,12 In HIT, IgG antibodies form a complex with platelet
factor 4 to activate platelets, alter endothelial cells, and increase
thrombin generation. Although ITP and usually DIT may lead to
bleeding complications, HIT paradoxically induces a
hypercoagulable state. Early identification is paramount because
thromboembolic complications develop in about 50% of cases,
most commonly deep vein thrombosis and pulmonary
embolus.12 HIT should be suspected in any patient who while on
heparin therapy has a >50% decrease in the platelet count from
baseline, particularly if the onset is 5 to 10 days after exposure
or if hypercoagulability develops. Thrombocytopenia is usually
moderate, with median platelets counts at 50,000 to 80,000/µL
and nadir counts rarely <20,000/µL.1,13 Two risks for HIT include
the administration of unfractionated heparin rather than low-
molecular-weight heparin (LMWH; incidence of HIT is 10 times
higher12) and the administration of heparin during or after major
surgery. In about 30% of cases, HIT has an acute onset.1 These
patients usually received heparin within the previous 3 months
and may have circulating platelet factor 4 antibodies. Pre-
existing antibodies may also cause anaphylactoid reactions
within 30 minutes of the intravenous bolus. Clinicians should
review platelet counts on days 5, 7, and 9 following the initiation
of heparin or following major surgery while the patient is on
heparin to monitor for HIT. Notably, up to 20% of cases of
thrombosis occur before or during the drop in the platelet count

and may not be preventable.12 Clinicians can use clinical scoring
systems such as the 4 T's: thrombocytopenia, thrombosis
(venous and arterial thrombosis, necrotic skin lesions at heparin
injection sites), timing, and exclusion of other causes of
thrombocytopenia to estimate the probability of HIT. Patients
with intermediate- or high-probability scores should discontinue
heparin and start argatroban, the direct thrombin inhibitor
approved for the treatment of HIT.12 Duplex ultrasound can be
used to evaluate for deep venous thrombosis, and platelet factor
4–heparin IgG immunoassays aid in confirmation.
Thrombotic thrombocytopenic purpura. Thrombotic

thrombocytopenic purpura (TTP) is a rare, life-threatening
disorder in which platelet microthrombi occlude the
microvasculature, causing ischemia in the brain, kidneys, heart,
and other organs. TTP is initiated by ultra-large precursors of
von Willebrand protein that are usually cleaved to normal size by
plasma enzyme ADAMTS13. Inhibition of this enzyme by an
autoantibody or toxin accounts for acquired forms of TTP,
whereas chronic or recurrent episodes suggest a congenital
deficiency. The ultra-large hyperactive multimers remain
attached to the endothelial cell surface and induce platelet
aggregation and consumption. Platelet and hyaline thrombi with
complete or partial blood vessel occlusion are the
histopathologic finding.14 The incidence of TTP is greater in
black female patients,14 and the peak incidence is in the fourth
decade. The mnemonic for the classic pentad of TTP clinical
manifestations is FART'N: fever, anemia, renal failure,
thrombocytopenia, and neurologic dysfunction; however, only
20% to 30% of patients have the complete pentad. The most
common presentation is petechiae with fluctuating neurologic
symptoms.6 Fever is present in 50% of patients, and 10% to
40% report “flulike symptoms” in the preceding weeks.14 TTP
must be considered in cases of thrombocytopenia and
microangiopathic hemolytic anemia alone. Neurologic
dysfunction may present as fluctuating levels of consciousness,
altered mental status, headache, seizures, paresthesias,
hemiplegia, visual changes, aphasia, dysarthria, and/or coma
(Table 4).
Click to enlarge
A critical step in the assessment of TTP is to rule out other

consumptive coagulopathies, such as disseminated
intravascular coagulation (DIC). Fibrinogen degradation products
are elevated in 50% of patients with TTP.14 In TTP, the normal
values for D-dimer, fibrinogen, parameters of liver function, PT,
and PTT help to distinguish it from DIC. Baseline laboratory tests
should be ordered, but treatment with plasma exchange should
be initiated as soon as possible, before the results are obtained
and preferably within 4 to 8 hours.15 Severely reduced
ADAMTS13 activity (<5%) with or without an inhibitor or antibody
confirms the TTP diagnosis and has a specificity of 90% in
distinguishing acute TTP from hemolytic uremic syndrome
(HUS). Measurement of ADAMTS13 is necessary in the workup
for TTP but is not a diagnostic criterion because the levels may
be normal in patients who otherwise have all the features of
TTP.14 Elevated levels of troponin T are seen in 50% of cases
of acute idiopathic TTP and are a poor prognostic indicator
because coronary artery occlusion is a frequent cause of early
death.15
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TTP is a medical emergency; the untreated mortality rate of 90%

can be reduced to 10% to 20% with prompt plasma exchange
(PEX; 3-5 L/d). PEX removes antibodies and replenishes normal
plasma proteins. Early death still occurs, in half of these cases
within 24 hours of presentation, primarily in women.15 It is critical
to differentiate TTP from other causes of thrombocytopenia early
because platelet transfusions, which may increase the risk for
vascular micro-occlusion, are contraindicated (unless life-
threatening bleeding is present). The incidence of symptomatic
heart failure is increased in patients who have received a recent
platelet transfusion.15 Fresh frozen plasma can be initiated if
there is any delay in PEX; however, PEX is preferred because a
larger amount of plasma can be given without fluid overload.
Packed red blood cells and oral folic acid can be given to correct
anemia. Immediately after PEX, adjunct corticosteroids are
administered. Daily PEX is continued until the platelet count and
LDH level are normal for a minimum of 2 days after complete
remission (platelet count >150,000/µL).15 Rituximab is

increasingly being used as a first-line agent for acute TTP and is
preferred for patients with neurologic or cardiac involvement15;
early administration is associated with faster remission and
fewer cycles of PEX.6 Once the platelet count is >50,000/µL,
initiate LMWH thromboprophylaxis.15 Patients with frequent
relapses of TTP are candidates for splenectomy.
Hemolytic uremic syndrome. HUS is a major thrombotic

microangiopathy characterized by signs of microangiopathic
hemolysis (as in TTP), thrombocytopenia, and variable
manifestations of organ involvement. Clinically and
pathologically, TTP and HUS overlap, but these entities are
distinctly different in pathogenesis. Severe deficiency of
ADAMTS13 is the hallmark of TTP but is not seen in HUS.
Additionally, the severe thrombocytopenia of TTP is not present
in HUS, in which ADAMTS13 levels are >5% to 10%.16 Most
commonly, HUS is associated with diarrhea due to enteric
infection with Shiga toxin–producing Escherichia coli 0157:H7
(STEC-HUS, the most common serotype) or Shigella species.
These pathogens are potent activators of the alternative
complement pathway. STEC-HUS is the most common cause of
acute renal failure in children and accounts for 90% of all cases
of HUS in this population.17 In North America, the incidence is
highest in children 1 to 5 years of age: 6.1/100,000 in children <5
years vs 2/100,000 in adults.16,17 Cattle and sheep are the main
reservoirs, and the major mode of transmission is the ingestion
of food contaminated with animal feces. After a 3- to 8-day
incubation period, watery or bloody diarrhea, nausea, vomiting,
and fever may occur. The risk for the development of HUS after
bloody diarrhea due to E. coli infection is about 15%.17 Factors
associated with HUS evolution include the use of anti-motility
agents and antibiotics, bloody diarrhea, leukocytosis, young age,
and female gender.17 There is also a rarer form of infection-
related HUS that is caused by disseminated Streptococcus
pneumoniae, often associated with sepsis, meningitis, or
pneumonia. Recovery is often spontaneous, but acute renal
failure that lasts about 2 weeks develops in 26% of patients.17
About 80% of patients recover, and STEC-HUS carries a 3% to
5% mortality rate.17
Atypical HUS is due to a chronic deficiency of complement

regulatory proteins, particularly factor H, factor I, and
thrombomodulin (membrane cofactor protein). The alternative
pathway is active in plasma and will cause a minor attack on
body tissues unless it is downregulated by these regulatory
proteins. Here, the pathway is continuously stimulated by the

activation of C3, which leads to a cascade reaction potentiating
platelet activation, aggregation, and complement-mediated
endothelial cell injury throughout the microvasculature. Atypical
HUS accounts for only 5% of all HUS cases, with an incidence of
2/million in adults and 3.3/million in children younger than 18
years; in 70% of pediatric cases, the onset is before age 2
years.16,17 Infection (respiratory or diarrheal) triggers the onset
of atypical HUS in 50% of adults and 80% of pediatric cases.17
As such, the presence of diarrhea cannot reliably distinguish
STEC-HUS from atypical HUS or TTP because diarrhea occurs
in one-third of atypical HUS cases and is not uncommon in TTP.
Atypical HUS has a worse outcome than STEC-HUS, with up to
50% of cases progressing to end-stage renal failure within a
year and 25% of patients dying during the acute phase.16
The same organs are affected in HUS and TTP, but in HUS the
lesions are most numerous in the renal vasculature and there is
minimal neurologic dysfunction. Acute kidney injury supports a
diagnosis of HUS rather than TTP; acute renal failure affects
<5% of patients with TTP at presentation.16 Of note, in 20% of
patients with an initial presentation of atypical HUS, although
some proteinuria or hematuria may be present, renal function is
preserved.16 The lungs are almost never involved in TTP,
whereas pulmonary disease is frequent in untreated atypical
HUS.16 It is essential to differentiate between these disorders
quickly because the PEX that is standard for TTP has no role in
HUS. Overall, patients with thrombocytopenia (<150,000/µL or
>25% decrease from baseline) plus signs of microangiopathic
hemolysis and at least one manifestation of organ damage
(neurologic, renal, or gastrointestinal most commonly) should be
treated for thrombotic microangiopathy, and time-sensitive PEX
should be initiated. Subsequent laboratory analysis will confirm
the diagnosis; the detection of toxin-producing bacteria in stool
culture or via serology or the presence of an anti-0157 antibody
titer supports a diagnosis of STEC-HUS; ADAMTS13 activity
<5% to 10% is likely TTP, and if >5% to 10% is likely atypical
HUS. Further investigation of atypical HUS includes screening
for complement system abnormalities (serum C3 and C4 levels,
factor H and factor I levels). As in TTP, platelet transfusions are
strongly contraindicated in HUS unless a severe hemorrhagic
condition is present. For STEC-HUS, treatment includes
(intravenous) fluid hydration, supportive care, and hemodialysis,
with renal transplant as needed. Antibiotic therapy is not needed.
In atypical HUS, PEX is the first-line treatment per expert
opinion, although the efficacy is variable according to mutated
factor.17 Eculizumab, a monoclonal anti-C5 antibody, was

recently approved for atypical HUS therapy; the data report
success in early use as well as in the prevention and treatment
of post-transplant recurrence.17 Renal transplant in atypical HUS
may not be recommended for patients with certain mutations.
Disseminated intravascular coagulation. In disseminated

intravascular coagulation (DIC), an underlying condition leads to
the systemic intravascular activation of coagulation; the
simultaneous generation of thrombin and fibrin results in
thrombosis in small to medium-size vessels. The process
culminates in organ ischemia and dysfunction and/or severe
bleeding due to platelet and clotting factor consumption. The
frequency of DIC in hospitalized patients is about 1.72%.18 The
most common association is severe sepsis or septic shock.
Clinically overt DIC may occur in 30% to 50% of patients with
gram-negative sepsis18 but is estimated to be as common in
patients with gram-positive sepsis. Other causes include the
following: major trauma, burns, prolonged surgery, massive
blood transfusion or ABO-incompatible transfusion, malignancy
(especially acute promyelocytic leukemia or non-Hodgkin
lymphoma), and obstetric complications (most commonly pre-
eclampsia; also retained fetus, amniotic fluid embolism,
placental abruption). An increase in tissue factor production and
activity is paramount in initiating DIC and is found to be
significant in injured tissue and in leukemic cells and solid
tumors.18 Other contributors, particularly in cases of septic DIC,
include elevated cytokines, elevations of plasminogen activator
inhibitor 1, endothelial activation, lipopolysaccharides, histones,
and activated leukocytes.
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Guidelines highlight four types of DIC based on the

predominance of hyperfibrinolysis or hypercoagulation.19 The
diagnosis and treatment of these types differ, and clinicians must
be aware that types may shift or change. In cases of
hyperfibrinolysis, as seen in patients with leukemia, obstetric
disease, or aortic aneurysm, bleeding-type DIC develops. In
cases ofhypercoagulation, as seen in patients with sepsis, organ
failure-type DIC develops. When both hypercoagulation and
hyperfibrinolysis have a weak presence, patients may be
asymptomatic. However, the strong presence of both factors, as
seen in major bleeding after surgery or in obstetric disease,
leads to massive bleeding or consumptive-type DIC. Guidelines
recommend that DIC be diagnosed with a combination of
laboratory markers trended serially rather than a single test. In
clinical practice, the diagnosis may be based on the following: an
underlying disease associated with DIC, an initial platelet count
<100,000/μL or rapidly declining, prolongation of the PT and PTT
(>1.5 times the normal value), the presence of fibrin degradation

products, and low levels of coagulation inhibitors such as
antithrombin III.18 The PT is prolonged in 50% of patients during
the clinical course.19 Elevated levels of fibrin degradation
products indicate ongoing hyperfibrinolysis together with low
levels of plasminogen and α2-antiplasmin. Serial monitoring of
fibrin degradation products may be used to evaluate the
response to therapy. A decreased fibrinogen level (<1.5 g/dL) is
observed in cases of DIC due to leukemia or obstetric disease
but is rare in patients with sepsis.19 Levels of major physiologic
anticoagulants, such as antithrombin III, protein C, and tissue
factor pathway inhibitor, are low in DIC and are associated with
increased mortality, particularly in sepsis.18 New assays
monitoring thrombin generation and its activation of the protein C
and fibrinolytic pathways are also being used to monitor DIC.
It is critical to identify and treat the underlying disorder because

DIC commonly spontaneously resolves once the trigger is
removed. Otherwise, treatment is individualized according to the
hemodynamic status of the patient and the type of DIC.
Guidelines recommend platelet transfusion and fresh frozen
plasma in patients who have DIC with active bleeding or those at
high risk for bleeding, particularly when the platelet count is
<50,000/µL.19 Large volumes of plasma (up to 6 units per day)
may be required to correct coagulation defects; an initial dose of
fresh frozen plasma of 15 mL/kg is clinically recommended.
Deficiencies in fibrinogen associated with the massive bleeding
type of DIC can be corrected with the administration of purified
fibrinogen concentrates or cryoprecipitate. The standard of care
in nonbleeding types of DIC is prophylaxis with unfractionated
heparin or LMWH and/or mechanical methods. Small studies
suggest that LMWH is superior to unfractionated heparin for
treating DIC because it has at least the same antithrombotic
potential with a decreased risk for bleeding.18,19 Heparin
mitigates the high risk for venous thromboembolism in DIC and
has the benefit of partially inhibiting the activation of coagulation.
It is particularly useful in those with clinically overt venous
thromboembolism or extensive fibrin deposition evidenced by
acral ischemia.18,19 Clinical studies have not shown that heparin
treatment significantly increases the incidence of bleeding, but it
is not recommended in patients with the bleeding type of
DIC.18,19 In studies of DIC in patients with severe sepsis, the 28-
day mortality was lower in the heparin-treated group than in the
placebo group.19 Particularly in cases of sepsis-related DIC, the
administration of antithrombin III and activated protein C
concentrates, which have anticoagulant and anti-inflammatory
effects, has been shown benefit in reducing DIC and mortality

and improving organ function.18
Considerations for pregnant patients
Platelet counts <150,000/µL are seen in 6% to 15% of women at

the end of pregnancy, and counts <100,000/µL are observed in
1%.1 These counts are most commonly gestational
thrombocytopenia (70% of cases, mild in an otherwise healthy
pregnancy); other causes are pre-eclampsia (21%) and ITP
(3%)1. Gestational thrombocytopenia is observed in the mid-
second to third trimester of pregnancy and is an extreme
variation of the physiologic decrease in platelets normally
observed; counts <70,000/µL are rare,1,2 and gestational
thrombocytopenia requires no change from routine obstetric
care.
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If there is no past history of thrombocytopenia except in a former

pregnancy, the thrombocytopenia should resolve spontaneously
within 1 to 2 months after delivery with no sequelae or
thrombocytopenia in the newborn. ITP occurs in 1/1000 to
2/1000 pregnancies but is the most common cause of isolated
thrombocytopenia in the first and early second trimesters.1 One-
third of cases are diagnosed during pregnancy, whereas two-
thirds of patients report pre-existing disease.1 In ITP, IgG
autoantibodies may cross the placenta and cause severe
neonatal thrombocytopenia in 9% to 15% of cases.1 A platelet
count <50,000/µL in pregnancy should be diagnosed as ITP.
No laboratory parameter predicts the platelet count in the fetus.

Pregnant women with platelet counts >30,000/μL without
bleeding do not require any treatment until week 36 of gestation
unless delivery is imminent.10 First-line management of ITP
does not change during pregnancy. Steroids or IVIG is
recommended, and these have relatively few fetal complications;
oral prednisone and prednisolone cross the placenta at a lower
rate than dexamethasone. Refractory ITP in pregnancy is

treated with combination steroid/IVIG or splenectomy, although
splenectomy should be avoided if possible. A platelet count
>50,000 /µL is usually sufficient for cesarean delivery.6 Pregnant
patients with vWD usually have no problems during pregnancy
but may be at risk for postpartum hemorrhage, even with
treatment, because vWF and factor VIII activity decrease after
childbirth.6 Severe thrombocytopenia or associated
hypertension, renal insufficiency, and/or microangiopathic
hemolytic anemia should prompt an evaluation for a more
serious obstetric condition, such as pre-eclampsia, TTP, or
HELPP (hemolysis, elevated liver enzymes, low platelet count)
syndrome.
Conclusion
The evaluation of most disorders of primary hemostasis begins

with a focused history and physical examination, complete blood
cell count with platelet trend, and examination of the peripheral
smear. The most common conditions encountered include ITP
and DIT, but clinicians must be aware of the extensive
differential diagnosis if they are to determine the relevance of the
platelet count as well as the patient's risk for bleeding,
thrombosis, and other complications.
Danielle Kruger, PA-C, MSEd, is an associate professor in the

Physician Assistant, Bachelor of Science program at St. John's
University College of Pharmacy and Health Sciences, and a
physician assistant practicing emergency medicine, and Director
of Physician Assistant Development at Coney Island Hospital in
Brooklyn, NY.
References
1. Stasi R. How to approach thrombocytopenia. Hematology Am

Soc Hematol Educ Program. 2012;2012:191-197.
2. George JN, Arnold DM. Approach to the adult with unexplained
thrombocytopenia. UpToDate.
https://www.uptodate.com/contents/approach-to-the-adult-with-
unexplained-thrombocytopenia. Updated October 19, 2017.
Accessed October 26, 2017.
3. Bowman M, Mundell G, Grabell J, et al. Generation and
validation of the Condensed MCMDM1-VWD Bleeding
Questionnaire for von Willebrand disease. J Thromb Haemost.
2008;6:2062-2066.
4. Ballas M, Kraut EH. Bleeding and bruising: a diagnostic work-up.
Am Fam Physician. 2008;77:1117-1124.
5. American Society of Hematology. 2012* clinical practice
guidelines on the evaluation and management of von Willebrand
disease (VWD).
http://www.hematology.org/Clinicians/Guidelines-Quality/Quick-
Reference.aspx#a3. Accessed October 26, 2017.
6. Thiagarajan P. Platelet disorders: overview of platelet disorders.
Medscape.http://emedicine.medscape.com/article/201722-
overview. Updated August 5, 2017. Accessed October 26, 2017.
7. Mohanty D, Shetty S. Von Willebrand Disease: an update. J
Blood Disorders Transf. 2014;5:238. doi:10.4172/2155-
9864.1000238
8. Simon D, Kunicki T, Nugent D. Platelet function defects.
Hemophilia. 2008;14:1240-1249.
9. Neunert C, Lim W, Crowther M, et al. The American Society of
Hematology 2011 evidence-based practice guideline for immune
thrombocytopenia. Blood. 2011;117(16):4190-4207.
10. Kessler CM. Immune thrombocytopenic purpura (ITP).
Medscape. www.emedicine.medscape.com/article/202158-
overview. Updated December 2, 2016. Accessed October 26,
2017.
11. Visentin GP, Liu CY. Drug-induced thrombocytopenia. Hematol
Oncol Clin North Am. 2007;21:685-696.
12. Solomon CG. Heparin-induced thrombocytopenia. N Engl J Med.
2015;373:252-261.
13. Cuker A, Crowther M. 2013 Clinical practice guideline on the
evaluation and management of adults with suspected heparin-
induced thrombocytopenia (HIT). American Society of
Hematology. Accessed October 26, 2017.
14. Saifan C, Nasr R, Mehta S, Acharya PS, El Sayegh S.
Thrombotic thrombocytopenic purpura. J Blood Disord Transfus.
2012;S3:001. doi:10.4172/2155- 9864.S3-001
15. Scully M, Hunt B, Benjamin S, et al; British Committee for
Standards in Haematology. Guidelines on the diagnosis and
management of thrombotic thrombocytopenic purpura and other
thrombotic microangiopathies. Br J Haematol. 2012;158:323-325.
doi:10.1111/j.1365-2141.2012.09167.x
16. Laurence J. Atypical hemolytic uremic syndrome (aHUS): making
the diagnosis. Clin Adv Hematol Oncol. 2012;10(10 Suppl 17):1-
12.
17. Salvadori M, Bertoni E. Update on hemolytic uremic syndrome:
diagnostic and therapeutic recommendations. World J Nephrol.
2013;2:56-76.
18. Dalainas I. Pathogenesis, diagnosis and management of
disseminated intravascular coagulation: a literature review. Eur
Rev Med Pharmacol Sci. 2008;12:19-31.
19. Wada H, Matsumoto T, Yamashita Y. Diagnosis and treatment of
disseminated intravascular coagulation (DIC) according to four
DIC guidelines. J Intensive Care. 2014,2:15.
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