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Symptom to Diagnosis: An Evidence­Based Guide, 3e

8: Bleeding Disorders

CHIEF COMPLAINT

PATIENT

Ms. A is a 24­year­old woman who comes to see you because her gums are bleeding when she brushes her teeth.

What is the differential diagnosis of bleeding? How would you frame the differential?

CONSTRUCTING A DIFFERENTIAL DIAGNOSIS

The framework for bleeding distinguishes between structural causes (ie, an injury to the tissue or organ), platelet­related causes, and clotting factor–
related causes. Bleeding due to platelet abnormalities, whether due to reduced number or abnormal function of platelets, is usually small vessel
bleeding, and produces such findings as petechiae, bruising, gum bleeding, or nosebleeds. The bleeding occurs immediately upon the injury that
induces it. Platelet­related bleeding is generally not quantitatively significant (ie, platelet­related bleeding tends not to cause serious blood loss
requiring red cell transfusions). Nonetheless, platelet­related bleeding can still be clinically important if a patient bleeds a small amount into the brain
(unusual unless the platelet count is < 10,000/mcL) or induces an abdominal hematoma from vigorous coughing, for example. By contrast, bleeding
due to coagulation factor deficiencies or inhibitors tends to be delayed; that is, a platelet plug slows or stops the bleeding immediately after an injury,
but the platelet plug is then not bolstered by the stable fibrin clot that is meant to definitively stop the bleeding. Bleeding due to coagulation factor
abnormalities is more likely to be quantitatively significant, generally occurring in joints, the gastrointestinal tract, brain, retroperitoneum, or at sites
of recent injury or medical or surgical intervention.

A. Structural causes

1. Tissue injury from trauma

2. Abnormality of the tissue such that minor trauma causes bleeding, such as a toothbrush causing gum bleeding from inflammatory gingival
disease

B. Bleeding due to platelet disorders

1. Disorders of platelet number (thrombocytopenia)

a. Decreased production of platelets

( 1 ) Medications (examples include valproic acid, linezolid, thiazide diuretics, gold compounds, antineoplastic chemotherapy drugs)

( 2 ) Bone marrow replacement by malignancy, fibrosis, granulomas

( 3 ) Bone marrow aplasia

( 4 ) Alcohol

( 5 ) B12 deficiency
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b. Increased
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( 1 ) Splenic sequestration
 ( 2 ) Bone marrow replacement by malignancy, fibrosis, granulomas
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( 3 ) Bone marrow aplasia Access Provided by:

( 4 ) Alcohol

( 5 ) B12 deficiency

b. Increased loss or consumption of platelets

( 1 ) Splenic sequestration

( 2 ) Autoimmune thrombocytopenia

( a ) Idiopathic (also called idiopathic thrombocytopenic purpura [ITP])

( b ) HIV

(c) Systemic lupus erythematosus (SLE)

( d ) Lymphoproliferative disorders

( e ) Medications (examples include heparin, phenytoin, carbamazepine, sulfonamides, quinine, antiplatelet drugs used for
coronary syndromes such as abciximab or tirofiban)

( 3 ) Disseminated intravascular coagulation (DIC)

( 4 ) Thrombotic thrombocytopenic purpura (TTP)

( 5 ) Sepsis

2. Disorders of platelet function

a. Congenital

( 1 ) von Willebrand disease

( 2 ) Other rare genetic abnormalities

b. Acquired

( 1 ) Medications, such as aspirin, nonsteroidal antiinflammatory drugs (NSAIDs)

( 2 ) Myeloproliferative disorders, such as essential thrombocythemia, polycythemia vera

( 3 ) Coating of platelets by abnormal proteins, such as in multiple myeloma and, occasionally, immune thrombocytopenia

( 4 ) Uremia

C. Bleeding due to clotting factor abnormalities

1. Congenital

a. Hemophilia A (the most common)

b. Other clotting factor deficiencies

2. Acquired

a. Deficiency of a factor or factors

( 1 ) Liver disease

( 2 ) Vitamin K deficiency (nutritional or due to warfarin therapy)

( 3 ) Abnormal
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a factor, eg, factor X adsorption to amyloid fibrils
8: Bleeding Disorders, Page 2 / 20
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) Consumption of factors, eg,
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( 5 ) Dilution of factors, eg, massive transfusion

 a. Deficiency of a factor or factors
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( 1 ) Liver disease Access Provided by:

( 2 ) Vitamin K deficiency (nutritional or due to warfarin therapy)

( 3 ) Abnormal adsorption of a factor, eg, factor X adsorption to amyloid fibrils

( 4 ) Consumption of factors, eg, DIC

( 5 ) Dilution of factors, eg, massive transfusion

b. Acquired inhibitor to clotting factor or factors

Figure 8­1 shows the diagnostic approach to bleeding disorders.

Figure 8­1.

Diagnostic approach to the bleeding patient.

aPTT, activated partial thromboplastin time; CAD, coronary artery disease; DIC, disseminated intravascular coagulation; GI, gastrointestinal; INR,
international normalized ratio; ITP, idiopathic thrombocytopenia purpura; NSAIDs, nonsteroidal antiinflammatory drugs; PT, prothrombin time; TTP,
thrombotic thrombocytopenic purpura.

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About 2 weeks ago, Ms. A noticed bleeding from her gums while she was brushing her teeth. The bleeding lasts only briefly, and she does not
consider it to be a large amountof blood. Her gums do not hurt, and she is timely with her dental care. At her last cleaning a month ago, she was told
all was well. She has also noted some tiny red dots on her ankles in the past week—they are not raised and do not itch or hurt. She notes that her last
menstrual period was somewhat heavier than usual, and she has had an intermittent headache over the last 2 days, partially relieved by
acetaminophen. Otherwise, she has taken no medications. On examination, she looks well and has normal vital signs. Her oral examination shows
evidence of recent gingival bleeding, and there are a few palatal petechiae. She also has petechiae on her antecubital fossae and ankles. There is no
lymphadenopathy. Chest and abdominal examinations are normal, with no splenomegaly noted.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis?
Given this differential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

There are several pivotal points in Ms. A’s presentation that suggest her bleeding is due to a platelet disorder: the bleeding occurs immediately after
the trauma of tooth brushing, she has petechiae on her skin, and the bleeding is small volume.

The second pivotal point is that her history further suggests that her platelet disorder is acquired. If she had a congenital platelet disorder, such as von
Willebrand disease, she might have had life­long heavy menses and other manifestations of bleeding. In this case, her symptoms just began 2 weeks
ago. A platelet count will confirm that her bleeding is related to thrombocytopenia, rather than platelet dysfunction, which is less commonly seen.
(When platelet dysfunction is suspected, a test such as the PFA­100 assay should be ordered. This test is a reproducible screening tool for platelet
function abnormalities. It measures the time to formation of a platelet plug in response to collagen along with adenosine diphosphate [ADP] or
epinephrine.) The most common cause of thrombocytopenia in a young woman with no signs of systemic illness is idiopathic autoimmune
thrombocytopenia. Although Ms. A’s headache is mild and she looks well, TTP can present with headache and thrombocytopenia and also tends to
occur in young women. Finally, it is critical to remember that the platelets are only 1 of the cell lines affected by bone marrow disorders, and that a
serious bone marrow condition (eg, leukemia) might first manifest as thrombocytopenia. A key step, then, is to decide if the thrombocytopenia is
isolated or part of a pancytopenia picture, such as one might encounter with acute leukemia.

Table 8­1 lists the differential diagnosis.

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Table 8­1.
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Diagnostic
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thrombocytopenia. Although Ms. A’s headache is mild and she looks well, TTP can present with headache and thrombocytopenia and also tends to
occur in young women. Finally, it is critical to remember that the platelets are only 1 of the cell lines affected by bone marrow
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serious bone marrow condition (eg, leukemia) might first manifest as thrombocytopenia. A key step, then,Access
is toProvided
decideby:if the thrombocytopenia is
isolated or part of a pancytopenia picture, such as one might encounter with acute leukemia.

Table 8­1 lists the differential diagnosis.

Table 8­1.
Diagnostic hypotheses for Ms. A

Diagnostic Hypotheses Demographics, Risk Factors, Symptoms and Signs Important Tests

Leading Hypothesis

ITP Young woman CBC: isolated low platelets, normal WBC and Hb
Gum bleeding Smear: Large platelet forms
Petechiae

Active Alternative—Must Not Miss

Acute leukemia Fever, CBC: reduced or increased WBC

Symptoms and signs of anemia Smear: immature WBC forms
Bleeding Bone marrow examination

TTP Neurologic symptoms CBC: anemia, thrombocytopenia

Bleeding Smear: schistocytes
Fever Serum LD
BUN, creatinine

Other Hypothesis

Medication related thrombocytopenia Bleeding, depending on how low platelets have fallen History of recent medication use

BUN, blood urea nitrogen; CBC, complete blood cell; Hg, hemoglobin; ITP, idiopathic thrombocytopenia purpura; LD, lactate dehydrogenase; TTP, thrombotic
thrombocytopenia purpura; WBC, white blood cell.

Ms. A’s laboratory tests indicate a WBC of 5600/mcL, RBC of 3.9 million/mcL, Hgb of 11.2 g/dL, HCT of 33.5%, and platelet count 8,000/mcL.
Examination of the peripheral blood smear shows markedly decreased platelets with some large platelet forms, and normal RBC and WBC
morphology.

Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?

Leading Hypothesis: ITP

Textbook Presentation

The classic presentation is a previously healthy person not exposed to medications that can cause thrombocytopenia in whom gum bleeding or
petechiae are present. The platelet count is low, with large platelets seen on peripheral blood smear; other cell lines are normal. Physical exam, other
than the minor bleeding, is normal.

Disease Highlights
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A. ITP is
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of Use This isPolicy
• Privacy the demographic group that commonly suffers from other autoimmune
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disorders.
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The classic presentation is a previously healthy person not exposed to medications that can cause thrombocytopenia in whom gum bleeding or
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petechiae are present. The platelet count is low, with large platelets seen on peripheral blood smear; other cell lines are normal. Physical exam, other
than the minor bleeding, is normal.

Disease Highlights

A. ITP is an autoimmune disorder primarily of young women. This is the demographic group that commonly suffers from other autoimmune
disorders.

B. A better term might be autoimmune thrombocytopenic purpura, as some cases are secondary to other conditions, such as lymphoproliferative
disorders, collagen vascular disorders such as SLE, or infectious or inflammatory disorders such as chronic hepatitis, HIV infection, or Crohn
disease.

C. The prevalence is approximately 100 cases per million persons.

Evidence­Based Diagnosis

A. ITP is a clinical diagnosis.

B. A bone marrow examination is not required for diagnosis.

1. If performed, it would likely show normal or increased megakaryocytes, indicating adequate platelet production and suggesting the
thrombocytopenia is due to peripheral destruction of platelets in the reticuloendothelial system.

2. A bone marrow examination should be done when the presentation is atypical: patient has splenomegaly or significant lymphadenopathy or
other cytopenias or the patient is older.

C. Serum antiplatelet antibody tests are about 50–60% sensitive, and not sufficiently specific to make the diagnosis of ITP.

1. They are not considered sufficiently reliable for general use in diagnosing ITP.

2. If there is serious consideration of a drug­induced cause of immune thrombocytopenia, it may be possible to demonstrate drug­related
antiplatelet antibodies.

D. A successful clinical trial of corticosteroid therapy may also serve as strong evidence of the correct diagnosis of ITP.

E. Serologic studies to evaluate for lupus erythematosus or HIV infection would also be indicated if there is any clinical suspicion for their presence.

Treatment

A. Prednisone is the initial treatment for all patients.

B. Patients who do not respond to prednisone or whose thrombocytopenia recurs when the prednisone is stopped undergo splenectomy, which
removes a site of antibody production as well as a site of reticuloendothelial system destruction of antibody­coated platelets.

C. In refractory cases, other immunosuppressants may be used, such as rituximab, azathioprine, or cyclophosphamide.

D. Thrombopoietin analogues such as romiplostim and eltrombopag have recently become available for treatment of refractory cases of ITP.

MAKING A DIAGNOSIS

Ms. A’s WBC count and hemoglobin are normal, eliminating leukemia as a possible diagnosis. Her reticulocyte production index is low and there are
no schistocytes seen on her blood smear, suggesting that she does not have a hemolytic anemia. Her neurologic exam is normal as is her serum
creatinine.

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Bleeding Disorders,
tests need to be done to exclude the alternative diagnoses? Page 6 / 20
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D. Thrombopoietin analogues such as romiplostim and eltrombopag have recently become available forUniversidad
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MAKING A DIAGNOSIS

Ms. A’s WBC count and hemoglobin are normal, eliminating leukemia as a possible diagnosis. Her reticulocyte production index is low and there are
no schistocytes seen on her blood smear, suggesting that she does not have a hemolytic anemia. Her neurologic exam is normal as is her serum
creatinine.

Have you crossed a diagnostic threshold for the leading hypothesis, ITP? Have you ruled out the active alternatives? Do
other tests need to be done to exclude the alternative diagnoses?

Alternative Diagnosis: TTP

Textbook Presentation

Patients with TTP appear systemically ill. The 5 classic manifestations are thrombocytopenia; microangiopathic hemolytic anemia; neurologic
abnormalities such as confusion, headache, lethargy, or seizures; fever; and acute kidney injury.

Disease Highlights

A. Only 2 or 3 of the classic manifestations are present in many patients.

B. Thrombocytopenia and microangiopathic hemolytic anemia must be present to diagnose TTP, regardless of whether the other manifestations are
present.

C. Neurologic abnormalities are present in about two­thirds of patients, acute kidney injury or renal failure in about half, and fever in about one­
quarter.

D. Pathophysiology

1. The ADAMTS13 enzyme is responsible for cleaving ultra­large von Willebrand factor multimers into smaller components.

2. An anti­ADAMTS13 antibody inactivates the enzyme; the trigger for antibody formation is unknown.

3. The lack of the enzyme leads to the ultra­large multimers causing platelet aggregation and clumping in the microcirculation, leading to
thrombocytopenia.

4. These clumps cause red blood cells passing over them to be physically damaged, leading to the characteristic finding on the blood smear of
schistocytes, or fragmented red blood cells.

Evidence­Based Diagnosis

A. A serum test demonstrating reduced ADAMTS13 activity and a positive test for the anti­ADAMTS13 antibody reliably establish the diagnosis.

B. The diagnosis of TTP is made clinically, since the ADAMTS13 assay result may take several days to return, and the disease has critical morbidity and
mortality if treatment is delayed.

1. Any patient with thrombocytopenia (usually below 30,000/mcL) and evidence of microangiopathic hemolysis (schistocytes on peripheral blood
smear, elevated serum lactate dehydrogenase (LD) level, reduced serum haptoglobin level) should raise concern about TTP.

2. If neurologic signs or acute kidney injury is present, the diagnosis becomes even more likely.

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Disorders, Page 7 / 20
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Treatment
 1. Any patient with thrombocytopenia (usually below 30,000/mcL) and evidence of microangiopathicUniversidad
hemolysis (schistocytes
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smear, elevated serum lactate dehydrogenase (LD) level, reduced serum haptoglobin level) shouldAccess
raiseProvided
concernby: about TTP.

2. If neurologic signs or acute kidney injury is present, the diagnosis becomes even more likely.

Think about TTP in patients with thrombocytopenia and signs of hemolytic anemia.

Treatment

A. Plasma exchange is the treatment of TTP. While it is complicated and expensive, it does not carry substantial medical risk.

1. Large volumes of plasma are removed from the patient and fresh plasma reinfused.

2. This removes the antibody to ADAMTS13, and provides plasma with a normal complement of the enzyme.

3. It is possible to treat TTP with plasma infusion alone, but plasma exchange allows for infusion of much higher volumes of plasma.

4. Plasma exchange is performed daily, typically for 7–14 days, while monitoring the platelet count and LD levels.

5. Prior to the advent of plasma exchange, the mortality rate for TTP was about 90%. With plasma exchange, the survival rate is now about 90%.

B. Immunosuppressive drugs such as prednisone or rituximab are also used in an effort to reduce the production of the anti­ADAMTS13 antibody.

It is essential to treat TTP as soon as it is suspected, even if the diagnosis is not absolutely firm.

CASE RESOLUTION

Ms. A’s presentation does not meet criteria for TTP. She has no other symptoms or signs of bone marrow dysfunction, no history of recent
medication use, and no underlying other conditions. Her bleeding is consistent with platelet­induced bleeding, and so the diagnosis of ITP appears
firm.

Ms. A begins treatment with prednisone at a dose of 1 mg/kg orally daily. After 1 week, her platelet count rises to 40,000/mcL, and after 2 weeks, to
130,000/mcL. She then begins a prednisone taper over many weeks, and her platelet count remains above 100,000/mcL.

The goal of therapy in ITP is a safe platelet count, typically a count above 30,000/mcL, rather than a normal count. If it is not possible to taper
prednisone off, or to a very low dose, while maintaining a safe platelet count, alternative therapies such as splenectomy or thrombopoietin analogues
are indicated, since the long­term risks of corticosteroids (infections, osteoporosis, adrenal suppression, muscle weakness, electrolyte disturbances)
should be avoided if possible.

CHIEF COMPLAINT

PATIENT

Mr. J is a 62­year­old man who underwent a coronary bypass graft operation 1 week ago for severe coronary artery disease. He has remained in the
hospital for management of a postoperative sternal wound infection, has been doing well, and is scheduled for discharge later in the day.

His past history is notable for an autoimmune hemolytic anemia several years ago, successfully treated with prednisone. He drank 6 beers per day
for years, quitting about 6 months ago. The laboratory pages you to report that his platelet count is 56,000/mcL.

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At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis?
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Given this differential diagnosis, what tests should be ordered?
are indicated, since the long­term risks of corticosteroids (infections, osteoporosis, adrenal suppression, muscle weakness, electrolyte disturbances)
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CHIEF COMPLAINT

PATIENT

Mr. J is a 62­year­old man who underwent a coronary bypass graft operation 1 week ago for severe coronary artery disease. He has remained in the
hospital for management of a postoperative sternal wound infection, has been doing well, and is scheduled for discharge later in the day.

His past history is notable for an autoimmune hemolytic anemia several years ago, successfully treated with prednisone. He drank 6 beers per day
for years, quitting about 6 months ago. The laboratory pages you to report that his platelet count is 56,000/mcL.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis?
Given this differential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

The most common causes of new thrombocytopenia in hospitalized patients are medications, heparin­induced thrombocytopenia (HIT), and sepsis.
Therefore, the first steps in diagnosing thrombocytopenia in a hospitalized patient are to review previous platelet counts to determine whether the
thrombocytopenia is new, review the medication list, and look for vital signs suggestive of sepsis. Because Mr. J has a history of autoimmune hemolytic
anemia, it is also important to consider autoimmune thrombocytopenia as an accompanying autoimmune phenomenon (also called Evans syndrome,
characterized by seeing spherocytes rather than schistocytes in the peripheral smear), although this would otherwise be uncommon in his age group.
Finally, he could have cirrhosis due to his extensive alcohol intake over the years, with hypersplenism causing mild­to­moderate thrombocytopenia.
Chronic autoimmune hemolytic anemia might also cause splenic enlargement. If hypersplenism is the cause, his platelet count at admission would
probably have been somewhat low, typically between 40,000/mcL and 120,000/mcL. Table 8­2 lists the differential diagnosis.

Table 8­2.
Diagnostic hypotheses for Mr. J.

Diagnostic Hypotheses Demographics, Risk Factors, Symptoms and Signs Important Tests

Leading Hypothesis

HIT Heparin exposure Platelet count

Cold toe HIT ELISA assay

Active Alternative—Must Not Miss

Autoimmune thrombocytopenia (idiopathic or Gum bleeding CBC: isolated low platelets, normal WBC
secondary) Petechiae and Hb
Known associated disease (SLE, HIV, autoimmune Smear: Large platelet forms
hemolytic anemia)

Hypersplenism Known cirrhosis History

Risk factors for liver disease Splenomegaly on exam or imaging

Sepsis Fever CBC

Rigors Blood cultures
Hypotension
Tachycardia

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erythematosus.
characterized by seeing spherocytes rather than schistocytes in the peripheral smear), although this would otherwise be uncommon in his age group.
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Finally, he could have cirrhosis due to his extensive alcohol intake over the years, with hypersplenism causing mild­to­moderate thrombocytopenia.
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Chronic autoimmune hemolytic anemia might also cause splenic enlargement. If hypersplenism is the cause, his platelet count at admission would
probably have been somewhat low, typically between 40,000/mcL and 120,000/mcL. Table 8­2 lists the differential diagnosis.

Table 8­2.
Diagnostic hypotheses for Mr. J.

Diagnostic Hypotheses Demographics, Risk Factors, Symptoms and Signs Important Tests

Leading Hypothesis

HIT Heparin exposure Platelet count

Cold toe HIT ELISA assay

Active Alternative—Must Not Miss

Autoimmune thrombocytopenia (idiopathic or Gum bleeding CBC: isolated low platelets, normal WBC
secondary) Petechiae and Hb
Known associated disease (SLE, HIV, autoimmune Smear: Large platelet forms
hemolytic anemia)

Hypersplenism Known cirrhosis History

Risk factors for liver disease Splenomegaly on exam or imaging

Sepsis Fever CBC

Rigors Blood cultures
Hypotension
Tachycardia

CBC, complete blood cell; ELISA, enzyme­linked immunosorbent assay; Hg, hemoglobin; HIT, heparin­induced thrombocytopenia; SLE, systemic lupus
erythematosus.

Mr. J’s vital signs are normal, and a recent nursing note reports that he finished his breakfast and looked fine. He is receiving antibiotics for the
wound infection and subcutaneous heparin every 8 hours for prophylaxis against deep venous thrombosis. His last platelet count was
175,000/mcL3 days ago. The rest of his CBC results from today include WBC 14,600/mcL and Hgb 11.8 g/dL, unchanged from previous Hgb levels. A
chemistry profile, including liver enzymes and albumin, is normal.

Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?

Mr. J’s thrombocytopenia is new, and he is receiving heparin, a very common cause of medication­related thrombocytopenia. He is clinically stable,
and so sepsis is not a serious consideration.

Leading Hypothesis: HIT

Textbook Presentation

The classic presentation of HIT is a hospitalized patient receiving heparin whose platelet count falls by more than 50% from baseline, though generally
to a level still above 50,000/mcL. There may be associated thrombosis, more commonly venous (deep venous thrombosis, pulmonary embolism,
venous limb gangrene)
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IP isdigits or extremity). Skin necrosis at the site of heparin injections may also be seen.
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Highlights

A. Caused by the development of an antibody directed against a heparin­platelet factor 4 complex; the antibody occurs more commonly with
Leading Hypothesis: HIT
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Textbook Presentation
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The classic presentation of HIT is a hospitalized patient receiving heparin whose platelet count falls by more than 50% from baseline, though generally
to a level still above 50,000/mcL. There may be associated thrombosis, more commonly venous (deep venous thrombosis, pulmonary embolism,
venous limb gangrene) than arterial (cold digits or extremity). Skin necrosis at the site of heparin injections may also be seen.

Disease Highlights

A. Caused by the development of an antibody directed against a heparin­platelet factor 4 complex; the antibody occurs more commonly with
unfractionated heparin than with low­molecular­weight heparin.

B. Develops in about 5% of patients who receive heparin.

C. Surgical patients are at higher risk.

D. HIT manifests between 5 and 10 days after starting any kind of heparin—full dose intravenous heparin, low­dose prophylactic heparin, or even just
heparin flushes to maintain patency of indwelling intravascular catheters. Thrombocytopenia may develop earlier in patients with recent heparin
exposure.

E. Thrombosis develops in about 50% of patients who have HIT, and the thrombosis may be evident at the same time as the platelet count drop.
Thrombosis may be arterial (previously called the white clot syndrome), although it is more often venous.

F. The platelet count does not usually drop below 50,000/mcL in HIT; a lower platelet count suggests another etiology.

Evidence­Based Diagnosis

A. The most sensitive, readily available, screening test is an enzyme­linked immunosorbent assay (ELISA) assay for anti­PF4 antibody.

1. It is nearly 100% sensitive, although specificity is between 75% and 85%. Thus, a negative test is very reassuring that HIT is not present, but
false­positive tests are not uncommon.

2. The serotonin­release assay is more specific but not readily available.

B. Because the poor specificity of the anti­PF4 assay leads to overdiagnosis of HIT, a pretest probability scoring system (the 4“T’s”) has been validated.

1. Thrombocytopenia

a. Fall of platelets by > 50% and nadir > 20,000/mcL = 2 points

b. Fall of platelets by 30–50% or nadir 10–19,000/mcL =1 point

c. Fall by < 30% or nadir < 10,000/mcL = 0 points

2. Timing of platelet fall

a. Clear onset between days 5 and 10 after exposure, or < 1 day if prior heparin exposure within 30 days = 2 points

b. Consistent with fall between 5 and 10 days, but some data missing, or fall > 10 days, or < 1 day if prior heparin exposure within 30–100 days =
1 point

c. Fall at < 4 days and without recent exposure = 0 points.

3. Thrombosis or other sequelae

a. Confirmed new thrombosis, skin necrosis, or acute systemic reaction after IV unfractionated heparin bolus = 2 points

b. Progressive or recurrent thrombosis, non­necrotizing skin lesions or suspected thrombosis that has not been proven = 1 point

c. None of the above = 0 points.

4. OTher causes for thrombocytopenia present:

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a. None apparent = 2 points
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b. Possible = 1 point

c. Definite = 0 points.
 b. Progressive or recurrent thrombosis, non­necrotizing skin lesions or suspected thrombosis that has not been
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c. None of the above = 0 points.

4. OTher causes for thrombocytopenia present:

a. None apparent = 2 points

b. Possible = 1 point

c. Definite = 0 points.

5. Test interpretation: 0–3 points: low probability; 4–5 points: intermediate probability; 6–8 points: high probability.

a. In 1 large series of 111 patients with a low pretest probability of HIT using this scoring system, only 1 had clinically significant HIT antibodies
(0.9%).

b. In contrast, the overall rate of clinically significant HIT antibodies was 11.4% and 34% in those with intermediate and high scores,
respectively.

6. An online calculator is available at http://www.qxmd.com/calculate­online/hematology/hit­heparin­induced­thrombocytopenia­probability

Treatment

A. Heparin must be discontinued whenever HIT is suspected, even when the anti­PF4 assay result is not yet available.

B. An alternative anticoagulant must be started to prevent HIT­associated thrombosis, regardless of whether the initial indication for anticoagulation
is still present; generally, a direct thrombin inhibitor such as argatroban or lepirudin is used.

1. Low­molecular­weight heparin may not be substituted: although the incidence of HIT with low­molecular­weight heparin is much lower than
with unfractionated heparin, once HIT occurs, there is too much risk for cross­reactivity.

2. Similarly, warfarin should not be used until the platelet count has recovered (this takes a few days) but can then be started while the direct
thrombin inhibitor is being given.

3. Anticoagulation should continue for 2–3 months.

C. Although not approved for this indication, fondaparinux, a factor X inhibitor, has sometimes been used as an alternative anticoagulant in patients
with HIT.

D. Surprisingly, patients with a history of HIT may safely be reexposed to heparin if necessary after a year has passed and the antibody has
presumably disappeared.

MAKING A DIAGNOSIS

Before you have finished reviewing Mr. J’s chart, the nurse pages you to report that he is complaining of severe pain in his right great toe. It is cool
and dusky when you examine it.

Have you crossed a diagnostic threshold for the leading hypothesis, HIT? Have you ruled out the active alternatives? Do
other tests need to be done to exclude the alternative diagnoses?

The findings of a painful, cool, and dusky toe suggest arterial occlusion. While post cardiac surgery patients can have arterial emboli from a left
ventricular clot or postoperative atrial fibrillation, the combination of new thrombocytopenia, heparin exposure, and thrombosis points toward HIT.
Mr. J’s “4T” score is 8, consistent with a high probability of HIT: 2 points for the degree of thrombocytopenia, 2 points for the time course, 2 points for
the presence of new thrombosis, and 2 points for lack of other apparent causes of thrombocytopenia (despite his alcohol history, his liver tests are
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normal, making
8: Bleeding cirrhosis and hypersplenism unlikely, and ITP is not associated with thrombosis).
Disorders, Page 12 / 20
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CASE RESOLUTION
 Universidad Peruana de Ciencias Aplicadas
The findings of a painful, cool, and dusky toe suggest arterial occlusion. While post cardiac surgery patients canProvided
Access have by:
arterial emboli from a left
ventricular clot or postoperative atrial fibrillation, the combination of new thrombocytopenia, heparin exposure, and thrombosis points toward HIT.
Mr. J’s “4T” score is 8, consistent with a high probability of HIT: 2 points for the degree of thrombocytopenia, 2 points for the time course, 2 points for
the presence of new thrombosis, and 2 points for lack of other apparent causes of thrombocytopenia (despite his alcohol history, his liver tests are
normal, making cirrhosis and hypersplenism unlikely, and ITP is not associated with thrombosis).

CASE RESOLUTION

You immediately stop all heparin exposure and start Mr. J on argatroban. His HIT ELISA assay is positive. His toe returns to normal, and his platelet
count increases to 180,000/mcL within 4 days. He is receiving warfarin therapy when he is discharged.

CHIEF COMPLAINT

PATIENT

Ms. W is a 56­year­old woman who comes to the office complaining of poor appetite for several weeks and black, tarry stools with generalized
weakness for 1 day.

She has no prior history of bleeding, and her 3 prior obstetric deliveries were uncomplicated. Her past history is notable for cirrhosis due to chronic
hepatitis C. Her medications include spironolactone and metoprolol; additionally, she has been taking ibuprofen for back pain.

On examination, she is pale. Her blood pressure is 110/80 mm Hg, pulse is 112 bpm, RR is 16 breaths per minute, temperature is 37.1°C. Her
conjunctivae are pale, mucous membranes moist, lungs clear, heart regular rhythm with a systolic flow murmur at the left sternal border, liver
minimally enlarged with a nodular edge, spleen palpable 3 cm below the left costal margin in the anterior axillary line, and she has no edema. Digital
rectal examination discloses black stool that is Hemoccult­positive.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis?
Given this differential diagnosis, what tests should be ordered?

Ms. W’s presentation suggests that she is having an upper gastrointestinal (GI) bleed. In addition to the specific GI causes of upper GI bleeding
discussed in Chapter 19, GI Bleeding, it is important to consider whether patients who are bleeding have an underlying platelet or coagulation disorder
contributing to the bleeding. Ms. W does have cirrhosis with splenomegaly that could lead to thrombocytopenia due to splenic sequestration; however,
the large volume of the bleeding may suggest a coagulation factor disorder.

The prothrombin time (PT) measures what is commonly called the extrinsic clotting pathway (Figure 8­2), wherein tissue factor from an injury activates
factor VII, followed by activation of the coagulation cascade through the "common pathway" factors (factors V, X, II [prothrombin] and I [fibrinogen]).
Because the source of tissue factor reagents used in the laboratory to trigger the cascade vary, the PT will vary among different laboratories when
testing the same sample. To overcome this problem of PT results not being comparable from one lab to another, the international normalized ratio
(INR) was developed, to standardize PT results based on a constant associated with each laboratory reagent. The INR, which is routinely reported along
with the PT, allows the clinician to feel confident that the data from different laboratories are comparable.

Figure 8­2.

The coagulation cascade. Organization of the coagulation system based on current assays. The intrinsic coagulation system consists of the proteins
factors XII, XI, IX, and VIII and prekallikrein (PK) and high molecular weight kininogen (HK). The extrinsic coagulation system consists of tissue factor
(tissue thromboplastin) and factor VII. The common pathway of the coagulation system consists of factors X, V, and II, and fibrinogen (I).
(Reproduced, with permission, from McPherson RA, Pincus MR, eds. Henry’s Clinical Diagnosis and Management by Laboratory Methods, 22nd ed.
Philadelphia, 2024­3­26
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Figure 8­2.
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The coagulation cascade. Organization of the coagulation system based on current assays. The intrinsicAccess coagulation system consists of the proteins
Provided by:

factors XII, XI, IX, and VIII and prekallikrein (PK) and high molecular weight kininogen (HK). The extrinsic coagulation system consists of tissue factor
(tissue thromboplastin) and factor VII. The common pathway of the coagulation system consists of factors X, V, and II, and fibrinogen (I).
(Reproduced, with permission, from McPherson RA, Pincus MR, eds. Henry’s Clinical Diagnosis and Management by Laboratory Methods, 22nd ed.
Philadelphia, Elsevier Saunders, 2011, page 791.)

The activated partial thromboplastin time (aPTT) measures what is commonly called the intrinsic clotting pathway, starting with factor XII and working
through factors XI, IX and VIII before entering the "common pathway."

In the evaluation of a prolonged clotting time, either PT or aPTT, one considers whether only 1 test is prolonged, and which factors contribute to each
test. For example, an isolated prolonged PT suggests a deficiency of factor VII, since that is the only factor unique to the PT assay. An isolated
prolonged aPTT raises concern about the 4 factors that are unique to the aPTT—factors, XII, XI, IX, and VIII. Prolongation of both the PT and aPTT raises
concern either about the factors in the common pathway—I, II, V, and X—or a defect in multiple factors. Table 8­3 summarizes commonly seen patterns
of factor deficiencies.

Table 8­3.
Common factor deficiency patterns.

Clinical Setting Factors Deficient PT, aPTT Results

Liver disease All but VIII1 Both prolonged

DIC Fibrinogen, V, VIII, platelets Both prolonged; thrombin time especially prolonged.

Vitamin K deficiency II, VII, IX, X PT and aPTT both prolonged, PT to greater extent

Warfarin effect II, VII, IX, X PT and aPTT both prolonged, PT to greater extent

1 The only factor not produced by hepatocytes.

aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; PT, prothrombin time.

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of clotting times is most commonly acquired, either due to acquired deficiencies (eg, from malnutrition or liver
8: Bleeding Disorders, Page 14 / 20
disease) or acquired factor inhibitors. (While congenital factor deficiencies such as hemophilia certainly cause prolonged clotting times, these are far
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less commonly seen, and patients are well aware of them, making complex diagnostic evaluations unnecessary.) In order to distinguish between a
factor deficiency and an inhibitor, it is often helpful to perform a mixing study, wherein one mixes 1:1 the patient’s plasma and normal plasma, to see if
test. For example, an isolated prolonged PT suggests a deficiency of factor VII, since that is the only factor unique to the PT assay. An isolated
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prolonged aPTT raises concern about the 4 factors that are unique to the aPTT—factors, XII, XI, IX, and VIII. Prolongation of both the PT and aPTT raises
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concern either about the factors in the common pathway—I, II, V, and X—or a defect in multiple factors. Table 8­3 summarizes commonly seen patterns
of factor deficiencies.

Table 8­3.
Common factor deficiency patterns.

Clinical Setting Factors Deficient PT, aPTT Results

Liver disease All but VIII1 Both prolonged

DIC Fibrinogen, V, VIII, platelets Both prolonged; thrombin time especially prolonged.

Vitamin K deficiency II, VII, IX, X PT and aPTT both prolonged, PT to greater extent

Warfarin effect II, VII, IX, X PT and aPTT both prolonged, PT to greater extent

1 The only factor not produced by hepatocytes.

aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; PT, prothrombin time.

In clinical practice, prolongation of clotting times is most commonly acquired, either due to acquired deficiencies (eg, from malnutrition or liver
disease) or acquired factor inhibitors. (While congenital factor deficiencies such as hemophilia certainly cause prolonged clotting times, these are far
less commonly seen, and patients are well aware of them, making complex diagnostic evaluations unnecessary.) In order to distinguish between a
factor deficiency and an inhibitor, it is often helpful to perform a mixing study, wherein one mixes 1:1 the patient’s plasma and normal plasma, to see if
the clotting time corrects. If it does correct, the normal plasma has provided the missing factor to the patient’s plasma, indicating the abnormality is
due to a factor deficiency. If it does not correct, the implication is that an inhibitor in the patient’s plasma is inactivating the clotting factor(s) from the
normal plasma. Such inhibitors may be exogenous, such as inadvertent heparin in the mixture; or endogenous, such as an acquired factor inhibitory
antibody.

Based on the data we have so far, Ms. W’s GI bleeding is most likely from the upper GI tract, probably induced by use of the NSAID ibuprofen. The
severity of the bleeding may be exacerbated by a coagulopathy related to her cirrhosis. The history of poor appetite for a few weeks raises the
consideration of vitamin K deficiency, and the presence of splenomegaly on examination suggests that thrombocytopenia due to splenic sequestration
may also be contributing.

Table 8­4 lists the differential diagnosis.

Table 8­4.
Diagnostic hypotheses for Ms. W.

Demographics, Risk Factors, Symptoms and

Diagnostic Hypotheses Important Tests
Signs

Leading Hypothesis

Coagulopathy due to liver History of hepatitis C or other chronic liver disease PT

disease Signs of GI bleeding aPTT
Jaundice, ascites Platelet count
LFTs

Active Alternatives—Must Not Miss

Vitamin K deficiency Lack of dietary vitamin K Prolonged PT and aPTT, with PT disproportionately prolonged
Recent use of antibiotics compared with aPTT
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to correct with mixing study
Demonstrable factor VIII inhibitor
severity of the bleeding may be exacerbated by a coagulopathy related to her cirrhosis. The history of poor appetite for a few weeks raises the
consideration of vitamin K deficiency, and the presence of splenomegaly on examination suggests that thrombocytopenia
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may also be contributing. Access Provided by:

Table 8­4 lists the differential diagnosis.

Table 8­4.
Diagnostic hypotheses for Ms. W.

Demographics, Risk Factors, Symptoms and

Diagnostic Hypotheses Important Tests
Signs

Leading Hypothesis

Coagulopathy due to liver History of hepatitis C or other chronic liver disease PT

disease Signs of GI bleeding aPTT
Jaundice, ascites Platelet count
LFTs

Active Alternatives—Must Not Miss

Vitamin K deficiency Lack of dietary vitamin K Prolonged PT and aPTT, with PT disproportionately prolonged
Recent use of antibiotics compared with aPTT

Acquired factor inhibitor Older patient Prolonged aPTT, as factor VIII most common example
Abrupt onset of serious bleeding manifestations Failure to correct with mixing study
Demonstrable factor VIII inhibitor

DIC Inciting cause, such as sepsis, tissue injury, shock, Thrombocytopenia Prolongation of PT and aPTT
obstetric crisis Reduced fibrinogen Elevated D­dimer and fibrin degradation
products

Other Hypothesis

Hypersplenism Splenomegaly on examination or radiographic Mild to moderate reductions in all cell lines
study

aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; GI, gastrointestinal; LFTs, liver function tests; PT, prothrombin time.

A CBC shows WBC 9400/mcL, Hgb 7.8 g/dL, platelet count 76,000/mcL. A chemistry profile shows mild elevation of the transaminases but is
otherwise normal. Her CBC 6 months ago showed an Hgb of 11.7 g/dL and platelet count of 80,000/mcL. Coagulation studies include a PT of 22
seconds (normal range 11–13 seconds), with an INR of 1.8 (normal 0.9–1.2). The aPTT is 39 seconds (normal 24–34 seconds).

Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?

Ms. W has the stable, moderate thrombocytopenia generally seen in patients with portal hypertension and hypersplenism. Moderate
thrombocytopenia such as this does not substantially increase the risk of bleeding, especially not the large volume GI bleeding she is experiencing. The
coagulation abnormalities she has can certainly contribute to large volume bleeding.

Leading Hypothesis: Liver Disease–Induced Coagulopathy

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The classic presentation of liver disease–induced coagulopathy is variable. Patients may be asymptomatic, only discovered to have a coagulopathy
incidentally on coagulation laboratory studies. Spontaneous bleeding is uncommon, but anything that stresses the patient (such as an injury, an
 Universidad Peruana de Ciencias Aplicadas
Ms. W has the stable, moderate thrombocytopenia generally seen in patients with portal hypertension and hypersplenism. Moderate
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thrombocytopenia such as this does not substantially increase the risk of bleeding, especially not the large volume GI bleeding she is experiencing. The
coagulation abnormalities she has can certainly contribute to large volume bleeding.

Leading Hypothesis: Liver Disease–Induced Coagulopathy

Textbook Presentation

The classic presentation of liver disease–induced coagulopathy is variable. Patients may be asymptomatic, only discovered to have a coagulopathy
incidentally on coagulation laboratory studies. Spontaneous bleeding is uncommon, but anything that stresses the patient (such as an injury, an
operative procedure, or perhaps drug­induced gastritis) may lead to more bleeding than one might normally anticipate with that event in someone
without liver disease.

Disease Highlights

A. Patients with liver disease–induced coagulopathy typically have a disproportionately longer PT (and therefore higher INR) than aPTT.

B. The coagulopathy is caused by impaired production of clotting factors by the diseased liver; the clotting factor with the shortest half­life, namely
factor VII, would be expected to be most prominently affected. Since the PT/INR is so sensitive to factor VII levels, that test is more notably
abnormal.

C. Coagulopathy is seen primarily in patients with severe liver disease. The liver has considerable reserve, and only when the impairment is severe
does one find significant coagulopathy.

Evidence­Based Diagnosis

A. In a patient with liver disease who is bleeding or in whom an invasive procedure is planned, the PT/INR and aPTT should be checked in order to
screen for coagulation factor deficiencies.

1. If the screening tests are prolonged, it may be worth checking the levels of factor VII, factor V, factor II, factor IX, and factor X as well as fibrinogen
to help determine which replacement therapy is most appropriate.

2. If factor VII is low but factor V normal, it suggests that vitamin K deficiency may be playing a role, whereas in severe liver impairment, both
factors V and VII are reduced.

3. Because all the clotting factors except factor VIII are produced in the hepatocytes, all of them except factor VIII may be low in severe liver disease.
Factor VIII is typically normal or even elevated in liver disease, a finding that may distinguish liver disease from DIC, in which factor VIII is low.

B. Another finding that may contribute to bleeding risk in severe liver disease is excessive fibrinolysis, the cause of which is a complex interplay
between the production of and hepatic clearance of fibrinolytic activators and inhibitors.

C. While it may seem paradoxical, there may also be increased risk of thrombosis in liver disease. Several findings may account for this: reduction of
the vitamin K­dependent anticoagulant proteins, protein C and protein S; and increases in factor VIII and sometimes von Willebrand factor.

Treatment

A. Correct the coagulopathy using fresh frozen plasma to replete clotting factors. If the plasma fibrinogen level is particularly low (eg, < 100 mg/dL),
infusion of cryoprecipitate may be helpful.

B. In severe cases, administration of recombinant activated factor VIIa may help stop the bleeding associated with liver disease; it is extremely
expensive, however, and carries some risk of inducing thrombosis.

MAKING A DIAGNOSIS

An esophagogastroduodenoscopy (EGD) shows a duodenal ulcer consistent with NSAID use. Ms. W is treated with a proton pump inhibitor and fresh
frozen plasma. Her PT and PTT normalize, and the bleeding stops.
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Have you crossed a diagnostic threshold for the leading hypothesis, liver disease–induced coagulopathy? Have you
B. In severe cases, administration of recombinant activated factor VIIa may help stop the bleeding associated with liver disease; it is extremely
expensive, however, and carries some risk of inducing thrombosis. Universidad Peruana de Ciencias Aplicadas
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MAKING A DIAGNOSIS

An esophagogastroduodenoscopy (EGD) shows a duodenal ulcer consistent with NSAID use. Ms. W is treated with a proton pump inhibitor and fresh
frozen plasma. Her PT and PTT normalize, and the bleeding stops.

Have you crossed a diagnostic threshold for the leading hypothesis, liver disease–induced coagulopathy? Have you
ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?

Alternative Diagnosis: Vitamin K Deficiency

Textbook Presentation

The usual presentation of vitamin K deficiency is a hospitalized patient who is found to have a prolonged PT/INR, rarely with bleeding manifestations.

Disease Highlights

A. The most common cause of vitamin K deficiency is inadequate oral intake.

B. Patients who have been hospitalized and need to start warfarin therapy may require smaller than expected doses to achieve therapeutic levels,
because they may be unduly sensitive as a result of baseline vitamin K deficiency.

C. Vitamin K deficiency can also occur with the recent use of antibiotics that alter the gut flora’s ability to convert vitamin K to an absorbable form.

Evidence­Based Diagnosis

A. As with liver disease, patients with vitamin K deficiency have PT/INR levels disproportionately longer than aPTT levels.

B. This is due to factor VII having the shortest half­life of the vitamin K–dependent factors (II, VII, IX, and X), thus making the factor VII–dependent
PT/INR more sensitive to vitamin K alterations.

C. The aPTT will also go up eventually, as the levels of factors II, IX and X, with much longer half­lives, fall.

Treatment

A. Vitamin K repletion, either orally or parenterally, is the treatment of choice.

1. If parenteral treatment is chosen, it should be administered subcutaneously or intravenously—not intramuscularly.

2. Intramuscular injections should be avoided in patients with coagulopathies, in order to avoid the development of hematomas in muscles that
can lead to neuropathy if a major nerve traverses the area.

3. Vitamin K administration takes 18–24 hours to have its effect, so if a patient with vitamin K deficiency is bleeding, fresh frozen plasma may be
required.

Alternative Diagnosis: DIC

Textbook Presentation

Disseminated intravascular coagulation (DIC, also called consumptive coagulopathy) is a catastrophic activation of the coagulation system that
classically presents as the abrupt onset of uncontrolled spontaneous diffuse bleeding from multiple sites (venipuncture sites, catheter sites,
endotracheal tubes, recent surgical sites) in patients with severe illness such as shock states, major trauma, sepsis, obstetric emergencies, and
advanced cancer.
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Highlights

A. The common denominator of conditions that cause DIC is tissue injury and activation of the clotting cascade via entry of procoagulants into the
Textbook Presentation
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Disseminated intravascular coagulation (DIC, also called consumptive coagulopathy) is a catastrophic activation of the coagulation system that
classically presents as the abrupt onset of uncontrolled spontaneous diffuse bleeding from multiple sites (venipuncture sites, catheter sites,
endotracheal tubes, recent surgical sites) in patients with severe illness such as shock states, major trauma, sepsis, obstetric emergencies, and
advanced cancer.

Disease Highlights

A. The common denominator of conditions that cause DIC is tissue injury and activation of the clotting cascade via entry of procoagulants into the
circulation.

B. A variety of conditions activate the clotting cascade.

1. Trauma

2. Advanced adenocarcinomas of any site, such as colon, pancreas, or lung.

3. Obstetric crises such as amniotic fluid embolism or placental abruption.

4. Acute promyelocytic leukemia, wherein the granules of the malignant promyelocytes activate the clotting system.

C. Although the classic presentation is major bleeding due to activation of the clotting cascade leading to secondary consumption of clotting factors,
in some cases clotting manifestations may predominate.

1. Patients with advanced cancer may have recurrent deep venous thrombosis or pulmonary embolism or arterial emboli in the extremities,
without signs of bleeding.

2. This is considered chronic DIC.

D. Renal, hepatic, and pulmonary dysfunction may accompany acute DIC.

Evidence­Based Diagnosis

A. In acute DIC, consumption of clotting factors is demonstrated by thrombocytopenia, prolongation of the PT/INR and aPTT, reduction of plasma
fibrinogen level, and increases in D­dimer and fibrin degradation products (FDP).

B. The D­dimer and FDP reflect fibrinolytic activity acting upon fibrin formed during the clotting process.

1. D­dimer is the product of lysis of cross­linked fibrin.

2. FDP is the product of lysis of both fibrin and fibrinogen.

3. Fibrinogen levels below 100 mg/dL may correlate with bleeding risk.

If DIC is suspected, testing should include platelet count, PT/INR, aPTT, fibrinogen, and D­dimer.

Treatment

A. Treat the underlying condition if possible.

B. Replete clotting factors that have been depleted, with platelet transfusions, fresh frozen plasma, and cryoprecipitate if fibrinogen is particularly
low.

C. In rare instances, the use of low­dose heparin is considered. While it is logical to consider undertaking anticoagulation if the initiation of the
process was coagulation, the additional bleeding risk is of great concern, and efforts are generally focused more on providing clotting factors while
addressing the underlying cause.

CASE RESOLUTION
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You instruct Ms. W to avoid all aspirin products and NSAIDs. She is seen by the dietician for review of vitamin K–rich foods. Her hemoglobin is stable
 low.
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C. In rare instances, the use of low­dose heparin is considered. While it is logical to consider undertaking anticoagulation if the initiation of the
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process was coagulation, the additional bleeding risk is of great concern, and efforts are generally focused more on providing clotting factors while
addressing the underlying cause.

CASE RESOLUTION

You instruct Ms. W to avoid all aspirin products and NSAIDs. She is seen by the dietician for review of vitamin K–rich foods. Her hemoglobin is stable
at a follow up visit 2 weeks later.

REFERENCES

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Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Predictive value of the 4Ts scoring system for heparin­induced thrombocytopenia: a systematic
review and meta­analysis. Blood. 2012 Nov 15;120(20):4160–7.

George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med. 2006 May 4;354(18):1927–35.

Greinacher A, Warkentin TE. Recognition, treatment, and prevention of heparin­induced thrombocytopenia: review and update. Thromb Res.
2006;118(2): 165–76.

Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee
for Standards in Haematology. Br J Haematol. 2009 Apr;145(1):24–33.

Linkins LA, Dans AL, Moores LK et al.; American College of Chest Physicians. Treatment and prevention of heparin­induced thrombocytopenia:
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence­Based Clinical Practice Guidelines
Chest. 2012 Feb;141(2 Suppl):e495S–530S.

Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA; American Society of Hematology. The American Society of Hematology 2011
evidence­based practice guideline for immune thrombocytopenia. Blood. 2011 Apr 21;117(16):4190–207.

Sallah S, Wan JYU, Nguyen NP, Hanrahan LR, Sigounas G. Disseminated intravascular coagulation in solid tumors: clinical and pathologic study.
Thromb Haemost. 2001 Sep;86(3):828–33.

Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011 Jul 14;365(2):147–56.

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