Bleeding and Bruising: A Diagnostic Work-up



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Primary care physicians are often asked about easy bruising, excessive bleeding, or risk of bleeding before surgery. A thorough history, including a family history, will guide the appropriate work-up, and a physical examination may provide clues to diagnosis. A standardized bleeding score system can help physicians to organize the patient's bleeding history and to avoid overlooking the most common inherited bleeding disorder, von Willebrand's disease. In cases of suspected bleeding disorders, initial laboratory evaluations should include a complete blood count with platelet count, peripheral blood smear, prothrombin time, and partial thromboplastin time. More specialized yet relatively simple tests, such as the Platelet Function Analyzer-100, mixing studies, and inhibitor assays, may also be helpful. These tests can help diagnose platelet function disorders, quantitative platelet disorders, factor deficiencies, and factor inhibitors.

Numerous disorders can cause abnormal bleeding and bruising, including platelet function disorders, quantitative platelet disorders, factor deficiencies, and factor inhibitors. Additionally, there are diseases that affect the connective tissue and integrity of the blood vessel, making the skin bruise more easily and vessels more prone to bleed. Table 1 lists the differential diagnosis of bleeding and bruising disorders. Table 2 1,2 shows the diagnostic work-up, which begins with a focused history.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

Because a positive family history increases the risk of a bleeding disorder, family history should be obtained in patients with a suspected bleeding disorder.

C

58, 11

The use of bleeding time to assess platelet function is discouraged; the Platelet Function Analyzer-100 is preferred.

C

1, 1724


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 1063 or http://www.aafp.org/afpsort.xml.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

View Table

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

Because a positive family history increases the risk of a bleeding disorder, family history should be obtained in patients with a suspected bleeding disorder.

C

58, 11

The use of bleeding time to assess platelet function is discouraged; the Platelet Function Analyzer-100 is preferred.

C

1, 1724


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 1063 or http://www.aafp.org/afpsort.xml.

Table 1

Differential Diagnosis of Bleeding and Bruising Disorders

Disorder Findings or clues to diagnosis

Bleeding

Platelet disorders (quantitative)

Bleeding, bruising, petechia, or purpura Consider idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, malignancy, viral disease

Platelet disorders (functional)

Consider in a patient with a lifelong history of bleeding despite negative laboratory work-up Consider glycoprotein disorders (Bernard-Soulier syndrome, Glanzmann thrombasthenia), storage pool disease, von Willebrand's disease If platelets are abnormally shaped, consider May-Hegglin anomaly, Wiskott-Aldrich syndrome

Hemophilia type A or B (factor VIII or IX deficiency) or other factor deficiencies

Classically presents with joint or soft-tissue bleeding; family history of bleeding in men (skipped generations)

Factor inhibitors

Presentation similar to hemophilia, but onset is typically sudden with no patient or family history of bleeding

Hereditary hemorrhagic telangiectasia

Telangiectasias over lips, tongue, nasal cavity, and skin; epistaxis

Vasculitis or cryoglobulinemia

Neuropathy; pulmonary-renal involvement; purpura

Leukemia

Abnormal complete blood count or peripheral blood smear

Disseminated intravascular coagulation

Bleeding from multiple sites; prolonged prothrombin time and partial thromboplastin time

Vitamin K deficiency

More common causes include malabsorption (bacterial overgrowth, celiac disease, chronic pancreatitis, inflammatory bowel disease, short-gut syndrome), poor diet (alcoholism, total parenteral nutrition) or drugs that bind vitamin K (cholestyramine [Questran]).

Bruising

Purpura simplex (easy bruising)

Typically found in women on the upper thighs and arms

Alcohol abuse

Social history

Abuse (including child abuse)

Atypical pattern of bruising or bleeding; bruises that pattern after objects; bruises in children who are not yet mobile; history that is inconsistent with the patient's injuries

Senile purpura

Dark ecchymosis in aged, thin skin; typically over extensor surfaces of forearms

Cushing's disease

Facial plethora; hirsutism; hyperglycemia; hypertension; poor wound healing; stria

Marfan's syndrome

Enlarged aortic root; eye involvement; mitral valve prolapse; scoliosis; pectus excavatum; stretch marks; tall and slim, with long limbs and digits

Vitamin C deficiency (scurvy)

Dietary history

Ehlers-Danlos syndrome or connective tissue diseases

Atrophic scarring or joint dislocations; hypermobile joints; skin hyperextensibility


note: Disorders are categorized as predominantly bleeding or bruising and are in order of relative frequency.

Table 1   Differential Diagnosis of Bleeding and Bruising Disorders

View Table

Table 1

Differential Diagnosis of Bleeding and Bruising Disorders

Disorder Findings or clues to diagnosis

Bleeding

Platelet disorders (quantitative)

Bleeding, bruising, petechia, or purpura Consider idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, malignancy, viral disease

Platelet disorders (functional)

Consider in a patient with a lifelong history of bleeding despite negative laboratory work-up Consider glycoprotein disorders (Bernard-Soulier syndrome, Glanzmann thrombasthenia), storage pool disease, von Willebrand's disease If platelets are abnormally shaped, consider May-Hegglin anomaly, Wiskott-Aldrich syndrome

Hemophilia type A or B (factor VIII or IX deficiency) or other factor deficiencies

Classically presents with joint or soft-tissue bleeding; family history of bleeding in men (skipped generations)

Factor inhibitors

Presentation similar to hemophilia, but onset is typically sudden with no patient or family history of bleeding

Hereditary hemorrhagic telangiectasia

Telangiectasias over lips, tongue, nasal cavity, and skin; epistaxis

Vasculitis or cryoglobulinemia

Neuropathy; pulmonary-renal involvement; purpura

Leukemia

Abnormal complete blood count or peripheral blood smear

Disseminated intravascular coagulation

Bleeding from multiple sites; prolonged prothrombin time and partial thromboplastin time

Vitamin K deficiency

More common causes include malabsorption (bacterial overgrowth, celiac disease, chronic pancreatitis, inflammatory bowel disease, short-gut syndrome), poor diet (alcoholism, total parenteral nutrition) or drugs that bind vitamin K (cholestyramine [Questran]).

Bruising

Purpura simplex (easy bruising)

Typically found in women on the upper thighs and arms

Alcohol abuse

Social history

Abuse (including child abuse)

Atypical pattern of bruising or bleeding; bruises that pattern after objects; bruises in children who are not yet mobile; history that is inconsistent with the patient's injuries

Senile purpura

Dark ecchymosis in aged, thin skin; typically over extensor surfaces of forearms

Cushing's disease

Facial plethora; hirsutism; hyperglycemia; hypertension; poor wound healing; stria

Marfan's syndrome

Enlarged aortic root; eye involvement; mitral valve prolapse; scoliosis; pectus excavatum; stretch marks; tall and slim, with long limbs and digits

Vitamin C deficiency (scurvy)

Dietary history

Ehlers-Danlos syndrome or connective tissue diseases

Atrophic scarring or joint dislocations; hypermobile joints; skin hyperextensibility


note: Disorders are categorized as predominantly bleeding or bruising and are in order of relative frequency.

Table 2

Evaluation of Bleeding Disorders

Prothrombin time Partial thromboplastin time Further evaluation Next step

Normal

Normal

Platelet Function Analyzer-100, which checks the amount of time it takes platelets to aggregate onto an aperture coated with a collagen/epinephrine membrane and a collagen/adenosine diphosphate membrane

Is there a prolonged aggregation time with both membranes?

  • Yes: Evaluate for von Willebrand's disease

  • No: If prolonged aggregation time is found only with the collagen/epinephrine membrane, look for drug effect, such as from aspirin. If neither are prolonged, further evaluation is warranted, based on clinical suspicion

Normal

Abnormal

Partial thromboplastin time mixing study

Does partial thromboplastin time correct (normalize)?

  • Yes: Factor VIII, IX, and XI assays. If factor VIII low, work-up for von Willebrand's disease

  • No: Screen for inhibitors (lupus anticoagulant and factor VIII inhibitor)

Abnormal

Normal

Determine if the patient is malnourished or if there is clinical suspicion for vitamin K deficiency

Does prothrombin time correct or normalize with administration of vitamin K?

  • Yes: Replace vitamin K as needed

  • No: Factor assay for factor VII

Abnormal

Abnormal

Consider disseminated intravascular coagulopathy

Consider factor assays for factor deficiencies

Verify no use of warfarin (Coumadin) or heparin

Verify no liver disease


Information from references 1 and 2.

Table 2   Evaluation of Bleeding Disorders

View Table

Table 2

Evaluation of Bleeding Disorders

Prothrombin time Partial thromboplastin time Further evaluation Next step

Normal

Normal

Platelet Function Analyzer-100, which checks the amount of time it takes platelets to aggregate onto an aperture coated with a collagen/epinephrine membrane and a collagen/adenosine diphosphate membrane

Is there a prolonged aggregation time with both membranes?

  • Yes: Evaluate for von Willebrand's disease

  • No: If prolonged aggregation time is found only with the collagen/epinephrine membrane, look for drug effect, such as from aspirin. If neither are prolonged, further evaluation is warranted, based on clinical suspicion

Normal

Abnormal

Partial thromboplastin time mixing study

Does partial thromboplastin time correct (normalize)?

  • Yes: Factor VIII, IX, and XI assays. If factor VIII low, work-up for von Willebrand's disease

  • No: Screen for inhibitors (lupus anticoagulant and factor VIII inhibitor)

Abnormal

Normal

Determine if the patient is malnourished or if there is clinical suspicion for vitamin K deficiency

Does prothrombin time correct or normalize with administration of vitamin K?

  • Yes: Replace vitamin K as needed

  • No: Factor assay for factor VII

Abnormal

Abnormal

Consider disseminated intravascular coagulopathy

Consider factor assays for factor deficiencies

Verify no use of warfarin (Coumadin) or heparin

Verify no liver disease


Information from references 1 and 2.

Illustrated Case Studies

CASE ONE

A 52-year-old man gave a lifelong history of easy bruising and excessive bleeding following tooth extractions. After taking aspirin, he developed severe nosebleeds. Family history was remarkable for heavy vaginal bleeding in his mother and sister.

CASE TWO

A 35-year-old woman presents with bruising of the upper thighs. She denies menorrhagia or other bleeding symptoms. She reports two vaginal deliveries, an appendectomy, and a tubal ligation, all without excessive bleeding. Her family history does not suggest a bleeding disorder and, except for the simple bruising, her physical examination is unremarkable.

CASE THREE

A 43-year-old woman was admitted to the hospital with a large hematoma in the right thigh. She had no history of trauma or spontaneous bleeding and had tolerated minor surgical procedures in the past without bleeding. Her family history was negative and she had not been on any medications associated with increased bleeding risk.

History and Physical Examination

Taking a personal history starts with a list of screening questions based on a bleeding score system (Table 3).3 This bleeding score system is a clinical decision rule to screen for von Willebrand's disease, the most common inherited bleeding disorder. This disease results from a quantitative or qualitative defect in von Willebrand's factor, which is required for platelet aggregation. Although the bleeding score system is intended for the diagnosis of von Willebrand's disease, it lists criteria necessary to diagnose other bleeding disorders as well.49 A history of bleeding that requires surgical intervention, blood transfusion, or replacement therapy is a significant red flag for a bleeding disorder and, therefore, receives a high number of points. More information on the bleeding score can be found at http://www.euvwd.group.shef.ac.uk/bleed_score.htm. Table 43 indicates the probability of von Willebrand's disease based on the bleeding score.

Table 3

Bleeding Score System for Evaluation of Bleeding History

Symptom Score
–1 0 1 2 3 4

Epistaxis

No or trivial (< 5 episodes per year)

> 5 episodes per year or lasts > 10 minutes

Consultation only*

Packing, cauterization, or antifibrinolytic

Blood transfusion, replacement therapy, or desmopressin (DDAVP)

Cutaneous (bruises, petechia, subcutaneous hematoma)

No or trivial (< 1 cm)

> 1 cm and no trauma

Consultation only*

Bleeding minor wounds

No or trivial (< 5 episodes per year)

> 5 episodes per year or lasts > 5 minutes

Consultation only*

Surgical hemostasis

Blood transfusion, replacement therapy, or desmopressin

Oral cavity (bleeding gums [spontaneous or with brushing], bites to lip and tongue, tooth eruption)

No

Bleeding noted at least once

Consultation only*

Surgical hemostasis or antifibrinolytic

Blood transfusion, replacement therapy, or desmopressin

Gastrointestinal bleeding (hematemesis, hematochezia, melena)

No

Associated with angiodysplasia, hemorrhoids, portal hypertension, ulcer

Spontaneous

Surgical hemostasis, blood transfusion, replacement therapy, desmopressin, or antifibrinolytic

Tooth extraction

No bleeding in at least two extractions

None performed or no bleed in one extraction

Bleeding noted in < 25% of all procedures

Bleeding noted in > 25% of all procedures, but no intervention

Resuturing or packing

Blood transfusion, replacement therapy, or desmopressin

Surgery

No bleeding in at least two surgeries

None performed or no bleeding in one surgery

Bleeding noted in < 25% of all procedures

Bleeding noted in > 25% of all procedures, but no intervention

Surgical hemostasis or antifibrinolytic

Blood transfusion, replacement therapy, or desmopressin

Menorrhagia

No

Consultation only*

Antifibrinolytics, pill use

Dilatation and curettage, iron therapy

Blood transfusion, replacement therapy, desmopressin, or hysterectomy

Postpartum hemorrhage

No bleeding in at least two deliveries

No deliveries or no bleeding in one delivery

Consultation only*

Dilatation and curettage, iron therapy, antifibrinolytics

Blood transfusion, replacement therapy, or desmopressin

Hysterectomy

Muscle hematomas

Never

Post-trauma, no therapy

Spontaneous, no therapy

Spontaneous or traumatic, requiring desmopressin or replacement therapy

Spontaneous or traumatic, requiring surgical intervention or blood transfusion

Hemarthrosis

Never

Post-trauma, no therapy

Spontaneous, no therapy

Spontaneous or traumatic, requiring desmopressin or replacement therapy

Spontaneous or traumatic, requiring surgical intervention or blood transfusion

Central nervous system bleeding

Never

Subdural, any intervention

Intracerebral, any intervention


note: This bleeding score system has not been prospectively validated.

*— Implies that a referral was made to a specialist for bleeding, but that no treatment was administered.

Adapted with permission from Tosetto A, Rodeghiero F, Castaman G, et al. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results for a multicenter European study (MCMDM-1 VWD). J Thromb Haemost. 2006;4(4):768.

Table 3   Bleeding Score System for Evaluation of Bleeding History

View Table

Table 3

Bleeding Score System for Evaluation of Bleeding History

Symptom Score
–1 0 1 2 3 4

Epistaxis

No or trivial (< 5 episodes per year)

> 5 episodes per year or lasts > 10 minutes

Consultation only*

Packing, cauterization, or antifibrinolytic

Blood transfusion, replacement therapy, or desmopressin (DDAVP)

Cutaneous (bruises, petechia, subcutaneous hematoma)

No or trivial (< 1 cm)

> 1 cm and no trauma

Consultation only*

Bleeding minor wounds

No or trivial (< 5 episodes per year)

> 5 episodes per year or lasts > 5 minutes

Consultation only*

Surgical hemostasis

Blood transfusion, replacement therapy, or desmopressin

Oral cavity (bleeding gums [spontaneous or with brushing], bites to lip and tongue, tooth eruption)

No

Bleeding noted at least once

Consultation only*

Surgical hemostasis or antifibrinolytic

Blood transfusion, replacement therapy, or desmopressin

Gastrointestinal bleeding (hematemesis, hematochezia, melena)

No

Associated with angiodysplasia, hemorrhoids, portal hypertension, ulcer

Spontaneous

Surgical hemostasis, blood transfusion, replacement therapy, desmopressin, or antifibrinolytic

Tooth extraction

No bleeding in at least two extractions

None performed or no bleed in one extraction

Bleeding noted in < 25% of all procedures

Bleeding noted in > 25% of all procedures, but no intervention

Resuturing or packing

Blood transfusion, replacement therapy, or desmopressin

Surgery

No bleeding in at least two surgeries

None performed or no bleeding in one surgery

Bleeding noted in < 25% of all procedures

Bleeding noted in > 25% of all procedures, but no intervention

Surgical hemostasis or antifibrinolytic

Blood transfusion, replacement therapy, or desmopressin

Menorrhagia

No

Consultation only*

Antifibrinolytics, pill use

Dilatation and curettage, iron therapy

Blood transfusion, replacement therapy, desmopressin, or hysterectomy

Postpartum hemorrhage

No bleeding in at least two deliveries

No deliveries or no bleeding in one delivery

Consultation only*

Dilatation and curettage, iron therapy, antifibrinolytics

Blood transfusion, replacement therapy, or desmopressin

Hysterectomy

Muscle hematomas

Never

Post-trauma, no therapy

Spontaneous, no therapy

Spontaneous or traumatic, requiring desmopressin or replacement therapy

Spontaneous or traumatic, requiring surgical intervention or blood transfusion

Hemarthrosis

Never

Post-trauma, no therapy

Spontaneous, no therapy

Spontaneous or traumatic, requiring desmopressin or replacement therapy

Spontaneous or traumatic, requiring surgical intervention or blood transfusion

Central nervous system bleeding

Never

Subdural, any intervention

Intracerebral, any intervention


note: This bleeding score system has not been prospectively validated.

*— Implies that a referral was made to a specialist for bleeding, but that no treatment was administered.

Adapted with permission from Tosetto A, Rodeghiero F, Castaman G, et al. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results for a multicenter European study (MCMDM-1 VWD). J Thromb Haemost. 2006;4(4):768.

Table 4

Diagnosis of von Willebrand's Disease Using the Bleeding Score

Bleeding score Likelihood ratio* Post-test probability (%)

−3

0.00

0.0

−2

0.04

0.2

−1

0.10

0.5

0

0.13

0.7

1

1.60

8.0

2

2.20

10.0

3

3.00

13.0

4

16.00

43.0


note: This table is based on a 5 percent pretest probability.

*— Likelihood ratio with a 95% confidence interval.

Adapted with permission from Tosetto A, Rodeghiero F, Castaman G, et al. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results for a multicenter European study (MCMDM-1 VWD). J Thromb Haemost. 2006;4(4):771.

Table 4   Diagnosis of von Willebrand's Disease Using the Bleeding Score

View Table

Table 4

Diagnosis of von Willebrand's Disease Using the Bleeding Score

Bleeding score Likelihood ratio* Post-test probability (%)

−3

0.00

0.0

−2

0.04

0.2

−1

0.10

0.5

0

0.13

0.7

1

1.60

8.0

2

2.20

10.0

3

3.00

13.0

4

16.00

43.0


note: This table is based on a 5 percent pretest probability.

*— Likelihood ratio with a 95% confidence interval.

Adapted with permission from Tosetto A, Rodeghiero F, Castaman G, et al. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results for a multicenter European study (MCMDM-1 VWD). J Thromb Haemost. 2006;4(4):771.

A positive family history increases the risk of a bleeding disorder and is reason to initiate a work-up,10,11 especially in women with menorrhagia.12 Many bleeding disorders have an inheritance pattern, including the X-linked recessive hemophilias. Family history is especially important in children because they may not have had the opportunity to experience a hemostatic challenge (e.g., surgery, delivery, tooth extraction). In a study of children referred to a tertiary care center with either a personal or family history of bleeding, a positive family history was significantly associated with a diagnosis of a bleeding disorder.10

The patient in case study one who had a history of bruising and bleeding after tooth extraction would have a bleeding score of at least 4 (epistaxis: 1; bruising: 1; and tooth extraction: 2). This score, coupled with his family history of menorrhagia in the mother and sister, creates a high index of suspicion for a bleeding disorder, even before any laboratory testing is obtained.

The bleeding score system assigns a negative number if there is no significant bleeding after a hemostatic challenge. The importance of the “negative history” is illustrated by the woman in case study two who had bruising on her upper thigh (score: 1); an appendectomy and tubal ligation without a significant bleed (score: −1); two vaginal deliveries without a significant bleed (score: −1); and no other bleeding symptoms (score: 0). This gives her a total bleeding score of −1.

As illustrated in case study three, a patient may have a low bleeding score and a negative family history, but still present with physical examination findings suggestive of a bleeding disorder. Pertinent physical examination findings of bleeding and bruising disorders are listed in the second column of Table 1.

Table 546 lists medications that cause bleeding or bruising. The physician should not rule out a bleeding disorder just because a patient is receiving one of these medications, especially if the patient has a high bleeding score. Medications may cause the disease to manifest itself with bleeding symptoms, as illustrated in case study one.

Table 5

Medications That Cause Bleeding and Bruising

Common

Aspirin

Clopidogrel (Plavix)

Heparin

Nonsteroidal anti-inflammatory drugs

Warfarin (Coumadin)

Rare

Cephalosporins

Ginkgo biloba

Gold

Interferon

Metaxalone (Skelaxin)

Penicillins

Propothiouricil

Selective serotonin reuptake inhibitors

Testosterone replacement

Tricyclic antidepressants


Information from references 4 through 6.

Table 5   Medications That Cause Bleeding and Bruising

View Table

Table 5

Medications That Cause Bleeding and Bruising

Common

Aspirin

Clopidogrel (Plavix)

Heparin

Nonsteroidal anti-inflammatory drugs

Warfarin (Coumadin)

Rare

Cephalosporins

Ginkgo biloba

Gold

Interferon

Metaxalone (Skelaxin)

Penicillins

Propothiouricil

Selective serotonin reuptake inhibitors

Testosterone replacement

Tricyclic antidepressants


Information from references 4 through 6.

Initial Laboratory Evaluation

Understanding of the complexity of hemostasis has greatly increased since it was originally described in 1964.13,14 Interactions of basic “ingredients” are required for a clot to form, and a qualitative or quantitative defect of any “ingredient” can result in a bleeding or bruising disorder. Knowledge of basic clot formation can help the physician to understand these disorders and their initial laboratory work-up, which includes complete blood count with platelet count, peripheral blood smear, prothrombin time (PT), and partial thromboplastin time (PTT).

COMPLETE BLOOD COUNT AND PERIPHERAL BLOOD SMEAR

A shortage of platelets (thrombocytopenia) can be detected on complete blood count. A peripheral blood smear can help to rule out pseudothrombocytopenia and to look for abnormally shaped platelets.

PT AND PTT

The PT measures the factors of the extrinsic and common pathways. Deficiencies of these factors (most notably factor VII) will prolong the PT. Vitamin K is required for the synthesis of the critical factors of these pathways; therefore, patients with vitamin K deficient conditions may have a prolonged PT.15

The PTT measures the factors of the intrinsic and common pathways. Deficiencies of these factors, including factor VIII (hemophilia A) and factor IX (hemophilia B), will prolong the PTT. Factor VIII levels may be low in patients with von Willebrand's disease; therefore, these patients could present with a prolonged PTT.1

Inhibitors, autoantibodies that attach to a factor and render it useless for clot formation, can also prolong the PTT. The most common inhibitors are the factor VIII inhibitors and the lupus anticoagulant (“lupus anticoagulant” is incorrectly named and typically presents more often as thrombosis than as bleeding). A factor VIII inhibitor should be suspected in anyone who has no history of bleeding, but develops significant bleeding (such as the woman with the large spontaneous hematoma in case study three) and has a prolonged PTT.16

Specialized Laboratory Tests

PLATELET FUNCTION ACTIVITY

Traditionally, the test of choice for evaluation of platelet function was bleeding time; however, the use of bleeding time to predict surgical bleeding has been questioned17,18 and its use has been discouraged or eliminated at some institutions.1,19 The Platelet Function Analyzer (PFA)-100 has been shown to be superior to bleeding time in detecting von Willebrand's disease.2022

The PFA-100 simulates the formation of the platelet plug in vivo by passing the patient's blood through an aperture coated with collagen/epinephrine and collagen/adenosine diphosphate. In patients with von Willebrand's disease and other platelet function disorders, the amount of time required for the platelets to aggregate from both collagen/epinephrine and collagen/adenosine diphosphate is prolonged. A prolonged time to clot to just collagen/epinephrine usually indicates a drug effect, such as from aspirin.

The reported sensitivity of the PFA-100 for diagnosing von Willebrand's disease and other platelet function disorders is 88 to 90 percent with a specificity of 86 to 94 percent.23,24 Studies have concluded that the PFA-100 is a useful screening test,23,24 but this conclusion is still being debated.2428 Although the PFA-100 is more sensitive than bleeding time, a negative result should not preclude further testing for von Willebrand's disease or other platelet function disorders. If the PFA-100 is negative, the physician should review the initial history to determine if further testing should be performed.

MIXING STUDIES AND INHIBITOR AND FACTOR ASSAYS

A mixing study determines if the patient has a clotting factor deficiency or an inhibitor to a factor. When one part of the patient's blood is mixed with one part of normal blood, the inhibitor in the patient's blood disables the factor in the normal blood. The PTT stays prolonged and does not “correct.” Inhibitor assays are then performed to identify which inhibitor is present. When the blood from a patient with a factor VIII deficiency is mixed with normal blood, the PTT should normalize or correct. Factor assays are then performed to identify which factor is deficient.

The sensitivity of the mixing study to detect a lupus anticoagulant is 95 percent with a specificity of 60 percent.29 In a study of 42 laboratories asked to analyze known samples,30 97.5 percent correctly identified the sample with a lupus anticoagulant and 90.2 percent correctly reported the negative serum sample as negative. However, 53.6 percent did not correctly identify the factor VIII inhibitor and many did poorly with contaminated specimens. Therefore, knowledge of a laboratory's limitations, especially when trying to identify an inhibitor that is not a lupus anticoagulant, is helpful when interpreting the results.

Referral

If the laboratory work-up does not diagnose a bleeding disorder, but there is still high suspicion based on personal and family history, the patient should be referred to a hematologist. If von Willebrand's disease, a factor VIII inhibitor, or factor deficiencies are discovered, referral is based on the diagnosis and severity, as well as the comfort level of the physician. If the history, physical examination, or the routine laboratory studies are abnormal in the preoperative assessment, surgery should be delayed until a cause can be determined with a work-up or by referral.

RESOLUTION OF CASE STUDIES

Case One. Laboratory testing included a normal blood count and platelet count. A PFA-100 test was abnormal to collagen/epinephrine and collagen/adenosine diphosphate. Further testing was diagnostic for von Willebrand's disease.

Case Two. A complete blood count, PT, PTT, and PFA-100 were normal. The patient was reassured that with a low bleeding score, a negative family history, and an unremarkable physical examination, she most likely has purpura simplex (easy bruising). She was told to follow up if her symptoms got worse or if she had any new symptoms.

Case Three. Laboratory evaluation included a hemoglobin count of 7 g per dL (70 g per L), a platelet count of 400 × 103 per μL (400 × 109 per L), a PT of 12 seconds, and a PTT of 100 seconds. A mixing study did not return the PTT to normal. Measurement of factor VIII showed a level of 1 percent, and an assay for the presence of a factor VIII inhibitor showed a high-titer inhibitor.

The Authors

MICHAEL BALLAS, MD, is a family physician at Wilson Care in Fort Loramie, Ohio. He received his medical degree from The Ohio State University in Columbus, and completed a family practice residency and a sports medicine fellowship at St. Elizabeth's Hospital (now called Franciscan Medical Center) in Dayton, Ohio.

ERIC H. KRAUT, MD, is a professor of internal medicine and director of benign hematology in the division of hematology and oncology at The Ohio State University. Dr. Kraut received his medical degree from Temple University School of Medicine in Philadelphia, Pa. He completed an internal medicine residency at the University of Pittsburgh (Pa.), and a hematology and oncology fellowship at The Ohio State University.

Address correspondence to Michael Ballas, MD, Wilson Care, 11531 State Route 66, Minster, OH 45865 (e-mail: mballas@nktelco.net). Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

REFERENCES

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2. Zehnder JL. Clinical use of coagulation tests. UpTo-Date, 2007. http://www.uptodate.com [Subscription required]. Accessed September 19, 2007.

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5. Valente MJ, Abramson N. Easy bruisability. South Med J. 2006;99(4):366–370.

6. Colon-Otero G, Cockerill KJ, Bowie EJ. How to diagnose bleeding disorders. Postgrad Med. 1991;90(3):145–150.

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