2.5: Hemostasis Problem- Solving

Question 1

2.5.1:

Answer 1

C. ITP

These clinical manifestations and laboratory results are consistent with ITP. ITP is an autoimmune thrombocytopenia. In children, acute ITP occurs after a viral infection, as was the case in this 3-year-old patient. Clinical manifestations are associated with petechiae, purpura, and mucous membrane bleeding, such as epistaxis and gingival bleeding. Abnormal laboratory tests include a very low PLT count, and other causes of thrombocytopenia should be ruled out in patients with suspected ITP.

Question 2

2.5.2:

Answer 2

B. von Willebrand disease

These clinical manifestations and laboratory results are consistent with von Willebrand
disease. von Willebrand disease is an inherited bleeding disorder caused by abnormal
PLT adhesion and aggregation. In von Willebrand disease, VWF is deficient or
dysfunctional. VWF enhances the release of factor VIII from the liver, and it also
forms a complex with factor VIII in the circulation. Deficient or dysfunctional VWF
results in decreased factor VIII as well and, therefore, an increase in APTT values. The
clinical manifestations associated with von Willebrand disease are easy bruising,
epistaxis, and bleeding after surgery. The diagnostic laboratory test shows abnormal
PLT aggregation to ristocetin, which is corrected by addition of normal plasma
containing VWF. APTT is prolonged as a result of the deficiency of factor VIII. Factor
VIII activity (VIII:C), VWF ristocetin cofactor activity (VWF:Rco), and VWF:
antigenic activity (VWF:antigen) are abnormal. The PLT count and PT are normal in
von Willebrand disease.

Question 3

2.5.3:

Answer 3

D. Cryoprecipitate

Cryoprecipitate contains fibrinogen, factor VIII, and VWF. FFP has all of the clotting
factors; however, it is not the best choice if cryoprecipitate is available.

Question 3

2.5.4: A 30-year-old woman develops signs and symptoms of thrombosis in her left lower leg
after 5 days of heparin therapy. The patient had had open-heart surgery 3 days previously and has been on heparin ever since. Which of the following would be most helpful in making the diagnosis?

A. Fibrinogen assay
B. PT
C. PLT count
D. Increased heparin dose

Answer 3

C. PLT count

The PLT count should be checked every other day in patients receiving heparin
therapy. HIT should be suspected in patients who are not responding to heparin therapy
and/or are developing thrombocytopenia (50% below the baseline value) and
thrombotic complications while on heparin therapy. Increase in heparin dose should be
avoided in patients with the clinical symptoms of thrombosis while they are receiving
heparin. Fibrinogen assay and PT are not the appropriate assays for monitoring heparin
therapy, nor are they used to test for HIT.

Question 4

2.5.5:

Answer 4

D. Factor VIII inhibitor

Factor VIII inhibitor is found in 20% to 25% of patients with hemophilia receiving
replacement therapy. It may also develop in patients with immunologic problems,
women after childbirth, and patients with lymphoproliferative and plasma cell
disorders, or it may develop in response to medications. Factor VIII inhibitor is an IgG
with an inhibitory effect that is time and temperature dependent. The presence of factor
VIII inhibitor causes elevated APTT in the face of a normal PT. Mixing studies in
factors VIII and IX deficiencies will correct the prolonged APTT both at the immediate
mixing stage and after incubation for 2 hours. APTT would not be corrected by mixing
studies in the presence of factor VIII inhibitor. In addition, factor VIII inhibitor is
associated with bleeding. Lupus anticoagulant is associated with thrombosis and not
bleeding unless it coexists with thrombocytopenia, which is not the case in this patient

Question 5

2.5.6:

Answer 5

C. Cirrhosis of the liver

The clinical presentation and laboratory results in this patient are indicative of cirrhosis
of the liver. Most of the clotting factors are made in the liver. A decrease in multiple
clotting factors is associated with prolonged PT and APTT. Macrocytosis and target
cells are present in liver disease. The liver changes the unconjugated bilirubin to
conjugated bilirubin. Conjugated bilirubin is excreted into the intestines, where
bilirubin is converted to urobilinogen and excreted into feces. In cirrhosis of the liver,
both necrosis and obstruction caused by scarring produce increases in unconjugated
and conjugated bilirubin, respectively. In addition, the liver enzymes are elevated (the
AST:ALT ratio is less than 1 in necrotic liver diseases, such as hepatitis, but not in
cirrhosis).

Question 6

2.5.7: When performing a mixing study, the patient’s APTT is corrected to 12% of normal. What is the most appropriate interpretation of these findings?

A. The APTT is considered corrected
B. The APTT is considered uncorrected
C. The laboratory protocol should be followed for the interpretation of correction
D. A circulating anticoagulant can be ruled out

Answer 6

C. The laboratory protocol should be followed for the interpretation of correction

Interpretation of correction studies varies among different laboratories. Some define correction when the mixing study result falls within 10% of the normal plasma; other
laboratories conclude correction when the mixing result falls within 5 seconds of normal plasma, or a value within the APTT reference range. Only 50% factor activity is required for normal PT or APTT. A circulating anticoagulant typically results in failure to correct the APTT with normal plasma.

Question 7

2.5.8: A standard blue-top tube filled appropriately (with 4.5 mL blood) was submitted to the laboratory for preoperative PT and APTT testing. The results of both tests were elevated. The patient’s PT and APTT from the previous day were within normal limits, and he was not on heparin therapy. Which is the most appropriate first step to investigate the abnormal results?

A. Report the result as obtained
B. Perform a mixing study
C. Check the sample for a clot
D. Report APTT only

Answer 7

C. Check the sample for a clot

A clot can form because of inadequate mixing of the sample after venipuncture, if the
blood fills the evacuated tube at a slow rate, or with traumatic venipuncture. In vitro,
blood clots result in consumption of the clotting factors and, therefore, prolongation of
PT, APTT, and other clot-based assays. If the clotting factors have been activated but
the clot formation is incomplete, it may result in shortening of PT and APTT.
Checking the sample for a clot is the most reasonable step in this case.

Question 8

2.5.9: A plasma sample submitted to the laboratory for PT testing has been stored for 25 hours
at 4°C. PT is shortened. What is the most probable cause?

A. Factor VII deficiency
B. Activation of factor VII caused by exposure to cold temperature
C. Lupus inhibitor
D. Factor X inhibitor

Answer 8

B. Activation of factor VII caused by exposure to cold temperature

Samples for evaluation of PT are stable for 24 hours if kept at room temperature.
Prolonged exposure to cold will activate factor VII, resulting in decreased PT

Question 8

2.5.10: APTT is not increased in a patient receiving heparin. Which of the following factors
may be associated with the lack of response to heparin therapy in this patient?

A. Protein C deficiency
B. AT deficiency
C. Protein S deficiency
D. Factor VIII deficiency

Answer 8

B. AT deficiency

AT deficiency in patients receiving heparin therapy may lead to heparin resistance
and, therefore, lack of prolongation of APTT. AT is a heparin cofactor and, as such,
increases heparin activity by 1,000-fold. Deficiency of AT is associated with poor
response to heparin therapy.

Question 9

2.5.11: A 50-year-old patient was admitted to the emergency department with a complaint of
pain in the right leg. The leg was red, swollen, and warm to the touch. DVT was suspected, and the patient was started on heparin therapy. Which of the following is
(are) the proper protocol(s) to evaluate patients receiving heparin therapy?

A. Baseline APTT and PLT count; APTT testing every 4 to 6 hours after the initial heparin bolus
B. Repeat APTT 5 days after heparin therapy to adjust the therapeutic dose
C. Monitor the PLT count daily and every other day after heparin therapy is completed
D. Monitor PT daily to adjust the therapeutic dose

Answer 9

A. Baseline APTT and PLT count; APTT testing every 4 to 6 hours after the initial heparin bolus

Baseline PLT count and APTT should be performed on all patients prior to
administration of heparin. APTT should be repeated every 4 to 6 hours after bolus
injection (high dose). Response to heparin therapy varies among patients for the
following reasons: heparin half-life is decreased in extended thrombosis, and the
anticoagulant activities of heparin change based on nonspecific binding of heparin to
plasma proteins. Therefore, heparin therapy should be closely monitored. Heparin
dosage can be adjusted based on the anti–factor Xa assay. In addition, the PLT count
should be monitored regularly during heparin therapy because decrease of the PLT
count to 50% below the baseline value is significant and may be associated with HIT.
PT is not used to monitor heparin therapy.

Question 9

2.5.12:

Answer 9

C. TTP

The clinical manifestations and laboratory results in this patient are consistent with
TTP. The clinical manifestations of TTP include MAHA, thrombocytopenia, fever,
renal failure, and neurological symptoms. The neurological symptoms in this patient
are manifested by headache, dizziness, nausea, and vomiting. Weakness and lethargy
are signs and symptoms of anemia. Low Hgb and Hct with normal MCV and MCHC
indicate a normocytic normochromic anemia. The presence of schistocytes in
peripheral blood, with low platelet counts and low haptoglobin, are consistent with
MAHA. The high BUN and creatinine levels are characteristic of renal failure. The
platelet count, performed on admission, was done on a hematology analyzer and was falsely elevated because of the presence of microcytes or fragmented RBCs. The
manual platelet count was much lower. The coagulation tests are normal in TTP. In
von Willebrand disease, the platelet count is normal and the APTT is usually
abnormal. ITP is characterized by thrombocytopenia but not hemolytic anemia (HA).
DIC is associated with a low platelet count, HA, and abnormal coagulation studies.
The acute onset of symptoms in this patient may be related to mitomycin used for the
treatment of gastric carcinoma in this patient.

Question 10

2.5.13:

Answer 10

C. Glanzmann thrombasthenia

These clinical manifestations and laboratory results are consistent with Glanzmann
thrombasthenia. Epistaxis and easy bruising are characteristics of platelet disorders.
The positive family history is indicative of an inherited bleeding disorder. Laboratory
tests reveal a low Hgb level caused by epistaxis. The normal platelet count rules out
any quantitative platelet disorder. The platelet count is typically low in Bernard–
Soulier syndrome. Normal PT and APTT, combined with a normal factor VIII assay,
rule out coagulation disorders. The laboratory tests that confirm an inherited platelet
disorder are PLT aggregation studies. PLT aggregation is normal to ristocetin and abnormal to ADP, EPI, and thrombin. These results are consistent with Glanzmann
thrombasthenia. PLT aggregation is abnormal to ristocetin in von Willebrand disease
and Bernard–Soulier syndrome.

Question 11

2.5.14:

Answer 11

D. Lupus anticoagulant

These clinical manifestations and laboratory results are consistent with lupus
anticoagulant. Pain and swelling in the patient’s right leg may be indicative of
thrombosis. As many as 48% of women with repeated spontaneous abortions have
lupus anticoagulant or/and antibody to phospholipid, such as anticardiolipin antibodies.
The unremarkable family history in this patient rules out an inherited thrombotic
disorder. Normal TT rules out fibrinogen disorders. Prolonged PT and APTT in the
absence of bleeding history eliminate the diagnosis of factor deficiency. The APTT test
performed on a mixture of patient plasma and normal plasma did not correct the
prolonged APTT. This result is indicative of an inhibitor. However, because the patient
is not bleeding, factor VIII inhibitor is not indicated. A negative anticardiolipin
antibody result rules out the possibility of anticardiolipin antibodies being responsible
for the patient’s clinical symptoms. The laboratory test result that confirms the
presence of a lupus anticoagulant is prolonged APTT that is not corrected when mixed
with normal plasma and that is neutralized by preincubation with platelet phospholipid
(an excess of platelet phospholipid neutralizes the antibody, resulting in normal
APTT).

Question 12

2.5.15: A 60-year-old patient was admitted to a hospital for a liver biopsy. The biopsy was scheduled for 11:00 a.m. The coagulation results obtained at the time of admission revealed prolonged PT with an INR of 4.5. What is the physician’s most appropriate
course of action?

A. Proceed with biopsy because prolonged PT is expected in liver disease
B. Postpone the procedure for a couple of days
C. Cancel the procedure and start the patient on vitamin K therapy
D. Put patient on vitamin K therapy and proceed with the procedure immediately

Answer 12

C. Cancel the procedure and start the patient on vitamin K therapy

Performing liver biopsy in a patient with a prolonged PT and a high INR could have
life-threatening consequences. In this patient, the prolonged PT is likely caused by
liver disease. Vitamin K is stored in the liver and is essential for activation of factors
II, VII, IX, and X. Vitamin K needs bile (secreted by the liver) for its absorption. In
liver disease characterized by obstruction, bile is not secreted into the gastrointestinal
tract, and therefore, vitamin K is poorly absorbed. The most logical course of action is
the following: Start the patient on vitamin K therapy, repeat the PT test 4 days after
starting vitamin K administration, and cancel the biopsy until the patient’s PT returns
to normal.

Question 13

2.5.16: A fresh blood sample was sent to the laboratory at 8:00 a.m. for the PT test. At 4:00 p.m., the doctor requested for the APTT test to be done on the same sample. What should the technologist do?

A. Rerun the APTT on the 8:00 a.m. sample and report the result
B. Request a new sample for APTT
C. Run the APTT in duplicate and report the average
D. Mix patient plasma with normal plasma and run the APTT

Answer 13

B. Request a new sample for APTT

According to the CLSI guidelines, samples for APTT should be centrifuged and tested
within 2 hours after collection. However, the sample is stable for 4 hours if stored at
4°C. APTT evaluates the clotting factors in the intrinsic and common coagulation
pathways, including factor VIII (intrinsic) and factor V (common). Factors VIII and V
are cofactors necessary for fibrin formation. However, they are both labile. Storage
beyond 4 hours causes falsely elevated APTT results. The medical laboratory scientist
should request a new sample for the APTT test.

Question 14

2.5.17: An APTT test is performed on a patient and the result is 50 sec (reference range 27–37 sec). The instrument flags the result because of failure of the delta check. The patient had had an APTT of 35 sec the previous day. The technologist calls the nursing unit to
check whether the patient is on heparin therapy. The patient is not receiving heparin. What is the next appropriate step?

A. Check the patient’s family history for inherited factor VIII deficiency
B. Check to see if the patient has received any other anticoagulant medications
C. Perform mixing studies
D. Perform a factor VIII assay

Answer 14

B. Check to see if the patient has received any other anticoagulant medications

Traditional anticoagulant drugs, such as heparin and warfarin, are well known. Newer
anticoagulant drugs are available for the treatment and prevention of thrombosis. Some
of these new drugs have AT or anti–factor Xa effects and, therefore, increase PT,
APTT, and TT. Examples of these drugs are argatroban, which inhibits thrombin, and
fondaparinux, which inhibits factor Xa.

Question 15

2.5.18: A patient was put on heparin therapy postoperatively for prevention of thrombosis. The
patient had the following laboratory results on admission: Platelet count = 350 × 109/L;
PT = 12 sec (reference: 10–13 sec); APTT = 35 sec (reference: 28–37). After 6 days of
heparin therapy, the patient complained of pain and swelling in her left leg. Her platelet
count dropped to 85 × 109/L, and her APTT result was 36 sec. The physician suspected
HIT and ordered the PLT aggregation test to be performed immediately. The heparin-
induced PLT aggregation test result was negative. Heparin therapy was continued.
Several days later, the patient developed a massive clot in her left leg that necessitated
amputation. Which of the following should have been recognized or initiated?
A. The patient should have been placed on LMWH
B. The heparin dose should have been increased
C. The negative PLT aggregation does not rule out HIT
D. The patient should have been placed on warfarin therapy

Answer 15

C. The negative PLT aggregation does not rule out HIT

Heparin therapy should be stopped immediately when clinical symptoms indicate
HIT. The blood sample should be tested at least 4 hours after heparin therapy is
discontinued. Early sampling for HIT testing may give a false-negative result because
of the neutralization of antibody by heparin. LMWH should not be used in patients
who develop HIT because LMWH can also cause HIT. Warfarin therapy can be started
in patients who respond to heparin therapy. Heparin therapy must overlap warfarin
therapy until the INR reaches a stable therapeutic range (2.0–3.0). Warfarin therapy
could not be used in this patient because of lack of response to heparin therapy. The
first step in the treatment of HIT is discontinuation of heparin, including intravenous
catheter flushes, heparin-coated indwelling catheters, UFH, and LMWH.

Question 16

2.5.19:

What steps should be taken before releasing these results?
A. No follow-up steps are needed; report the results as obtained
B. Report Hgb and Hct results, adjust the anticoagulant volume, and redraw a new sample for
PT and APTT
C. Call the nurse and ask if the patient is receiving heparin
D. Because the patient is severely anemic, multiply the PT and APTT results by two and report the results

Answer 16

B. Report Hgb and Hct results, adjust the anticoagulant volume, and redraw a new sample for
PT and APTT

The anticoagulant:blood ratio should be adjusted for the PT and APTT tests in
patients with a severe anemia. The standard anticoagulant volume (0.5 mL) is not
sufficient for the large quantity of plasma in these patients, causing unreliable PT and
APTT results. The low Hgb and Hct in this patient were caused by severe bleeding
during surgery. To get accurate PT and APTT results, the amount of anticoagulant is
adjusted according to the following formula: (0.00185)(V) (100–H) = C, where V =
blood volume in mL; H = patient’s Hct; and C = volume of anticoagulant in mL. A
new sample should be drawn to rerun the PT and APTT. There are other causes for
decreased PT and APTT, such as increased fibrinogen and increased factor VIII;
however, the preanalytical variables affecting unreliable results should be ruled out
first. Heparin therapy would increase PT and APTT.

Question 17

2.5.20:

Answer 17

B. Factor V inhibitor

The absence of a positive family history in this patient indicates acquired
coagulopathy. Because both the PT and APTT test results are abnormal, the clotting
factor involved is most probably in the common pathway. The lack of correction by
mixing studies suggests the presence of an inhibitor. Factor V antibodies are the most
common antibodies among the clotting factors of the common pathway (I, II, V, and
X). Factor V antibodies are reported to be associated with surgery; some antibiotics,
such as streptomycin; exposure to blood products or the bovine form of “fibrin glue.
”
Patients with antibodies to factor V may require long-term therapy with
immunosuppressive drugs. Acute bleeding episodes may be treated by platelet
transfusions. The PT test is normal in patients with factor VIII deficiency and factor
VIII inhibitor. Lupus anticoagulant is not present with bleeding unless associated with
coexisting thrombocytopenia.