Hemostasis And Its Regulation

1.

A 21-year-old woman with no significant medical history presents for evaluation of gingival bleeding. She also complains of heavy menses. She denies having any bleeding problems in the past. Physical examination reveals only gingival bleeding with minimal manipulation. Results of today's laboratory evaluation are as follows: leukocyte count, 8,000; hemoglobin, 14; platelets, 245,000; coagulation, normal. The platelet size is normal. Further evaluation reveals a suboptimal platelet aggregation response to ristocetin. The results of the rest of the aggregation testing are normal. Which of the following is the most likely diagnosis for this patient?

A.

Vitamin C deficiency
B.

Vitamin K deficiency
C.

Von Willebrand disease
D.

Bernard-Soulier disease
E.

None of the above

Correct Answer
C. Von Willebrand disease

Explanation
To test aggregation, dilute concentrations of platelet agonists (e.g., adenosine diphosphate [ADP], epinephrine, collagen, and ristocetin) are added to citrated platelet-rich plasma. With the weak agonists, such as ADP and epinephrine, the initial primary wave of aggregation is followed by a secondary wave. The secondary wave reflects the induction of the platelet release reaction, in which platelet granule contents are released to augment further platelet aggregation. A suboptimal secondary wave is seen with platelet storage pool defects in which either platelet granule content is diminished or its release activity is impaired. The latter is commonly associated with aspirin intake or uremia-related thrombocytopathy. Patients with von Willebrand disease have a suboptimal platelet aggregation response to ristocetin but a normal response to the other agonists.

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2.

A 45-year-old woman is hospitalized after presenting to the emergency department with dyspnea. She has a history of systemic lupus erythematosus. She is diagnosed with a pulmonary thromboembolism. Her laboratory evaluation is unremarkable except for a partial thromboplastin time (PTT) of 50 sec (before the initiation of any therapy). Anticoagulation therapy is started with an unfractionated heparin drip. In addition, the patient is tested for lupus anticoagulant. The hematologist advises that the patient's anti-factor Xa activity level be monitored to confirm that the heparin level is therapeutic. Of the following, which is a therapeutic anti-factor Xa activity level for this patient?

A.

0.5 to 1.2 units/ml 4-6 hours after last dose of low-molecular-weight heparin
B.

0.3-0.7 units/ml
C.

5 units/ml
D.

0.1 units/ml
E.

None of the above

Correct Answer
A. 0.5 to 1.2 units/ml 4-6 hours after last dose of low-molecular-weight heparin

Explanation
A prolonged clotting time (e.g., activated PTT [aPTT] of 60 seconds [normal, 28 to 30 seconds]) can be caused by either a clotting factor deficiency or an inhibitor. An inhibitor is generally an antibody directed against a specific clotting factor or against a phospholipid-protein complex, the so-called lupus anticoagulant. An anti–factor Xa activity of 0.5 to 1.2 units/ml at 4 to 6 hours after the last dose of low-molecular-weight heparin is considered therapeutic. The anti-factor Xa activity test can also be used to determine the plasma heparin level when the calibration curve used is based on known concentrations of heparin. This test is done by an automated analyzer and provides more accurate monitoring of heparin's anticoagulant activity than does aPTT. The therapeutic heparin level is generally in the range of 0.3 to 0.7 units/ml.

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3.

A 54-year-old man with a history of hypertension presents to clinic for preoperative evaluation. He is scheduled to undergo an elective hernia repair. He has a history of easy bruising and of excessive and prolonged bleeding after tooth extractions. Routine laboratory studies are done and the patient's bleeding time is determined. The platelet count and bleeding time are both normal. For this patient, which of the following statements are true?

A.

He should receive a platelet transfusion before the operation
B.

A normal bleeding time does not accurately predict risk of hemorrhage
C.

His surgery should be cancelled
D.

He is not at risk for excessive bleeding because his platelet count is normal
E.

None of the above

Correct Answer
B. A normal bleeding time does not accurately predict risk of hemorrhage

Explanation
Hemostasis, the process of blood clot formation, is a coordinated series of responses to vessel injury. It requires complex interactions between platelets, the clotting cascade, blood flow and shear, endothelial cells, and fibrinolysis.Assessment of bleeding time primarily measures platelet function. A spring-loaded device is used to make a standard skin incision on the forearm. A prolonged bleeding time in a patient with a platelet count higher than 100,000/µl suggests impaired platelet function. The bleeding time is difficult to standardize, and a normal bleeding time does not predict the safety of surgical procedures or accurately predict hemorrhage. Consequently, this test should not be used as a general screening test in a preoperative setting.

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4.

A 34-year-old woman presents to clinic for a follow-up visit. She had a complicated hospital course 1 year ago. Initially, she was hospitalized with pneumonia and bacteremia. During hospitalization, she developed deep vein thrombosis in her right leg. At the time, a hypercoaguable workup only revealed a low protein S level (the test was performed before the initiation of warfarin). The patient received anticoagulation therapy for 6 months. Repeat laboratory evaluation 6 weeks after completing her warfarin regimen reveals a normal protein S level. For this patient, which of the following statements are true?

A.

She has protein S deficiency
B.

She should once again receive anticoagulation therapy
C.

The initial protein S level was low because the binding protein was increased
D.

The patient should not have been treated with anticoagulation
E.

None of the above

Correct Answer
C. The initial protein S level was low because the binding protein was increased

Explanation
Protein C and protein S both show some structural similarity to the vitamin K-dependent clotting factors (prothrombin, factor VII, factor IX, and factor X). Protein S circulates in two forms: a free form, in which it is active as an anticoagulant, and a bound, inactive form, in which it is complexed to C4b-binding protein of the complement system. C4b-binding protein acts as an acute-phase reactant. The resultant increase in inflammatory states reduces the activity of free protein S, enhancing the likelihood of thrombosis.

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5.

An 18-year-old man with a medical history significant for a "bleeding disorder" presents for evaluation of easy bruising. He denies experiencing any bleeding at this time. Results of today's laboratory evaluation are as follows: leukocyte count, 6,000; Hb, 13; platelets, 200,000; prothrombin time, 13 sec; and PTT, 70 sec. His repeat PTT was 67 sec. A mixing study was performed with correction of the PTT. Which of following is the most likely diagnosis?

A.

Factor VIII deficiency
B.

Lupus Anticoagulant
C.

Factor VIII inhibitor
D.

Glanzmann thrombasthenia
E.

None of the above

Correct Answer
A. Factor VIII deficiency

Explanation
A prolonged clotting time (e.g., aPTT of 60 seconds [normal, 28 to 30 seconds]) can be caused by either a clotting factor deficiency or an inhibitor. An inhibitor is generally an antibody directed against a specific clotting factor or against a phospholipid-protein complex, the so-called lupus anticoagulant. In a mixing study, one volume of a patient's plasma is mixed with an equal volume of normal plasma. The resulting mixture provides at least 50% of a deficient factor and corrects the abnormality. If the problem is caused by an inhibitor, the resulting plasma mixture still has a prolonged clotting time. A mixing study should always be done when a prolonged clotting time is noted.

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