Excessive Bleeding or Clotting (Case 28)
Rebecca Kruse-Jarres MD, MPH
Case: A 74-year-old woman is in good general health except for hypothyroidism, which is well controlled on thyroid hormone replacement. Over the past month she noticed that she started bruising easily. She had never before had a problem with easy bruising, prolonged bleeding from cuts, or other unusual bleeding. She goes to see her primary-care physician, who orders a bleeding time. She presents to the ED 5 days after the test because she is still bleeding from the test site. She has multiple bruises covering her arms, trunk, and legs.
Differential Diagnosis
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Immune thrombocytopenic purpura (ITP) |
DIC |
Acquired factor VIII deficiency |
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Drug-induced thrombocytopenia |
Vitamin K deficiency |
Thrombotic thrombocytopenic purpura (TTP) |
Speaking Intelligently
When I encounter a patient with bleeding, the most important approach is to take a detailed history and perform a physical examination. First, I like to establish whether the bleeding disorder is of a chronic nature. Is this a condition the patient had all of his or her life, and do I have to think about congenital causes (such as hemophilia or von Willebrand’s disease), or is this of recent onset and more likely an “acquired” condition?
If the problem seems to have been going on for a significant portion of the patient’s life, it is crucial to get a good family history of any family member with bleeding tendencies and to draw a pedigree to establish the inheritance pattern.
If the bleeding is of more recent onset, it is critical to elicit any changes in the patient’s life that may have been contributory, such as new medications, newly diagnosed other medical conditions, other associated symptoms, and recent travel.
Finally, it is important to separate disorders of primary hemostasis from disorders of secondary hemostasis. Patients with primary hemostatic disorders usually present with superficial bleeding such as easy bruisability, gum bleeding, or menorrhagia; the primary hemostatic system involves platelets, von Willebrand factor, and a vessel wall. Patients with disorders of secondary hemostasis, such as factor deficiencies, usually present with deep bleeding such as cerebral hemorrhage or bleeding into muscles and joints.
PATIENT CARE
Clinical Thinking
• She also appears to have a disorder of primary hemostasis.
• The physical exam may point to other possible etiologies, such as a hematologic malignancy, which can cause thrombocytopenia.
History
• DIC may accompany disorders such as malignancy or sepsis.
Physical Examination
• Determine the pattern and location of blood loss.
• Look for bruising, petechiae, and bleeding from cuts, surgical sites, and IV access sites.
• Evaluate for possible oropharyngeal, GI, and genitourinary bleeding.
• Assess the mouth for signs of “wet” purpura characterized by blood-filled blisters.
Tests for Consideration
| Clinical Entities | Medical Knowledge |
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Immune Thrombocytopenic Purpura |
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Pφ |
In ITP, an antibody binds to the platelet surface, causing premature removal of platelets from the circulation by the phagocytic cells of the reticuloendothelial system. The autoantibody causing ITP is most often targeted to platelet glycoprotein (GP) IIb/IIIa or platelet GP Ib/IX; bound antibody leads to platelet removal by binding to Fc receptors on the membrane of macrophages, followed by removal by the spleen. ITP is also characterized by decreased platelet production. |
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TP |
There is spontaneous onset of petechiae and/or bruising or other spontaneous bleeding, such as epistaxis. Severe bleeding is rare, despite very low platelet counts. |
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Usually the platelet count is very low (<5000/µL), PT/PTT are normal, PFA-100 (due to thrombocytopenia) is prolonged, RBC and WBC counts are normal, and a peripheral smear is normal except for thrombocytopenia and large platelets. This is a diagnosis of exclusion and should be considered if no other cause of thrombocytopenia can be identified. Pseudothrombocytopenia caused by platelet clumping or aggregation around leukocytes when ethylenediamine tetraacetic acid (EDTA) is used in the collection tube should be excluded by repeating the platelet count in a tube containing citrate or heparin as the anticoagulant. |
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Tx |
Prednisone 1 mg/kg daily for 2–4 weeks, with a gradual taper, is the initial treatment. If unresponsive to prednisone, most adult patients may require splenectomy or other immunosuppressive therapy (such as cyclophosphamide, azathioprine, or rituximab). Intravenous immune globulin (IVIG) may increase very low platelet counts, but the effect is transient (days to weeks). Platelet transfusions are unnecessary, unless there is severe bleeding. A hematologist should be consulted in patients suspected of having ITP. See Cecil Essentials 53. |
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Disseminated Intravascular Coagulation |
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Pφ |
DIC is defined as sustained, disseminated, and excessive coagulation without the ability to neutralize activated products of coagulation. This leads to consumption of coagulation products and platelets, leading to both bleeding and thrombosis. Consumption of platelets causes thrombocytopenia. |
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TP |
Consider DIC in a patient with underlying cancer (typically mucin-producing adenocarcinomas), sepsis, trauma, or after obstetric complications. Acute promyelocytic leukemia is also often associated with DIC. Typical patients present with signs of excessive clotting (e.g., deep venous thrombosis) and/or excessive bleeding (e.g., oozing from around IV catheter sites). |
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Dx |
Moderately decreased platelet count, prolonged PT and aPTT, elevated D-dimer, decreased fibrinogen, and increased fibrin degradation products. Peripheral blood smear shows decreased platelets and fragmented RBCs (schistocytes). |
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Tx |
Supportive, by treating underlying cause. Patients with bleeding may need fresh-frozen plasma to replace coagulation factors, or platelet transfusion. Heparin is rarely used because of the potential for increasing risk of bleeding, and there is no improvement in outcome. See Cecil Essentials 53. |
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Pφ |
Formation of an autoantibody against factor VIII. May occur in older patients and those with autoimmune disease, cancer, lymphoproliferative disorders, and in women during the postpartum period. |
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TP |
Spontaneous bleeding occurs, often in soft tissues (such as spontaneous bleeding into joints). Prolonged bleeding from cuts and with surgeries or procedures has also been described. |
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Dx |
Prolonged aPTT with a normal PT; no correction with a mixing study. The platelet count is normal. There is decreased factor VIII level (usually <30%), with a detectable factor VIII inhibitor level. |
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Tx |
Factor VIII bypassing agents such as activated factor VII or activated prothrombin complex concentrates (which contain factors VII, IX, X, and prothrombin) can be given to stop acute bleeding. Definitive treatment of the inhibitor is difficult and can be achieved through IVIG or immune-suppressive agents such as prednisone, cyclophosphamide, vincristine, or rituximab. See Cecil Essentials 53. |
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Drug-Induced Thrombocytopenia |
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Pφ |
Platelets are the first response to epithelial damage. They are activated at the site of injury to form a temporary plug until the coagulation factors can produce a more permanent clot. Certain medications (such as quinine, antibiotics, and heparin) have been associated with development of thrombocytopenia. |
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TP |
Patients seldom present with bleeding from thrombocytopenia unless the platelet count is <10,000/µL. At that point, petechiae and mucosal (e.g., GI, epistaxis, gums) bleeding can occur. |
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Dx |
Decreased platelet count; normal PT and aPTT. |
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Tx |
Stop the offending medication. There is seldom a need for platelet transfusion if the platelet count is >10,000/µL. See Cecil Essentials 53, 54. |
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Pφ |
Vitamin K is necessary for the synthesis of the extrinsic coagulation factors (factors II, VII, IX, and X). Vitamin K can become deficient during periods of malnutrition or with antibiotic usage that decreases synthesis of vitamin K by bacterial flora. |
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TP |
The diagnosis should be considered with bruising or bleeding in a patient with malnutrition, or in a patient on prolonged antibiotic therapy. |
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Dx |
Prolonged PT (may also see a prolonged aPTT, if severe); PT mixing study that corrects; low serum albumin in a malnourished patient; and clinical suspicion. |
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Tx |
Replace vitamin K by mouth (5–10 mg) or intravenously. Patients with acute bleeding require administration of fresh-frozen plasma to replace the missing clotting factors. See Cecil Essentials 53. |
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Thrombotic Thrombocytopenic Purpura |
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Pφ |
TTP is a disorder of the systemic circulation caused by microvascular aggregation of platelets in the brain and other organs. Patients have unusually large multimers of von Willebrand factor (vWF) in their plasma. ADAMTS13, a disintegrin and metalloprotease, cleaves large multimers of vWF; patients with deficiencies or antibodies to ADAMTS13 can develop platelet aggregates in the microvasculature. TTP can also be seen in patients with cancer, transplant recipients, and following administration of chemotherapeutic agents and other drugs. |
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TP |
The typical pentad of findings in patients with TTP is thrombocytopenia, microangiopathic hemolytic anemia, fever, renal insufficiency, and neurologic deficits; all five findings do not have to be present to establish the diagnosis. |
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Dx |
The diagnosis should always be considered in patients with thrombocytopenia and microangiopathic hemolytic anemia. The main consideration in the differential diagnosis is DIC, which can be excluded in patients with normal PT, aPTT, and D-dimer. |
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Tx |
The treatment of choice is urgent plasma exchange transfusion. See Cecil Essentials 29, 31, 49, 54. |
Practice-Based Learning and Improvement: Evidence-Based Medicine
Title
Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group.
Authors
Rock GA, Shumak KH, Buskard NA
Institution
Multi-institutional
Reference
N Engl J Med 1991;325:393–397
Problem
The best treatment for TTP is unknown; both plasma infusion and plasma exchange seemed effective.
Intervention
Prospective randomized trial comparing plasma exchange with plasma infusion for the treatment of TTP
Outcome/effect
Plasma exchange is more effective than plasma infusion in the treatment of TTP.
Historical significance/comments
This has established plasmapheresis as the standard of care for the treatment of TTP.
Interpersonal and Communication Skills
Be Prepared for Conversations with Patients
When called to see a patient whose workup is in progress, the consultant may be the first to know that the bone marrow or CT scan ordered by the primary-care team reveals a likely diagnosis of advanced malignancy. In such a situation, a consultant should be very careful when talking with the patient. Consult the primary-care team first to determine who should discuss the diagnosis and in what setting. Before explaining matters to the patient, determine what the patient knows about his or her condition. The patient’s answer guides the explanation. Medical students and residents, who are often first to evaluate a requested consultation, should be cognizant of this dilemma and should consult with attending physicians before finding themselves “trapped” in a discussion that they may not be prepared to conduct.
Professionalism
Understand the Patient’s Right to Refuse Treatment
A patient of yours with a bleeding disorder has had a large upper GI hemorrhage and presents in the ED with a critically low hemoglobin. While you are obtaining informed consent to begin transfusing packed RBCs, the patient informs you that she is a Jehovah’s Witness and cannot accept the transfusion. She is tachycardic and hypotensive. Situations like these can be hard to accept from the treating physician perspective. Learning more about a particular patient’s cultural or religious beliefs can be very helpful in understanding the implications of particular recommended therapies on the patient. For Jehovah’s Witnesses, accepting blood from a source other than themselves is against the scriptural teachings of their religion. Even in a life-threatening situation, the right answer is always to respect patient autonomy.
Describe Medication Reconciliation
Patients with bleeding disorders need to be monitored frequently; often they need laboratory work and adjustment of their treatment weekly, if not more frequently. Some of these patients may also have other comorbid conditions that require use of additional medications that may need to be periodically adjusted. Given multiple changes in medication, it is important to adequately reconcile what the patient is taking across the continuum of care. This can be done on an outpatient basis and requires dedicated staff, such as a nurse or nurse practitioner working closely with the patient and their physician. If the patient is hospitalized, a process must be followed for accurate and complete medication reconciliation as follows:
The home medication list is compared to the current list and reconciled on admission, transfer, and discharge.
The home medication list should include dose, route, and frequency of administration.
Any discrepancies must be reconciled and documented.
The patient must receive an updated list of medications upon discharge.
The medication list must be provided to the next provider of care upon discharge or transfer to another facility.
