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Abstract
Disseminated intravascular coagulation (DIC) is an acquired coagulation disorder that may occur in a wide variety of clinical conditions. Suspicion of DIC should lead to a differential diagnosis that includes primary fibrinolysis and other bleeding diatheses such as thrombocytopenias of diverse etiology. Confirmation of the diagnosis of DIC should always prompt a search for an underlying medical disorder, including sepsis, severe trauma, solid and hematological malignancies, obstetrical complications, and vascular disorders. Here, we describe an unusual case of acute bleeding and DIC as the presenting manifestation of metastatic prostate cancer in a 60-year-old man. Treatment with a luteinizing hormone-releasing hormone (LHRH) agonist and a short course of an antiandrogen, together with supportive measures (i.e., clotting factors, heparin, and platelets), led to normalization of all coagulation parameters within 1 week, and to clinical improvement and decline in the serum level of prostate-specific antigen (PSA). We discuss the pathogenesis, differential diagnosis, and association of DIC with prostate cancer along with the management of this condition.
EXTEM Extrinsic activation by tissue factor to monitor the coagulation process via the extrinsic pathway including the clotting time, the contribution of platelets and fibrinogen to clot quality, as well as the stability of the clot over time. Not sensitive to heparin up to 5U/ml unfractionated heparin (UFH) in blood. Start studying MLT 250 Hematology Practice Exam Questions. Learn vocabulary, terms, and more with flashcards, games, and other study tools. Teaching Cases. ASH Teaching Cases emphasize standard approaches to classic hematologic problems and are designed to simulate the steps involved in diagnosing a patient, from taking the history and performing a physical exam, to ordering and interpreting lab tests, to making a final diagnosis and following the clinical course of the disease. Coagulation Laboratory: Methods, Standards & Cost Effective Testing. Hematology and Hemostasis. Understanding coagulation results Case Studies. Upon discharge from hospital the patient continued oral warfarin anticoagulation (six months), and the use of compression stockings (nine months).
Pediatric Coagulation Case Studies for Blood Bankers. March 5, 2009. Josephson, MD Associate Director, Children’s Healthcare of Atlanta Blood and Tissue Services Associate Professor, Pathology and Pediatrics Emory University School of Medicine.
Disseminated intravascular coagulation (DIC) is an acquired coagulation disorder that may occur in a wide variety of clinical conditions. Suspicion of DIC should lead to a differential diagnosis that includes primary fibrinolysis and other bleeding diatheses such as thrombocytopenias of diverse etiology. Confirmation of the diagnosis of DIC should always prompt a search for an underlying medical disorder, including sepsis, severe trauma, solid and hematological malignancies, obstetrical complications, and vascular disorders. Here, we describe an unusual case of acute bleeding and DIC as the presenting manifestation of metastatic prostate cancer.
CASE PRESENTATION
A 60-year-old white male presented with a 4-day history of bleeding from the gums, diffuse spontaneous ecchymoses, mild fatigue, and bone pain. The patient described a 6-month history of pain localized to his right thigh with extension to the posterior part of his right leg. His past medical history included atrial fibrillation, hypercholesterolemia, and hypertension, all well controlled with medication. He had never smoked and had moderate alcohol consumption until 1 year ago.
When he presented at another hospital, he had dry blood in his mouth but no active bleeding. His blood pressure was 138/64, his pulse rate was 57, and his temperature was 37.3°C. There was no peripheral lymphadenopathy. Chest was clear to auscultation and the liver and the spleen were not palpable. Examination of the lower extremities showed confluent ecchymoses involving the left ankle, and the posterior of both thighs (Figs. 1 and and22).
Confluent ecchymoses on the right thigh.
Confluent ecchymoses on the left ankle.
Laboratory evaluation revealed hemoglobin of 13.4 g/dL (normal: 14 to 16 g/dL), platelets of 107 × 103/μL (normal: 150 to 400 × 103/μL), and total leukocytes of 8.1 × 103/mm3 (normal: 4.0 to 11 × 103/mm3). His prothrombin time was 22.8 seconds (normal: 11.5 to 15.5 seconds), and his INR was 1.92 (normal: 1 to 1.25). The activated partial thromboplastin time (aPTT) was 45 seconds (normal: 25.2 to 36 seconds), the serum fibrinogen was <0.30 g/L (normal: 1.3 to 3.5 g/L), and the plasma concentration of d-dimers was >4 μg/mL (normal:≤0.40 μg/mL). Plasma levels of factors V, VII, XIII, and activated protein C as well as serum creatinine and liver function tests were within normal limits. Examination of a blood smear was consistent with a normochromic, normocytic anemia, with reduced platelets and large forms, and possible blasts with folded nuclei. Shortly after admission, all coagulation parameters worsened (INR=2.92; PT=32 seconds; aPTT=55 seconds) and the ecchymoses increased in number and extent.
The patient was transferred to our institution with a diagnosis of DIC, and probable acute leukemia (most likely acute promyelocytic leukemia [APL]). A bone marrow biopsy was performed and the patient was started empirically on all-trans-retinoic acid and supportive treatment for DIC. Twenty-four hours later, a test for serum prostate-specific antigen (PSA) obtained at the referring hospital was reported as PSA=257 ng/mL (normal: <4 ng/mL). A digital rectal exam revealed a small nodule in the posterior right lobe of the prostate with no other abnormalities. The bone marrow biopsy confirmed the presence of metastatic prostate cancer and no blasts were found on re-evaluation of the blood smear. A bone scan and computed tomography imaging indicated the presence of extensive mixed lytic and sclerotic bone lesions involving the spine, and upper and lower extremities.
The patient was started on an antiandrogen (bicalutamide), and subsequently received a luteinizing hormone-releasing hormone (LHRH) agonist (leuprolide). After 1 week of treatment, the coagulation parameters had returned to normal, except for slightly low levels of serum fibrinogen and slightly elevated d-dimers. There was substantial improvement in his pain, although he continued to have moderate discomfort localized to the upper right leg. There was no further bleeding. The patient was discharged and completed palliative radiation to the right hip and upper femur (20 Gy in 5 fractions) as an outpatient. On subsequent follow-up visits, there was a progressive decrease in serum level of PSA (to 0.56 ng/mL at 3 months after diagnosis) and the patient presented no symptoms.
DISCUSSION
Case Studies In Hematology And Coagulation
Disseminated intravascular coagulation is a clinicopathologic syndrome that is not a specific disease but a manifestation of an underlying disorder. Therefore, recognition that a patient has DIC mandates a search for an underlying clinical condition. The pathogenesis of DIC proceeds from the simultaneous occurrence of systemic fibrin production with impaired mechanisms to prevent coagulation and inadequate fibrinolysis. Increased formation and abnormal removal of fibrin, through thrombin generation, will lead to widespread intravascular deposition of this protein, resulting in thrombotic occlusion of midsize and small vessels. Simultaneous use and subsequent depletion of platelets and clotting factors, resulting from the ongoing coagulation, may induce severe bleeding.,
The clinical presentation of DIC depends on the underlying condition that triggers this medical disorder. Some patients may have a mild or protracted clinical course, with consumption of coagulation factors and minor or no symptoms. This clinical scenario has been referred to as chronic or low-grade DIC and is mostly observed in patients with underlying mucin production because of malignant tumors or vasculitis. In other patients, activation of the fibrinolytic system may dominate over the excessive coagulation, resulting in massive generation of thromboplastic material and consumption of hemostatic elements. This presentation is referred to as acute bleeding DIC and it has been associated most often with sepsis, obstetrical complications, gross tissue injury, or promyelocytic leukemia.,
Laboratory studies used in the diagnosis of patients with DIC include tests of thrombin and plasmin generation (d-dimers and the protamine paracoagulation assay for fibrin monomer) and tests of hemostatic function that delineate the severity of consumption of coagulation factors (PT, PTT, and thrombin time). The diagnosis of DIC should not be made without at least 1 positive test indicative of thrombin generation. The most frequent laboratory abnormalities observed are thrombocytopenia, elevated fibrin/fibrinogen degradation products, prolonged PT, prolonged thrombin time, prolonged PTT, and low fibrinogen.
A number of clinical disorders not associated with DIC can result in acquired bleeding diathesis and laboratory hemostatic abnormalities and should always be considered in the differential diagnosis. These include: (1) thrombocytopenia: Because of primary bone marrow failure; infiltrative marrow process, such as leukemia; endothelial-mediated platelet activation, such as in vasculitis or thrombotic thrombocytopenic purpura (TTP); or immunologic destruction, such as in idiopathic thrombocytopenic purpura. (2) Primary fibrinolysis (PF): There is independent generation of plasmin without concomitant thrombin generation. Patients have low fibrinogen and elevated fibrin degradation products. In addition, patients with liver disease and PF may present with thrombocytopenia secondary to splenic sequestration. The differential diagnosis in these patients will be determined by a shortened euglobin clot lysis test and a negative protamine coagulation assay for fibrin monomers.
In the case reported above, presentation with acute bleeding DIC (typical of APL), along with an erroneous interpretation of a first blood smear, led to a wrong diagnosis. Consideration of the differential diagnosis is essential when dealing with DIC and no evident cause, and an underlying malignancy should always be considered. Although traditionally associated with low-grade DIC, the present and other published cases provide evidence to link prostate cancer with acute bleeding DIC.–
The association of DIC with solid and hematological malignancies has been extensively documented., Ten to 15% of patients with metastatic tumors have some evidence of DIC, and it is present in approximately 15% of patients with acute leukemia. An analysis of DIC in patients with solid tumors revealed that the most common laboratory abnormalities are thrombocytopenia, hypofibrinogenemia, and elevated serum levels of d-dimers and fibrinogen degradation products. Mechanisms leading to DIC in patients with cancer are unclear, but probably involve procoagulant factors that are expressed on the surface of tumor cells. Older age, male sex, primary tumor necrosis, and advanced tumor stage were found to be risk factors for DIC in a multivariate analysis.
Coagulation Case Studies Answers
Disseminated intravascular coagulation is the most frequent coagulation disorder in patients with prostate cancer.10, It may occur as a result of the introduction of thromboplastic substances into the blood stream after a biopsy of either the primary tumor or a metastatic site, or it may develop as a manifestation of advanced disease., However, DIC as a first manifestation of prostate cancer is unusual.–,
Optimal management of DIC associated with prostate cancer requires treatment of the tumor in combination with supportive measures to control the abnormal coagulation. Hormonal treatment with an LHRH agonist in conjunction with a previous short course of an antiandrogen to avoid a “flare” reaction is the treatment of choice in patients who are likely to be hormone sensitive. The use of high-dose ketoconazole (200 to 400 mg t.i.d.) has been described as an effective way to bring about a rapid decrease in serum testosterone level through inhibition of adrenal production of testosterone, and is indicated in patients with life-threatening DIC because of severe uncontrolled bleeding. Chemotherapy is reserved for patients who do not respond to hormone manipulations, and resolution of DIC has been reported following treatment with various cytotoxic combinations.– Some radiopharmaceuticals have successfully reverted cases of coagulopathy in patients with an androgen-independent prostate cancer, although their role remains controversial., Once treatment has been directed at the primary illness, therapy can be directed to the DIC itself. The severity of bleeding, the platelet count, and the levels of coagulation factors will determine the need to replace blood components. The use of heparin is still debated in the management of DIC. Two nonrandomized studies showed benefit and no increase in bleeding in patients with DIC., Fresh-frozen plasma and cryoprecipitate can be recommended when faced with life-threatening episodes of bleeding.
Other coagulopathies less frequently associated with prostate cancer include TTP, thrombosis (i.e., venous thrombosis or pulmonary embolism), primary fibrinolysis, and acquired factor VIII inhibitor development. The differential diagnosis between these entities is based on platelet count, coagulation parameters, and clinical findings. Primary fibrinolysis is characterized by the absence of elevated d-dimers and normal platelet and antithrombin III levels. Clinical findings such as fever, renal failure, and neurological abnormalities along with thrombocytopenia, microangiopathic anemia, and normal coagulation times, will define TTP.
In summary, we present a case that illustrates the importance of an appropriate differential diagnosis when trying to determine the process underlying DIC. The case illustrates how an erroneous interpretation of a diagnostic test may lead to a wrong diagnosis. The presence of DIC in the absence of an obvious cause should prompt a search for malignancy, including a complete physical exam with a rectal examination to detect prostate cancer. Special consideration should be given to those cases of DIC that present as severe bleeding episodes in whom a treatable disease such as prostate cancer could be easily diagnosed and promptly treated.
REFERENCES
Abstract
Disseminated intravascular coagulation (DIC) is an acquired coagulation disorder that may occur in a wide variety of clinical conditions. Suspicion of DIC should lead to a differential diagnosis that includes primary fibrinolysis and other bleeding diatheses such as thrombocytopenias of diverse etiology. Confirmation of the diagnosis of DIC should always prompt a search for an underlying medical disorder, including sepsis, severe trauma, solid and hematological malignancies, obstetrical complications, and vascular disorders. Here, we describe an unusual case of acute bleeding and DIC as the presenting manifestation of metastatic prostate cancer in a 60-year-old man. Treatment with a luteinizing hormone-releasing hormone (LHRH) agonist and a short course of an antiandrogen, together with supportive measures (i.e., clotting factors, heparin, and platelets), led to normalization of all coagulation parameters within 1 week, and to clinical improvement and decline in the serum level of prostate-specific antigen (PSA). We discuss the pathogenesis, differential diagnosis, and association of DIC with prostate cancer along with the management of this condition.
Disseminated intravascular coagulation (DIC) is an acquired coagulation disorder that may occur in a wide variety of clinical conditions. Suspicion of DIC should lead to a differential diagnosis that includes primary fibrinolysis and other bleeding diatheses such as thrombocytopenias of diverse etiology. Confirmation of the diagnosis of DIC should always prompt a search for an underlying medical disorder, including sepsis, severe trauma, solid and hematological malignancies, obstetrical complications, and vascular disorders. Here, we describe an unusual case of acute bleeding and DIC as the presenting manifestation of metastatic prostate cancer.
CASE PRESENTATION
A 60-year-old white male presented with a 4-day history of bleeding from the gums, diffuse spontaneous ecchymoses, mild fatigue, and bone pain. The patient described a 6-month history of pain localized to his right thigh with extension to the posterior part of his right leg. His past medical history included atrial fibrillation, hypercholesterolemia, and hypertension, all well controlled with medication. He had never smoked and had moderate alcohol consumption until 1 year ago.
When he presented at another hospital, he had dry blood in his mouth but no active bleeding. His blood pressure was 138/64, his pulse rate was 57, and his temperature was 37.3°C. There was no peripheral lymphadenopathy. Chest was clear to auscultation and the liver and the spleen were not palpable. Examination of the lower extremities showed confluent ecchymoses involving the left ankle, and the posterior of both thighs (Figs. 1 and and22).
Confluent ecchymoses on the right thigh.
Confluent ecchymoses on the left ankle.
Laboratory evaluation revealed hemoglobin of 13.4 g/dL (normal: 14 to 16 g/dL), platelets of 107 × 103/μL (normal: 150 to 400 × 103/μL), and total leukocytes of 8.1 × 103/mm3 (normal: 4.0 to 11 × 103/mm3). His prothrombin time was 22.8 seconds (normal: 11.5 to 15.5 seconds), and his INR was 1.92 (normal: 1 to 1.25). The activated partial thromboplastin time (aPTT) was 45 seconds (normal: 25.2 to 36 seconds), the serum fibrinogen was <0.30 g/L (normal: 1.3 to 3.5 g/L), and the plasma concentration of d-dimers was >4 μg/mL (normal:≤0.40 μg/mL). Plasma levels of factors V, VII, XIII, and activated protein C as well as serum creatinine and liver function tests were within normal limits. Examination of a blood smear was consistent with a normochromic, normocytic anemia, with reduced platelets and large forms, and possible blasts with folded nuclei. Shortly after admission, all coagulation parameters worsened (INR=2.92; PT=32 seconds; aPTT=55 seconds) and the ecchymoses increased in number and extent.
The patient was transferred to our institution with a diagnosis of DIC, and probable acute leukemia (most likely acute promyelocytic leukemia [APL]). A bone marrow biopsy was performed and the patient was started empirically on all-trans-retinoic acid and supportive treatment for DIC. Twenty-four hours later, a test for serum prostate-specific antigen (PSA) obtained at the referring hospital was reported as PSA=257 ng/mL (normal: <4 ng/mL). A digital rectal exam revealed a small nodule in the posterior right lobe of the prostate with no other abnormalities. The bone marrow biopsy confirmed the presence of metastatic prostate cancer and no blasts were found on re-evaluation of the blood smear. A bone scan and computed tomography imaging indicated the presence of extensive mixed lytic and sclerotic bone lesions involving the spine, and upper and lower extremities.
The patient was started on an antiandrogen (bicalutamide), and subsequently received a luteinizing hormone-releasing hormone (LHRH) agonist (leuprolide). After 1 week of treatment, the coagulation parameters had returned to normal, except for slightly low levels of serum fibrinogen and slightly elevated d-dimers. There was substantial improvement in his pain, although he continued to have moderate discomfort localized to the upper right leg. There was no further bleeding. The patient was discharged and completed palliative radiation to the right hip and upper femur (20 Gy in 5 fractions) as an outpatient. On subsequent follow-up visits, there was a progressive decrease in serum level of PSA (to 0.56 ng/mL at 3 months after diagnosis) and the patient presented no symptoms.
DISCUSSION
Disseminated intravascular coagulation is a clinicopathologic syndrome that is not a specific disease but a manifestation of an underlying disorder. Therefore, recognition that a patient has DIC mandates a search for an underlying clinical condition. The pathogenesis of DIC proceeds from the simultaneous occurrence of systemic fibrin production with impaired mechanisms to prevent coagulation and inadequate fibrinolysis. Increased formation and abnormal removal of fibrin, through thrombin generation, will lead to widespread intravascular deposition of this protein, resulting in thrombotic occlusion of midsize and small vessels. Simultaneous use and subsequent depletion of platelets and clotting factors, resulting from the ongoing coagulation, may induce severe bleeding.,
The clinical presentation of DIC depends on the underlying condition that triggers this medical disorder. Some patients may have a mild or protracted clinical course, with consumption of coagulation factors and minor or no symptoms. Cuatro visiones historia universal pdf. This clinical scenario has been referred to as chronic or low-grade DIC and is mostly observed in patients with underlying mucin production because of malignant tumors or vasculitis. In other patients, activation of the fibrinolytic system may dominate over the excessive coagulation, resulting in massive generation of thromboplastic material and consumption of hemostatic elements. This presentation is referred to as acute bleeding DIC and it has been associated most often with sepsis, obstetrical complications, gross tissue injury, or promyelocytic leukemia.,
Laboratory studies used in the diagnosis of patients with DIC include tests of thrombin and plasmin generation (d-dimers and the protamine paracoagulation assay for fibrin monomer) and tests of hemostatic function that delineate the severity of consumption of coagulation factors (PT, PTT, and thrombin time). The diagnosis of DIC should not be made without at least 1 positive test indicative of thrombin generation. The most frequent laboratory abnormalities observed are thrombocytopenia, elevated fibrin/fibrinogen degradation products, prolonged PT, prolonged thrombin time, prolonged PTT, and low fibrinogen.
A number of clinical disorders not associated with DIC can result in acquired bleeding diathesis and laboratory hemostatic abnormalities and should always be considered in the differential diagnosis. These include: (1) thrombocytopenia: Because of primary bone marrow failure; infiltrative marrow process, such as leukemia; endothelial-mediated platelet activation, such as in vasculitis or thrombotic thrombocytopenic purpura (TTP); or immunologic destruction, such as in idiopathic thrombocytopenic purpura. (2) Primary fibrinolysis (PF): There is independent generation of plasmin without concomitant thrombin generation. Patients have low fibrinogen and elevated fibrin degradation products. In addition, patients with liver disease and PF may present with thrombocytopenia secondary to splenic sequestration. The differential diagnosis in these patients will be determined by a shortened euglobin clot lysis test and a negative protamine coagulation assay for fibrin monomers.
In the case reported above, presentation with acute bleeding DIC (typical of APL), along with an erroneous interpretation of a first blood smear, led to a wrong diagnosis. Consideration of the differential diagnosis is essential when dealing with DIC and no evident cause, and an underlying malignancy should always be considered. Although traditionally associated with low-grade DIC, the present and other published cases provide evidence to link prostate cancer with acute bleeding DIC.–
The association of DIC with solid and hematological malignancies has been extensively documented., Ten to 15% of patients with metastatic tumors have some evidence of DIC, and it is present in approximately 15% of patients with acute leukemia. An analysis of DIC in patients with solid tumors revealed that the most common laboratory abnormalities are thrombocytopenia, hypofibrinogenemia, and elevated serum levels of d-dimers and fibrinogen degradation products. Mechanisms leading to DIC in patients with cancer are unclear, but probably involve procoagulant factors that are expressed on the surface of tumor cells. Older age, male sex, primary tumor necrosis, and advanced tumor stage were found to be risk factors for DIC in a multivariate analysis.
Disseminated intravascular coagulation is the most frequent coagulation disorder in patients with prostate cancer.10, It may occur as a result of the introduction of thromboplastic substances into the blood stream after a biopsy of either the primary tumor or a metastatic site, or it may develop as a manifestation of advanced disease., However, DIC as a first manifestation of prostate cancer is unusual.–,
Optimal management of DIC associated with prostate cancer requires treatment of the tumor in combination with supportive measures to control the abnormal coagulation. Hormonal treatment with an LHRH agonist in conjunction with a previous short course of an antiandrogen to avoid a “flare” reaction is the treatment of choice in patients who are likely to be hormone sensitive. The use of high-dose ketoconazole (200 to 400 mg t.i.d.) has been described as an effective way to bring about a rapid decrease in serum testosterone level through inhibition of adrenal production of testosterone, and is indicated in patients with life-threatening DIC because of severe uncontrolled bleeding. Chemotherapy is reserved for patients who do not respond to hormone manipulations, and resolution of DIC has been reported following treatment with various cytotoxic combinations.– Some radiopharmaceuticals have successfully reverted cases of coagulopathy in patients with an androgen-independent prostate cancer, although their role remains controversial., Once treatment has been directed at the primary illness, therapy can be directed to the DIC itself. The severity of bleeding, the platelet count, and the levels of coagulation factors will determine the need to replace blood components. The use of heparin is still debated in the management of DIC. Two nonrandomized studies showed benefit and no increase in bleeding in patients with DIC., Fresh-frozen plasma and cryoprecipitate can be recommended when faced with life-threatening episodes of bleeding.
Other coagulopathies less frequently associated with prostate cancer include TTP, thrombosis (i.e., venous thrombosis or pulmonary embolism), primary fibrinolysis, and acquired factor VIII inhibitor development. The differential diagnosis between these entities is based on platelet count, coagulation parameters, and clinical findings. Primary fibrinolysis is characterized by the absence of elevated d-dimers and normal platelet and antithrombin III levels. Clinical findings such as fever, renal failure, and neurological abnormalities along with thrombocytopenia, microangiopathic anemia, and normal coagulation times, will define TTP.
In summary, we present a case that illustrates the importance of an appropriate differential diagnosis when trying to determine the process underlying DIC. The case illustrates how an erroneous interpretation of a diagnostic test may lead to a wrong diagnosis. The presence of DIC in the absence of an obvious cause should prompt a search for malignancy, including a complete physical exam with a rectal examination to detect prostate cancer. Special consideration should be given to those cases of DIC that present as severe bleeding episodes in whom a treatable disease such as prostate cancer could be easily diagnosed and promptly treated.