Haemopoietic System/Haematology/Blood/Blood Products Flashcards
An 80-year-old man is planned for emergency surgery due to a strangulated direct hernia. He has been on clopidogrel after he sustained an acute myocardial infarction 10 months ago. Which one of the following is the next best in management prior to the surgery?
A. Give platelets and proceed to the surgery.
B. Give DDAVP and proceed to the surgery.
C. Give cryoprecipitate and proceed to the surgery.
D. Stop clopidogrel and proceed to the surgery.
E. Give vitamin K intravenously.
A. Give platelets and proceed to the surgery.
Strangulated hernias require immediate surgery to prevent severe complications like bowel perforation, peritonitis, and death.
- Increased Bleeding Risk: Patients on clopidogrel have an increased risk of bleeding during and after surgery due to its effect on platelets.
- Platelet Transfusion: Before surgery, platelet transfusion may be necessary to counteract clopidogrel’s effects.
- For patients with coronary stents, antiplatelet therapy should not be stopped, except for certain surgeries like spinal, intracranial, extraocular, TURP, or major plastic reconstructive procedures.
- For these surgeries, antiplatelet therapy can be stopped in patients with a low risk of stent thrombosis.
- Desmopressin (DDAVP): Used with fresh frozen plasma for patients with Von-Willebrand disease, not for clopidogrel.
- Cryoprecipitate: Replenishes coagulation factors, not effective against clopidogrel’s effects on platelets.
- Stopping Clopidogrel: Not useful immediately as it takes 7 days for the effects to diminish.
- Vitamin K: Used for reversing warfarin, not clopidogrel.
-
Elective Surgery:
- Postpone for at least 6 weeks (ideally 3 months) after bare metal stenting.
- Postpone for 12 months after drug-eluting stents.
-
Risks:
- Stopping antiplatelet therapy increases the risk of death or heart attack, especially with stents.
- Continuation of aspirin is often favored to prevent stent thrombosis despite the increased bleeding risk.
-
Emergency Surgery:
- Proceed without stopping antiplatelet therapy.
- Consider platelet transfusion if major bleeding is anticipated.
- Strangulated hernias need immediate surgery.
- Patients on clopidogrel should get a platelet transfusion before surgery to reduce bleeding risk.
- Do not stop antiplatelet therapy for patients with coronary stents, except in certain surgeries or emergency cases.
Strangulated hernias are genuine emergencies requiring immediate surgery. Failing to do so can lead to bowel perforation, peritonitis and death. This patient, however, is on clopidogrel and has an increased risk of intra- or post-operative bleeding due to effect of clopidogrel on platelet function. Since abdominal surgery is associated with marked risk of bleeding in this patient, platelets should be given prior to the surgery to counteract the effect of clopidogrel. If this patient had a coronary stent, antiplatelet therapy should have not been ceased. Exceptions to this include patients with coronary stents who are undergoing spinal, intracranial, extraocular TURP or major plastic reconstructive procedures. For these operations, patients at low risk of stent thrombosis should have their antiplatelet therapy routinely ceased perioperatively.
(Option B) Desmopressin (DDAVP), often in conjunction with fresh frozen plasma, is used for preoperative management of patients with Von-Willebrand disease in whom there is deficiency of factor VIII.
(Option C) Cryoprecipitate replenish coagulation factors with no effect on platelet activity inhibited by clopidogrel.
(Option D) It takes approximately 7 days for effects of antiplatelet drugs to suitably diminish. Stopping clopidogrel now will not decrease the chance of bleeding immediately and is not useful.
(Option E) Vitamin K is used for warfarin reversal and has no effect on platelet function.
TOPIC REVIEW
Coronary stent thrombosis is an uncommon but clinically devastating complication of coronary artery stenting that usually results in significant myocardial infarction or death. Approximately 40% of reported cases have occurred in the context of non-cardiac surgery (NCS) performed in patients with coronary artery stents, in whom dual antiplatelet therapy or clopidogrel alone has been ceased.
In patients with coronary disease, cessation of aspirin or clopidogrel is associated with an approximate 2-3 fold increase in subsequent death or myocardial infarction. This risk is further elevated in patients with intracoronary stent and is of added concern because the dramatic consequences of stent occlusion. There is uncertainty regarding the risks of stent thrombosis in individual patients, and in particular how to balance this risk against that of surgical complications if antiplatelet therapy is continued throughout the perioperative period.
The following are current recommendations regarding antiplatelet agents and non-cardiac surgery:
- Elective non-cardiac surgery should be deferred for at least 6 weeks and ideally 3 months following PCI with bare metal stenting.
- Elective surgery should be deferred for 12 months following drug eluting stents because of a likely increased risk of death/myocardial infarction/stent thrombosis.
- Despite the observation that dual antiplatelet therapy increases the likelihood of bleeding for most surgical procedures, the consequences of bleeding are less significant than those of stent thrombosis.
- The risk benefit ratio would favor continuation of aspirin in most patients and dual antiplatelet therapy in many patients with prior coronary artery stenting who are undergoing non-cardiac surgery.
- Exceptions to this include patients undergoing spinal, intracranial, extraocular TURP or major plastic reconstructive procedures. For these operations, patients at low risk of stent thrombosis should have their antiplatelet therapy routinely ceased perioperatively.
- In patients with coronary artery disease in whom NO stent has been placed, antiplatelets can be stopped 7 days before the surgery.
- In the event of emergency, surgery should be proceeded to without cessation of antiplatelet therapy. platelet transfusion might be considered in selected patients in anticipation or occurrence of major bleeding.
- In other situations than bare metal stents and drug eluting stents placed within the past 6 weeks and 12 months respectively, antiplatelet medications should be stopped 1 week (7 days) before the procedure.
** http://www.csanz.edu.au/wp-content/uploads/2014/12
http://www.racgp.org.au/afp/2014/december/new-oral
A 6-year-old girl with sickle cell disease is brought to your practice for routine follow-up. She is completely asymptomatic and has never had a sickle cell crisis. She takes no medications. Physical examination is unremarkable. Which one of the following complications is more likely to occur earliest in this patient?
A. Splenic infarction.
B. Bone infarction.
C. Splenic sequestration.
D. Stroke.
E. Acute coronary ischemia.
B. Bone infarction.
- Cause: Inherited disorder due to homozygosity for abnormal hemoglobin S (HBs).
- Main Issues: Vaso-occlusive phenomena (blocked blood flow) and hemolysis (destruction of red blood cells).
-
Bone Infarction:
- Early Presentation: Often the first symptom.
- Symptoms: Acute pain in hands and/or feet, known as dactylitis or hand-foot syndrome.
- Prevalence: Occurs in 40% of all patients and 50% of children before age two.
-
Acute Pain Episodes:
- Second Most Common Initial Symptom.
- Most Common Symptom After Age Two.
-
Splenic Sequestration:
- Third Most Common Initial Symptom.
- Symptoms: Enlarged spleen and sudden drop in hemoglobin levels.
- Prevalence: Occurs in 20% of all patients and one-third of children before age two.
- Vaso-Occlusion in Organs: Leads to acute and chronic multisystem failure, causing lifelong disabilities and early death.
- SCD Symptoms Start Early: Pain in bones, acute pain episodes, and splenic issues are common.
- Vaso-Occlusion: Affects many organs over time, leading to severe complications.
Understanding these key points about SCD can help recognize and manage the disease effectively.
Vaso-occlusive phenomena and hemolysis are the clinical hallmarks of sickle cell disease (SCD) that is an inherited disorder due to homozygosity for the abnormal hemoglobin S (HBs). Vaso-occlusion results in recurrent painful episodes and a variety of serious organ system complications that can lead to lifelong disabilities and early death. Clinical signs and symptoms typically develop at an early age.
Bone infarction is the most common earliest presenting symptoms. This often presents as acute pain in the hands and/or feet, and is often the initial symptom occurring in 40% of all patients in general and 50% of children who become symptomatic before the age of two years. The cause is bone marrow infarction. Since pain tends to involve bones with highest bone marrow activity, and because marrow activity changes with age, different bone pain patterns are predictable. During the first 18 months of life, the metatarsal and metacarpals can be involved, presenting as dactylitis or hand-foot syndrome.
An acute episode of pain is the second most common initial presentation and the most common symptom after the age of two years.
Splenic sequestration is the third most common presenting symptom, occurring in 20% of patients overall and one-third of children before the age two years. Over time, vaso-occlusion can occur in virtually every organ system, accounting for the characteristic acute and chronic multisystem failure associated with the disease.
A 27-year-old man presents to the emergency department with pallor and jaundice. On physical examination, the spleen is palpated two cm below the costal margin. A blood exam reveals a reticulocyte count of 18% (normal 0-2%) and microspherocytosis. A Coomb’s test is positive. Which one of the following is the most likely cause of this clinical picture?
A. Acquired autoimmune hemolytic disease.
B. Hereditary spherocytosis.
C. Congenital autoimmune hemolytic disease.
D. Myeloproliferative disorder.
E. Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
**A. Acquired autoimmune hemolytic disease **
- Symptoms: Pallor and jaundice indicate ongoing hemolysis (destruction of red blood cells).
- Clinical Signs: Palpable spleen (splenomegaly) and high reticulocyte count suggest chronicity.
-
Diagnostic Tests:
- Positive Coombs Test: Confirms autoimmune hemolytic disease by detecting antibodies against red blood cells.
- Microspherocytosis: Abnormal round-shaped red blood cells seen on peripheral smear.
-
Acquired Autoimmune Hemolytic Disease:
- Likely Cause: Presents with pallor, jaundice, positive Coombs test, and microspherocytosis.
- Explanation: Immune system mistakenly attacks red blood cells.
-
Hereditary Spherocytosis (Option B):
- Symptoms: Episodes of jaundice and pallor due to hemolytic anemia.
- Peripheral Smear: Shows characteristic spherocytosis (round-shaped red blood cells).
- Coombs Test: Negative because hemolysis is not autoimmune.
-
Congenital Autoimmune Hemolytic Disease (Option C):
- Timing: Presents early in life, which contrasts with chronic autoimmune hemolytic disease.
-
Myeloproliferative Disorders (Option D):
- Association: Not typically associated with hemolysis.
-
G6PD Deficiency (Option E):
- Clinical Features: Presents earlier in life with specific triggers causing hemolysis.
- Autoimmune Nature: Absent, and Coombs test would be negative.
- Autoimmune Hemolytic Disease: Manifests with pallor, jaundice, splenomegaly, high reticulocyte count, positive Coombs test, and microspherocytosis.
- Differential Diagnosis: Consider hereditary spherocytosis for similar symptoms with a negative Coombs test.
Understanding these distinctions helps in diagnosing and managing autoimmune hemolytic disease effectively.
The pallor and jaundice indicate the hemolytic nature of the process. With a palpable spleen and a high reticulocyte count, the process has been chronic and probably long-standing. With the positive Coombs test, the autoimmune nature of the condition is ensured with high certainty; therefore, of the options acquired autoimmune hemolytic disease is the most likely cause to consider. Microspherocytosis can be seen in cases of autoimmune hemolytic disease.
(Option B) Hereditary spherocytosis leads to episodes of jaundice and pallor caused by hemolytic anemia, and characteristic spherocytosis on peripheral smear; however, Coombs test is negative because the hemolysis is not autoimmune in nature.
Option C) Congenital autoimmune hemolytic disease would have presented much earlier in life.
(Option D) Myeloproliferative disorders are not associated with hemolysis.
(Option E) G6PD would have demonstrated its clinical features earlier in life. The condition is not autoimmune and Coombs test would be negative.
** Medscape - Hemolytic Anemia**
A group of college students are admitted to the emergency department with bruises over their skin, dark-colored urine and shock one week after they were back from camping in a forest. Which one of the following is most likely to be the cause of this presentation?
A. Giardia lamblia.
B. Escherichia coli.
C. Disseminated intravascular coagulopathy.
D. Staphylococcus aureus.
E. Ross River fever.
**B. Escherichia coli. **
The bruises over the skin (petechial rash), kidney involvement, and mental status alteration are consistent with thrombotic thrombocytopenic purpura (TTP) as the most likely diagnosis.
TTP is a rare blood disorder characterized by clotting in small blood vessels resulting in a low platelet count. In its full blown form, the disease consists of the pentad of (1) microangiopathic hemolytic anemia,
(2) thrombocytopenic purpura,
(3) neurological abnormalities,
(4) fever (non-infectious), and
(5) renal disease.
TTP can affect any organ system, but involvement of the peripheral blood, the central nervous system, and the kidneys causes the clinical manifestation.
Neurological manifestations include alteration in mental status, seizures, hemiplegia, paresthesias, visual disturbances, and aphasia. Patients may notice dark urine from hemoglobinuria. Severe bleeding from thrombocytopenia is unusual, but petechiae are common. Fever may occur in 50% of patients
E-coli O157:H7, E-coli O104:H4 and some other Shiga toxin-producing bacteria are the most common cause in children with TTP and hemolytic uraemic syndrome (HUS). In adults, many cases are idiopathic, but the same bacteria can cause these diseases as well. In adults immunosuppression and pregnancy can be other possible causes.
Since a group of persons are affected simultaneously, it is very likely that E-coli has been the etiology of the TTP.
(Option A) Giardia lamblia infection manifest with a different clinical picture including diarrhoea (non-bloody), flatulence, and crampy abdominal pain.
(Option C) DIC can present with similar picture (bleeding, shock, renal dysfunction, hepatic dysfunction, and central nervous system problems); however, the coincidence makes E-coli infection a more likely diagnosis.
(Option D) Staphylococcus aureus causes acute gastroenteritis with vomiting (more prominent) and diarrhea. Petechiae, neurological manifestations and shock are not present.
(Option E) Ross River fever is a mosquito-borne disease presenting with fever, rash, and polyarhtralgia.
*http://www.merckmanuals.com/professional/hematolog
*http://emedicine.medscape.com/article/206598-clini
A 70-year-old man from a low-level-of-care nursing home is brought to the hospital after he had a fall 3 hours ago. He is on warfarin for atrial fibrillation (AF). Laboratory studies show that he has an INR of 4.9. A CT scan of the head is ordered which is normal. Other investigations are unremarkable. Which one of the following is the next best step in management?
A. Stop warfarin.
B. Skip one dose of warfarin.
C. Give fresh frozen plasma (FFP).
D. Give vitamin K.
E. Repeat CT scan of the head in 2 days.
**B. Skip one dose of warfarin. **
The therapeutic range of warfarin for most patients varies between 2 to 3.5 (2-3, or occasionally 2.5-3.5).
Increased INR beyond therapeutic levels are associated with higher risk of bleeding. For patients with an INR above the therapeutic range but less than 5, who are not bleeding, skipping the next dose of warfarin and resuming lower doses once the INR is within the therapeutic range is the recommended management.
Ceasing warfarin, FFP, vitamin K (intravenously) and Prothrombinex are used in situations where there is active bleeding or the risk of bleeding is high.
*https://www.health.qld.gov.au/publications/clinica
*http://www.uptodate.com/contents/management-of-war
*https://www.mja.com.au/journal/2013/198/4/update-c
Which one of the following is the most common cause of anemia in geriatric population?
A. Iron deficiency anemia from blood loss.
B. Nutritional anemia from vitamin B12 deficiency.
C. Anemia of chronic disease.
D. Hemolytic anemia.
E. Myelodysplastic anemia.
**C. Anemia of chronic disease. **
Chronic diseases are the most common causes of anemia in the geriatric population accounting for 30-45% of cases. Iron deficiency is the second most common cause.
Cause: Percentage of cases
Chronic diseases 30-45%
Iron deficiency 15-30%
Post-hemorrhagic 5-10%
Vitamin B12/B9 deficiency 5-10% Chronic leukemia and lymphoma 5% Myelodysplastic syndromes 5%
No identifiable cause 15-25%
* AAFP - Anemia in the Elderly
* Evaluation and Management of Anemia in the Elderly
A 32-year-old African male presents to the Emergency Department with fatigue, jaundice, dark-colored urine and acute decrease in hemoglobin for the past four days. Liver function tests are normal, except for an elevated unconjugated bilirubin level. Which one of the laboratory results would be most consistent with the diagnosis of hemolysis due to glucose-6-phosphate dehydrogenase deficiency?
A. Spherocytosis.
B. Schistocytosis.
C. Positive Coomb’s test.
D. Heinz bodies.
E. Elliptocytosis.
**D. Heinz bodies. **
Summary
• G6PD Deficiency: Diagnosed with Heinz bodies and bite cells in a blood smear and confirmed by G6PD activity measurement. • Hereditary Spherocytosis: Identified by spherocytes on a blood smear. • MAHA (e.g., HUS, TTP): Diagnosed with the presence of schistocytes. • Immune-Mediated Hemolytic Anemia: Confirmed with a positive Coombs test. • Hereditary Elliptocytosis: Identified by the presence of elliptocytes in the blood.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency in human, affecting 400 million people worldwide, with a high prevalence in people of African, Asian, and Mediterranean descent. The condition is inherited as an X-linked recessive disorder. It is polymorphic with more than 300 variants.
G6PD deficiency can present as neonatal hyperbilirubinemia. People with this disorder can experience episodes of brisk hemolysis in response to oxidative stresses or, less commonly, have chronic hemolysis. However, many individuals with G6PD deficiency are asymptomatic.
G6PD deficiency confers partial protection against malaria.
The diagnosis of G6PD deficiency can be made on the basis of a well-documented history, evidence of hemolysis, a peripheral-blood smear showing Heinz bodies (erythrocytes with denatured hemoglobin) and ‘bite cells’. Measurement of G6PD activity while the patient is in remission is the gold-standard diagnostic test for G6PD deficiency.
G6PD deficiency should be suspected in all patients with non-immune acute hemolysis and no spherocytosis on laboratory testing.
(Option A) Spherocytes are characteristic feature in hereditary spherocytosis.
(Option B) Schistocytes are seen in microangiopathic hemolytic anemia (MAHA) associated with hemolytic uremic syndrome and thrombotic thrombocytopenic purpura (TTP).
(Option C) Positive Coombs test is the characteristic feature of immune-mediates hemolytic anemia.
(Option E) Elliptocytosis, also known and ovalocytosis, is a feature of hereditary elliptocytosis – an inherited disorder in which an abnormally large number of patient’s red blood cells are elliptical rather than the typical biconcave disc-shaped.
* UpToDate - Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency
* Medscape - Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
A 32-year-old woman, accompanied by his brother, presents with complaint that every time she gets a cut, it takes a long for the bleeding to stop. She also mentions that she is distressed with her heavy periods, for which she has to use 10 pads a day. Her brother mentions that she has been like that since he can remember. She is otherwise healthy with no significant finding on physical examination. Which one of the following is the most likely diagnosis?
A. Hemophilia A.
B. Stuart disease.
C. Von Willebrand disease.
D. Factor IX deficiency.
E. Immune thrombocytopenic purpura (ITP).
**C. Von Willebrand disease. **
Long-standing history of prolonged bleeding after trauma and history of menorrhagea in an otherwise healthy woman is highly suggestive of Von Willebrand disease as the most likely cause.
Von Willebrand disease (VWD) is an inherited disease with many different types (22 types) and clinical pictures. Almost all types cause mild bleeding problems with excellent prognosis. The most common types often have an autosomal dominant inheritance. This disease is very common (1 in 100 population) and is the most common inherited bleeding disorder.
Von Willebrand factor is a circulating factor that is attached to factor VIII. This factor by gluing platelets together and to the vascular lining plays the earliest role in coagulation. Because the clinical disease can be very mild, most cases will never be diagnosed, but if symptomatic, the symptoms can include:
- Easy bruising
- Mucosal bleeding (e.g. epistaxis, menorrhagoea, gastrointestinal bleeding, etc)
- No history of hemarthroses or intramuscular hematomas (except for type 3 that is very rare but can have musculoskeletal manifestations)
- Prolonged bleeding after trauma or surgery
(Option A) Hemophilia A presents with factor type of bleeding (deep and delayed). As both haemophilia A and B are X-linked, women can all be carriers. Homozygous females never born.
(Option B) Stuart disease or factor X (Stuart-Prower factor) deficiency is one of the world’s rarest factor deficiencies. Factor X is a vitamin K-dependent factor that serves as the first enzyme in the common pathway of thrombus formation. It can cause both platelet and factor types of bleeding.
(Option D) Like hemophilia A, factor IX deficiency (haemophilia B) is never seen in an alive woman.
(Option E) ITP presents with petechiae and bruising rather than prolonged bleeding. Furthermore, compared to VWD, chronic ITP in adults is less common.
A 27-year-old man presents with sudden onset of jaundice, pallor, and dark urine three days after taking of primaquine for malaria. On blood tests, hemoglobin is 52 g/L (120-160g/L) and unconjugated bilirubin is elevated. Blood film shows ‘bite cells’. Which one of the following is the most likely diagnosis?
A. Iron deficiency anemia.
B. Glucose-6-phosphate dehydrogenase deficiency.
C. Anemia due to blood loss.
D. Acute hepatitis.
E. Chronic renal failure.
**B. Glucose-6-phosphate dehydrogenase deficiency. **
Development of jaundice after use of primaquine is suggestive of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
The typical presentation is sudden onset of jaundice, pallor, and dark urine, with or without abdominal and back pain. This is associated with an abrupt fall in the hemoglobin concentration of 30-40 g/L during which time the peripheral blood smear reveals red cell fragments, microspherocytes, and eccentrocytes or “bite” cells.
Special stains show** Heinz bodies**, which are collections of denatured globin chains often attached to the red cell membrane.
Episodes of acute hemolytic anemia are triggered by oxidative stress. Infections are the most common triggering factor.
Iron deficiency anemia, anemia due to blood loss and anemia of chronic renal failure are not associated with elevated unconjugated bilirubin. This fining is a feature of hemolytic anemia.
* UpToDate - Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency
* Medscape - Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
A 23-year-old African man presents to your clinic with pallor and dark urine after he took cotrimoxazole for an acute respiratory infection. Blood investigations are significant for hemoglobin of 90 g/L and a reticulocyte count of 5%. Both direct and indirect Coombs tests are negative. Serum electrophoresis shows type A hemoglobin. There is no family history of such presentation. Which one of the following is the most likely diagnosis?
A. Glucose-6-phosphate dehydrogenase deficiency.
B. Autoimmune hemolytic anemia.
C. Sickle cell anemia.
D. Thalassemia.
E. Hereditary spherocytosis.
A. Glucose-6-phosphate dehydrogenase deficiency.
Of the options, glucose-6-phosphate (G6PD) deficiency is the most likely diagnosis.
G6PD deficiency is an X-linked enzymatic defect that can cause hemolysis after oxidative stresses such as acute illness or ingestion of specific drugs. The most commonly implicated drugs are sulfa drugs (e.g., cotrimoxazole), primiquine, dapsone, quinidine and nitrofurantoin. The most common type of oxidant stress, however, is infections not drugs.
Type-A G6PD deficiency is the milder form and is more common among black people, whereas type B is mostly seen in patients of north Mediterranean origin. Type B has a more severe presentation.
The usual presentation is similar to all hemolytic anemias i.e. low hemoglobin, high LDH, decreased haptoglobin, elevated bilirubin (mostly indirect) and increased reticulocyte count in the presence of a normal MCV. An elevated reticulocyte count is a criterion for hemolysis but is not specific for it.
(Option B) Negative Coombs test rules out the possibility of autoimmune hemolytic anemia.
Options C and D) With normal hemoglobin (hemoglobin A, which includes two normal α chains and two normal β chains) on serum electrophoresis, sickle cell disease and thalassemia are excluded.
(Option E) With a negative family history of hereditary spherocytosis, this disease is less likely to be the cause of hemolysis in this patient. Another clue against such diagnosis is that hereditary spherocytosis manifestation occur much earlier in life.
* UpToDate - Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency
* Medscape - Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
A 23-year-old woman presents to your practice with complaint of breathlessness while climbing stairs. On blood tests, she has hemoglobin of 7 g/dL. Which one of the following is the most appropriate next step in management?
A. Transfusion of packed cells.
B. Colonoscopy.
C. Small bowel biopsy.
D. Parenteral iron.
E. Fecal occult blood test (FOBT).
A. Transfusion of packed cells.
According to guidelines, transfusion of packed red cells is not indicated for those with Hb >10 g/dL. The lower threshold varies from 6 g/dL to 8 g/dL; however, hemoglobin level alone cannot be used to determine the need for packed cell transfusion.
It is recommended that symptomatic anemia be treated with transfusion of packed cells in all patients with Hb<10 g/dL, regardless of the Hb level, provided that the symptoms are severe enough and are clearly related to the anemia rather than the underlying condition. This is true regardless of the underlying etiology of the anemia.
Colonoscopy (option B), FOBT (option E), or small biopsy (option C) may be indicated as attempts to spot the source or iron loss or deficiency where iron deficiency is the underlying cause of anemia. Before proceeding to such tests, iron deficiency should be diagnosed by iron studies. Iron replacement (most commonly by oral supplementation) is the treatment of established iron deficiency anemia. Parentral iron (option D) may be used in very severe cases of iron deficiency anemia.
NOTE – According to most references, exertion-related symptoms of anemia are not indications for transfusion of packed cells. In this question, however, the only acceptable option will be transfusion of packed cells, as no other option is correct regarding this clinical scenario.
* MJA - Diagnosis and management of iron deficiency anaemia: a clinical update * NCBI - Blood Transfusion - Recommendations for the transfusion of red blood cells
Accompanied by his wife, a 68-year-old man is brought to the emergency department. The wife mentions that her husband woke up with a nagging headache. One hour later, he started to develop slurred speech and weakness of the right arm. She mentioned that her husband has been on a pill for his cardiac condition for the past 3 months, but she cannot remember the name. Since his pulse seems irregular, you assume that the pill is warfarin and check an INR which comes back 4.5. A non- contrast CT scan of the head reveals intracranial hemorrhage. Which one of the following is the next best action to take?
A. Give fresh frozen plasma (FFP).
B. Give FFP and vitamin K.
C. Give protamine sulfate.
D. Give vitamin K.
E. Switch to unfractionated heparin.
**B. Give FFP and vitamin K. **
Managing Warfarin-Associated Bleeding
Scenario:
A patient on warfarin therapy presents with major or life-threatening bleeding.
Key Points:
-
Warfarin and Bleeding:
- Warfarin is an anticoagulant used to prevent blood clots.
- Bleeding is a common complication, and the risk increases with higher INR values.
- Major or life-threatening bleeding requires immediate reversal of warfarin’s effects.
Management Steps:
-
Administer Prothrombin Complex Concentrate (PCC):
- PCC is the preferred treatment for rapidly reversing the effects of warfarin.
- PCC contains clotting factors II, IX, and X, and sometimes VII.
- Advantages of PCC over Fresh Frozen Plasma (FFP) include:
- Rapid reconstitution and infusion.
- Fast onset of action (10-15 minutes).
- No need for blood group matching.
- Lower risk of viral transmission and other transfusion reactions.
-
Give Fresh Frozen Plasma (FFP) if PCC is Unavailable:
- FFP can be used to reverse warfarin effects if PCC is not available.
- Large volumes are required.
-
Administer Vitamin K:
- Give 5-10mg of vitamin K intravenously.
- Vitamin K helps sustain the reversal of warfarin’s effects.
- It takes 6-8 hours to start working and 24 hours for full effect.
-
Stop Warfarin:
- Discontinue warfarin immediately, but note that this alone is not enough to manage acute bleeding.
Options Explanation:
-
Option A: FFP alone:
- FFP reverses warfarin effects but needs to be combined with vitamin K to maintain the reversal.
-
Option C: Protamine sulfate:
- Protamine sulfate is an antidote for heparin, not warfarin.
-
Option D: Vitamin K alone:
- Vitamin K alone is not sufficient for immediate reversal; it works slowly.
-
Option E: Switching to heparin:
- This does not address the immediate bleeding issue and does not counteract warfarin effects.
Conclusion:
For managing major or life-threatening bleeding in a patient on warfarin, give FFP and vitamin K. This combination quickly reverses the effects of warfarin and sustains the reversal, ensuring the patient’s safety.
Prothrombin Complex Concentrate (PCC):
- Preferred for rapid reversal.
- Fast onset, fewer complications.
Fresh Frozen Plasma (FFP):
- Used if PCC is unavailable.
- Requires large volumes.
Vitamin K:
- Administer intravenously.
- Sustains warfarin reversal.
Stop Warfarin:
- Discontinue immediately but not sufficient alone.
- PCC first, FFP if no PCC.
- Vitamin K to sustain.
- Stop warfarin but don’t rely on this alone.
Prothrombinex-VF:
• A three-factor PCC (factors II, IX, and X) used in Australia and New Zealand. • Can reverse warfarin effects successfully, often without FFP, in stable patients. • For severe bleeding or INR > 10, it’s recommended to use Prothrombinex-VF with FFP to provide enough factor VII.
When Prothrombinex-VF is not available:
• Use the maximum dose of FFP. • Combine with vitamin K1 for sustained reversal.
Key Points:
• PCC is preferred for fast and effective warfarin reversal. • FFP is used if PCC is unavailable, especially for severe bleeding. • Always combine with vitamin K1 for sustained effect.
Summary:
• Use PCC (preferably Prothrombinex-VF) with FFP for severe bleeding. • PCC acts fast and has fewer risks compared to FFP alone. • For severe cases, always add vitamin K1.
By following this structured approach, you can effectively manage warfarin-associated bleeding and ensure optimal patient outcomes.
Bleeding is the most common complication of warfarin therapy and is related to the INR value. Although incremental rises in INR increase the risk of bleeding, most intracranial bleedings occurs in patients with an INR in the therapeutic range. Such events occur in 0.5-1.0% of patients with AF per year.
In the event of major or life-threatening bleeding associated with warfarin use, prothrombin complex concentrate (PCC) with or without FFP is the most appropriate next step in management. FFP in large volumes should be used if PCC is not available. In major or life-threatening bleedings, 5-10mg of vitamin K should also be given in conjunction with PCC or FFP to sustain the reversal effect. Cessation of warfarin should be considered in all patients with bleeding; however, cessation of warfarin alone is not going to change the immediate management plan that is reversing its effects immediately.
(Option A) FFP alone immediately reverses the warfarin effect, but vitamin K is aslo necessary to sustain the response after the effect of FFP wears out.
(Option C) Protamine sulfate is the antidote to heparin with no effect on warfarin.
(Option D) Vitamin K is an effective antidote to the anticoagulation effect of warfarin. Despite this, data are lacking to show that its use improves outcome in life-threatening bleeding. The usual dose is 5-10mg administered orally or intravenously. Intravenous route achieves a more rapid response compared with oral administration, with an onset of action between 6-8 hours. However, both routes achieve a similar correction of the INR by 24 hours. Vitamin K is the treatment of choice if the goal is to normalize the INR and no immediate counteraction against major organ bleeding or life-threatening bleeding is prompted. Intravenous administration is the preferred method.
(Option E) Switching to heparin does not decrease the risk of bleeding; nor does it counteract warfarin effects.
TOPIC REVIEW
Prothrombin complex concentrate (PCC) comes in two forms. One formulated with three factors (II, IX and X) and the other with four factors (II, VII, IX and X). Advantages of PCC over FFP include rapid reconstitution into a small volume for infusion over 20–30 minutes, fast onset of action (10-15 minutes), no requirement to check a patient’s blood group, minimal risk of viral transmission due to pathogen reduction and inactivation steps during manufacturing, and reduced risk of other clinical adverse reactions such as transfusion-associated circulatory overload or transfusion-associated acute lung injury. Prothrombinex-VF, a three-factor PCC, is the only product currently in routine use in Australia and New Zealand for warfarin reversal. Despite instructions by the Warfarin Reversal Consensus Guidelines published in 2004 recommended that it be supplemented with FFP, there have been several reports of successful use of Prothrombinex-VF without addition of FFP. Prothrombinex-VF has been used successfully to electively reverse anticoagulation in patients on warfarin therapy with a stable INR, and achieved the target INR in over 90% of patients. However, since the efficacy of Prothrombinex-VF alone has not been extensively evaluated for patient with major or life-threatening bleeding or INR > 10, current recommendation is that Prothrombinex-VF is supplemented with FFP for addition of adequate amounts of factor VII to ensure optimal reversal of the anticoagulant effect of warfarin when major or life-threatening bleeding is a concern.
For life-threatening (critical organ) and clinically significant bleeds, the consensus is to use the maximum dose of Prothrombinex-F (with vitamin K1 and FFP) and the maximum amount of FFP when Prothrombinex-VF is unavailable.
Recommendations for managing patients on warfarin therapy with bleeding are summarized in the following table:
(TABLE) (Attached with question)
Recommendations for managing patients on warfarin therapy with a high INR but no bleeding are summarized in the following table:
(TABLE) (See photo below)
https://www.mja.com.au/journal/2013/198/4/update-c
A 67-year-old man in brought to the emergency department with sudden-onset severe headache and confusion. He was diagnosed with atrial fibrillation (AF) 4 months ago, for which he has been on warfarin since then. Blood studies show an INR of 3.5. A CT scan of the head reveals intracerebral hemorrhage. Which one of the following is the most appropriate next step in management?
A. Stop warfarin.
B. Vitamin K.
C. Fresh frozen plasma (FFP).
D. Increase the dose of warfarin.
E. Reduce the dose of warfarin.
**C. Fresh frozen plasma (FFP). **
Bleeding is the most common complication of warfarin therapy and is related to the INR value. Although the risk of hemorrhage is directly related to the INR value, most events of intracranial hemorrhage occur in patients with an INR within the therapeutic range. Such events occur in 0.5-1.0% of patients with AF per year.
In the event of major or life-threatening bleeding associated with warfarin use, prothrombin complex concentrate (PCC) with or without FFP is the most appropriate next step in management. FFP in large volumes should be used if PCC is not available.
(Option A) Cessation of warfarin should be considered in all patients with bleeding; however, cessation of warfarin alone is not going to change the immediate manage plan that is reversing its effects immediately.
(Option B) Vitamin K is an effective antidote for the anticoagulation effect of warfarin. Despite this, data are lacking to show that its use improves outcome in life-threatening bleedings. The usual dose is 5-10mg administered orally or intravenously. Intravenous route achieves a more rapid response compared with oral administration, with an onset of action between 6-8 hours. However, both routes achieve a similar correction of INR by 24 hours. In major or life-threatening bleeds, 5-10mg of vitamin K should be given in conjunction with PCC or FFP to sustain the reversal effect. Vitamin K is the treatment of choice for patients on warfarin therapy with bleeding in whom the aim is to normalize the INR (not immediate counteraction against major organ bleeding or life-threatening bleeding), vitamin K given intravenously is the preferred treatment.
(Option D) Increasing the dose of warfarin worsens the condition and not a correct option. Reducing the dose of warfarin can lead to decreased INR in long-term. It does not counteract the bleeding.
(Option E) While the patient is bleeding, dose reduction of the warfarin is not an appropriate option. Dose reduction is an option for patients with INRs beyond the target but no active bleeding.
* MJA - An update of consensus guidelines for warfarin reversal
A 73-year-old man presents to the emergency department with fracture of the right femoral neck after he sustained a fall at home. He underwent coronary artery drug eluting stent placement 2 months ago, and has been on clopidogrel since then. A full blood count (FBC) is normal; however, he has several bruises over his body. He requires surgery for fixation of the fracture. Which one of the following is the most appropriate management of this patient?
A. Stop clopidogrel and proceed with surgery in one week.
B. Do the surgery now.
C. Administer fresh frozen (FFP) plasma and proceed with the surgery.
D. Give platelets and proceed with the surgery.
E. Switch to heparin and perform the surgery in 7 days.
**B. Do the surgery now. **
Femoral neck fractures require emergency surgical fixation because other measures like traction or rest pose more risk to the patient than the risk of bleeding associated with antiplatelet therapy. For patients who need immediate surgery, it should not be delayed.
In this case, the patient has a coronary stent and is on clopidogrel, an antiplatelet therapy that should continue for at least 12 months to prevent stent thrombosis. Stopping clopidogrel significantly increases the risk of serious complications. Therefore, the patient should undergo emergency surgery while remaining on clopidogrel.
A review of Australian data from 181 patients with proximal femoral fractures found no significant difference in bleeding, transfusion requirements, complications, or length of stay between patients on clopidogrel or aspirin and those not on these medications.
- (Options A and E): Delaying emergency surgery is incorrect.
- (Option C): Fresh frozen plasma (FFP) reverses heparin and warfarin effects but does not affect platelet function inhibited by clopidogrel.
- (Option D): Platelet transfusion is only considered when the risk of bleeding greatly outweighs the benefits of antiplatelet therapy. For this patient, platelet transfusion may cause stent thrombosis and is not advisable unless the bleeding risk is extraordinarily high.
In summary, the patient should have emergency surgery while continuing clopidogrel.
Femoral neck fracture requires emergency surgical fixation, because other measures such as traction or rest pose a more significant risk to the patient than does the risk of bleeding associated with antiplatelet therapy. Patients for whom surgery cannot be deferred should be operated on immediately. Any option suggesting deferral of the surgery is inappropriate. On the other hand, this patient has undergone coronary stenting with drug-eluting stent and requires at least 12 months of antiplatelet therapy. Cessation of antiplatelet therapy is associated with significantly increased risk of stent thromobosis and grave complications; hence antiplatelet therapy should be continued. He should undergo emergecny surgery while he is on clopidogrel.
Of note, an Australian retrospective review of 181 patients with proximal femoral fracture demonstrated no significant difference in the amount of bleeding, transfusion requirement, complications rate, or length of stay in 16 patients taking clopidogrel and in 48 taking aspirin compared to others.
(Options A and E) Deferral of an emergency surgery is incorrect.
(Option C) FFP reverses the effect of heparin and warfarin. It has no effect on inhibited action of platelets.
(Option D) Platelet transfusion might be considered in selected patients in whom the risk of major bleeding clearly outweighs the benefits of counteracting the antiplatelet therapy. However, transfusion of platelets in this patient may result in stent thrombosis and is not advisable. The only exception is when the risk of bleeding is so high that remarkably outweighs the risk of stent thrombosis.
* http://www.csanz.edu.au/wp-content/uploads/2014/12
*http://www.aafp.org/afp/2010/1215/p1484.html
*http://www.racgp.org.au/afp/2014/december/new-oral
*http://bja.oxfordjournals.org/content/111/suppl_1/
A 66-year-old man presents with altered bowel habits, decreased stool caliber and rectal bleeding in the form of blood covering the stool. Investigations show that he has a colorectal cancer. He is planned for surgical tumor resection. Currently, he is on warfarin due to atrial fibrillation (AF) and has an INR of 2.5. Which one of the following is the most appropriate option to consider for warfarin reversal prior to the surgery?
A. Proceed with the surgery.
B. Give vitamin K before the surgery. C. Give fresh frozen plasma (FFP) and proceed with the surgery.
D. Wait for 3 months.
E. Switch to clopidogrel and perform the surgery in one week.
**B. Give vitamin K before the surgery. **
This patient, as a candidate for a surgical procedure, is at increased risk of intra- or post-operative bleeding due to warfarin therapy. Resection of a colonic tumor is an elective procedure that allows for planned action for warfarin reversal. In those surgical candidates with an INR of 2-3, cessation of warfarin 4-5 days before the surgery and administration of vitamin K (3mg, intravenously) the evening before the surgery is the preferred plan.
(Option A) Proceeding with a major surgery without warfarin reversal is associated with a significantly increased risk of bleeding and not appropriate.
(Option C) FFP was the correct answer if this patient required emergency surgery. Prothrombinex-VF (or if unavailable FFP) is used for rapid reversal of warfarin effect (in minutes) for urgent surgical procedures associated with increased risk of bleeding. Using FFP for warfarin reversal in elective procedures is not appropriate.
(Option D) Deferring the surgery for 3 months is unnecessary and inappropriate because warfarin reversal can be achieved in 5 days, maximum. There is also no other medical condition to preclude surgery in this patient.
(Option E) Clopidogrel is an antiplatelet medication. Switching to clopidogrel not only does not counteract the effect of warfarin, but it also adds to the risk of bleeding by inhibiting platelet aggregation.
https://www.mja.com.au/journal/2013/198/4/update-c
A 22-year-old woman comes to the emergency department complaining of epistaxis for the past 12 hours. She denies any trauma to her nose and face. On examination, she is noted to have several bruises over her chest, arms and legs and petechiae on the inner side of her lower lip. Laboratory tests revealed a platelet count of 223000/mm3, a PT of 12 seconds, and a prolonged APTT of 57 seconds. Her blood tests are otherwise normal. Which one of the following could be the most likely diagnosis?
A. Hemophilia.
B. Von Willebrand disease.
C. Factor XII deficiency.
D. Hemolytic uremic syndrome (HUS).
E. Idiopathic thrombocytopenic purpura (TTP).
**B. Von Willebrand disease. **
On approach to a bleeding disorder, the first thing to consider is evaluating whether it is platelet versus factor type of bleeding.
- Platelet type of bleeding is superficial and causes gingival bleeding, epistaxis, ecchymoses, petechiae and purpura.
- Factor type of bleeding occurs more deeply in joints or muscles causing hematomas.
- Gastrointestinal, genitourinary, or central nervous system bleeding could be caused by both types.
This patient has platelet type of bleeding in the presence of a normal platelet count, a normal PT and prolonged ATTP. The clinical and laboratory picture is highly suggestive of Von Willebrand disease as the most likely diagnosis.
Von Willebrand disease is the most common hereditary bleeding disorder affecting 1% of population and characterized by a defect in production of Von Willebrand factor (VIIIa). Of all affected persons, 1% may become symptomatic at any age. Von Willebrand presents with superficial bleeding tendency in the presence of normal platelet count and PT, but an often elevated APTT. The reason for increased ATTP is the fact that defect in Von Willebrand factor results in decreased factor VIII level of activity.
(Option A) Hemophilia is only expressed in male individuals. Females can only carry the gene, as the pattern of inheritance is X-linked recessive.
(Option C) Factor XII deficiency is a very rare genetic disease which never causes bleeding. Hemolytic uremic syndrome is characterised by the presence the helmet cells (schistocytes or fragmented re cells) on the peripheral blood smear with features of haemolytic anemia such as decreased red cell counts and hemoglobin, reticulocytosis, elevated LDH, and probably jaundice.
(Option D) The primary clot formation and homeostasis is the function of platelets. After endothelial lining is damaged, Factor VIII and Von Willebrand factor are released from underneath the epithelial cells and cause the platelets not adhere to each and to the endothelial lining. Several hours later (after the fibrin clot is formed) a metaloprotease (ADAMTS13) dissolves the Von Willebrand factor to let the blood stream washes the platelets away. The deficiency of this enzyme leads to hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). A microangiopathic hemolytic anemia is the essence of the diagnosis. This patient does not have hemolytic anemia.
(Option E) Immune thrombocytopenia (ITP) typically occurs in a young otherwise healthy patient and is characterized by isolated fall in platelet count and platelet type of bleeding.
A 56-year-old woman is brought to the emergency department with sudden-onset severe epigastric pain. On examination, she has a blood pressure of 90/55mmHg, heart rate of 110bpm, and respiratory rate of 22 breaths per minute. There is abdominal guarding and rigidity, as well as marked tenderness and rebound tenderness over the epigastric area. A chest X-ray reveals free air under the right hemi-diaphragm. Based on clinical findings, a perforated peptic ulcer is diagnosed and the patient is planned for emergency laparotomy. She is on warfarin due to deep vein thrombosis (DVT) that developed 2 weeks ago. Which one of the following is the most appropriate next step in management?
A. Stop warfarin, give vitamin K and do the surgery.
B. Proceed with the surgery.
C. Give fresh frozen plasma (FFP) and proceed with the surgery.
D. Add intravenous heparin and perform the surgery.
E. Stop warfarin, give her heparin and proceed with the surgery.
**C. Give fresh frozen plasma (FFP) and proceed with the surgery. **
This patient is in need of emergency life-saving surgery in the setting of perforated peptic ulcer disease and clinical manifestation of peritonitis (abdominal rigidity and guarding). In the event of need for life-saving or emergency surgeries where deferring the surgery is not possible, warfarin effect should be reversed immediately using prothrombin complex concentrate (CCP) (Prothrombinex-VF®), or fresh frozen plasma (FFP) if CCP unavailable, regardless of the risk of potential VTE if warfarin is temporarily stopped. Any option offering addition of vitamin K to cessation of warfarin and administration of CCP (or FFP) would be the most appropriate management (not an option).
(Option A) Cessation of warfarin and administration of vitamin K was the method of choice if the patient had an INR of 2-3 within the past 2-4 weeks and there was a time window for deferral of the surgery for at least 24 hours. In such cases, vitamin K is given intravenously the evening before the surgery and INR is checked on the day of the surgery. An INR of ≤1.5 is safe to proceed with the surgery. If INR is >1.5 Prothrombinex-VF® should be given (FFP is used if Prothrombinex-VF is not available)
(Option B) Proceeding with the surgery without warfarin reversal is associated with significant risk of intra- or post-operative bleeding and not recommended.
(Option D) Addition of heparin adds to the risk of bleeding.
(Option E) Cessation of warfarin and bridging with heparin is indicated in patients with high risk of VTE, who are planned for elective surgery. The protocol is not used for emergency procedures.
TOPIC REVIEW
Management of patients on warfarin therapy who are undergoing an invasive procedure is according to the following table:
A 55-year-old man has been on warfarin for AF for the past 3 months. He presented with an incarcerated inguinal hernia and was booked for emergent surgery. Warfarin was stopped and fresh frozen plasma was given. Which one of the following is the time to resume warfarin therapy?
A. 12 hours post-op.
B. 48 hours post-op.
C. Immediately after recovery from anesthesia.
D. 5 days post-op.
E. When INR is less than 1.8 again.
**A. 12 hours post-op. **
For those, whose warfarin therapy has been stopped before major surgical procedures, it is recommended that the previous maintenance dose of warfarin be resumed on the night of surgery (12-24 hours).
In addition to warfarin, low molecular weight heparin (LMWH) in prophylactic dose or unfractionated heparin (UFH) with slow infusion is started at the same time. The target APTT is 1.5 times the normal. LMWH or UFH is continued for at least 5 days and is ceased 48 after the target INR is reached (≥1.8).
References * https://www.mja.com.au/journal/2013/198/4/update-c * https://www.seslhd.health.nsw.gov.au/rhw/manuals/d
A 65-year-old woman underwent an emergency surgery for a strangulated femoral hernia 2 days ago. She was on warfarin that was ceased before the surgery and fresh frozen plasma was given. Which one of the following is the most appropriate action to take regarding resuming anticoagulation?
A. Start the patient on LMVH.
B. Start the patient on unfractionated heparin.
C. Resume warfarin.
D. Resume warfarin and start LMWH. E. Resume warfarin after one week.
D. Resume warfarin and start LMWH.
For patients whose warfarin therapy has been stopped before major surgical procedures, it is recommended that the previous maintenance dose of warfarin be resumed on the night of surgery (12-24 hours) and prophylactic dose of LMWH started at the same time.
Unfractionated heparin (UFH) can substitute LMWH as a second-line option. Unlike LMWH, UFH use requires monitoring to a target APTT of 1.5 times the normal. If unfractionated heparin (UFH) is used bolus injection should be avoided and slow infusion used. LMWH or UFH is continued for at least 5 days and is ceased 48 after the target INR is reached (≥1.8). The reason for co-administration of LMWH or UFH is the fact that warfarin initially increases the risk of thromboembolism.
References * https://www.mja.com.au/journal/2013/198/4/update-c * https://www.seslhd.health.nsw.gov.au/rhw/manuals/d
Which one of the following hereditary conditions is associated with highest risk of venous thromboembolism (VTE)?
A. Anti-thrombin deficiency.
B. Protein C deficiency.
C. Protein S deficiency.
D. Factor V Leiden.
E. Lupus anticoagulant.
**A. Anti-thrombin deficiency. **
In addition to conditions such as immobility, obesity, oral contraceptive pills, etc., there are a variety of inherited factors that contribute to VTE. These factors are also known as strong, medium and weak risk factors.
Anti-thrombin deficiency, protein C deficiency (option B), and protein S deficiency (option C), are associated with high risk of VTE. Among this group members, anti-thrombin deficiency, formerly known as anti-thrombin III deficiency, confers the highest risk of VTE..
(Option D) Factor 5 Leiden is a moderate risk factor for VTE.
(Option E) Lupus anticoagulant is also a factor for both VTE and arterial thromboembolism but is an acquired condition not an inherited one. The prevalence is 1 to 5% of population and even more in the elderly and those with a comorbid condition such as cancer. The risk of developing VTE in an individual with lupus anticoagulant is approximately 6-8%.
References * American Heart Association - Risk Factors for Venous Thromboembolism * MedScape - Genetics of Venous Thromboembolism * PubMed - Venous Thromboembolism: Classification, Risk Factors, Diagnosis, and Management
