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a bleeding disorder🚧 施工中
a bleeding disorder
Philip Hoffman, MD
CHIEF COMPLAINT
PATIENT
Ms. A is a 24-year-old woman who comes to see you because her gums are bleeding when she brushes her teeth.
What is the differential diagnosis of bleeding? How would you frame the differential?
CONSTRUCTING A DIFFERENTIAL DIAGNOSIS
The framework for bleeding distinguishes between structural causes (ie, an injury to the tissue or organ), platelet-related causes, and clotting factor–related causes. Bleeding due to platelet abnormalities, whether due to reduced number or abnormal function of platelets, is usually small vessel bleeding, and produces such findings as petechiae, bruising, gum bleeding, or nosebleeds. The bleeding starts and persists immediately following the injury that induces it. Platelet-related bleeding is generally not quantitatively significant (ie, platelet-related bleeding tends not to cause serious blood loss requiring red cell transfusions). Nonetheless, platelet-related bleeding can still be clinically important if a patient bleeds a small amount into the brain (unusual unless the platelet count is < 10,000/mcL) or induces an abdominal hematoma from vigorous coughing, for example. By contrast, bleeding due to coagulation factor deficiencies or inhibitors tends to be delayed; that is, a platelet plug slows or stops the bleeding immediately after an injury, but the platelet plug is then not bolstered by the stable fibrin clot that is meant to definitively stop the bleeding. Bleeding due to coagulation factor abnormalities is more likely to be quantitatively significant, generally occurring in joints, the gastrointestinal (GI) tract, brain, retroperitoneum, or at sites of recent injury or medical or surgical intervention.
A. Structural causes
1. Tissue injury from trauma
2. Abnormality of the tissue such that minor trauma causes bleeding, such as a toothbrush causing gum bleeding from inflammatory gingival disease
B. Bleeding due to platelet disorders
1. Disorders of platelet number (thrombocytopenia)
a. Decreased production of platelets
(1) Medications (examples include valproic acid, linezolid, thiazide diuretics, gold compounds, antineoplastic chemotherapy drugs)
(2) Bone marrow replacement by malignancy, fibrosis, granulomas
(3) Bone marrow aplasia
(4) Suppression of megakaryocyte production by heavy alcohol use
(5) Vitamin B12 deficiency (megaloblastic hematopoiesis is a DNA synthetic defect affecting all cell lines, not only erythroid)
b. Increased loss or consumption of platelets
(1) Splenic sequestration (platelet count usually stays above 40,000/mcL)
(2) Autoimmune thrombocytopenia
(a) Idiopathic (also called idiopathic thrombocytopenic purpura [ITP])
(b) HIV
(c) Systemic lupus erythematosus (SLE)
(d) Lymphoproliferative disorders
(e) Hepatitis C
(f) Medications (examples include heparin, phenytoin, carbamazepine, sulfonamides, quinine, antiplatelet drugs used for coronary syndromes such as abciximab or tirofiban)
(3) Disseminated intravascular coagulation (DIC)
(4) Thrombotic thrombocytopenic purpura (TTP)
(5) Sepsis
2. Disorders of platelet function
a. Congenital
(1) von Willebrand disease
(2) Other rare genetic abnormalities
b. Acquired
(1) Medications, such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs). In some instances, the drugs are administered with the intention of inhibiting platelet function, such as aspirin or clopidogrel for cardiovascular disease.
(2) Myeloproliferative disorders, such as essential thrombocythemia, polycythemia vera
(3) Coating of platelets by abnormal proteins, such as in plasma cell myeloma (formerly multiple myeloma) and, occasionally, immune thrombocytopenia
(4) Uremia
C. Bleeding due to clotting factor abnormalities
1. Congenital
a. Hemophilia A (the most common)
b. Other clotting factor deficiencies
2. Acquired
a. Deficiency of a factor or factors
(1) Liver disease
(2) Vitamin K deficiency (nutritional or due to warfarin therapy)
(3) Abnormal adsorption of a factor, eg, factor X adsorption to amyloid fibrils
(4) Consumption of factors, eg, DIC
(5) Dilution of factors, eg, massive transfusion
b. Acquired inhibitor to clotting factor or factors
Figure 8-1 shows the diagnostic approach to bleeding disorders.
Figure 8-1. Diagnostic approach to the bleeding patient.
About 2 weeks ago, Ms. A noticed bleeding from her gums while she was brushing her teeth. The bleeding lasts only briefly, and she does not consider it to be a large amount of blood. Her gums do not hurt, and she is timely with her dental care. At her last cleaning a month ago, she was told all was well. She has also noted some tiny red dots on her ankles in the past week—they are not raised and do not itch or hurt. She notes that her last menstrual period was somewhat heavier than usual, and she has had an intermittent headache over the last 2 days, partially relieved by acetaminophen. Otherwise, she has taken no medications. On examination, she looks well and has normal vital signs. Her oral examination shows evidence of recent gingival bleeding, and there are a few palatal petechiae. She also has petechiae on her antecubital fossae and ankles. There is no lymphadenopathy. Chest and abdominal examinations are normal, with no splenomegaly noted.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?
RANKING THE DIFFERENTIAL DIAGNOSIS
There are several pivotal points in Ms. A’s presentation that suggest her bleeding is due to a platelet disorder: the bleeding occurs immediately after the trauma of tooth brushing, she has petechiae on her skin, and the bleeding is small volume.
The second pivotal point is that her history further suggests that her platelet disorder is acquired. If she had a congenital platelet disorder, such as von Willebrand disease, she might have had life-long heavy menses and other manifestations of bleeding. In this case, her symptoms just began 2 weeks ago. A platelet count will confirm that her bleeding is related to thrombocytopenia, rather than platelet dysfunction, which is less commonly seen. (If the platelet count is normal, platelet dysfunction should be suspected, and a test such as the PFA-100 assay should be ordered. This test is a reproducible screening tool for platelet function abnormalities. It measures the time to formation of a platelet plug in response to collagen along with adenosine diphosphate [ADP] or epinephrine.) The most common cause of thrombocytopenia in a young woman with no signs of systemic illness is idiopathic autoimmune thrombocytopenia. Although Ms. A’s headache is mild and she looks well, TTP can present with headache and thrombocytopenia and also tends to occur in young women. Finally, it is critical to remember that the platelets are only 1 of the cell lines affected by bone marrow disorders, and that a serious bone marrow condition (eg, acute leukemia) might first manifest as thrombocytopenia. A key step, then, is to decide if the thrombocytopenia is isolated or part of a pancytopenia picture, such as one might encounter with acute leukemia.
Table 8-1 lists the differential diagnosis.
Table 8-1. Diagnostic hypotheses for Ms. A.
Ms. A’s laboratory tests indicate a WBC of 5600/mcL, RBC of 3.9 million/mcL, Hb of 11.2 g/dL, HCT of 33.5%, and platelet count 8000/mcL. The reticulocyte production index is 1.0. Examination of the peripheral blood smear shows markedly decreased platelets with some large platelet forms, and normal RBC and WBC morphology.
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
Leading Hypothesis: ITP
Textbook Presentation
The classic presentation is gum bleeding or petechiae in a previously healthy person not exposed to medications that can cause thrombocytopenia. The platelet count is low, with large platelets seen on peripheral blood smear; other cell lines are normal. Physical exam, other than the minor bleeding, is normal.
Disease Highlights
A. ITP is an autoimmune disorder primarily of young women. This is the demographic group that commonly suffers from other autoimmune disorders such as SLE or thyroid disease.
B. A better term might be autoimmune thrombocytopenic purpura, since some cases are not idiopathic but are secondary to other conditions, such as lymphoproliferative disorders, collagen vascular disorders (eg, SLE), or infectious disorders (eg, chronic hepatitis or HIV infection).
C. The prevalence is approximately 100 cases per million persons.
Evidence-Based Diagnosis
A. ITP is a clinical diagnosis.
B. A bone marrow examination is not required for diagnosis.
1. If performed, it would likely show normal or increased megakaryocytes, indicating adequate platelet production and suggesting the thrombocytopenia is due to peripheral destruction of platelets in the reticuloendothelial system.
2. A bone marrow examination should be done when the presentation is atypical, for example:
a. Patient has splenomegaly or significant lymphadenopathy or other cytopenias
b. The patient is older.
C. Serum antiplatelet antibody tests are about 50–60% sensitive and not sufficiently specific to make the diagnosis of ITP.
1. They are not considered sufficiently reliable for general use in diagnosing ITP.
2. If there is serious consideration of a drug-induced cause of immune thrombocytopenia, it may be possible to demonstrate drug-related antiplatelet antibodies in reference laboratories.
D. A successful clinical trial of corticosteroid therapy may also serve as strong evidence of the correct diagnosis of ITP.
E. Serologic studies are indicated if SLE, hepatitis C, or HIV infection is suspected.
Treatment
A. High-dose corticosteroid, such as prednisone or dexamethasone, is the initial treatment for all patients.
B. Patients who do not respond to corticosteroids or whose thrombocytopenia recurs when the corticosteroids are stopped may undergo splenectomy, which removes a site of antibody production as well as a site of reticuloendothelial system destruction of antibody-coated platelets.
C. In refractory cases, other immunosuppressants may be used, such as rituximab, azathioprine, or cyclophosphamide.
D. Thrombopoietin analogues such as romiplostim and eltrombopag have become more widely used for treatment of refractory cases of ITP.
MAKING A DIAGNOSIS
Ms. A’s WBC count and Hb are normal, eliminating leukemia as a possible diagnosis. Her blood smear does not show schistocytes (seen in microangiopathic hemolytic anemia), suggesting that she does not have TTP. Further, her reticulocyte production index is low and there are no spherocytes, suggesting that she does not have immune hemolytic anemia accompanying the immune thrombocytopenia. Her neurologic exam is normal as is her serum creatinine.
Have you crossed a diagnostic threshold for the leading hypothesis, ITP? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?
Alternative Diagnosis: TTP
Textbook Presentation
Patients with TTP appear systemically ill. The 5 classic manifestations are thrombocytopenia; microangiopathic hemolytic anemia; neurologic abnormalities such as confusion, headache, lethargy, or seizures; fever; and acute kidney injury.
Disease Highlights
A. Only 2 or 3 of the classic manifestations are present in many patients.
B. Thrombocytopenia and microangiopathic hemolytic anemia must be present to diagnose TTP, regardless of whether the other manifestations are present.
C. Neurologic abnormalities are present in about two-thirds of patients, acute kidney injury or kidney dysfunction in about half, and fever in about one-quarter.
D. Pathophysiology
1. The ADAMTS13 enzyme is responsible for cleaving ultra-large von Willebrand factor multimers into smaller components.
2. An anti-ADAMTS13 antibody inactivates the enzyme; the trigger for antibody formation is unknown.
3. The lack of the enzyme leads to the ultra-large von Willebrand multimers causing platelet aggregation and clumping in the microcirculation, leading to thrombocytopenia.
4. These clumps cause red blood cells passing over them to be physically damaged, leading to the characteristic finding on the blood smear of schistocytes, or fragmented red blood cells.
Evidence-Based Diagnosis
A. A plasma test demonstrating reduced ADAMTS13 activity and a positive test for the anti-ADAMTS13 antibody reliably establish the diagnosis.
B. The diagnosis of TTP is made clinically, since the ADAMTS13 assay result may take several days to return, and the disease has critical morbidity and mortality if treatment is delayed.
1. Any patient with thrombocytopenia (usually below 30,000/mcL) and evidence of microangiopathic hemolysis (schistocytes on peripheral blood smear, elevated serum lactate dehydrogenase (LD) level, reduced serum haptoglobin level) should raise concern about TTP.
2. If neurologic signs or acute kidney injury is present, the diagnosis becomes even more likely.
3. The “PLASMIC” score is a way to predict the likelihood of finding a low ADAMTS13 activity level diagnostic for TTP.
a. It is based on the presence or absence of 7 clinical features:
(1) Platelet count < 30,000/mcL
(2) Hemolysis
(3) Absence of active cancer
(4) Absence of solid organ or stem cell transplantation
(5) Mean corpuscular volume < 90 fl
(6) INR < 1.5
(7) Creatinine < 2.0 mg/dL
b. If 6 or 7 of these features are present, the likelihood of ADAMTS13 activity being < 10% is very high.
Think about TTP in patients with thrombocytopenia and signs of hemolytic anemia.
Treatment
A. Plasma exchange is the mainstay of treatment of TTP. While it is complicated and expensive, it does not carry substantial medical risk.
1. Large volumes of plasma are removed from the patient and fresh plasma reinfused.
2. This removes the antibody to ADAMTS13 and provides plasma with a normal complement of the enzyme.
3. It is possible to treat TTP initially with plasma infusion alone, but plasma exchange allows for infusion of much higher volumes of plasma; hence, more efficient removal of antibody and infusion of enzyme.
4. Plasma exchange is performed daily, typically for 7–14 days, while monitoring the platelet count and LD levels.
5. Prior to the advent of plasma exchange, the mortality rate for TTP was about 90%. With plasma exchange, the survival rate is now about 90%.
B. Immunosuppressive drugs such as prednisone or rituximab are also used in an effort to reduce the production of the anti-ADAMTS13 antibody.
TTP should be treated when suspected. A definitive diagnosis is not necessary to initiate treatment.
CASE RESOLUTION
Ms. A’s presentation does not meet criteria for TTP. Her bleeding is consistent with platelet-induced bleeding confirmed by her thrombocytopenia. There is no evidence to suggest decreased production (no pancytopenia, medication use or underlying condition) making platelet destruction most likely. Finally, this appears to be immune-mediated rather than microangiopathic given the lack of schistocytes or hemolysis making the diagnosis of ITP appear firm. Ms. A begins treatment with prednisone at a dose of 1 mg/kg orally daily. After 1 week, her platelet count rises to 40,000/mcL, and after 2 weeks, to 130,000/mcL. She then begins a prednisone taper over many weeks, and her platelet count remains above 100,000/mcL.
The goal of therapy in ITP is a safe platelet count, typically a count above 30,000/mcL, rather than a normal count. If it is not possible to taper prednisone off, or to a very low dose, while maintaining a safe platelet count, alternative therapies such as splenectomy or thrombopoietin analogues are indicated, since the long-term risks of corticosteroids (infections, osteoporosis, adrenal suppression, muscle weakness, electrolyte disturbances) should be avoided if possible.
CHIEF COMPLAINT
PATIENT
Mr. J is a 62-year-old man who underwent a coronary bypass graft operation 1 week ago for severe coronary artery disease. He has remained in the hospital for management of a postoperative sternal wound infection, has been doing well, and is scheduled for discharge later in the day. His past history is notable for an autoimmune hemolytic anemia several years ago, successfully treated with prednisone. He drank 6 beers per day for years, quitting about 6 months ago. The laboratory pages you to report that his platelet count is 56,000/mcL.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?
RANKING THE DIFFERENTIAL DIAGNOSIS
The most common causes of new thrombocytopenia in hospitalized patients are medications, particularly heparin-induced thrombocytopenia (HIT), and sepsis. Therefore, the first steps in diagnosing thrombocytopenia in a hospitalized patient are to review previous platelet counts to determine whether the thrombocytopenia is new, review the medication list, and look for vital signs suggestive of sepsis. Because Mr. J has a history of autoimmune hemolytic anemia, it is also important to consider autoimmune thrombocytopenia as an accompanying autoimmune phenomenon (also called Evans syndrome, characterized by seeing spherocytes rather than schistocytes in the peripheral smear), although this would otherwise be uncommon in his age group. Finally, he could have cirrhosis due to his extensive alcohol intake over the years, with hypersplenism causing mild-to-moderate thrombocytopenia. Chronic autoimmune hemolytic anemia might also cause splenic enlargement. If hypersplenism is the cause, his platelet count at admission would probably have been somewhat low, typically between 40,000/mcL and 120,000/mcL. Table 8-2 lists the differential diagnosis.
Table 8-2. Diagnostic hypotheses for Mr. J.
Mr. J’s vital signs are normal, and a recent nursing note reports that he finished his breakfast and looked fine. He is receiving antibiotics for the wound infection and subcutaneous heparin every 8 hours for prophylaxis against deep venous thrombosis. His last platelet count was 175,000/mcL 3 days ago. The rest of his CBC results from today include WBC 14,600/mcL and Hb 11.8 g/dL, unchanged from previous Hb levels. A chemistry profile, including liver enzymes and albumin, is normal.
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
Mr. J’s thrombocytopenia is new, and he is receiving heparin, a very common cause of medication-related thrombocytopenia. He is clinically stable, and so sepsis is not a serious consideration.
Leading Hypothesis: HIT
Textbook Presentation
The classic presentation of HIT is a hospitalized patient receiving heparin whose platelet count falls by more than 50% from baseline, though generally to a level still above 50,000/mcL. There may be associated thrombosis, either venous (deep venous thrombosis, pulmonary embolism, venous limb gangrene) or arterial (cold digits or extremity). Skin necrosis at the site of heparin injections may also be seen.
Disease Highlights
A. Caused by the development of an antibody directed against a heparin-platelet factor 4 complex; the antibody occurs more commonly with unfractionated heparin than with low-molecular-weight heparin. The antibody causes aggregation and activation of platelets, which paradoxically increases the risk of thrombosis.
B. Develops in about 5% of patients who receive heparin.
C. Surgical patients are at higher risk.
D. HIT manifests between 5 and 10 days after starting any kind of heparin—full-dose intravenous heparin, low-dose prophylactic heparin, or even just heparin flushes to maintain patency of indwelling intravascular catheters. Thrombocytopenia may develop earlier in patients with recent heparin exposure.
Any exposure to heparin, including small heparin flushes, can lead to HIT.
E. Thrombosis develops in about 50% of patients who have HIT, and the thrombosis may be evident at the same time as the platelet count drop, though it may also be delayed by several days or weeks. Thrombosis may be arterial (previously called the white clot syndrome), although it is more often venous.
F. The platelet count does not usually drop below 50,000/mcL in HIT; a lower platelet count suggests another etiology.
Evidence-Based Diagnosis
A. The most sensitive, readily available screening test is an enzyme-linked immunosorbent assay (ELISA) for anti-PF4 antibody.
1. It is nearly 100% sensitive, although specificity is between 75% and 85%. Thus, a negative test is very reassuring that HIT is not present, but false-positive tests are not uncommon.
2. The serotonin-release assay (SRA) is more specific but not readily available; it can be run if a false-positive ELISA is suspected.
B. Because the poor specificity of the anti-PF4 assay leads to overdiagnosis of HIT, a pretest probability scoring system (the 4“T’s”) has been validated.
1. Thrombocytopenia
a. Fall of platelets by > 50% and nadir > 20,000/mcL = 2 points
b. Fall of platelets by 30–50% or nadir 10–19,000/mcL = 1 point
c. Fall by < 30% or nadir < 10,000/mcL = 0 points
2. Timing of platelet fall
a. Clear onset between days 5 and 10 after exposure, or < 1 day if prior heparin exposure within 30 days = 2 points
b. Consistent with fall between 5 and 10 days, but some data missing, or fall > 10 days, or < 1 day if prior heparin exposure within 30–100 days = 1 point
c. Fall at < 4 days and without recent exposure = 0 points.
3. Thrombosis or other sequelae
a. Confirmed new thrombosis, skin necrosis, or acute systemic reaction after IV unfractionated heparin bolus = 2 points
b. Progressive or recurrent thrombosis, non-necrotizing skin lesions or suspected thrombosis that has not been proven = 1 point
c. None of the above = 0 points.
4. OTher causes for thrombocytopenia present:
a. None apparent = 2 points
b. Possible = 1 point
c. Definite = 0 points.
5. Test interpretation: 0–3 points: low probability; 4–5 points: intermediate probability; 6–8 points: high probability.
a. In 1 large series of 111 patients with a low pretest probability of HIT using this scoring system, only 1 had clinically significant HIT antibodies (0.9%).
b. In contrast, the overall rate of clinically significant HIT antibodies was 11.4% and 34% in those with intermediate and high scores, respectively.
6. An online calculator is available at http://www.qxmd.com/calculate-online/hematology/hit-heparin-induced-thrombocytopenia-probability
Treatment
A. Heparin must be discontinued whenever HIT is suspected, even when the anti-PF4 assay result is not yet available.
B. An alternative anticoagulant must be started to prevent HIT-associated thrombosis, regardless of whether the initial indication for anticoagulation is still present; generally, a direct thrombin inhibitor such as argatroban is used.
1. Low-molecular-weight heparin may not be substituted: although the incidence of HIT with low-molecular-weight heparin is much lower than with unfractionated heparin, once HIT occurs, there is too much risk for cross-reactivity.
2. Similarly, warfarin should not be used until the platelet count has recovered (this takes a few days) but can then be started while the direct thrombin inhibitor is being given.
3. Anticoagulation should continue for 2–3 months.
C. Although not specifically approved for this indication, fondaparinux, a factor X inhibitor, has sometimes been used as an alternative anticoagulant in patients with HIT.
D. Surprisingly, patients with a history of HIT may safely be reexposed to heparin, if necessary, after a year has passed and the antibody has presumably disappeared. This may be an issue particularly for patients requiring extracorporeal circulatory support for cardiac surgery, for example.
MAKING A DIAGNOSIS
Before you have finished reviewing Mr. J’s chart, the nurse pages you to report that he is complaining of severe pain in his right great toe. It is cool and dusky when you examine it.
Have you crossed a diagnostic threshold for the leading hypothesis, HIT? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?
The findings of a painful, cool, and dusky toe suggest arterial occlusion. While post-cardiac surgery patients can have arterial emboli from a left ventricular clot or postoperative atrial fibrillation, the combination of new thrombocytopenia, heparin exposure, and thrombosis points toward HIT. Mr. J’s “4T” score is 8, consistent with a high probability of HIT: 2 points for the degree of thrombocytopenia, 2 points for the time course, 2 points for the presence of new thrombosis, and 2 points for lack of other apparent causes of thrombocytopenia (despite his alcohol history, his liver tests are normal, making cirrhosis and hypersplenism unlikely, and ITP is not associated with thrombosis).
CASE RESOLUTION
You immediately stop all heparin exposure and start Mr. J on argatroban. His HIT ELISA assay is positive. His toe returns to normal, and his platelet count increases to 180,000/mcL within 4 days. He is receiving warfarin therapy when he is discharged.
CHIEF COMPLAINT
PATIENT
Ms. W is a 56-year-old woman who comes to the office complaining of poor appetite for several weeks and black, tarry stools with generalized weakness for 1 day.
She has no prior history of bleeding, and her 3 prior obstetric deliveries were uncomplicated. Her past history is notable for cirrhosis due to chronic hepatitis C. Her medications include spironolactone and metoprolol; additionally, she has been taking ibuprofen for back pain.
On examination, she is pale. Her blood pressure is 110/80 mm Hg, pulse is 112 bpm, RR is 16 breaths per minute, temperature is 37.1°C. Her conjunctivae are pale, mucous membranes moist, lungs clear, heart regular rhythm with a systolic flow murmur at the left sternal border, liver minimally enlarged with a nodular edge, spleen palpable 3 cm below the left costal margin in the anterior axillary line, and she has no edema. Digital rectal examination discloses black stool that is Hemoccult-positive.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?
Ms. W’s presentation suggests that she is having an upper GI bleed. In addition to the specific GI causes of upper GI bleeding discussed in Chapter 19, GI Bleeding, it is important to consider whether patients who are bleeding have an underlying platelet or coagulation disorder contributing to the bleeding. Ms. W does have cirrhosis with splenomegaly that could lead to thrombocytopenia due to splenic sequestration; however, the large volume of the bleeding suggests a coagulation factor disorder.
The prothrombin time (PT) measures what is commonly called the “extrinsic” clotting pathway (Figure 8-2), wherein tissue factor from an injury activates factor VII, followed by activation of the coagulation cascade through the “common pathway” factors (factors V, X, II [prothrombin] and I [fibrinogen]). Because the source of tissue factor reagents used in the laboratory to trigger the cascade vary, the PT will vary among different laboratories when testing the same sample. To overcome this problem of PT results not being comparable from one laboratory to another, the international normalized ratio (INR) was developed, to standardize PT results based on a constant associated with each laboratory reagent. The INR, which is routinely reported along with the PT, allows the clinician to be confident that the data from different laboratories are comparable.
Figure 8-2. The coagulation cascade. Organization of the coagulation system based on current assays. The intrinsic coagulation system consists of the proteins factors XII, XI, IX, and VIII and prekallikrein (PK) and high molecular weight kininogen (HK). The extrinsic coagulation system consists of tissue factor (tissue thromboplastin) and factor VII. The common pathway of the coagulation system consists of factors X, V, and II, and fibrinogen (I). (Reproduced with permission from McPherson RA, Pincus MR: Henry’s Clinical Diagnosis and Management by Laboratory Methods, 22nd ed. Philadelphia, PA: Elsevier/Saunders; 2011.)
The activated partial thromboplastin time (aPTT) measures what is commonly called the “intrinsic” clotting pathway, starting with factor XII and working through factors XI, IX, and VIII before entering the common pathway.
In the evaluation of a prolonged clotting time, either PT or aPTT, one considers whether only one test is prolonged, and which factors contribute to each test. For example, an isolated prolonged PT suggests a deficiency or inhibitor of factor VII, since that is the only factor unique to the PT assay. An isolated prolonged aPTT raises concern about the 4 factors that are unique to the aPTT—factors XII, XI, IX, and VIII. Prolongation of both the PT and aPTT raises concern either about the factors in the common pathway—I, II, V, and X—or a defect in multiple factors. Table 8-3 summarizes commonly seen patterns of factor deficiencies.
Table 8-3. Common factor deficiency patterns.
In clinical practice, prolongation of clotting times is most commonly acquired, either due to acquired deficiencies (eg, from malnutrition or liver disease) or acquired factor inhibitors. (While congenital factor deficiencies such as hemophilia certainly cause prolonged clotting times, these are far less commonly seen, and patients are generally well aware of them, making complex diagnostic evaluations unnecessary.) In order to distinguish between a factor deficiency and an inhibitor, it is often helpful to perform a mixing study, wherein one mixes 1:1 the patient’s plasma and normal plasma, to see if the clotting time corrects. If it does correct, the normal plasma has provided the missing factor to the patient’s plasma, indicating the abnormality is due to a factor deficiency. If it does not correct, the implication is that an inhibitor in the patient’s plasma is inactivating the clotting factor(s) from the normal plasma. Such inhibitors may be exogenous, such as inadvertent heparin in the mixture; or endogenous, such as an acquired factor inhibitory antibody.
Based on the data we have so far, Ms. W’s GI bleeding is most likely from the upper GI tract, probably gastritis or ulceration induced by use of the NSAID ibuprofen. Patients with cirrhosis and portal hypertension often develop esophageal and gastric varices, which can also be a cause of bleeding. The severity of the bleeding may be exacerbated by a coagulopathy related to her cirrhosis. The history of poor appetite for a few weeks raises the consideration of vitamin K deficiency due to lack of intake, and the presence of splenomegaly on examination suggests that thrombocytopenia due to splenic sequestration may also be contributing.
Table 8-4 lists the differential diagnosis.
Table 8-4. Diagnostic hypotheses for Ms. W.
A CBC shows WBC 9400/mcL, Hb 7.8 g/dL, platelet count 76,000/mcL. A chemistry profile shows mild elevation of the transaminases but is otherwise normal. Her CBC 6 months ago showed an Hb of 11.7 g/dL and platelet count of 80,000/mcL. Coagulation studies include a PT of 22 seconds (normal range 11–13 seconds), with an INR of 1.8 (normal 0.9–1.2). The aPTT is 39 seconds (normal 24–34 seconds).
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
Ms. W has the stable, moderate thrombocytopenia generally seen in patients with portal hypertension and hypersplenism. Moderate thrombocytopenia such as this does not substantially increase the risk of bleeding, especially not the large volume GI bleeding she is experiencing. The coagulation abnormalities she has can certainly contribute to large volume bleeding.
Leading Hypothesis: Liver Disease–Induced Coagulopathy
Textbook Presentation
The classic presentation of liver disease–induced coagulopathy is variable. Patients may be asymptomatic, only discovered to have a coagulopathy incidentally on coagulation laboratory studies. Spontaneous bleeding is uncommon, but anything that stresses the patient (such as an injury, an operative procedure, or perhaps NSAID-induced gastritis) may lead to more bleeding than one might normally anticipate with that event in someone without liver disease.
Disease Highlights
A. Patients with liver disease–induced coagulopathy typically have a disproportionately longer PT (and therefore higher INR) than aPTT.
B. The coagulopathy is caused by impaired production of clotting factors by the diseased liver; the clotting factor with the shortest half-life, namely factor VII, would be expected to be most prominently affected. Since the PT/INR is so sensitive to factor VII levels, that test is more notably abnormal.
C. Coagulopathy is seen primarily in patients with severe liver disease. The liver has a considerable reserve, and only when the impairment is severe does one find significant coagulopathy.
Evidence-Based Diagnosis
A. In a patient with liver disease who is bleeding or in whom an invasive procedure is planned, the PT/INR and aPTT should be checked in order to screen for coagulation factor deficiencies.
1. If the screening tests are significantly prolonged, one should check the levels of factor VII, factor V, factor II, factor IX, and factor X as well as fibrinogen to help determine which replacement therapy is most appropriate.
2. If factor VII is low but factor V normal, it suggests that vitamin K deficiency may be playing a role (especially if history notes poor appetite for several weeks, suggesting an inadequate intake of vitamin K during that time), whereas in severe liver impairment, both factors V and VII are reduced.
3. Because all the clotting factors except factor VIII are produced in the hepatocytes, all of them except factor VIII may be low in severe liver disease. Factor VIII is typically normal or even elevated in liver disease, a finding that may distinguish liver disease from DIC, in which factor VIII is low.
B. Another finding that may contribute to bleeding risk in severe liver disease is excessive fibrinolysis, the cause of which is a complex interplay between the production of and hepatic clearance of fibrinolytic activators and inhibitors.
C. While it may seem paradoxical, there may also be an increased risk of thrombosis in liver disease. Several findings may account for this: reduction of the vitamin K–dependent anticoagulant proteins, protein C and protein S; and increases in factor VIII and sometimes von Willebrand factor.
Treatment
A. Correct the coagulopathy using fresh frozen plasma to replete clotting factors. If the plasma fibrinogen level is particularly low (eg, < 100 mg/dL), infusion of cryoprecipitate may be helpful.
B. In severe cases, administration of recombinant activated factor VIIa may help stop the bleeding associated with liver disease; it is extremely expensive, however, and carries some risk of inducing thrombosis.
MAKING A DIAGNOSIS
An esophagogastroduodenoscopy (EGD) shows a duodenal ulcer consistent with NSAID use. Her factor VII level is 20%; factor V level, 40%; factor II, 60%; factor IX, 50%; factor X, 55%; factor VIII, 122%. Ms. W is treated with a proton pump inhibitor and fresh frozen plasma. Her PT and PTT normalize, and the bleeding stops.
Have you crossed a diagnostic threshold for the leading hypothesis, liver disease–induced coagulopathy? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?
Alternative Diagnosis: Vitamin K Deficiency
Textbook Presentation
The usual presentation of vitamin K deficiency is a hospitalized patient who is found to have a prolonged PT/INR, rarely with bleeding manifestations.
Disease Highlights
A. The most common cause of vitamin K deficiency is inadequate oral intake.
B. Patients who have been hospitalized and need to start warfarin therapy may require smaller than expected doses to achieve therapeutic levels, because they may be unduly sensitive as a result of baseline vitamin K deficiency.
C. Vitamin K deficiency can also occur with the recent use of antibiotics that alter the gut flora’s ability to convert ingested vitamin K to its absorbable form.
Evidence-Based Diagnosis
A. As with liver disease, patients with vitamin K deficiency have PT/INR levels disproportionately longer than aPTT levels.
B. This is due to factor VII having the shortest half-life of the vitamin K–dependent factors (II, VII, IX, and X), thus making the factor VII–dependent PT/INR more sensitive to vitamin K alterations.
C. The aPTT will also go up eventually, as the levels of factors II, IX and X, with much longer half-lives, fall.
Treatment
A. Vitamin K repletion, either orally or parenterally, is the treatment of choice.
1. If parenteral treatment is chosen, it should be administered subcutaneously or intravenously—not intramuscularly.
2. Intramuscular injections should be avoided in patients with coagulopathies, in order to avoid the development of hematomas in muscles that can lead to neuropathy if a major nerve traverses the area.
B. Vitamin K administration takes 18–24 hours to have its effect, so if a patient with vitamin K deficiency is bleeding, fresh frozen plasma or four-factor prothrombin complex concentrate, which contains factors II, VII, IX, and X, may be required.
Alternative Diagnosis: DIC
Textbook Presentation
Disseminated intravascular coagulation (DIC, also called consumptive coagulopathy) is a catastrophic activation of the coagulation system that classically presents as the abrupt onset of uncontrolled spontaneous diffuse bleeding from multiple sites (venipuncture sites, catheter sites, endotracheal tubes, recent surgical sites) in patients with severe illness such as shock states, major trauma, sepsis, obstetric emergencies, and advanced cancer.
Disease Highlights
A. The common denominator of conditions that cause DIC is tissue injury and activation of the clotting cascade via entry of procoagulants into the circulation.
B. A variety of conditions activate the clotting cascade.
1. Trauma
2. Advanced adenocarcinomas of any site, such as colon, pancreas, or lung.
3. Obstetric crises such as amniotic fluid embolism or placental abruption.
4. Acute promyelocytic leukemia, wherein the granules of the malignant promyelocytes activate the clotting system.
C. Although the classic presentation is major bleeding due to activation of the clotting cascade leading to secondary consumption of clotting factors, in some cases clotting manifestations may predominate.
1. Patients with advanced cancer may have recurrent deep venous thrombosis or pulmonary embolism or arterial emboli in the extremities without signs of bleeding.
2. This is considered chronic DIC.
D. Renal, hepatic, and pulmonary dysfunction may accompany acute DIC.
Evidence-Based Diagnosis
A. In acute DIC, consumption of clotting factors is demonstrated by thrombocytopenia, prolongation of the PT/INR and aPTT, reduction of plasma fibrinogen level, and increases in D-dimer and fibrin degradation products (FDP).
B. The D-dimer and FDP reflect fibrinolytic activity acting upon fibrin formed during the clotting process.
1. D-dimer is the product of lysis of cross-linked fibrin.
2. FDP is the product of lysis of both fibrin and fibrinogen.
3. Fibrinogen levels below 100 mg/dL may correlate with bleeding risk.
If DIC is suspected, testing should include platelet count, PT/INR, aPTT, fibrinogen, and D-dimer.
Treatment
A. Treat the underlying condition if possible.
B. Replete clotting factors that have been depleted, with platelet transfusions, fresh frozen plasma, and cryoprecipitate if fibrinogen is particularly low.
C. In rare instances, the use of low-dose heparin is considered. While it is logical to consider undertaking anticoagulation if the initiation of the process was coagulation, the additional bleeding risk is of great concern, and efforts are generally focused more on providing clotting factors while addressing the underlying cause.
CASE RESOLUTION
You instruct Ms. W to avoid all aspirin products and NSAIDs. She is seen by the dietitian for review of vitamin K–rich foods. Her Hb is stable at a follow-up visit 2 weeks later.
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