2: Hematology Flashcards
Which 6 coagulation factors are vitamin K dependent?
- Factor II
- Factor VII
- Factor IX
- Factor X
- Protein C
- Protein S
[UpToDate: Depending upon the cause of deficiency, vitamin K can be administered in doses of one to 25 mg via oral, intramuscular, subcutaneous, or intravenous routes. When vitamin K deficiency occurs in patients who are also receiving coumarin-like anticoagulants, doses of vitamin K should be minimized in order to prevent refractoriness to further anticoagulation.
Vitamin K status can be determined indirectly by measuring vitamin K-dependent factors (ie, prothrombin, factors VII, IX, X, or protein C). In patients who are vitamin K deficient, levels of these factors often are less than 50% of normal. Measurement of des-gamma-carboxyprothrombin (DCP) in plasma is another more sensitive way of determining vitamin K deficiency. In normal subjects, DCP is zero; it is elevated in vitamin K deficiency from whatever cause and/or liver disease.]
What are the 5 components of the prothrombin complex?
- Factor Xa
- Factor Va
- Calcium
- Platelet factor 3
- Prothrombin
[Medscape: Prothrombin complex concentrate (PCC) is an inactivated concentrate of factors II, IX, and X, with variable amounts of factor VII. Guidelines recommend the use of PCC in the setting of life-threatening bleeds, but little is known on the most effective dosing strategies and how the presenting international normalized ratio affects response to therapy.]
[Wikipedia: Prothrombin complex concentrate (PCC), also known as factor IX complex, is a medication made up of blood clotting factors II, IX, and X. Some versions also contain factor VII. It is used to treat and prevent bleeding in hemophilia B if pure factor IX is not avaliable. It may also be used in those with not enough of these factors due to other reasons such as warfarin therapy. It is given by slow injection into a vein.]
What are the 3 thrombolytic agents?
- Streptokinase (High antigenicity)
- Urokinase
- Tissue plasminogen activator (tPA)
[UpToDate: Recombinant tissue type plasminogen activator (tPA, alteplase), streptokinase (SK), and recombinant human urokinase (UK) are the best studied thrombolytic agents for the treatment of acute PE, that are approved by the US Food and Drug Administration (FDA). Other thrombolytic agents include lanoteplase, tenecteplase, and reteplase. The characteristics of SK, tPA, and UK are described briefly here, with greater detail presented elsewhere.
tPA is a naturally occurring enzyme produced by a number of tissues including endothelial cells. tPA binds to fibrin, which increases its affinity for plasminogen and enhances plasminogen activation.
SK is a polypeptide derived from beta-hemolytic streptococcus cultures. It binds to plasminogen, forming an active enzyme that activates plasmin. Among the thrombolytic agents, it is the least expensive but most commonly associated with adverse effects, including allergic reactions and hypotension.
Urokinase is also a plasminogen activator that is normally present in the urine. It is the major activator of fibrinolysis in the extravascular compartment, in contrast to tPA which is largely responsible for initiating intravascular fibrinolysis. Because the FDA-approved duration for tPA delivery is two hours, streptokinase and urokinase are rarely used today.]
What is the treatment for a hemophilia A patient with epistaxis, intracerebral hemorrhage, or hematuria?
Factor VIII concentrate of cryoprecipitate
[UpToDate: Serious or life-threatening bleeding in a patient with hemophilia is a medical emergency that requires prompt evaluation and immediate therapy with replacement factor. For patients with potentially serious or life-threatening bleeding, it is important to initiate treatment immediately, even before the diagnostic assessment is completed.
Serious or life-threatening bleeding includes any of the following:
- Bleeding in the central nervous system.
- Ocular bleeding.
- Bleeding in the hip.
- Deep muscle bleeding with neurovascular compromise or the potential for neurovascular complications.
- Intra-abdominal bleeding.
- Bleeding that could affect the airway (eg, into the throat or neck).
- Bleeding severe enough to result in anemia and potentially require red blood cell transfusion(s).
- Prolonged bleeding that is not adequately responding to home-based therapy.
- Iliopsoas bleeding.
- Significant injuries such as motor vehicle accidents or falls from distances of several feet or more.
An acutely hemorrhaging hemophilic patient should be transported to a facility equipped to handle the event that has the appropriate replacement products. Guidelines from the United Kingdom Haemophilia Centre Doctors Organization (UKHCDO) suggest that the maximum time between arrival to the hospital and clinical assessment should not exceed 15 minutes, and if treatment for bleeding is required, the maximum time to its delivery should not exceed 30 minutes. If the patient has the appropriate replacement therapy at home, this product may be administered before leaving or on route to the facility, as long as the bleeding is not life-threatening and this does not result in delays. In life-threatening circumstances, emergency medical transport should be called and the products should be administered on-route.
As noted above, factor administration should not be delayed while awaiting imaging studies in a patient with a concerning injury or suspected central nervous system bleeding. All significant head injuries must be considered nontrivial unless proven otherwise by observation and imaging (eg, with computed tomography [CT] or magnetic resonance imaging [MRI]). If there is doubt about the seriousness of bleeding, it is preferable to treat the patient as if the bleeding is serious (ie, “if in doubt, treat”). Further, the importance of urgently giving the factor infusion outweighs considerations of the specific factor preparation (ie, “give the appropriate product that is available rather than spending time trying to obtain a different product”).
Other hemostatic therapies for individuals with inhibitors or those whose bleeding is not controlled by factor infusion are presented below.
For severe bleeding, the factor activity level should be maintained above 50% at all times. An immediate dose of factor should be given to raise the peak factor level to 80% to 100%, and additional doses should be timed to occur when a factor activity level of approximately 50% is achieved, so the patient’s circulating factor level does not drop below 50%. Another option is to give a dose of factor to raise the level to 80% to 100%, followed by continuous infusion to maintain a consistent hemostatic level. Administration of factor should not be delayed while awaiting imaging studies.]
Which coagulation factor helps crosslink fibrin?
Factor XIII
[UpToDate: Activated factor XIII stabilizes and crosslinks overlapping fibrin strands.]
Which condition is diagnosed by a prolonged PTT that is not corrected by FFP, a positive Russell Viper venom time, and a false-positive RPR test for syphilis?
Anti-phospholipid antibody syndrome
[UpToDate: Antibody testing in patients with suspected APS involves immunoassays for antibodies to cardiolipin and beta2-glycoprotein (GP) I and a functional assay for the lupus anticoagulant (LA) phenomenon:
Anticardiolipin antibodies (aCL); immunoglobulin G (IgG) and/or IgM by enzyme-linked immunosorbent assay (ELISA).
Anti-beta2-GP I antibodies; IgG and/or IgM by ELISA.
LA testing is a three-step procedure:
- Demonstration of a prolonged phospholipid-dependent screening test of hemostasis. Commonly used screening tests include the dilute Russell viper venom time (dRVVT) and an activated partial thromboplastin time (aPTT) that has been optimized for this purpose (aPTT or lupus aPTT).
- Mixing patient plasma with normal plasma fails to correct the prolonged screening test(s). This eliminates the possibility that prolongation of the screening test is due to a coagulation factor deficiency. If the coagulation test remains prolonged after the addition of normal plasma, an inhibitor is present.
- Addition of excess phospholipid shortens or corrects the prolonged coagulation test (demonstration of phospholipid-dependence).
LA are characterized by correction of the prolonged clotting time with added phospholipid but not with control plasma, confirming that the coagulation inhibitor is phospholipid-dependent.
The above aPL testing is consistent with recommendations from the revised Sapporo classification criteria
A history of a false positive serologic test for syphilis may also be a clue to the presence of antiphospholipid antibodies (aPL). This phenomenon occurs because the antigen used in the Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests contains cardiolipin.]
Which type of von Willebrand’s disease causes the most severe bleeding?
Type III
[UpToDate: Von Willebrand factor (VWF) plays an important role in primary hemostasis by binding to both platelets and endothelial components, forming an adhesive bridge between platelets and vascular subendothelial structures at sites of endothelial injury and between adjacent platelets in areas with high shear. It also contributes to fibrin clot formation by acting as a carrier protein for factor VIII, which has a greatly shortened half-life and abnormally low concentration unless it is bound to VWF. Von Willebrand disease (VWD) is characterized by mutations that lead to a decrease in the level or impairment in the action of von Willebrand factor (VWF).
Type 1 VWD, an autosomal dominant disease, is the most common, accounting for approximately 75% of patients. The clinical presentation of type 1 VWD varies from mild to severe as determined by bleeding symptoms, but some individuals are asymptomatic and detected incidentally in studies investigating a relative for VWD. Type 1 VWD represents a partial quantitative deficiency of von Willebrand factor; many of the mutations remain undefined.
Type 2 VWD contains four subtypes in which VWF is qualitatively abnormal, as demonstrated by VWF multimer patterns, RIPA, and an abnormally low VWF activity to antigen ratio (types 2A, 2B, and 2M), or by other special assays such as a quantitative assay of the patient’s VWF binding capacity for factor VIII (type 2N). Type 2A accounts for approximately 10% to 15% of cases of VWD, and is usually transmitted as an autosomal dominant trait. Affected patients typically present with moderate to moderately severe bleeding. Type 2B VWD accounts for approximately 5% of cases of VWD, and is transmitted as an autosomal dominant trait. Affected patients generally present with moderate or moderately severe bleeding. The abnormal VWF in this disorder has a “gain of function”, binding more readily to the platelet receptor, glycoprotein Ib. The increase in binding of larger multimers to platelet GP Ib results in their loss from the circulation and, in some patients, thrombocytopenia occurs due to clearance or sequestration of the small platelet aggregates that are formed.
Type 3 VWD is a rare disease. Affected patients present with severe bleeding involving both the skin and mucous membrane surfaces (due to decreased VWF) and soft tissues and joints (due to the low concentration of factor VIII). Type 3 VWD is characterized by a marked decrease or absence of detectable VWF due to homozygous or compound heterozygous mutations, some of which result in loss of VWF mRNA expression.]
Which type of von Willebrand’s disease is characterized by a reduced quantity of vWF?
Type I
[Tx: recombinant Factor VIII and vWF, DDAVP, cryoprecipitate]
[UpToDate: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting up to 1% of the population as assessed by random laboratory screening, although only approximately 1% of these individuals are appreciably symptomatic. It is characterized by mutations that lead to a decrease in the level or impairment in the action of von Willebrand factor (VWF). Most cases are transmitted as an autosomal dominant trait that affects males and females equally. There are also acquired forms of VWD that are caused by several different pathophysiologic mechanisms.
Von Willebrand factor (VWF) plays an important role in primary hemostasis by binding to both platelets and endothelial components, forming an adhesive bridge between platelets and vascular subendothelial structures at sites of endothelial injury and between adjacent platelets in areas with high shear. It also contributes to fibrin clot formation by acting as a carrier protein for factor VIII, which has a greatly shortened half-life and abnormally low concentration unless it is bound to VWF.
Type 1 VWD, an autosomal dominant disease, is the most common, accounting for approximately 75% of patients. The clinical presentation of type 1 VWD varies from mild to severe as determined by bleeding symptoms, but some individuals are asymptomatic and detected incidentally in studies investigating a relative for VWD. Type 1 VWD represents a partial quantitative deficiency of von Willebrand factor; many of the mutations remain undefined.
Type 2 VWD contains four subtypes in which VWF is qualitatively abnormal, as demonstrated by VWF multimer patterns, RIPA, and an abnormally low VWF activity to antigen ratio (types 2A, 2B, and 2M), or by other special assays such as a quantitative assay of the patient’s VWF binding capacity for factor VIII (type 2N). Type 2A accounts for approximately 10% to 15% of cases of VWD, and is usually transmitted as an autosomal dominant trait. Affected patients typically present with moderate to moderately severe bleeding. Type 2B VWD accounts for approximately 5% of cases of VWD, and is transmitted as an autosomal dominant trait. Affected patients generally present with moderate or moderately severe bleeding. The abnormal VWF in this disorder has a “gain of function”, binding more readily to the platelet receptor, glycoprotein Ib. The increase in binding of larger multimers to platelet GP Ib results in their loss from the circulation and, in some patients, thrombocytopenia occurs due to clearance or sequestration of the small platelet aggregates that are formed.
Type 3 VWD is a rare disease. Affected patients present with severe bleeding involving both the skin and mucous membrane surfaces (due to decreased VWF) and soft tissues and joints (due to the low concentration of factor VIII). Type 3 VWD is characterized by a marked decrease or absence of detectable VWF due to homozygous or compound heterozygous mutations, some of which result in loss of VWF mRNA expression.]
Hemophilia A results from a deficiency in what?
Factor VIII
[UpToDate: The factor VIII gene is one of the largest genes known, comprising about 0.1% of the X chromosome. The gene that encodes factor VIII is divided into 26 exons that span 186,000 base pairs. Factor VIII contains several areas of internal homology, consisting of a heavy chain with A1 and A2 domains; a connecting region with a B domain; and a light chain with A3, C1, and C2 domains.
Some of these domains have specific functions. For example, different epitopes on the C2 domain are responsible for binding to the procoagulant phospholipid phosphatidylserine on activated platelets and endothelial cells, von Willebrand factor (which importantly slows the catabolism of factor VIII), factor Xa, and thrombin. Two domains contribute to the binding of factor IXa (A2 domain and the A1/A3-C1-C2 dimer).
Hemophilia A genes — Examination of hemophilic genes has not demonstrated a uniform abnormality. Instead, numerous different mutations in the factor VIII gene have been described.]
What is the treatment for Factor VII deficiency?
Recombinant factor VII concentrate or FFP
[UpToDate: Bleeding can be managed with recombinant human factor VII in the activated form (rFVIIa; NovoSeven RT, Niastase, Niastase RT), which became available in 1999; or factor VII concentrates, which are available in some European countries.
Recommended dosing of rFVIIa is 15 to 30 mcg/kg every 12 hours, and dosing of factor VII concentrates is 30 to 40 international units/kg, repeated every 6 to 12 hours, with the goal of maintaining factor VII activity levels above 15% to 20%. Higher doses may be required in severe or life-threatening bleeding.]
In addition to thrombocytopenia, what can heparin-induced thrombocytopenia (HIT) cause?
Platelet aggregation and thrombosis
[Forms a white clot]
[UpToDate: HIT results from an autoantibody directed against endogenous platelet factor 4 (PF4) in complex with heparin. This antibody activates platelets and can cause catastrophic arterial and venous thrombosis with a mortality rate as high as 20%; although, more recently with improved recognition and early intervention, these rates have been reported as below 2%. In those suspected of having HIT based on clinical grounds, all exposure to heparin should be eliminated immediately and a non-heparin anticoagulant should be administered until a complete diagnosis can be made.]
Which coagulation factor gets activated during cardiopulmonary bypass, resulting in a hypercoagulable state?
Factor XII (Hageman factor)
What is deficient in Bernard Soulier syndrome?
GpIb receptor on platelets is deficient resulting in platelets being unable to bind collagen
What is deficient in Glanzmann’s thrombocytopenia?
GpIIb/IIIa receptor on platelets is deficient resulting in platelets being unable to bind to each other
[UpToDate: Glanzmann thrombasthenia is an autosomal recessive bleeding disorder characterized by a defect in the platelet integrin αIIbβ3 (integrin alphaIIbbeta3; previously known as GPIIb/IIIa); clinical manifestations are limited to bleeding, which is mostly mucocutaneous. The presence of mucocutaneous bleeding and a normal platelet count but with single isolated platelets without any platelet clumping on examination of a non-anticoagulated peripheral blood smear should raise the possibility of this disorder. Platelet aggregometry is distinctly abnormal.
This disorder may also occur in combination with defects in leukocyte function in the disorder leukocyte adhesion deficiency III, and should be suspected in infants with concomitant leukocytosis, delayed separation of the umbilical cord, or severe bacterial infections.
Antibodies to integrin αIIbβ3 and/or HLA antigens may occur in subjects with Glanzmann thrombasthenia who have received multiple platelet transfusions, resulting in refractoriness to such transfusions.
The use of recombinant factor VIIa and other hemostatic agents in such settings has been helpful in controlling bleeding, although controlled efficacy studies are lacking.]
How does aspirin prolong bleeding time?
It inhibits cyclooxygenase in platelets, decreasing levels of TXA2
[UpToDate: Irreversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, via acetylation, which results in decreased formation of prostaglandin precursors; irreversibly inhibits formation of prostaglandin derivative, thromboxane A2, via acetylation of platelet cyclooxygenase, thus inhibiting platelet aggregation; has antipyretic, analgesic, and anti-inflammatory properties.]
Which patients are especially susceptible to Warfarin-induced skin necrosis?
Patients with relative protein C deficiency
[UpToDate: Warfarin-induced skin necrosis is a complication of warfarin therapy in which the patient develops demarcated areas of purpura and necrosis due to vascular occlusion. The appearance may be similar to that of neonatal purpura fulminans and may affect one or more areas of skin including the extremities, breasts, trunk, or penis.
The mechanism of warfarin-induced skin necrosis involves a transient hypercoagulable state during initial warfarin administration that in turn leads to vascular occlusion and tissue infarction followed by extravasation of blood.
The half-lives vary among the vitamin K-dependent coagulation factors (factors II, VII, IX, and X) and natural anticoagulants (protein S and protein C), and as a result, the factors with the shorter half-lives (half-lives for factor VII and protein C of 8 and 14 hours, respectively) are depleted more rapidly than the others. Laboratory studies of thrombin generation using an assay for the activation of prothrombin using the generation of fragment F1+2 have suggested that effects on protein C (ie, a procoagulant effect) predominate over effects on factor VII in vivo.
The skin lesions in warfarin-induced skin necrosis typically form during the first few days of warfarin therapy, often in the setting of large loading doses of 10 or more milligrams of warfarin per day. If the patient is receiving heparin and warfarin therapy, the lesions may appear upon discontinuation of the heparin. The lesions typically marginate over a period of hours from an initial central erythematous macule, similar to neonatal purpura fulminans. If a product containing protein C is not rapidly administered, the affected cutaneous areas become edematous, develop central purpuric zones, and ultimately become necrotic. Biopsy of the lesions is not generally performed, but if a biopsy is obtained it may show diffuse microthrombi within dermal and subcutaneous capillaries, venules, and deep veins, with endothelial cell damage, resulting in ischemic skin necrosis and marked red blood cell extravasation. These findings are indistinguishable from other thrombotic skin lesions including antiphospholipid syndrome (APS), disseminated intravascular coagulation (DIC), and heparin-induced thrombocytopenia (HIT).
The incidence of warfarin-induced skin necrosis in individuals with protein C deficiency is unknown, as most descriptions are in the form of case reports. Warfarin-induced skin necrosis is not pathognomonic for protein C deficiency; it has been described in individuals with other inherited thrombophilias (factor V Leiden mutation, protein S deficiency) and transient reductions of protein C levels (eg, in the setting of cancer).]
What is the half-life of Bivalrudin?
25 minutes
[Metabolized by proteinase enzymes in the blood]
[UpToDate:
- Normal renal function (CrCl ≥90 mL/minute): 25 minutes
- Severe renal impairment (CrCl 10 to 29 mL/minute): 57 minutes
- Dialysis-dependent patients (off dialysis): 3.5 hours]
Which system in the body clears Heparin?
The reticuloendothelial system
[UpToDate: Heparin is metabolized by the liver and may be partially metabolized in the reticuloendothelial system . It is excreted in the urine (small amounts as unchanged drug). At therapeutic doses, elimination occurs rapidly via nonrenal mechanisms. With very high doses, renal elimination may play more of a role; however, dosage adjustment remains unnecessary for patients with renal impairment.
LMW heparins are primarily excreted by the kidney, so their biological half-life may be prolonged in patients with renal failure. Uremia may also contribute to increased bleeding risk. As a result, most trials have excluded patients with creatinine clearance (CrCl) ≤30 mL/min. In a systematic review and meta-analysis of studies that evaluated bleeding risk in individuals with renal insufficiency who were receiving a LMW heparin, patients with a CrCl ≤30 mL/min receiving LMW heparin were more likely to have bleeding than those with a CrCl >30 mL/min, (odds ratio [OR] 2.25; 95% CI 1.19-4.27). Individuals with CrCl ≤30 mL/min who were receiving enoxaparin at therapeutic doses had higher levels of anti-factor Xa activity compared with individuals without renal insufficiency or those who had dose adjustments based on renal function or anti-factor Xa activity, although anti-factor Xa activity measurements in patients on LMW heparin have not been correlated with clinical events. In contrast, tinzaparin and dalteparin do not appear to bioaccumulate in individuals with this degree of renal insufficiency, although less rigorous evidence is available for these products.
Options for management depend on the degree of renal insufficiency and the available LMW heparin. For those with a CrCl ≤30 mL/min, use of unfractionated heparin avoids the problems associated with impaired renal clearance of LMW heparin. If LMW heparin is used in an individual with renal insufficiency, dose-reduction and/or adjustment based on anti-factor Xa levels may be appropriate, especially for enoxaparin.]
What is the appropriate treatment for a patient with 2 or more prior DVTs or a significant PE who develops a postoperative DVT?
Lifetime Warfarin
[UpToDate: Most patients with a first episode of venous thromboembolism (VTE; proximal deep venous thrombosis [DVT] and/or pulmonary embolus [PE]) are anticoagulated for a finite period of 3 to 12 months. Select patients benefit from indefinite anticoagulation which is administered with the primary goal of reducing the lifetime risk of recurrent thrombosis and VTE-associated death.
The decision to anticoagulate indefinitely should be individualized and based upon an estimate of the risk of recurrence and bleeding in the context of the patient’s values and preferences. In general, the following applies.
For most patients with a first episode of unprovoked proximal DVT, unprovoked symptomatic PE, or active cancer in whom the risk of bleeding is low to moderate, we suggest indefinite anticoagulation rather than stopping therapy after 3 to 12 months (Grade 2B). In patients with a recurrent episode of unprovoked VTE, we recommend indefinite anticoagulation rather than stopping therapy after 3 to 12 months (Grade 1B).
Indefinite anticoagulation should not be routinely administered to patients with a provoked episode of VTE with major transient risk factors (eg, surgery, cessation of hormonal therapy) (Grade 1B). We also avoid indefinite anticoagulation in those with a high bleeding risk; however, should the risk for bleeding resolve, indefinite anticoagulation may be reconsidered.
For most patients with recurrent provoked VTE or a first episode of provoked VTE with irreversible, multiple, or minor risk factors, a first episode of unprovoked isolated distal DVT or an unprovoked episode of incidental PE, therapy must be individualized based upon a careful assessment of patient-specific risks of bleeding and thrombosis. There are wide variations in both the recurrence risk and benefit in these populations.]
What platelet concentration do we want before and after surgery?
- Greater than 50,000 before surgery
- Greater than 20,000 after surgery
[UpToDate: The concept of a “safe” platelet count is imprecise, lacks evidence-based recommendations, and depends on the disorder and on the patient (even with the same disorder). The following may be used as guides, but should not substitute for clinical judgment based on individual patient and disease factors:
- Surgical bleeding generally may be a concern with platelet counts <50,000/microL (<100,000/microL for some high-risk procedures such as neurosurgery or major cardiac or orthopedic surgery).
- Severe spontaneous bleeding is most likely with platelet counts <20,000 to 30,000/microL, especially below 10,000/microL.
It is also important to consider other factors that may affect bleeding risk (eg, platelet function defects, coagulation abnormalities). When present, these factors may contribute to bleeding risk and may be more concerning than the low platelet count.]
What is the treatment for uremic platelet dysfunction?
Hemodialysis
[DDAVP and platelets can be given if this is not fully effective]
[UpToDate: Patients who are actively bleeding or who are about to undergo a surgical procedure should have correction of platelet dysfunction. Treatment options include correction of anemia, desmopressin (dDAVP), dialysis, estrogens, or cryoprecipitate. Therapies vary in their onset and duration of action, and most have been shown only to reduce the bleeding time or in vitro tests of platelet function rather than to reduce active bleeding or the risk of bleeding with invasive procedures.
Raising the hemoglobin to approximately 10 g/dL may reduce the bleeding time. The improvement in platelet function will persist for as long as the hemoglobin remains elevated. Erythropoietic-stimulating agents (ESAs) may also have a direct beneficial effect on platelet function.
Desmopressin provides the simplest and most rapid acute treatment for platelet dysfunction in the uremic patient. Administration of desmopressin at a dose of 0.3 mcg/kg given in 50 mL of saline over 15 to 30 minutes intravenously or by subcutaneous injection is preferred; a dose of 3 mcg/kg can also be given intranasally. The improvement in bleeding time begins within 1 hour and lasts 4 to 8 hours. The response to subsequent doses is generally diminished (tachyphylaxis).
Either hemodialysis or peritoneal dialysis can partially correct the bleeding time in approximately two-thirds of uremic patients. Hemodialysis should be performed without systemic anticoagulation.
Prolonged control of bleeding may be achieved by the administration of conjugated estrogens (0.6 mg/kg intravenously daily for five days, 2.5 to 25 mg orally per day, or 50 to 100 mcg of transdermal estradiol twice weekly). These agents begin to act on the first day, with peak control reached over five to seven days; the duration of action is 1 week or more after therapy has been discontinued.
The infusion of cryoprecipitate (10 units intravenously every 12 to 24 hours) can shorten the bleeding time in many uremic patients. The improvement in bleeding time begins within 1 hour and lasts 4 to 24 hours. Potential infectious complications limit the use of cryoprecipitate to patients with life-threatening bleeding who are resistant to treatment with desmopressin and blood transfusions.]
What is the inheritance pattern of hemophilia B?
Sex-linked recessive
[UpToDate: Factor VIII deficiency (hemophilia A) affects 1 in 5000 to 10,000 males; roughly 60% have severe disease, with factor VIII activity less than 1% of normal.
Factor IX deficiency (hemophilia B) affects 1 in 25,000 to 30,000 males; approximately one-half have mild to moderate disease, with factor IX activity greater than 1% of normal.
Severe factor VIII or factor IX deficiency leads to bleeding because of the role these factors play in the intrinsic pathway X-ase (ten-ase). The X-ase complex consists of activated factor IX (factor IXa) as the protease; activated factor VIII (factor VIIIa), calcium, and phospholipids as the cofactors; and factor X as the substrate.
Hemophilia A and B are X-linked recessive disorders, which explains who is likely to bleed and the modes of genetic transmission. These hemophilias occur almost exclusively in a male having one defective copy of the relevant gene on his X chromosome (ie, he is hemizygous for the defect). Because the affected male will transmit a normal Y chromosome to all his sons and an abnormal X chromosome to all his daughters, his sons will not be affected and all of his daughters will be carriers (ie, they are heterozygous for the defect).]
What is the normal half-life of PMNs?
1-2 days
What is the treatment for Bernard Soulier syndrome?
Platelets
[UpToDate: Inherited platelet disorders with giant platelets are quite rare. These include platelet glycoprotein abnormalities (eg, Bernard-Soulier syndrome), deficiency of platelet alpha granules (eg, gray platelet syndrome), the May-Hegglin anomaly, which also involves the presence of abnormal neutrophil inclusions (ie, Döhle-like bodies), and some kindreds with type 2B von Willebrand disease (the Montreal platelet syndrome).
Patients with these disorders who have bleeding diatheses are usually treated with platelet transfusions. In a small study in subjects with MYH9-RD and platelet counts <50,000/microL, treatment with the non-peptide thrombopoietin receptor agonist eltrombopag resulted in major responses (ie, platelet counts of at least 100,000/microL or three times baseline) in 8 of the 12 so treated. Bleeding tendency disappeared in 8 of the 10 subjects with bleeding symptoms at baseline.]
What is the treatment for a patient with a pulmonary embolism who is in shock despite massive inotropes and pressors?
Take patient to OR
[UpToDate: In patients with PE who are hemodynamically unstable or who become unstable due to recurrence despite anticoagulation, we suggest more aggressive therapies than anticoagulation including the following:
Thrombolytic therapy is indicated in most patients, provided there is no contraindication. Systemic thrombolytic therapy is a widely accepted indication for patients with PE who present with, or whose course is complicated by, hemodynamic instability. Catheter-directed thrombus removal with or without thrombolysis can also be administered in select patients (eg, those at high risk of bleeding, those with shock who will likely die before systemic thrombolysis can take effect (eg, within hours), and those who have failed systemic thrombolysis).
Embolectomy is indicated in patients with hemodynamically unstable PE in whom thrombolytic therapy is contraindicated. It is also a therapeutic option in those who fail thrombolysis. Emboli can be removed surgically or using a catheter. The choice between these options depends upon available expertise, the presence or absence of a known diagnosis of PE, and the anticipated response to such therapies. As an example, when a patient has severe hemodynamic instability and standard dose thrombolysis is contraindicated, catheter-directed techniques may be preferred if the expertise is available. One advantage of this approach is that both diagnostic and therapeutic interventions can be applied simultaneously.]
What is the treatment for thrombolytic overdose?
Aminocaproic acid (Amicar)
[UpToDate: Tranexamic acid and epsilon-aminocaproic acid are lysine analogues that bind to the kringle domains of plasminogen and disrupt interactions between plasminogen (and plasmin) and lysine residues within fibrin. Tranexamic acid binds plasminogen and plasmin more avidly than epsilon-aminocaproic acid does, and may produce a more potent anti-hemorrhagic effect.
These antifibrinolytic agents have been recommended for use in settings where fibrinolysis is prominent, such as when tissues with high fibrinolytic activity are involved (eg, oropharynx, prostate, endometrium) or in selected patients with hemorrhagic shock who have an elevated D-dimer and depleted fibrinogen.]
What is a natural inhibitor of plasmin that is released from the endothelium?
Alpha-2 antiplasmin
[UpToDate: Alpha-2-antiplasmin is secreted by the liver and is also present within platelets. It can be crosslinked into the fibrin clot by factor XIIIa, and plays an important role in making thrombi resistant to plasmin by complexing with it. Plasmin released into the circulation is rapidly inactivated by alpha-2-antiplasmin. However, alpha-2-antiplasmin is present in lower concentrations than is plasminogen and therefore can become depleted while plasmin is continuing to be generated.]
How many days before surgery should Clopidogrel (Plavix) be stopped?
7 days
[UpToDate: Many patients take both aspirin and platelet P2Y12 receptor blocker therapy to prevent coronary stent thrombosis. Premature cessation of dual antiplatelet therapy is associated with an increased risk for stent thrombosis. Except for emergent settings, we recommend that surgery be delayed and therapy with P2Y12 receptor blocker and aspirin be continued for at least the minimum recommended duration for each stent type.
If surgery must be performed before these minimum time periods, it is best to consult with the treating cardiologist and surgeon. In this setting, we suggest that surgery be performed in centers with 24-hour interventional cardiology coverage. If the risk of major bleeding appears greater than the risk of stent thrombosis, P2Y12 receptor blocker therapy should be discontinued for as brief a period as possible. Aspirin should be continued during this period if at all possible. Clopidogrel and ticagrelor should be discontinued at least five days before surgery, and prasugrel at least seven days. Although rarely used, the half-life of ticlopidine is 24 to 32 hours, but after long-term administration it increases to over 90 hours, so it should be discontinued at least 10 days before surgery. These drugs should be resumed as early as possible in the postoperative period. Whether or not a loading dose should be given at the time of resumption should be discussed with the surgeon and cardiologist, since it would take 5 to 10 days to attain maximal platelet function inhibition with resumption of clopidogrel at a maintenance dose (75 mg/day).
For patients who are continuing on dual antiplatelet therapy but who have already received the minimum duration of therapy for their stent type, the P2Y12 receptor blocker may be stopped, surgery performed, and the receptor blocker restarted following surgery.
Continuing clopidogrel in the perioperative period for peripheral artery and carotid procedures is reasonable as the bleeding risk appears low.
There are no data on the safety of dipyridamole if continued in the perioperative period. Like aspirin, factors to consider in deciding whether to continue or hold dipyridamole reflect a balance between the risk of bleeding and risk of ischemic events. If discontinued, the drug should be stopped at least two days before surgery. Aggrenox (combination aspirin and dipyridamole) should be discontinued 7 to 10 days before surgery.
Cilostazol should be discontinued for at least 2-3 days prior to elective surgery, but the manufacturer recommends stopping it at least five days before. Claudication symptoms may recur when the medication is stopped, but should respond once cilostazol is reinitiated postoperatively.]
How are the bleeding time (ristocetin test), PT, and PTT affected in von Willebrand’s disease?
- Bleeding time is prolonged
- PT is normal
- PTT can be normal or abnormal
[UpToDate: The bleeding time (BT) is a measure of the interaction of platelets with the blood vessel wall. It is prolonged in patients with some intrinsic platelet disorders and in moderately severe and severe VWD, but is often normal in those with mild or moderate VWD. Although the BT does not correlate well with any specific plasma VWF assay, it is helpful diagnostically if it is abnormal. It has been suggested that the levels of ristocetin cofactor and VWF:Ag in platelets correlate better with the BT than the plasma values of these tests.
Patients with VWD have a normal prothrombin time (PT), and the activated partial thromboplastin time (aPTT) may be normal or prolonged, depending on the degree of reduction of the factor VIII level.
The prothrombin time (PT) measures the time it takes plasma to clot when exposed to tissue factor, which assesses the extrinsic and common pathways of coagulation.
The activated partial thromboplastin time (aPTT, PTT) measures the time it takes plasma to clot when exposed to substances that activate the contact factors, which assesses the intrinsic and common pathways of coagulation.]
Which measure of coagulation is best for determining liver synthetic function?
Prothrombin time (PT/INR)
[UpToDate: Blood tests commonly obtained to evaluate the health of the liver include liver enzyme levels, tests of hepatic synthetic function, and the serum bilirubin level. Elevations of liver enzymes often reflect damage to the liver or biliary obstruction, whereas an abnormal serum albumin or prothrombin time may be seen in the setting of impaired hepatic synthetic function. The serum bilirubin in part measures the liver’s ability to detoxify metabolites and transport organic anions into bile.]
What INR value is a relative contraindication to performing surgery?
Greater than 1.5
[UpToDate: If it has been determined that warfarin discontinuation is appropriate, we typically discontinue warfarin five days before elective surgery (ie, last dose of warfarin is given on day minus 6) and, when possible, check the PT/INR on the day before surgery. If the INR is >1.5, we administer low dose oral vitamin K (eg, 1 to 2 mg) to hasten normalization of the PT/INR and recheck the following day. We proceed with surgery when the INR is ≤1.4. An INR in the normal range is especially important in patients undergoing surgery associated with a high bleeding risk (eg, intracranial, spinal, urologic) or if neuraxial anesthesia is to be used.
This timing of warfarin discontinuation is based on the biological half-life of warfarin (36 to 42 hours) and the observed time for the PT/INR to return to normal after stopping warfarin (eg, 2 to 3 days for the INR to fall to below 2.0; 4 to 6 days to normalize). Normalization of the INR may take longer in patients receiving higher-intensity anticoagulation (INR 2.5 to 3.5), and in elderly individuals. Half-lives of other vitamin K antagonists also differ (eg, 8 to 11 hours for acenocoumarol; 3 to 5 days for phenprocoumon; approximately three days for fluindione).
For a procedure that requires more rapid normalization of the INR, additional interventions may be needed to actively reverse the anticoagulant.
This discontinuation schedule will produce a period of several days with subtherapeutic anticoagulation. As an example, it is estimated that if warfarin is withheld for five days before surgery and is restarted as soon as possible afterwards, patients would have a subtherapeutic INR for approximately eight days (four days before and four days after surgery). Thus, for patients at very high or high thromboembolic risk, bridging may be appropriate.]
How are the PT and PTT affected in disseminated intravascular coagulation (DIC)?
- Prothrombin time (PT) is prolonged
- Partial thromboplastin time (PTT) is prolonged
[UpToDate: Laboratory findings of DIC may include the following:
Prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT). Prolonged PT will lead to increase in the international normalized ratio (INR) for the PT. These abnormalities are more typical of acute than chronic DIC.
Hypofibrinogenemia, which is more common with acute than chronic DIC. Importantly, patients with sepsis, malignancy, and other inflammatory conditions may have markedly increased production of fibrinogen since fibrinogen functions as an acute phase reactant; thus, a plasma fibrinogen level within the normal range may represent a substantial consumption (and a significant abnormality) for that patient despite being in the normal range.
Increased D-dimer, which is seen in both acute and chronic DIC.
Thrombocytopenia, which is seen more typically with acute than chronic DIC. The platelet count is typically mildly to moderately reduced; platelet counts below 20,000/microL are less commonly seen.
Microangiopathic hemolytic anemia (MAHA), with schistocytes and helmet cells seen on the peripheral blood smear. These changes may be less pronounced than those seen in other thrombotic microangiopathies such as thrombotic thrombocytopenic purpura (TTP). Severe anemia due to microangiopathic hemolysis is uncommon, although most of the underlying conditions responsible for DIC can cause anemia due to other mechanisms (eg, bone marrow suppression, anemia of chronic disease/inflammation). MAHA can be seen in both acute and chronic DIC.]
By what mechanism does low molecular weight heparin (enoxaparin and fondaparinux) work?
Binds and activates antithrombin III but increases neutralization of just Xa and thrombin
[Not reversed with protamine]
[UpToDate: Low molecular weight (LMW) heparin is prepared by depolymerization of unfractionated heparin using chemical methods or enzymes. LMW heparin preparations for clinical use have been produced by several companies.
The pharmacokinetic properties of LMW heparin include a very high bioavailability after subcutaneous injection, a longer half-life than unfractionated heparin, and much less interindividual variation in the anticoagulant response to a given dose. The anticoagulant response (anti-Xa activity) to a fixed dose of LMW heparin is highly correlated with the patient’s body weight. These pharmacokinetic properties make it possible to give LMW heparin subcutaneously once or twice daily to patients WITHOUT the need for laboratory monitoring of the anticoagulant response or dose adjustment unless pregnancy, morbid obesity, or renal failure is present. In the presence of such conditions, anti-Xa level measurement has been recommended for proper dosing.
Anti-Xa levels should be measured four hours after subcutaneous injection; the dose of LMW heparin should be titrated to achieve a level of 0.6 to 1.0 international units/mL if administered twice daily, or 1.0 to 2.0 international units/mL if administered once daily. Some individual LMW heparin preparations have specific dosage recommendations for the very obese and those with marked renal impairment.]
What is the treatment for polycythemia vera?
Phlebotomy and Aspirin
[UpToDate: Hematocrit control – In subjects without active thrombosis and those not at risk for thrombosis (ie, age <60, no prior thrombosis), we recommend that the hematocrit be kept within the normal range via the use of serial phlebotomy, rather than by the use of myelosuppressive agents (Grade 1A).
- A standard one unit phlebotomy (500 mL) should reduce the hematocrit by 3 percentage points in a normal-sized adult (eg, from 46% to 43%).
- Optimal control is to keep the hematocrit continuously below 45% in men and 42% in women.
- Since phlebotomy is effective in controlling PV by producing a state of relative or absolute iron deficiency, iron supplementation should not be given.
Patients at high risk for thrombosis – For patients at high risk for thrombosis (ie, age >60, prior thrombosis) we recommend that treatment with phlebotomy be supplemented with the use of a myelosuppressive agent. (Grade 1C). For this purpose we prefer the use of hydroxyurea over an alkylating agent or interferon alpha.
- If not otherwise contraindicated because of a history of major bleeding or intolerance, we suggest that aspirin be given to all patients (Grade 2C). The appropriate dose is 75 to 100 mg/day. Treatment with higher doses should be avoided.
Alternative myelosuppressive agents – We suggest the use of interferon alpha (IFNa) in patients with refractory pruritus, in high-risk women of childbearing potential, and in the patient refractory to all other medications (eg, hydroxyurea) (Grade 2B).
Control of leukocytosis – There is not sufficient information in the literature to support the use of hydroxyurea for low- or intermediate-risk patients with PV and leukocytosis.]
Which blood storage product contains high levels of all coagulation factors, protein C, protein S, and antithrombin III?
Fresh frozen plasma (FFP)
[UpToDate: Fresh Frozen Plasma (FFP) is prepared from single units of whole blood or from plasma collected by apheresis techniques. It is frozen at -18 to -30°C within eight hours of collection and, when appropriately stored, is usable for one year from the date of collection. Standard FFP units derived from a single unit of whole blood have a volume of approximately 200 to 250 mL; “jumbo” units prepared by apheresis may be as large as 600 mL.
FFP contains all of the coagulation factors and other proteins present in the original unit of blood, slightly diluted by the citrate-containing anticoagulant solution used to collect the blood.]
Which surface receptors are involved in binding platelets together to form a platelet plug?
GpIIb/IIIa
[UpToDate: The process of transforming GPIIb/IIIa (alphaIIb-beta3) on the platelet surface into a competent receptor for fibrinogen was one of the most elusive aspects of platelet signaling. It is the final common pathway in platelet responses to most agonists, making it a frequent target for drug development. Circulating platelets do not normally bind fibrinogen or stick to each other unless they have been activated. The reasons for this are multiple, but are ultimately due to the inability of fibrinogen or fibrin to bind to the resting conformation of GPIIb/IIIa.
Platelet activation alters the conformation, or competency, of GPIIb/IIIa, allowing fibrinogen binding. The process whereby intracellular events alter GPIIb/IIIa on the cell surface is referred to as “inside-out” signaling. The process requires the binding of talin and kindling-3 to the cytoplasmic tail of GPIIIa. The binding of these two proteins to the cytoplasmic side of the receptor opens the extracellular side and thereby allows it to bind fibrinogen. Normally, this should occur only at sites of vascular injury. Additionally, a series of intracellular signaling events are initiated and propagated, including tyrosine and serine/threonine kinase and phosphatase activation, as a consequence of fibrinogen binding and platelet aggregation (so called “outside-in” signaling).
Working against this tendency to platelet activation are a number of internal and external controls that dampen the intracellular signals that would otherwise allow inappropriate platelet activation, thereby contributing to such complications as myocardial infarction or stroke. These controls include tight regulation of the cytosolic Ca++ concentration, intracellular phosphatases that limit signaling through kinase-dependent pathways, extracellular ADPases that hydrolyze released ADP, and the inhibitory effects of PGI2 and nitric oxide (NO) released from endothelial cells. Collectively, these provide a threshold that helps to prevent platelet activation at inappropriate times and places.]
What gets released from the endothelium and converts plasminogen to plasmin?
Tissue plasminogen activator
[UpToDate: The tPA molecule is predominantly an endothelial cell enzyme. Its release is stimulated by a variety of substances including thrombin, serotonin, bradykinin, cytokines, and epinephrine. In plasma it circulates as a complex with its natural inhibitor PAI-1 and is rapidly cleared by the liver.
Analogous to the prothrombin complex, the rapid generation of plasmin by tPA optimally takes place on a surface, the fibrin clot. Both tPA and fibrinogen bind to fibrin via recognition of lysine residues in the fibrin clot. When bound to fibrin, the binding interaction aligns tPA and plasminogen on the fibrin surface so that the catalytic efficiency of tPA is increased several hundred-fold.]
How are 99% of patients with bleeding disorders discovered?
Abnormal bleeding with tooth extraction or tonsillectomy
By what mechanism do thrombolytics work?
They activate plasminogen
[UpToDate: Plasminogen, the precursor molecule to plasmin, binds fibrin and tissue plasminogen activator (tPA). This ternary complex leads to conversion of the proenzyme plasminogen to active, proteolytic plasmin.
Plasmin has broad substrate specificity and, in addition to fibrin, cleaves fibrinogen and a variety of plasma proteins and clotting factors. Plasmin cleaves the polymerized fibrin strand at multiple sites and releases fibrin degradation products (FDPs). One of the major FDPs is D-dimer, which consists of two D domains from adjacent fibrin monomers that have been crosslinked by activated factor XIII. Plasmin also cleaves factor XIIIa, but not factor XIII, leading to reduced fibrin crosslinking.
The plasminogen/plasminogen-activator system is complex, paralleling the coagulation cascade. Plasmin activity is regulated by vascular endothelial cells that secrete both serine protease plasminogen activators (tissue-type plasminogen activator and urokinase-type plasminogen activator) and plasminogen activator inhibitors (PAI-1 and PAI-2).
Recombinant tissue type plasminogen activator (tPA, alteplase), streptokinase (SK), and recombinant human urokinase (UK) are the best studied thrombolytic agents for the treatment of acute PE, that are approved by the US Food and Drug Administration (FDA). Other thrombolytic agents include lanoteplase, tenecteplase, and reteplase.
tPA is a naturally occurring enzyme produced by a number of tissues including endothelial cells. tPA binds to fibrin, which increases its affinity for plasminogen and enhances plasminogen activation.
SK is a polypeptide derived from beta-hemolytic streptococcus cultures. It binds to plasminogen, forming an active enzyme that activates plasmin. Among the thrombolytic agents, it is the least expensive but most commonly associated with adverse effects, including allergic reactions and hypotension.
Urokinase is also a plasminogen activator that is normally present in the urine. It is the major activator of fibrinolysis in the extravascular compartment, in contrast to tPA which is largely responsible for initiating intravascular fibrinolysis. Because the FDA-approved duration for tPA delivery is two hours, streptokinase and urokinase are rarely used today.]
What normally links GpIIb/IIIa receptors together?
Fibrin
Which medication activates antithrombin III up to 1000x its normal activity?
Heparin
[UpToDate: Heparin is an endogenously produced, linear polysaccharide that consists of repeating units of pyranosyluronic acid and glucosamine residues. Endogenous heparin and heparin-binding proteins have a variety of anticoagulant, anti-inflammatory, and possibly antiangiogenic effects, which are incompletely understood.
The form of heparin used clinically as an anticoagulant is isolated from porcine (pig) or bovine (cow) intestines. It has a mixture of different length polysaccharides, with a mean size of approximately 45 saccharide units, corresponding to a mean molecular weight of approximately 15,000 daltons (range 3000 to 30,000 daltons). Low molecular weight (LMW) heparins are derived from unfractionated heparin by enriching for the shorter polysaccharides to produce a product with a mean length of approximately 15 saccharide units, corresponding to a mean molecular weight of approximately 4000 to 5000 daltons (range 2000 to 9000 daltons). Fondaparinux, which consists of the minimal AT-binding region of heparin, contains 5 saccharide units (ie, pentasaccharide) and has an approximate molecular weight of 1700 daltons.
Heparins act indirectly by binding to antithrombin (AT, formerly called AT III, also known as heparin cofactor I) rather than by binding directly to coagulation factors. Binding of heparin to AT is mediated by a unique pentasaccharide sequence in heparin that is randomly distributed along the heparin chains. The binding site for heparins on AT is located at the AT amino terminus. Binding of heparin to this site on AT induces a conformational change in AT, which converts AT from a slow to a rapid inactivator of coagulation factors (eg, thrombin [factor IIa], factor Xa). The enhancement of AT anticoagulant activity by heparins is on the order of 1000- to 4000-fold.
Both unfractionated and LMW heparins efficiently inactivate factor Xa via AT. However, unfractionated heparin is a much more efficient inactivator of thrombin because thrombin inactivation requires the formation of a ternary complex between heparin, AT, and thrombin, and this ternary complex can form only when heparin chains are at least 18 saccharide units long. These 18-saccharide-long units are present to a much smaller extent in LMW heparins and are absent from fondaparinux. Thus, unfractionated heparin, LMW heparin, and fondaparinux all inactivate factor Xa, but unfractionated heparin also inhibits thrombin. Fondaparinux appears to have nearly pure anti-factor Xa activity.]
Which 3 contributors in the coagulation cascade are degraded by Protein C?
- Factor V
- Factor VIII
- Fibrinogen
[UpToDate: As clot formation progresses, thrombin (factor IIa) binds to thrombomodulin (TM), an integral membrane protein on the endothelial cell surface.
Binding of thrombin to TM induces a conformational change in thrombin (factor IIa), which drastically changes its substrate specificity such that it loses all of its procoagulant functions (eg, platelet activation, fibrin clot formation) and instead acquires the ability to activate protein C. Activation of protein C by the thrombin-TM complex is enhanced by an endothelial receptor for protein C (EPCR). As a testament to this TM-induced change of function for thrombin, a knockout mouse model in which the TM gene was ablated was associated with unfettered activation of the coagulation system and widespread thrombosis. Conversely, a naturally-occurring TM mutation (C1611A) that causes TM to be shed from the endothelial surface and circulate at very high levels in the plasma is associated with a bleeding phenotype.
Activated protein C (APC), in association with protein S on phospholipid surfaces, proteolytically inactivates factors Va and VIIIa, thereby inactivating the prothrombinase and the intrinsic X-ase, respectively.]
What can prostate surgery cause to be released, leading to the activation of plasminogen and subsequent thrombolysis?
Urokinase
[Treatment is aminocaproic acid]
[UpToDate: Surgery of the prostate, for both benign and malignant disease is well known to be associated with a risk of significant bleeding as the urogenital system is rich in urokinase. Not only local fibrinolytic reactions, but also disseminated intravascular coagulation (DIC) has been associated with prostate surgery. Hence, there has been long-standing interest in the role of preoperative hematologic screening tests. One study measured the preoperative PT, aPTT, fibrinogen, and platelet count in 165 consecutive patients undergoing prostate surgery. Benign prostatic hypertrophy (BPH) was present in 116 patients, adenocarcinoma in 45 patients, and both diagnoses in four patients. Two patients had thrombocytopenia with bone marrow examination showing metastatic disease; studies for the presence of DIC were normal and these two patients had uneventful prostatic biopsies. One patient with normal preoperative values developed DIC after biopsy, while three patients with BPH had normal screening tests but experienced bleeding due to local fibrinolysis. It could be concluded that the hematologic screening tests were not helpful in predicting bleeding complications, either due to faulty surgical hemostasis or hematologic problems.]
What is the most common congenital hypercoagulability disorder?
Factor V Leiden mutation
[UpToDate: Factor V, encoded by the F5 gene, is a procoagulant clotting factor that amplifies the production of thrombin, the central enzyme that converts fibrinogen to fibrin, which leads to clot formation. Factor V is synthesized as an inactive factor that circulates in plasma. A small amount of thrombin at the site of a wound activates factor V by limited proteolysis. This activated factor V (factor Va) then serves as a cofactor in the prothrombinase complex, which cleaves prothrombin to generate more thrombin, in a positive feedback loop.
Thrombin (bound to thrombomodulin on the surface of endothelial cells) also slows its own production by creating a separate negative feedback loop. It does this by converting protein C to activated protein C (aPC), a protease that acts as a potent natural anticoagulant. aPC degrades activated factor Va (and activated factor VIIIa, upstream in the coagulation cascade), ultimately reducing thrombin production. aPC uses protein S as a cofactor in all of its cleavage reactions.
Factor V Leiden (FVL) results from a single point mutation in the factor V gene (guanine to adenine at nucleotide 1691), which leads to a single amino acid change (replacement of arginine with glutamine at amino acid 506); hence the names factor V R506Q and factor V Arg506Gln. This abolishes the Arg506 cleavage site by aPC in factor V and factor Va. This defect was initially termed “aPC resistance” because the anticoagulant activity of aPC was reduced in a modified activated partial thromboplastin time (aPTT) assay.
aPC-mediated cleavage of factor V and Va have different consequences for protein function. aPC cleavage of the procoagulant factor Va causes factor Va degradation, whereas aPC cleavage of the anticoagulant factor V enhances factor V function. FVL is insensitive to both of these cleavages because it lacks the Arg506 cleavage site. Thus, the FVL mutation simultaneously increases coagulation by creating two distinct changes in the coagulation cascade:
- Enhanced procoagulant role of factor Va – aPC destroys factor Va in a series of sequential cleavages. The first cleavage at Arg506 exposes additional cleavage sites at Arg306 and Arg679. Since activated FVL cannot be cleaved at Arg506, these other sites remain buried in the protein, resulting in 20-fold slower degradation of activated FVL. The extended presence of activated FVL results in continued thrombin generation.
- Reduced anticoagulant role of factor V – aPC cleavage of unactivated factor V at position 506 enhances its ability to act as a cofactor in the degradation of factors Va and VIIIa. Since unactivated FVL cannot be cleaved at Arg506, it is less effective as a cofactor for aPC, resulting in reduced degradation of factors Va and VIIIa.
The reduced cleavage of activated FVL by aPC and the impaired cleavage of unactivated FVL by aPC appear to contribute equally to the phenomenon of FVL-associated aPC resistance and the ensuing hypercoagulable state. The FVL mutation accounts for more than 95% of cases of hereditary aPC resistance, with the remainder of aPC resistance cases due to other inherited mutations and other acquired factors.
The dual roles of factor V also help to explain why the risk of thrombosis is greater in patients homozygous or pseudohomozygous for FVL (ie, compound heterozygous for FVL and factor V deficiency). In contrast, the plasma of FVL heterozygotes contains both FVL and normal factor V. The normal factor V has aPC cofactor activity for the inactivation of factor VIIIa, affording some protection against thrombosis.]
Besides converting fibrinogen into fibrin, what two functions does thrombin have?
- Activates Factors V and VIII
- Activates platelets
Thromboxane (TXA2) is released from platelets for what purpose?
It increases platelet aggregation and promotes vasoconstriction
[UpToDate: Intact endothelial cells in proximity to disrupted endothelium release arachidonic acid from cell membrane phospholipids by phospholipase A2. The enzyme cyclooxygenase-1 (COX-1 or prostaglandin endoperoxide H synthase-1) converts arachidonic acid into thromboxane A2 (TxA2) in platelets, while prostacyclin (PGI2), a dominant product of the endothelium, appears to largely derive from COX-2, the production of which is induced by laminar blood flow under physiologic conditions.
TxA2 is a potent stimulator of platelet aggregation and produces vasoconstriction, while PGI2, via activation of adenylate cyclase, blocks platelet aggregation and antagonizes TxA2-mediated vasoconstriction.
- Low dose aspirin irreversibly acetylates and inhibits COX-1 and only weakly inhibits COX-2. Since platelets cannot make new COX-1, the inhibition of TxA2 is permanent for the life of the platelet.
- In comparison, endothelial cells can make new COX-1 as well as COX-2 and higher doses of aspirin are required for inhibition of PGI2 production.
This distinction underlies the hypothesized mechanism for the benefit of low-dose aspirin in cardiovascular disease, as well as the increased cardiac toxicity of the selective COX-2 inhibitors.]
What is the half-life of Argatroban?
50 minutes
[Metabolized by the liver]
[UpToDate: Argatroban is a parenteral small molecule direct thrombin inhibitor with a half-life of 24 minutes. Its effect is monitored by the aPTT, although dose-dependent increases also occur in the prothrombin time. Steady-state anticoagulation is reached 1 to 3 hours after intravenous administration; after discontinuation, the aPTT returns to normal within 2 hours.
Since argatroban is mostly metabolized by the liver, dose adjustment is required in the presence of hepatic dysfunction. A conservative lower starting dose (eg, 0.5 to 1.2 mcg/kg per minute) is appropriate in patients total serum bilirubin >1.5 mg/dL (25.5 micromol/L) as well as in those with combined hepatic/renal dysfunction, heart failure, severe anasarca, or who are postcardiac surgery. In such patients it is prudent to check the aPTT at four-hour intervals after drug initiation or dose change. Dose adjustment is not required in the presence of isolated renal impairment.]
What are the 4 absolute contraindications to thrombolytic therapy?
- Active internal bleeding
- Recent CVA or neurosurgery (within 3 months)
- Intracranial pathology
- Recent GI bleeding
[UpToDate: In every patient in whom thrombolysis is contemplated, the risk of bleeding should always be considered. We believe that the importance of the contraindication depends on the strength of the indication. As an example, a contraindication is of more concern if the indication for systemic thrombolytic therapy is RV dyskinesis, than if the indication is shock.
Absolute or major contraindications to systemic thrombolytic therapy in acute PE include an intracranial neoplasm, recent (ie, <2 months) intracranial or spinal surgery or trauma, history of a hemorrhagic stroke, active bleeding or bleeding diathesis, or nonhemorrhagic stroke within the previous three months. Relative contraindications include severe uncontrolled hypertension (ie, systolic blood pressure >200 mmHg or diastolic blood pressure >110 mmHg), nonhemorrhagic stroke older than three months, surgery within the previous 10 days, pregnancy, and others. Thrombolytic therapy may cause moderate bleeding in menstruating women, but it has rarely been associated with major hemorrhage. Therefore, menstruation is not a contraindication to thrombolytic therapy.
As an alternative to thrombolytic therapy, catheter or surgical embolectomy may be warranted if the necessary resources and expertise are available. The decision of whether to pursue one of these approaches should be based on local expertise. Catheter and surgical embolectomy are discussed in detail separately.]
How does Factor V Leiden mutation cause thrombosis?
It causes resistance to activated protein C
[The defect is on factor V]
[UpToDate: Factor V, encoded by the F5 gene, is a procoagulant clotting factor that amplifies the production of thrombin, the central enzyme that converts fibrinogen to fibrin, which leads to clot formation. Factor V is synthesized as an inactive factor that circulates in plasma. A small amount of thrombin at the site of a wound activates factor V by limited proteolysis. This activated factor V (factor Va) then serves as a cofactor in the prothrombinase complex, which cleaves prothrombin to generate more thrombin, in a positive feedback loop.
Thrombin (bound to thrombomodulin on the surface of endothelial cells) also slows its own production by creating a separate negative feedback loop. It does this by converting protein C to activated protein C (aPC), a protease that acts as a potent natural anticoagulant. aPC degrades activated factor Va (and activated factor VIIIa, upstream in the coagulation cascade), ultimately reducing thrombin production. aPC uses protein S as a cofactor in all of its cleavage reactions.
Factor V Leiden (FVL) results from a single point mutation in the factor V gene (guanine to adenine at nucleotide 1691), which leads to a single amino acid change (replacement of arginine with glutamine at amino acid 506); hence the names factor V R506Q and factor V Arg506Gln. This abolishes the Arg506 cleavage site by aPC in factor V and factor Va. This defect was initially termed “aPC resistance” because the anticoagulant activity of aPC was reduced in a modified activated partial thromboplastin time (aPTT) assay.
aPC-mediated cleavage of factor V and Va have different consequences for protein function. aPC cleavage of the procoagulant factor Va causes factor Va degradation, whereas aPC cleavage of the anticoagulant factor V enhances factor V function. FVL is insensitive to both of these cleavages because it lacks the Arg506 cleavage site. Thus, the FVL mutation simultaneously increases coagulation by creating two distinct changes in the coagulation cascade:
- Enhanced procoagulant role of factor Va – aPC destroys factor Va in a series of sequential cleavages. The first cleavage at Arg506 exposes additional cleavage sites at Arg306 and Arg679. Since activated FVL cannot be cleaved at Arg506, these other sites remain buried in the protein, resulting in 20-fold slower degradation of activated FVL. The extended presence of activated FVL results in continued thrombin generation.
- Reduced anticoagulant role of factor V – aPC cleavage of unactivated factor V at position 506 enhances its ability to act as a cofactor in the degradation of factors Va and VIIIa. Since unactivated FVL cannot be cleaved at Arg506, it is less effective as a cofactor for aPC, resulting in reduced degradation of factors Va and VIIIa.
The reduced cleavage of activated FVL by aPC and the impaired cleavage of unactivated FVL by aPC appear to contribute equally to the phenomenon of FVL-associated aPC resistance and the ensuing hypercoagulable state. The FVL mutation accounts for more than 95% of cases of hereditary aPC resistance, with the remainder of aPC resistance cases due to other inherited mutations and other acquired factors.]
What is another name for factor II?
Prothrombin
[UpToDate: Prothrombin (factor II; F2) is the precursor of thrombin, the end-product of the coagulation cascade. Thrombin in turn proteolytically cleaves fibrinogen to fibrin, which becomes crosslinked to form a fibrin clot. Thrombin also acts on a variety of other hemostatic components including platelets, factor VIII (cofactor for factor X activation by factor IXa), factor V (cofactor for prothrombin activation by factor Xa), factor XIII (crosslinks fibrin), and thrombin-activatable fibrinolysis inhibitor (TAFI; regulates clot lysis).]
In which syndrome do patients have a prolonged partial thromboplastin time (PTT) while being hypercoagulable?
Anti-phospholipid antibody syndrome
[Not all of these patients have SLE]
[UpToDate: Antiphospholipid antibody syndrome (APS) is defined by two major components:
Presence in the serum of at least one type of autoantibody known as an antiphospholipid antibody (aPL). The aPL are directed against phospholipid-binding plasma proteins.
The occurrence of at least one of the following clinical features: venous or arterial thromboses and/or pregnancy morbidity.
Although most of the clinical manifestations of APS can occur in other disease populations, in patients with APS, they occur by definition in the context of aPL. aPL are directed against serum proteins bound to anionic phospholipids and may be detected as:
- Lupus anticoagulants (LA)
- Anticardiolipin antibodies
- Antibodies to beta2-glycoprotein I
APS occurs either as a primary condition or in the setting of an underlying systemic autoimmune disease, particularly systemic lupus erythematosus (SLE).
Clinical suspicion for antiphospholipid syndrome (APS) should be raised in the following settings:
- Occurrence of one or more otherwise unexplained venous or arterial thrombotic events, especially in young patients
- One or more specific adverse outcomes related to pregnancy, including fetal death after 10 weeks gestation, premature birth due to severe preeclampsia or placental insufficiency, or multiple embryonic losses (<10 weeks gestation)
- Otherwise unexplained thrombocytopenia or prolongation of a test of blood coagulation (eg, activated partial thromboplastin time [aPTT])
Other clinical characteristics aside from those described above include livedo reticularis, valvular heart disease, and neurologic findings such as cognitive deficits and white matter lesions. A systemic autoimmune disease diagnosis, especially systemic lupus erythematosus (SLE), should increase the suspicion for APS in the setting of appropriate clinical symptoms. A history of a false positive serologic test for syphilis may also be a clue to the presence of antiphospholipid antibodies (aPL).
In patients suspected of having APS, we perform a thorough medical history, physical examination, and antibody testing for aPL. We generally perform initial antibody testing around the time of a clinical event, followed by confirmatory testing at least 12 weeks later. Antibody testing in patients with suspected APS includes the following:
- Anticardiolipin antibodies (aCL); immunoglobulin G (IgG) and/or IgM by enzyme-linked immunosorbent assay (ELISA)
- Anti-beta2-glycoprotein (GP) I antibodies; IgG and/or IgM by ELISA.
- Lupus anticoagulant (LA) testing with dilute Russell viper venom time (dRVVT) and/or aPTT, or another combination as the initial screening tests.
It may be appropriate to pursue additional laboratory testing or evaluate patients for other possible causes of thromboembolism and/or adverse pregnancy outcomes. This may include testing for other causes of thromboembolism and unexplained cytopenias and evaluation for SLE.
The diagnosis of APS is based on a combination of clinical features and laboratory findings. Although the classification criteria were designed for research purposes, we diagnose APS in patients who meet the revised Sapporo classification criteria.]
What is the treatment for anti-phospholipid antibody syndrome?
Heparin and Warfarin
[UpToDate: Antiphospholipid antibody syndrome (APS) is defined by two major components:
- Presence in the serum of at least one type of autoantibody known as an antiphospholipid antibody (aPL). The aPL are directed against phospholipid-binding plasma proteins.
- The occurrence of at least one of the following clinical features: venous or arterial thromboses and/or pregnancy morbidity.
Although most of the clinical manifestations of APS can occur in other disease populations, in patients with APS, they occur by definition in the context of aPL. aPL are directed against serum proteins bound to anionic phospholipids and may be detected as:
- Lupus anticoagulants (LA)
- Anticardiolipin antibodies
- Antibodies to beta2-glycoprotein I
APS occurs either as a primary condition or in the setting of an underlying systemic autoimmune disease, particularly systemic lupus erythematosus (SLE).
The therapy for the non-obstetric manifestations of antiphospholipid antibody syndrome (APS) is largely the same regardless of whether the disorder is classified as primary APS or as APS secondary to systemic lupus erythematosus (SLE). The mainstay of treatment for APS includes the following antithrombotic medications:
- Heparin
- Warfarin
- Aspirin
Many patients with coexisting SLE are also treated with hydroxychloroquine (HCQ), which may have some benefit for patients at risk for complications of APS.]
What is the intrinsic pathway of coagulation?
- (Exposed collagen + Prekallikrein + HMW kininogen + Factor XII) Activate Factor XI
- Factor XIa Activates Factor IX
- (Factor IXa + Factor VIIIa) Activate Factor X
- (Factor Xa + Factor Va) converts Prothrombin to Thrombin
- Thrombin converts Fibrinogen to Fibrin
How does Heparin work?
It binds and activates anti-thrombin III, resulting in a 1000 fold increase in its activity
[UpToDate: Heparins act indirectly by binding to antithrombin (AT, formerly called AT III, also known as heparin cofactor I) rather than by binding directly to coagulation factors. Binding of heparin to AT is mediated by a unique pentasaccharide sequence in heparin that is randomly distributed along the heparin chains. The binding site for heparins on AT is located at the AT amino terminus. Binding of heparin to this site on AT induces a conformational change in AT, which converts AT from a slow to a rapid inactivator of coagulation factors (eg, thrombin [factor IIa], factor Xa). The enhancement of AT anticoagulant activity by heparins is on the order of 1000- to 4000-fold.
Both unfractionated and LMW heparins efficiently inactivate factor Xa via AT. However, unfractionated heparin is a much more efficient inactivator of thrombin because thrombin inactivation requires the formation of a ternary complex between heparin, AT, and thrombin, and this ternary complex can form only when heparin chains are at least 18 saccharide units long. These 18-saccharide-long units are present to a much smaller extent in LMW heparins and are absent from fondaparinux. Thus, unfractionated heparin, LMW heparin, and fondaparinux all inactivate factor Xa, but unfractionated heparin also inhibits thrombin. Fondaparinux appears to have nearly pure anti-factor Xa activity.]
Besides inhibiting thrombin, which 3 coagulation factors does antithrombin III inhibit?
- Factor IX
- Factor X
- Factor XI
[UpToDate: Antithrombin (AT, previously called AT III, also known as heparin cofactor I) is a natural anticoagulant. It inhibits thrombin (factor IIa), factor Xa, and other serine proteases in the coagulation cascade such as factor IXa.
AT is a serine protease inhibitor (serpin), a specific type of enzyme inhibitor. AT has a reactive center at position Arg393-Ser394 that interacts with the active site serine residue of the coagulation factor protease, and a heparin-binding site, which is distinct from the reactive center. Following the administration of heparin (unfractionated or low molecular weight [LMW]) or fondaparinux, AT activity is accelerated dramatically due to a conformational change leading to enhanced exposure of the reactive center in AT induced by heparin binding. This conformational change converts AT from a slow inactivator of coagulation factors such as thrombin (factor IIa) to a rapid inactivator (1000-fold increase in AT activity); the specific coagulation factor(s) affected depend on the size of the heparin molecule. It is thought that endogenous heparan sulfates in the intact endothelium provide this role in normal physiology, in turn localizing the inhibitor activity of AT to the endothelial surface of blood vessels and maintaining the fluidity of blood. AT may also have other roles such as reducing platelet adhesion to fibrinogen.]
What is the most common type of von Willebrand’s disease?
Type I (Often only has mild symptoms)
[70% of cases]
[UpToDate: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting up to 1% of the population as assessed by random laboratory screening, although only approximately 1% of these individuals are appreciably symptomatic. It is characterized by mutations that lead to a decrease in the level or impairment in the action of von Willebrand factor (VWF). Most cases are transmitted as an autosomal dominant trait that affects males and females equally. There are also acquired forms of VWD that are caused by several different pathophysiologic mechanisms.
Von Willebrand factor (VWF) plays an important role in primary hemostasis by binding to both platelets and endothelial components, forming an adhesive bridge between platelets and vascular subendothelial structures at sites of endothelial injury and between adjacent platelets in areas with high shear. It also contributes to fibrin clot formation by acting as a carrier protein for factor VIII, which has a greatly shortened half-life and abnormally low concentration unless it is bound to VWF.
Type 1 VWD, an autosomal dominant disease, is the most common, accounting for approximately 75% of patients. The clinical presentation of type 1 VWD varies from mild to severe as determined by bleeding symptoms, but some individuals are asymptomatic and detected incidentally in studies investigating a relative for VWD. Type 1 VWD represents a partial quantitative deficiency of von Willebrand factor; many of the mutations remain undefined.
Type 2 VWD contains four subtypes in which VWF is qualitatively abnormal, as demonstrated by VWF multimer patterns, RIPA, and an abnormally low VWF activity to antigen ratio (types 2A, 2B, and 2M), or by other special assays such as a quantitative assay of the patient’s VWF binding capacity for factor VIII (type 2N). Type 2A accounts for approximately 10% to 15% of cases of VWD, and is usually transmitted as an autosomal dominant trait. Affected patients typically present with moderate to moderately severe bleeding. Type 2B VWD accounts for approximately 5% of cases of VWD, and is transmitted as an autosomal dominant trait. Affected patients generally present with moderate or moderately severe bleeding. The abnormal VWF in this disorder has a “gain of function”, binding more readily to the platelet receptor, glycoprotein Ib. The increase in binding of larger multimers to platelet GP Ib results in their loss from the circulation and, in some patients, thrombocytopenia occurs due to clearance or sequestration of the small platelet aggregates that are formed.
Type 3 VWD is a rare disease. Affected patients present with severe bleeding involving both the skin and mucous membrane surfaces (due to decreased VWF) and soft tissues and joints (due to the low concentration of factor VIII). Type 3 VWD is characterized by a marked decrease or absence of detectable VWF due to homozygous or compound heterozygous mutations, some of which result in loss of VWF mRNA expression.]
How does Warfarin work?
Prevents vitamin K-dependent decarboxylation of glutamic residues on vitamin K-dependent factors
[UpToDate: Hepatic synthesis of coagulation factors II (half-life 42 to 72 hours), VII (half-life 4 to 6 hours), IX, and X (half-life 27 to 48 hours), as well as proteins C and S, requires the presence of vitamin K. These clotting factors are biologically activated by the addition of carboxyl groups to key glutamic acid residues within the proteins’ structure. In the process, “active” vitamin K is oxidatively converted to an “inactive” form, which is then subsequently reactivated by vitamin K epoxide reductase complex 1 (VKORC1). Warfarin competitively inhibits the subunit 1 of the multi-unit VKOR complex, thus depleting functional vitamin K reserves and hence reduces synthesis of active clotting factors.]
Why cant platelets resynthesize cyclooxygenase?
They lack DNA
[UpToDate: The megakaryocyte is the hematopoietic cell that produces platelets. Evidence for this relationship was first provided in 1906 by James Homer Wright, who demonstrated that circulating platelets and a giant bone marrow cell now known to be the megakaryocyte shared common tinctorial properties when subjected to a modified Romanofsky stain. Wright went on to show that megakaryocytes sent out pseudopodia into the bone marrow sinusoids from which platelets appeared to be shed.
This model of how megakaryocytes produce platelets remains with us to this day. Wright also demonstrated in normal and abnormal human physiology that changes in platelet number were associated only with changes in the megakaryocytes. Since these seminal observations, much has become known about megakaryocytes and how they produce platelets. The characteristics of megakaryocytes, how they regulate platelet production, and their role in pathologic processes will be described here.
CHARACTERISTICS — In lower vertebrate species such as fish and birds, all the circulating blood cells, including the erythrocytes and the platelets (called thrombocytes), are nucleated and are produced by diploid bone precursor cells. However, in higher vertebrates, platelets are produced by a different mechanism whose evolutionary advantage is unclear. Enucleate platelets are generated from bone marrow megakaryocytes that have a number of unique properties.
In humans, megakaryocytes normally account for approximately 0.05% to 0.1% of all nucleated bone marrow cells. Their number increases as the demand for platelets rises. In contrast to the erythrocyte, which has a diameter of 7 to 8 microns and a volume of 85 to 100 fL, megakaryocytes have an average diameter of 20 to 25 microns and a volume of 4700 ± 100 fL. Some of the largest megakaryocytes have diameters of 50 to 60 microns and volumes of 65,000 to 100,000 fL.
Each megakaryocyte produces a total of 1000 to 3000 platelets. Although it has long been assumed that larger megakaryocytes make more platelets, this has never been conclusively demonstrated.
Mature megakaryocytes are invariably polyploid and contain from two (4N) to 32 (64N) times the normal diploid amount of DNA; the mean value is 16N in humans. This polyploidy appears to result in functional gene amplification, perhaps to increase protein synthesis in parallel with megakaryocyte enlargement. Few other cells are normally polyploid (eg, occasional hepatocytes and macrophages have 4N or 8N DNA content).
Unlike the polyploid hepatocytes and macrophages, whose DNA is contained in multiple separate nuclei, the DNA in the megakaryocytes is contained within one highly lobulated nuclear envelope in which each lobule represents one diploid amount (2N) of DNA. This is the result of a process referred to as endomitosis.]
What can occur when a patient is placed on Coumadin without being heparinized first?
Warfarin-induced skin necrosis from relative hyperthrombotic state
[This occurs because of short half-life of protein C and S, which are first to decrease compared with the procoagulation factors]
[UpToDate: Warfarin-induced skin necrosis is a complication of warfarin therapy in which the patient develops demarcated areas of purpura and necrosis due to vascular occlusion. The appearance may be similar to that of neonatal purpura fulminans and may affect one or more areas of skin including the extremities, breasts, trunk, or penis.
The mechanism of warfarin-induced skin necrosis involves a transient hypercoagulable state during initial warfarin administration that in turn leads to vascular occlusion and tissue infarction followed by extravasation of blood.
The half-lives vary among the vitamin K-dependent coagulation factors (factors II, VII, IX, and X) and natural anticoagulants (protein S and protein C), and as a result, the factors with the shorter half-lives (half-lives for factor VII and protein C of 8 and 14 hours, respectively) are depleted more rapidly than the others. Laboratory studies of thrombin generation using an assay for the activation of prothrombin using the generation of fragment F1+2 have suggested that effects on protein C (ie, a procoagulant effect) predominate over effects on factor VII in vivo.]
What is the appropriate treatment for a patient with 1 prior DVT who develops a postoperative DVT?
Warfarin for 1 year
[UpToDate: Most patients with a first episode of venous thromboembolism (VTE; proximal deep venous thrombosis [DVT] and/or pulmonary embolus [PE]) are anticoagulated for a finite period of 3 to 12 months. Select patients benefit from indefinite anticoagulation which is administered with the primary goal of reducing the lifetime risk of recurrent thrombosis and VTE-associated death.
The decision to anticoagulate indefinitely should be individualized and based upon an estimate of the risk of recurrence and bleeding in the context of the patient’s values and preferences. In general, the following applies.
For most patients with a first episode of unprovoked proximal DVT, unprovoked symptomatic PE, or active cancer in whom the risk of bleeding is low to moderate, we suggest indefinite anticoagulation rather than stopping therapy after 3 to 12 months (Grade 2B). In patients with a recurrent episode of unprovoked VTE, we recommend indefinite anticoagulation rather than stopping therapy after 3 to 12 months (Grade 1B).
Indefinite anticoagulation should not be routinely administered to patients with a provoked episode of VTE with major transient risk factors (eg, surgery, cessation of hormonal therapy) (Grade 1B). We also avoid indefinite anticoagulation in those with a high bleeding risk; however, should the risk for bleeding resolve, indefinite anticoagulation may be reconsidered.
For most patients with recurrent provoked VTE or a first episode of provoked VTE with irreversible, multiple, or minor risk factors, a first episode of unprovoked isolated distal DVT or an unprovoked episode of incidental PE, therapy must be individualized based upon a careful assessment of patient-specific risks of bleeding and thrombosis. There are wide variations in both the recurrence risk and benefit in these populations.]
What normally links GpIb receptors to collagen?
von Willebrand factor (vWF)
Anti-phospholipid antibody syndrome is characterized by antibodies to which 2 phospholipids?
- Cardiolipin
- Lupus anticoagulant
[UpToDate: Although most of the clinical manifestations of APS can occur in other disease populations, in patients with APS, they occur by definition in the context of aPL. aPL are directed against serum proteins bound to anionic phospholipids and may be detected as:
- Lupus anticoagulants (LA)
- Anticardiolipin antibodies
- Antibodies to beta2-glycoprotein I
APS occurs either as a primary condition or in the setting of an underlying systemic autoimmune disease, particularly systemic lupus erythematosus (SLE).]
Which type of von Willebrand’s disease is characterized by a defect in vWF molecule itself leading to vWF not working well?
Type II
[Tx: recombinant factor VIII and vWF, cryoprecipitate]
[UpToDate: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting up to 1% of the population as assessed by random laboratory screening, although only approximately 1% of these individuals are appreciably symptomatic. It is characterized by mutations that lead to a decrease in the level or impairment in the action of von Willebrand factor (VWF). Most cases are transmitted as an autosomal dominant trait that affects males and females equally. There are also acquired forms of VWD that are caused by several different pathophysiologic mechanisms.
Von Willebrand factor (VWF) plays an important role in primary hemostasis by binding to both platelets and endothelial components, forming an adhesive bridge between platelets and vascular subendothelial structures at sites of endothelial injury and between adjacent platelets in areas with high shear. It also contributes to fibrin clot formation by acting as a carrier protein for factor VIII, which has a greatly shortened half-life and abnormally low concentration unless it is bound to VWF.
Type 1 VWD, an autosomal dominant disease, is the most common, accounting for approximately 75% of patients. The clinical presentation of type 1 VWD varies from mild to severe as determined by bleeding symptoms, but some individuals are asymptomatic and detected incidentally in studies investigating a relative for VWD. Type 1 VWD represents a partial quantitative deficiency of von Willebrand factor; many of the mutations remain undefined.
Type 2 VWD contains four subtypes in which VWF is qualitatively abnormal, as demonstrated by VWF multimer patterns, RIPA, and an abnormally low VWF activity to antigen ratio (types 2A, 2B, and 2M), or by other special assays such as a quantitative assay of the patient’s VWF binding capacity for factor VIII (type 2N). Type 2A accounts for approximately 10% to 15% of cases of VWD, and is usually transmitted as an autosomal dominant trait. Affected patients typically present with moderate to moderately severe bleeding. Type 2B VWD accounts for approximately 5% of cases of VWD, and is transmitted as an autosomal dominant trait. Affected patients generally present with moderate or moderately severe bleeding. The abnormal VWF in this disorder has a “gain of function”, binding more readily to the platelet receptor, glycoprotein Ib. The increase in binding of larger multimers to platelet GP Ib results in their loss from the circulation and, in some patients, thrombocytopenia occurs due to clearance or sequestration of the small platelet aggregates that are formed.
Type 3 VWD is a rare disease. Affected patients present with severe bleeding involving both the skin and mucous membrane surfaces (due to decreased VWF) and soft tissues and joints (due to the low concentration of factor VIII). Type 3 VWD is characterized by a marked decrease or absence of detectable VWF due to homozygous or compound heterozygous mutations, some of which result in loss of VWF mRNA expression.]
Which coagulation factor has the shortest half-life?
Factor VII
By what mechanism does Hirudin (Hirulog; from leeches) work?
Irreversible direct thrombin inhibition
[Most potent direct thrombin inhibitor]
[UpToDate: The direct thrombin inhibitors (eg, hirudin, bivalirudin, lepirudin) bind to and inactivate one or more of the active sites on the thrombin molecule.
The prototypic agent of this class, hirudin, is a peptide derived from the saliva of the medicinal leech. Hirudin selectively binds to and inhibits both the fibrinogen recognition and catalytic sites of thrombin. Peptide analogues of hirudin include bivalirudin (previously called hirulog), which also binds to the substrate recognition and catalytic sites of thrombin, and the arginine derivative argatroban, which competitively inhibits the thrombin catalytic site.]
By what mechanism does Bivalrudin work?
Reversible direct thrombin inhibition
[UpToDate: Bivalirudin acts as a specific and reversible direct thrombin inhibitor; it binds to the catalytic and anionic exosite of both circulating and clot-bound thrombin. Catalytic binding site occupation functionally inhibits coagulant effects by preventing thrombin-mediated cleavage of fibrinogen to fibrin monomers, and activation of factors V, VIII, and XIII. Shows linear dose- and concentration-dependent prolongation of ACT, aPTT, PT, and TT.]
Which anticoagulant does not work in patients with antithrombin III deficiency?
Heparin
[UpToDate: In some individuals with hereditary or acquired AT deficiency, anticoagulation with heparin is ineffective and the aPTT cannot be adequately prolonged. This occurs because heparin is an indirect inhibitor of thrombin and factor Xa, and requires adequate levels of circulating AT in order be effective.
Some patients with heparin resistance due to AT deficiency may benefit from AT replacement. This was illustrated in a cohort of nine children with hereditary AT deficiency who were treated with heparin for a thromboembolic event, two required AT replacement therapy for anticoagulation to reach therapeutic levels. AT replacement has also been reported in patients undergoing extracorporeal membrane oxygenation or cardiopulmonary bypass.]
What does the prothrombin complex do?
It forms on platelets and catalyzes the formation of thrombin
How long do the effects of FFP last?
6 hours
[Half-life of factor VII is 4-6 hours]
[UpToDate: Fresh frozen plasma (FFP) is separated from freshly drawn blood by removing the red blood cells, white blood cells, and platelets. It is then frozen for storage and thawed when needed for transfusion. Once it has thawed, the plasma must be transfused within 24 hours or the concentrations of factor V and factor VIII begin to decline. FFP is the most commonly used plasma product, in part because it can ameliorate deficiencies of any of the circulating coagulation factors. FFP needs to be ABO-compatible, but does not require crossmatching or Rh typing.]
Which 5 coagulation factors affect prothrombin time?
- Factor II
- Factor V
- Factor VII
- Factor X
- Fibrinogen
When is cryoprecipitate useful?
In treating patients with von Willebrand’s disease and hemophilia A (Factor VIII deficiency)
[UpToDate: Cryoprecipitate (Cryoprecipitated antihemophilic factor [AHF]; cryo) is the insoluble material that comes out of solution after plasma is frozen and thawed at 4°C (between 1 and 6°C). It is rich in certain plasma proteins, especially fibrinogen.
Cryoprecipitate can only be made from FFP, which has been frozen within eight hours of blood collection; it cannot be made from PF24 (plasma that was frozen within 24 hours of whole blood collection), because the level of factor VIII in PF24 is lower than FFP.
Cryoprecipitate contains most of the fibrinogen (factor I), factor VIII, factor XIII, von Willebrand factor (VWF), and fibronectin derived from one unit of Fresh Frozen Plasma (FFP). Thus, one unit of Cryoprecipitate contains the following proteins in a volume of approximately 5 to 20 mL:
- Fibrinogen – >150 mg of fibrinogen (range: 150 to 250 mg); half-life: 100 to 150 hours
- Factor VIII – >80 international units (range: 80 to 150 units); half-life: 12 hours
- Factor XIII – 50 to 75 units; half-life of 150 to 300 hours
- von Willebrand factor – 100 to 150 units; half-life: 24 hours
Fibronectin is also present, although there is no dosage requirement and the concentration is not measured.]
What does fibrin do?
It links platelets together
What is the appropriate treatment for a patient with no history of DVT who develops a postoperative DVT?
Warfarin for 6 months
[UpToDate: A decision regarding the optimal duration of anticoagulation must take into account the presence or absence of provoking events, risk factors for recurrence and bleeding, and the individual patient’s preferences and values. Although there is agreement on the minimum length of time a patient with a first episode of DVT should be treated - 3 months - the optimal length of time is not known. For most patients with a first episode of DVT (provoked and unprovoked, proximal and distal), anticoagulants should be administered for three months rather than for shorter periods (eg, 4 or 6 weeks). Most experts also agree that extending anticoagulation beyond three months is considered in select populations.]
How many days before surgery should Aspirin be stopped?
7 days
[Patients will have prolonged bleeding time]
[UpToDate: Aspirin acetylates COX-1, causing it to be irreversibly inactivated. Since platelets lack the ability to synthesize significant amounts of protein, inactivation of COX-1 by aspirin blocks thromboxane A2 synthesis for the life of the platelet (ie, approximately 7 days). Platelets that do not synthesize thromboxane A2 normally have impaired stimulation by ADP, epinephrine, arachidonic acid, and low doses of collagen and thrombin, but normal responses to the major platelet agonists, collagen and thrombin. Hence, aspirin is the most commonly used drug for antithrombotic therapy.]
Heparin-induced thrombocytopenia (HIT) causes thrombocytopenia by what mechanism?
Antiplatelet antibodies (IgG PF4 antibody) resulting in platelet destruction
[UpToDate: HIT results from an autoantibody directed against endogenous platelet factor 4 (PF4) in complex with heparin. This antibody activates platelets and can cause catastrophic arterial and venous thrombosis with a mortality rate as high as 20%; although, more recently with improved recognition and early intervention, these rates have been reported as below 2%. In those suspected of having HIT based on clinical grounds, all exposure to heparin should be eliminated immediately and a non-heparin anticoagulant should be administered until a complete diagnosis can be made.]
Which blood storage product contains the highest concentration of vWF-VIII?
Cryoprecipitate
[It also has high levels of fibrinogen]
[UpToDate: Cryoprecipitate (Cryoprecipitated antihemophilic factor [AHF]; cryo) is the insoluble material that comes out of solution after plasma is frozen and thawed at 4°C (between 1 and 6°C). It is rich in certain plasma proteins, especially fibrinogen.
Cryoprecipitate can only be made from FFP, which has been frozen within eight hours of blood collection; it cannot be made from PF24 (plasma that was frozen within 24 hours of whole blood collection), because the level of factor VIII in PF24 is lower than FFP.
Cryoprecipitate contains most of the fibrinogen (factor I), factor VIII, factor XIII, von Willebrand factor (VWF), and fibronectin derived from one unit of Fresh Frozen Plasma (FFP). Thus, one unit of Cryoprecipitate contains the following proteins in a volume of approximately 5 to 20 mL:
Fibrinogen – >150 mg of fibrinogen (range: 150 to 250 mg); half-life: 100 to 150 hours
Factor VIII – >80 international units (range: 80 to 150 units); half-life: 12 hours
Factor XIII – 50 to 75 units; half-life of 150 to 300 hours
von Willebrand factor – 100 to 150 units; half-life: 24 hours
Fibronectin is also present, although there is no dosage requirement and the concentration is not measured.]
How does Thromboxane (TXA2) increase platelet aggregation and promote vasoconstriction?
It triggers release of calcium in platelets which exposes GPIIb/IIIa receptor and causes platelet-platelet binding
[UpToDate: Thromboxane A2 is produced from arachidonate in platelets by the aspirin-sensitive cyclooxygenase (COX) pathway. Once formed, thromboxane A2 can diffuse across the plasma membrane and activate other platelets via a G alpha-subclass q-coupled receptor known as the thromboxane receptor (also called thromboxane A2 receptor or prostanoid TP receptor). Thromboxane A2, like ADP, amplifies the initial signal for platelet activation, thereby helping to stimulate additional platelets. This process is effective locally, and is limited by the brief half-life of thromboxane A2. This helps to confine the spread of platelet activation to the original area of injury.
Of note, platelets only express COX-1. Therefore, aspirin and other non-selective COX inhibitors block platelet activation; in contrast, selective COX-2 inhibitors should not do so.]
What is the role of Protein S in anticoagulation?
It is a protein C cofactor
[UpToDate: Protein S is named for Seattle, Washington, where it was originally discovered and purified. Protein S is a vitamin K-dependent glycoprotein, but it is not a zymogen of a serine protease enzyme. It serves as a cofactor for activated protein C, which inactivates procoagulant factors Va and VIIIa, reducing thrombin generation. Protein S also serves as a cofactor for activated protein C in enhancing fibrinolysis and can directly inhibit prothrombin activation via interactions with other coagulation factors.
Protein S deficiency impairs this normal control mechanism, increasing the risk of thrombosis.
Protein S is synthesized by hepatocytes, endothelial cells, and megakaryocytes. It undergoes vitamin K-dependent gamma-carboxylation, which is required for its activity.]
What is the treatment of a stable patient with a pulmonary embolism?
Heparin or suction catheter-based intervention
[Thrombolytics have not shown an improvement in survival]
[UpToDate: We suggest the following approach for most hemodynamically stable (ie, normotensive) patients with minor/low-risk PE:
- For those in whom the risk of bleeding is low, anticoagulant therapy is indicated.
- For those who have contraindications to anticoagulation or have an unacceptably high bleeding risk, placement of an inferior vena cava (IVC) filter should be performed.
- For those in whom the risk of bleeding is moderate or high, therapy should be individualized according to the assessed risk-benefit ratio and values and preferences of the patient. As an example, a patient >75 years who is at risk of falling is not an ideal candidate for anticoagulation; anticoagulation may be considered if a vena cava filter cannot be placed (eg, inability to access the IVC due to extensive thrombus or tumor).
- For most hemodynamically stable patients, we recommend against thrombolytic therapy (eg, low risk patients).
For hemodynamically stable (ie, normotensive) patients with intermediate-risk/submassive PE who are anticoagulated, should be monitored closely for deterioration. Thrombolysis and/or catheter-based therapies may be considered on a case-by-case basis when the benefits are assessed by the clinician to outweigh the risk of hemorrhage. Examples of such patients include those who have a large clot burden, severe RV enlargement/dysfunction, high oxygen requirement, and/or are severely tachycardic.]
How are the PT and PTT affected in Hemophilia B?
- Prothrombin time (PT) is normal
- Partial thromboplastin time (PTT) is prolonged
[UpToDate: Hemophilia is characterized by a prolonged activated partial thromboplastin time (aPTT). However, the aPTT may be normal in individuals with milder factor deficiencies (eg, factor activity level >15%).
In patients with hemophilia, the aPTT corrects in mixing studies, unless an inhibitor is present, which only applies to individuals who have received factor infusions or who have another autoantibody such as a lupus anticoagulant or an acquired factor inhibitor. Thus, mixing studies that do not show correction of a prolonged aPTT suggest an alternative diagnosis such as an acquired factor inhibitor.
The platelet count and prothrombin time (PT) are normal in hemophilia. Thrombocytopenia and/or prolonged PT suggest another diagnosis instead of (or in addition to) hemophilia.
Measurement of the factor activity level (factor VIII in hemophilia A; factor IX in hemophilia B) shows a reduced level compared with normal controls (generally <40%).
The plasma von Willebrand factor antigen (VWF:Ag) is normal in hemophilia. If VWF:Ag is reduced, this suggests the possibility of von Willebrand disease (VWD) rather than (or in addition to) hemophilia.]
What are the 7 minor (but not absolute) contraindications to thrombolytic therapy?
- Minor surgery
- Recent CPR
- Atrial fibrillation with mitral valve disease
- Bacterial endocarditis
- Hemostatic defects (IE renal or liver disease)
- Diabetic hemorrhagic retinopathy
- Pregnancy
[UpToDate: In every patient in whom thrombolysis is contemplated, the risk of bleeding should always be considered. We believe that the importance of the contraindication depends on the strength of the indication. As an example, a contraindication is of more concern if the indication for systemic thrombolytic therapy is RV dyskinesis, than if the indication is shock.
Absolute or major contraindications to systemic thrombolytic therapy in acute PE include an intracranial neoplasm, recent (ie, <2 months) intracranial or spinal surgery or trauma, history of a hemorrhagic stroke, active bleeding or bleeding diathesis, or nonhemorrhagic stroke within the previous three months. Relative contraindications include severe uncontrolled hypertension (ie, systolic blood pressure >200 mmHg or diastolic blood pressure >110 mmHg), nonhemorrhagic stroke older than three months, surgery within the previous 10 days, pregnancy, and others. Thrombolytic therapy may cause moderate bleeding in menstruating women, but it has rarely been associated with major hemorrhage. Therefore, menstruation is not a contraindication to thrombolytic therapy.
As an alternative to thrombolytic therapy, catheter or surgical embolectomy may be warranted if the necessary resources and expertise are available. The decision of whether to pursue one of these approaches should be based on local expertise. Catheter and surgical embolectomy are discussed in detail separately.]
What are the 4 indications for a Greenfield filter (IVC filter)?
- Contraindication to anticoagulation
- Documented PE while on anticoagulation
- Free-floating IVC, ilio-femoral, or deep femoral DVT
- Recent pulmonary embolectomy
[UpToDate: The primary indication for inferior vena cava (IVC) filter placement is when anticoagulation is contraindicated and when recurrent PE occurs despite therapeutic anticoagulation. However, it may be appropriate as an adjunct to anticoagulation in patients in whom another embolic event would be poorly tolerated (eg, poor cardiopulmonary reserve, or severe hemodynamic or respiratory compromise), although clinical data are lacking. Filters are not routinely placed as an adjunct in patients with PE.
Filter placement is also sometimes used in patients with a high risk of recurrence in whom it is anticipated that anticoagulation may need to be discontinued because of bleeding. Examples include patients at moderate risk of bleeding who cannot receive fresh frozen plasma or red cells (eg, due to religious preference), and patients with metastatic malignancy who are at a high risk for both recurrence and bleeding.
Although filters are not routinely placed as an adjunct in patients with PE, some experts place them in patients at risk of decompensation due to cardiorespiratory compromise. We agree that the adjunctive use of filters should not be routine but placement may be individualized and should take into consideration the risk of recurrence and bleeding, patient preferences, institutional expertise, medical morbidities, and surgical complications.]
Which medication acts by inhibiting the ADP receptor on platelet cell membranes.
Clopidogrel (Plavix)
[Irreversibly inhibits the P2Y12 subtype of ADP receptor, which is important in activation of platelets and eventual cross-linking by fibrin]
[UpToDate: Clopidogrel is a thienopyridine that inhibits ADP-dependent platelet aggregation.
The CAPRIE trial randomly assigned 19,185 patients with recent stroke, myocardial infarction (MI), or symptomatic peripheral artery disease (divided roughly equally between these three enrolling diseases) to treatment with aspirin (325 mg) or clopidogrel (75 mg). The primary end point, a composite outcome of stroke, MI, or vascular death, was significantly reduced with clopidogrel treatment compared with aspirin treatment (5.3% vs 5.8% annually, relative risk reduction 8.7%, 95% CI 0.3%-16.5%).
The benefit of clopidogrel over aspirin in the CAPRIE trial varied based on enrolling disease. Most of the benefit was observed in patients with peripheral artery disease, and the difference in composite outcome between clopidogrel and aspirin treatment in patients with recent stroke and myocardial infarction was not significant. However, the strength of these observations is limited, since they are based on subgroup analyses.
Polymorphisms in the hepatic enzymes involved in the metabolism of clopidogrel (eg, CYP1A2, CYP3A4, CYP2C19) or within the platelet P2Y12 receptor may affect the ability of clopidogrel to inhibit platelet aggregation. However, there are no convincing prospective data to support routine testing for clopidogrel resistance with in vitro tests of platelet function or genotyping in patients with cardiovascular disease, particularly for those with a history of stroke or transient ischemic attack (TIA). A 2010 clinical alert from the American College of Cardiology Foundation and the American Heart Association noted that adherence to existing guidelines for the use of antiplatelet therapy should remain the basis for therapy, and further that there is insufficient evidence to recommend routine platelet function testing or genetic testing for clopidogrel.
The side effect profile of clopidogrel is favorable compared with aspirin, with a slightly higher frequency of rash and diarrhea, but a slightly lower frequency of gastric upset or gastrointestinal bleeding. Unlike its close relative ticlopidine, severe neutropenia is not seen more frequently with clopidogrel than with aspirin.]
What is the inheritance pattern of von Willebrand’s disease?
- Types I and II are autosomal dominant
- Type III is autosomal recessive
[UpToDate: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting up to 1% of the population as assessed by random laboratory screening, although only approximately 1% of these individuals are appreciably symptomatic. It is characterized by mutations that lead to a decrease in the level or impairment in the action of von Willebrand factor (VWF). Most cases are transmitted as an autosomal dominant trait that affects males and females equally. There are also acquired forms of VWD that are caused by several different pathophysiologic mechanisms.
Von Willebrand factor (VWF) plays an important role in primary hemostasis by binding to both platelets and endothelial components, forming an adhesive bridge between platelets and vascular subendothelial structures at sites of endothelial injury and between adjacent platelets in areas with high shear. It also contributes to fibrin clot formation by acting as a carrier protein for factor VIII, which has a greatly shortened half-life and abnormally low concentration unless it is bound to VWF.
Type 1 VWD, an autosomal dominant disease, is the most common, accounting for approximately 75% of patients. The clinical presentation of type 1 VWD varies from mild to severe as determined by bleeding symptoms, but some individuals are asymptomatic and detected incidentally in studies investigating a relative for VWD. Type 1 VWD represents a partial quantitative deficiency of von Willebrand factor; many of the mutations remain undefined.
Type 2 VWD contains four subtypes in which VWF is qualitatively abnormal, as demonstrated by VWF multimer patterns, RIPA, and an abnormally low VWF activity to antigen ratio (types 2A, 2B, and 2M), or by other special assays such as a quantitative assay of the patient’s VWF binding capacity for factor VIII (type 2N). Type 2A accounts for approximately 10% to 15% of cases of VWD, and is usually transmitted as an autosomal dominant trait. Affected patients typically present with moderate to moderately severe bleeding. Type 2B VWD accounts for approximately 5% of cases of VWD, and is transmitted as an autosomal dominant trait. Affected patients generally present with moderate or moderately severe bleeding. The abnormal VWF in this disorder has a “gain of function”, binding more readily to the platelet receptor, glycoprotein Ib. The increase in binding of larger multimers to platelet GP Ib results in their loss from the circulation and, in some patients, thrombocytopenia occurs due to clearance or sequestration of the small platelet aggregates that are formed.
Type 3 VWD is a rare disease. Affected patients present with severe bleeding involving both the skin and mucous membrane surfaces (due to decreased VWF) and soft tissues and joints (due to the low concentration of factor VIII). Type 3 VWD is characterized by a marked decrease or absence of detectable VWF due to homozygous or compound heterozygous mutations, some of which result in loss of VWF mRNA expression.]
Which surface receptor is involved in binding platelets to collagen during formation of a platelet plug?
Gp1b receptor
By what mechanism does Argatroban work?
Reversible direct thrombin inhibition
[Used in patients with HITT]
[UpToDate: A direct, highly-selective thrombin inhibitor. Reversibly binds to the active thrombin site of free and clot-associated thrombin. Inhibits fibrin formation; activation of coagulation factors V, VIII, and XIII; activation of protein C; and platelet aggregation.]
Partial thromboplastin time (PTT) measures most coagulation factors except for which 2?
- Factor VII
- Factor XIII
[UpToDate: The activated partial thromboplastin time (aPTT, PTT) measures the time it takes plasma to clot when exposed to substances that activate the contact factors, which assesses the intrinsic and common pathways of coagulation.
The aPTT test is performed by recalcifying citrated plasma in the presence of a thromboplastic material that does not have tissue factor activity (hence the term partial thromboplastin) and a negatively charged substance (eg, celite, kaolin [aluminum silicate], silica), which results in contact factor activation, thereby initiating coagulation via the intrinsic clotting pathway. The thromboplastic material provides a source of phospholipids.
The normal range for the aPTT varies by laboratory and reagent instrument combination, and local institutional ranges should be used. In most laboratories, the normal range is approximately 25 to 35 seconds.]
How long does it take FFP to have an effect on coagulation?
Effect is immediate
Prostacyclin (PGI2) is released from the endothelium for what purpose?
It decreases platelet aggregation and promotes vasodilation
[It is antagonistic to TXA2]
[UpToDate: Intact endothelial cells in proximity to disrupted endothelium release arachidonic acid from cell membrane phospholipids by phospholipase A2. The enzyme cyclooxygenase-1 (COX-1 or prostaglandin endoperoxide H synthase-1) converts arachidonic acid into thromboxane A2 (TxA2) in platelets, while prostacyclin (PGI2), a dominant product of the endothelium, appears to largely derive from COX-2, the production of which is induced by laminar blood flow under physiologic conditions.
TxA2 is a potent stimulator of platelet aggregation and produces vasoconstriction, while PGI2, via activation of adenylate cyclase, blocks platelet aggregation and antagonizes TxA2-mediated vasoconstriction.
- Low dose aspirin irreversibly acetylates and inhibits COX-1 and only weakly inhibits COX-2. Since platelets cannot make new COX-1, the inhibition of TxA2 is permanent for the life of the platelet.
- In comparison, endothelial cells can make new COX-1 as well as COX-2 and higher doses of aspirin are required for inhibition of PGI2 production.
This distinction underlies the hypothesized mechanism for the benefit of low-dose aspirin in cardiovascular disease, as well as the increased cardiac toxicity of the selective COX-2 inhibitors.]
What is the extrinsic pathway of coagulation?
- Tissue factor (injured cells)
- Factor VII -> Activated Factor X
- Factor Xa + Factor Va -> convert Prothrombin to Thrombin
- Thrombin -> converts Fibrinogen to Fibrin
What is the treatment for heparin-induced thrombocytopenia (HIT)?
Stop heparin and start argatroban (direct thrombin inhibitor) to anticoagulate
[UpToDate: Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of exposure to heparin (ie, unfractionated heparin, low molecular weight [LMW] heparin) that occurs in up to 5% of patients exposed, regardless of the dose, schedule, or route of administration. HIT results from an autoantibody directed against platelet factor 4 (PF4) in complex with heparin. HIT antibodies activate platelets and can cause catastrophic arterial and venous thrombosis, with a mortality rate as high as 20%, although with improved recognition and early intervention, mortality rates below 2% have been reported.
For patients with a presumptive clinical diagnosis heparin-induced thrombocytopenia (HIT) or a confirmed diagnosis of HIT based on HIT antibody testing, we recommend immediate anticoagulation with a non-heparin anticoagulant (eg, argatroban, danaparoid, fondaparinux, bivalirudin) rather than discontinuation of heparin alone, unless there is a strong contraindication (eg, bleeding, high bleeding risk). This applies to all patients, regardless of the initial indication for and dose of heparin (eg, full-dose anticoagulation, heparin flushes).
Patients who develop HIT will have an ongoing need for anticoagulation due to the risk of thrombosis associated with HIT, and possibly also for the condition for which heparin was administered originally. Heparin cessation alone is often not sufficient since patients with HIT remain at risk for subsequent thrombosis, especially during the period when the HIT antibody continues to activate platelets.
For patients with normal renal and hepatic function, any of the alternative anticoagulants can be used, and the choice can be based on availability and institutional and/or clinician preference. We generally use intravenous argatroban infusion; fondaparinux can be used if there is a need for a subcutaneous agent.]
What is the treatment for Factor V Leiden mutation?
Heparin or Warfarin
[UpToDate: Most individuals who are heterozygous for the FVL mutation without a personal history of thrombosis are unlikely to be aware they have a genetic defect. However, some individuals may be tested inadvertently or become aware of their FVL mutation status from genome sequencing.
For these individuals, our general approach is to treat them similarly to the general population. We do not administer prophylactic anticoagulants or antiplatelet agents unless there is a clinical indication such as an acute medical illness or surgery for which routine thromboprophylaxis is indicated. We also do not perform screening for other inherited thrombophilias in these asymptomatic individuals as a way to estimate their risk of VTE, because there are no data to support this practice.
Individuals who are homozygous or pseudohomozygous for the FVL mutation, as well as those who are heterozygous for FVL and another thrombophilic mutation, are at greater risk for VTE than FVL heterozygotes. There are no data that show a benefit of long-term anticoagulation in these patients, and we generally do not anticoagulate them. However, anticoagulation might be appropriate for such an asymptomatic individual who places an especially high value on preventing thrombosis (eg, due to massive, unprovoked pulmonary embolism in a family member).
Individuals with the FVL mutation who undergo surgery should generally be treated as a high-risk group and receive prophylactic anticoagulation to reduce the risk of VTE (eg, with low molecular weight heparin, fondaparinux, or unfractionated heparin); this is especially true for patients with a prior personal history of VTE. FVL homozygotes undergoing surgery should be managed as a higher risk group in the perioperative setting, even in the absence of a personal thrombosis history.
The initial treatment of venous thromboembolism (VTE) in individuals with the FVL mutation is the same as that of the general population, with anticoagulation unless there is a contraindication. The presence of the FVL mutation does not influence the choice of anticoagulant.
The duration of anticoagulation depends on the risk of recurrent VTE, which is similar in FVL heterozygotes to VTE recurrence risk in the general population; similar to the general population, the duration of anticoagulation in these individuals is an individualized decision. Similar to the general population, we are more likely to advise indefinite anticoagulation in those whose VTE is unprovoked, life-threatening, at an unusual site such as the mesenteric or portal vein, or more than 1 episode of VTE. For individuals with heterozygous FVL mutation and a single provoked VTE, indefinite anticoagulation generally is not required after an initial 3 to 6 months of treatment.]
Which procoagulant agent works by preventing fibrinolysis by inhibiting plasmin?
Aminocaproic acid (Amicar)
[UpToDate: Tranexamic acid and epsilon-aminocaproic acid are lysine analogues that bind to the kringle domains of plasminogen and disrupt interactions between plasminogen (and plasmin) and lysine residues within fibrin. Tranexamic acid binds plasminogen and plasmin more avidly than epsilon-aminocaproic acid does, and may produce a more potent anti-hemorrhagic effect.
These antifibrinolytic agents have been recommended for use in settings where fibrinolysis is prominent, such as when tissues with high fibrinolytic activity are involved (eg, oropharynx, prostate, endometrium) or in selected patients with hemorrhagic shock who have an elevated D-dimer and depleted fibrinogen.]
Which type of von Willebrand’s disease is characterized by a complete deficiency in vWF?
Type III
[Tx: Recombinant factor VIII and vWF, cryoprecipitate. DDAVP will not work]
[UpToDate: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting up to 1% of the population as assessed by random laboratory screening, although only approximately 1% of these individuals are appreciably symptomatic. It is characterized by mutations that lead to a decrease in the level or impairment in the action of von Willebrand factor (VWF). Most cases are transmitted as an autosomal dominant trait that affects males and females equally. There are also acquired forms of VWD that are caused by several different pathophysiologic mechanisms.
Von Willebrand factor (VWF) plays an important role in primary hemostasis by binding to both platelets and endothelial components, forming an adhesive bridge between platelets and vascular subendothelial structures at sites of endothelial injury and between adjacent platelets in areas with high shear. It also contributes to fibrin clot formation by acting as a carrier protein for factor VIII, which has a greatly shortened half-life and abnormally low concentration unless it is bound to VWF.
Type 1 VWD, an autosomal dominant disease, is the most common, accounting for approximately 75% of patients. The clinical presentation of type 1 VWD varies from mild to severe as determined by bleeding symptoms, but some individuals are asymptomatic and detected incidentally in studies investigating a relative for VWD. Type 1 VWD represents a partial quantitative deficiency of von Willebrand factor; many of the mutations remain undefined.
Type 2 VWD contains four subtypes in which VWF is qualitatively abnormal, as demonstrated by VWF multimer patterns, RIPA, and an abnormally low VWF activity to antigen ratio (types 2A, 2B, and 2M), or by other special assays such as a quantitative assay of the patient’s VWF binding capacity for factor VIII (type 2N). Type 2A accounts for approximately 10% to 15% of cases of VWD, and is usually transmitted as an autosomal dominant trait. Affected patients typically present with moderate to moderately severe bleeding. Type 2B VWD accounts for approximately 5% of cases of VWD, and is transmitted as an autosomal dominant trait. Affected patients generally present with moderate or moderately severe bleeding. The abnormal VWF in this disorder has a “gain of function”, binding more readily to the platelet receptor, glycoprotein Ib. The increase in binding of larger multimers to platelet GP Ib results in their loss from the circulation and, in some patients, thrombocytopenia occurs due to clearance or sequestration of the small platelet aggregates that are formed.
Type 3 VWD is a rare disease. Affected patients present with severe bleeding involving both the skin and mucous membrane surfaces (due to decreased VWF) and soft tissues and joints (due to the low concentration of factor VIII). Type 3 VWD is characterized by a marked decrease or absence of detectable VWF due to homozygous or compound heterozygous mutations, some of which result in loss of VWF mRNA expression.]
What is the most common congenital bleeding disorder?
Von Willebrand’s disease
[UpToDate: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting up to 1% of the population as assessed by random laboratory screening, although only approximately 1% of these individuals are appreciably symptomatic. It is characterized by mutations that lead to a decrease in the level or impairment in the action of von Willebrand factor (VWF). Most cases are transmitted as an autosomal dominant trait that affects males and females equally. There are also acquired forms of VWD that are caused by several different pathophysiologic mechanisms.]
What is the treatment for hyperhomocysteinemia?
Folic acid and B12
[UpToDate: The majority of hyperhomocysteinemia is caused by low levels of folate and vitamin B12 in patients with or without the thermolabile variant of MTHFR. Correcting nutritional inadequacy of folic acid, vitamin B12, and choline (betaine) will lower homocysteine levels. A diet rich in fruits, vegetables, and low-fat dairy products and low in saturated and total fat also can lower fasting serum homocysteine.
In patients who are treated beyond diet, the treatment varies with the underlying cause, but generally involves vitamin supplementation with folic acid, vitamin B12, and vitamin B6.]
What links GpIb receptor on platelets to collagen?
von Willebrand factor (vWF)
What is the treatment for antithrombin III deficiency?
Recombinant AT-III concentrate or FFP followed by Heparin and then Warfarin
[FFP has the highest concentration of AT-III]
[UpToDate: Anticoagulation is appropriate for individuals with hereditary AT deficiency who develop a thromboembolic event. In addition, prophylactic anticoagulation may be used in certain high-risk setting such as pregnancy or surgery.
AT replacement has been used in patients with hereditary AT deficiency who develop an acute venous thromboembolism (VTE), especially individuals with an unusually severe thrombosis, recurrent thrombosis despite adequate anticoagulation, or heparin resistance (ie, patients receiving heparin for whom a therapeutic aPTT cannot be achieved despite the administration of very large doses of unfractionated heparin). Alternatively, a direct thrombin inhibitor such as argatroban, which does not require AT function, may be used. Decisions regarding therapy are individualized depending on whether the patient is anticoagulated at the time the VTE develops (which would favor use of AT replacement) and the initial aPTT response to heparin therapy (heparin resistance would favor AT replacement; heparin resistance with AT unavailable would favor switching to a non-heparin anticoagulant such as argatroban).
Which 4 contributors in the coagulation cascade are degraded by Plasmin?
- Factor V
- Factor VIII
- Fibrinogen
- Fibrin
[This leads to a loose platelet plug]
[UpToDate: Plasminogen, the precursor molecule to plasmin, binds fibrin and tissue plasminogen activator (tPA). This ternary complex leads to conversion of the proenzyme plasminogen to active, proteolytic plasmin.
Plasmin has broad substrate specificity and, in addition to fibrin, cleaves fibrinogen and a variety of plasma proteins and clotting factors. Plasmin cleaves the polymerized fibrin strand at multiple sites and releases fibrin degradation products (FDPs). One of the major FDPs is D-dimer, which consists of two D domains from adjacent fibrin monomers that have been crosslinked by activated factor XIII. Plasmin also cleaves factor XIIIa, but not factor XIII, leading to reduced fibrin crosslinking.
The plasminogen/plasminogen-activator system is complex, paralleling the coagulation cascade. Plasmin activity is regulated by vascular endothelial cells that secrete both serine protease plasminogen activators (tissue-type plasminogen activator and urokinase-type plasminogen activator) and plasminogen activator inhibitors (PAI-1 and PAI-2).]
What are the 6 major (but not absolute) contraindications to thrombolytic therapy?
- Recent (less than 10 days) surgery, organ biopsy, or obstetric delivery
- Left heart thrombus
- Active peptic ulcer
- Recent major trauma
- Uncontrolled hypertension
- Recent eye surgery
[UpToDate: In every patient in whom thrombolysis is contemplated, the risk of bleeding should always be considered. We believe that the importance of the contraindication depends on the strength of the indication. As an example, a contraindication is of more concern if the indication for systemic thrombolytic therapy is RV dyskinesis, than if the indication is shock.
Absolute or major contraindications to systemic thrombolytic therapy in acute PE include an intracranial neoplasm, recent (ie, <2 months) intracranial or spinal surgery or trauma, history of a hemorrhagic stroke, active bleeding or bleeding diathesis, or nonhemorrhagic stroke within the previous three months. Relative contraindications include severe uncontrolled hypertension (ie, systolic blood pressure >200 mmHg or diastolic blood pressure >110 mmHg), nonhemorrhagic stroke older than three months, surgery within the previous 10 days, pregnancy, and others. Thrombolytic therapy may cause moderate bleeding in menstruating women, but it has rarely been associated with major hemorrhage. Therefore, menstruation is not a contraindication to thrombolytic therapy.
As an alternative to thrombolytic therapy, catheter or surgical embolectomy may be warranted if the necessary resources and expertise are available. The decision of whether to pursue one of these approaches should be based on local expertise. Catheter and surgical embolectomy are discussed in detail separately.]
