Bleeding Diatheses

Bleeding Diatheses

Bleeding Diatheses Part 1

What is a difference between primary and secondary prophylaxis for hemophilia?

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Primary before your first bleeding event
Secondary after your first bleeding of that

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What is the recommendation for prophylaxis for severe hemophilia in the United States?

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After the first or second bleed

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What is the difference in dosing /frequency /response to hemophilia A versus B?

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Hemophilia A factor VIII is 1 unit per kilogram increase is about 2% and can be repeated every 8-12
hours
Hemophilia B factor IX 1 unit per kilogram is a about 1% increase and can be repeated every 12-24 hours

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How much does factor VIII replacement increase the activity level of factor VIII?

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1 unit per kilogram increased by 2% repeat every 8-12 hours

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What can lead to a false negative when a diagnosis is suspicious for hemophilia?

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Mild hemophilia with normal PTT because it is an acute phase reactant

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What anatomic location can newborns have their blood sampled from to rule out hemophilia?

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Umbilical cord

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What are the activity level cut-offs for mild/moderate and severe hemophilia?

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Mild 5-40% moderate 1-5% severe less than 1%

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What are 3 causes of acquired hemophilia?

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Cancer, increasing age, pregnancy

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Which Intron inversion is most common in hemophilia?

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Intron 22 inversion

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How can women acquire hemophilia?

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Nonrandomized chromosome inactivation

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What are the 4 different replacement products with type II and type III von Willebrand disease?

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Humate-P, Alphanate, Koate

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What is the treatment difference between type I, type II and type III von Willebrand disease?

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Type I desmopressin
Type II and type III blood products

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How can you confirm desmopressin efficacy?

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Check ristocetin activity 1-hour post infusion as well as VWF antigen level, factor VIII level 1-hour post and 4-hour post

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What is a treatment for type I von Willebrand disease?

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Desmopressin and Amicar

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What are 3 types of acquired von Willebrand disease?

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Autoantibodies seen with Hashimoto, Von Willebrand factor binding to cancer cells such as Wilms
tumor and lymphoma, high proteolytic activity of high molecular weight multimers under shear stress

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Which 2 types of von Willebrand disease should be sent for genetic testing?

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Type 2N and type 3

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What ristocetin to antigen ratio can distinguish type 2A von Willebrand disease from type I and type III?

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Ristocetin to antigen ratio of approximately 0.5

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When should you be suspicious of von Willebrand disease type 2N?

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Autosomal dominant family history and no response to factor VIII infusions

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How can you confirm type 2B von Willebrand disease?

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LD-RIPA

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What is the pattern for von Willebrand factor ristocetin and von Willebrand antigen for type I von
Willebrand disease?

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Von Willebrand factor ristocetin and von Willebrand factor antigen both 2 standard deviations below
average,also the ristocetin to antigen ratio of approximately 1.0

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What are the confirmatory test besides ristocetin for von Willebrand disease?

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LDRIPA, collagen assay, latex assay, lysis

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Which types of von Willebrand disease can be detected by a multimer assay?

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Type I, type III, type to a and type to be

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Which test is the gold standard for von Willebrand disease?

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Von Willebrand factor ristocetin cofactor assay

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What can occur with factor VIII and von Willebrand factor during an acute bleed?

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Increased 2-5 fold in the acute phase

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When is the PFA-100 useful for von Willebrand disease?

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Only for very very low levels of von Willebrand disease

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Which 2 types of von Willebrand disease can be detected with low factor VIII levels?

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Type III and type 2N

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What are the values of VWF:Ag, VWF:RCoA, FVIII:C for type 3 VWD?

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Von Willebrand antigen: undetectable
Von Willebrand ristocetin: undetectable

Factor VIII: undetectable

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What is inheritance of type III von Willebrand disease?

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Autosomal recessive

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What is the biology of type 2N von Willebrand disease?

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Type Normandie, mutation leading to low factor VIII binding capacity

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What is the difference between type 2B and type 2M von Willebrand disease?

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Type 2B – gain of function mutation with high platelet binding and high clearance
Type 2M loss of function mutation leading to low interaction with platelet receptor and low ristocetin

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Which of the type 2 von Willebrand disease has a deficiency of intermediate and high molecular weight
multimers?

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Type 2A

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What is unique about the blood group type O and Von Willebrand disease?

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25% lower baseline von Willebrand factor levels

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How can you differentiate between type I versus type IC von Willebrand disease?

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In the multimer assay, there is missing heavy multimers

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How do you test to see if Von Willebrand disease is secondary to increased clearance versus decreased
production?

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If von Willebrand factor pro peptide to the von Willebrand factor ratio is greater than 1.0 that is
elevated clearance

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Where are the 2 mechanisms at the cellular level of von Willebrand disease type I?

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Problem with intracellular transport and increased clearance by the liver and kidney

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What is a concentration difference for von Willebrand factor that defines type I?

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Less than 20 international units per deciliter

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What are the 4 types of different von Willebrand disease?

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Type I and type III are quantitative issue
Type II, has 4 subtypes are qualitative issues
Type 2A – high number of large multimers
Type 2B – increased platelet adhesion
Type 2M – von Willebrand factor-dependent platelet infusion
Type 2N – low factor VIII binding

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What are the 2 functions of von Willebrand factor?

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Carry factor VIII and platelet adherence to sub-endothelium

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Where is von Willebrand factor stored?

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Platelets and endothelial cells

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What is the inheritance of von Willebrand disease?

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Autosomal dominant

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What is approved in the European Union for Glanzman’s?

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Recombinant factor VII

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What is the main side effect of recombinant factor VII?

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Thromboses

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What are some treatment options for platelet related bleeding?

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Desmopressin, anti-fibrinolytics, estrogen, recombinant factor VII, tranexamic acid, Amicar

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What is the mechanism of Amicar?

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Lysine analog

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Which bleeding disorder besides VWD can be missed if there is normal PT/PTT?

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Factor XIII, PAI-1, Alpha-2-P

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What are some options to manage bleeding from high INR besides vitamin K?

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FFP, factor VIIa, activated protein C

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How does hemophilia cause increased bleeding?

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low thrombin generation on the platelet surface therefore low thrombin leads to low factor XIII / TAFI
henceresistance to fibrinolysis

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What are the normal values of von Willebrand factor to ristocetin ratio, von Willebrand factor antigen
and ristocetin to antigen ratios?

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Von Willebrand factor 50-200
Von Willebrand factor antigen and 50–200
Ristocetin to antigen less than 0.5-0.70

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What tests can distinguish von Willebrand’s disease type 2M from 2N in von Willebrand disease?

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2M and 2N both have low factor VIII levels and normal multimer assays

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Which tests can assess if there is a fibrinolytic defect in a bleeding patient ?

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Euglobulin clot lysis time, thrombo-elastogram, serum levels for PAI-1, alpha-2 AP, TPA, plasminogen

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What is the normal reference range for the euglobulin clot lysis time ?

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2-6 hours

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How are fibrinolytic pathway defects diagnosed?

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Euglobulin clot lysis time

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What clinical scenario should make you suspicious of a fibrinolytic defect mediated bleed?

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Delayed bleeding, status post surgery and trauma in conjunction with another coagulopathy

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What are the causes of a fibrinolytic pathway defect?

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Liver disease, DIC, status post prostate surgery, antiphospholipid treatment

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Which 2 downstream proteins does tPA diminish?

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PAI-1 and alpha-2–AP

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What are the 2 different available synthetic products for factor XIII deficiency?

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CORIFACT – recombinant factor XIII
RIASTOP – fibrinogen concentrate

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What condition/disease can cause factor XIII deficiency?

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Cardiac bypass and inflammatory bowel disease

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What syndrome / disease can cause a factor II deficiency?

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Antiphospholipid syndrome

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What are the targets of activated protein C?

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Factor V and factor VIII

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On which cell surface does the factor VIII and factor IX complex form?

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Platelet surface

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What mediates the binding of factor VIII and factor IX to the platelet surface?

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Factor Va

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What mediates to binding the factor VIII and factor IX to the platelet surface?

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Factor Va

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What are the 3 natural anticoagulants?

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Protein C, protein S, antithrombin

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What occurs after alpha IIB beta 3 receptor is activated?

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Alpha-2 B beta 3 high outside in signaling and high granular release

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Which surface receptor mediates outside-in signaling?

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Alpha-IIb-Beta-3

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What is the difference between a primary and secondary coagulation defect ?

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Primary – platelets and VWF mediated
Secondary – coagulation factor mediated

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What are the 2 phases of the coagulation cascade?

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Primary: thrombin burst with factor VII + factor X complex converting prothrombin to thrombin
Secondary: thrombin burst with factor VIII + factor IX + platelet complex activating factor X into factor Xa

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How does Amicar work?

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Lysine analogue which blocks the activation of plasminogen to plasma

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When is the only time you would recommend testing the family member with prothrombin 20210?

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If OCP use is planned in a female

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What non-bleeding events can be seen with low fibrinogen levels?

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Miscarriage and thrombosis

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What ALL therapy can suppress fibrinogen levels?

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L-Asparaginase

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If a rare factor is suspected what treatment can be offered?

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Plasma and Amicar

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What are the cut-off levels for increased bleeding with the rare factor deficiencies?

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Factor XI less than 20%
Factor 2, 5, 13, fibrinogen undetectable

Factor VII, X less than 10%

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What is a typical factor XIII deficiency presentation?

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Umbilical stump bleed with or without intracerebral hemorrhage

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What are the rare bleeding disorders?

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Factor II, 7, 5, 10, 13, fibrinogen deficiency

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What genetic defect causes factor V and factor VIII combined deficiency?

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Cargo transport gene MCFD2 and LMAN2

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What can cause factor V deficiency?

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Topical thrombin and cephalosporins

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What causes low factor X levels in amyloidosis?

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Adsorption of factor X onto the surface of the immune complex

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What syndrome can cause low thrombin levels?

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Antiphospholipid syndrome

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What genetic disease causes hypofibrinogenemia?

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Kasabach-Merritt syndrome

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What are 4 causes of acquired rare factor deficiencies?

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warfarin use, liver disease, topical bovine thrombin, amyloidosis leading to low factor X levels

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What is a poor prognostic marker for hemophilia patients?

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Severe hemophilia, + inhibitor, no response to IPI

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How can you treat acquired hemophilias?

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Steroids, cyclophosphamide, rituximab

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What is the risk of using bypass products in acquired hemophilia patients?

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High-risk of bleeding because of advancing age and other comorbidities

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What prophylaxis should be used in positive inhibitor patients with hemophilia prior to surgery?

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recombinant factor VIIa preferred, activated protein C is also an option

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What is the advantage of recombinant factor VIIa versus activated protein C with respect to inhibitors
in hemophilia?

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recombinant factor VII has no factor VIII or factor IX therefore no stimulation leading to
high IPI success

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What 2 proteins in activated protein C drive hemostasis?

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Factor Xa and prothrombin

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What are some typical bypass agents used for high inhibitor factor VIII and factor IX patients?

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Activated protein C and recombinant factor VII

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Which patients should get ITI?

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Hem B because of anaphylaxis and nephrotic syndrome

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What Bethesda unit range is ideal for starting IPI?

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Between 5-10

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What is a long-term management option for Hemophilia A patients with a notable inhibitor for hemophilia?

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ITI

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Which products should be used for severe bleeds in high-inhibitors hemophilia A patients?

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Bypass products factor VII

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What phenomenon is seen with high titer factor VIII inhibitors?

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anamnestic response

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How do you overcome low titer factor VIII inhibitors?

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Increase the dose of replacement products

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What is a definition of low and high titer inhibitors?

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Low titer less than 5 Bethesda units
High titer greater than 5 Bethesda units

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What is a difference between hemophilia A and hemophilia B with respect to inhibitors?

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Hemophilia A 25% of severe patients
Hemophilia B less than 5% of severe patients

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What can you treat mild hemophilia patients with?

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Desmopressin and antifibrinolytics such as amicar and TXA

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What are the doses of musculoskeletal/joint versus limb and life-threatening bleed factor concentrates?

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Musculoskeletal: factor VIII 25 units per kilogram, factor IX 50 units per kilogram, recombinant factor IX
70 units per kilogram
Life-threatening 50, 100, 120 respectively

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Which hemophilia patients should be offered primary prophylaxis?

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Ones with severe bleeds or patients that have had a few moderate fleets

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