Deck 2 Flashcards
Dx for bleeding disorder with an elevated PT that completely corrects with PT mix
Factor VII deficiency—tx with rFVIIa prior to invasive procedures
Why is a negative family history common in ppl with factor VII deficiency?
It is autosomal recessive
Elevated PT/PTT with complete correction and normal thrombin time suggests what?
Common pathways deficiency but NOT fibrinogen. The remaining factors are II, V, and X
What is the treatment for factor II deficiency?
Prothrombin deficiency; tx = PCC
How long to hold DOAC, assuming normal renal function, prior to minor surgery? Major?
2 days prior to minor; 3 days prior to major
Assuming normal renal function, how many days after minor surgery until restarting DOAC? Major surgery?
1 day after for minor, 2 days after for major
Assuming normal renal function, for how many days before and after minor surgery should a DOAC be held? Major?
2 days before minor, restart 1 day after; for major stop 3 days prior and restart 2 days after
Dosing of apixaban and rivaroxaban for extended AC after 6 months of full dose AC
Apixaban 2.5 mg bid
Rivaroxaban 10 mg daily
What is the main difference in MOA of LMWH and fondaparinux?
LMWH inhibits Xa AND IIa (thrombin) by potentiating antithrombin but fondaparinux only inhibits Xa also longer half life (4 vs 18 hr)
How does LMWH inhibit IIa?
By potentiating antithrombin (antithrombin III— nb IIa is thrombin) main effect is on Xa though
For patients on LMWH what is the ideal timing to check anti-Xa level? Therapeutic range?
3-4 hours after injection; 0.6-1.2 U/mL
What is the therapeutic range for twice daily LMWH vs once daily on anti-Xa? When should you check level?
0.6-1.2 for twice daily; 1-2 for once daily; either way should check 3-4 hours after injection
In a patient who cannot be on other anticoagulants other than LMWH who develops recurrent thrombosis on LMWH what is the mgmt?
Increase dose 25-33%
How many points on 4T are considered low risk?
<3 points (<5% probability)
How many points on 4T is intermediate risk for HIT
4-5 points (~14% probability)
How many points on 4T is high risk of HIT?
6-8 (~64% probability)
On the 4T score there are a max of 8 points and 3 general categories- low risk, intermediate risk, and high risk. What are the general probabilities associated with each?
Low risk <5%
Intermediate 14%
High risk 64%
What are the 2 available functional HIT assays?
Serotonin Release Assay (SRA) and heparin-induced platelet activation (HIPA)
What are the 2 parenteral DTIs for HIT?
Argatroban safe in renal impairment
Bivalrudin safe in hepatic impairment (sounds like bilirubin)
What are the clinical criteria for pregnancy comorbidity in APS?
One or more fetal deaths > 10th week gestation
One or more deaths before 34th week due to eclampsia, preeclampsia, or placental insufficiency
Three or more deaths <10th week
If there is concern for PT/INR confounding due lupus anticoagulant what else can be used to monitor warfarin efficacy? Therapeutic range?
Chromogenic Factor X; 20-40%
When might you use a chromogenic factor X assay for warfarin? Therapeutic range?
If concern about nonreliable PT/INR ie due to lupus inhibitor; 20-40%
MC MPN associated with Budd Chiari
Polycythemia Vera
In PNH there is an acquired mutation in which gene?
PIGA (phosphotidylinositol-glycan class A)
Which vitamin K dependent factor has the shortest half life?
FVII
What are the factors inhibited by warfarin and what pathways are they in?
II (common), VII (extrinsic PT), IX (intrinsic PTT), X (common) and then protein C/S
Protein C and its cofactor, protein S, break down what factors
Factor V (common) and factor VIII (intrinsic PTT)
Mgmt of INR > 10 not bleeding
Vitamin K PO, hold next dose
Mgmt of an SVT 5 cm In length or less than 3 cm away from saphenofemoral junction
45 days LMWH
Prothrombin Roman numeral
Factor II
What factors may cause an isolated elevation of PTT that corrects with mixing?
VIII, IX, and XI (Hem A, B, and C) and XII, prekallikrein and HMWK
Suspicion in a pt with baseline moderate hemophilia A with baseline 6% who undergoes surgery and presents a few weeks later with joint bleed and factor <1%
Development of inhibitor in response to factor administration; new level is lower than baseline
Another way FEIBA may show up on an exam as an option for bypassing agents is ______
Activated PCC
For rapid acting factor repletion (not long acting Fc or pegylated) what is the dose of FIX repletion? FVIII?
FIX concentrate is 1u/kg to raise 1%
FVIII is 0.5 u/kg to raise 1%
For subsequent dosing is 1x or 0.5x (desired-actual) but for 100% repletion in severe hemophilia that is assumed to be 100-0
Genetics of FXI def (Hemophilia C)
Autosomal Dominant—usually Ashkenazi Jews
Mgmt of FMHx of VTE with pt who is homozygous prothrombin 20210 gene mutation in pregnancy
Antepartum and postpartum LMWH
Activated C, with its cofactor _____, cleaves which factors?
Protein S— cleave FV (common pathway) and FVIII (intrinsic; PT pathway)
Normally, factors V and VIII are cleaved by _______
Activated Protein C (with its cofactor Protein S)
What is a type I protein C deficiency?
Low protein C activity and low protein C antigen
What is type II protein C deficiency?
Low protein C activity with normal antigen (qualitative defect)
Differentiate type I and II protein C deficiency
Type I low protein C activity and low antigen; Type II low activity and normal antigen
Reversal agent of dabigatran
Idarucizimab
TAFI is converted to TAFIa by ______
Thrombin! It is thrombin activatable fibrinolysis inhibitor
What molecule acts by cleaving C-terminal lysine residues from fibrin fragments and in so doing disrupts recruitment of plasminogen
TAFI (Thrombin Activatable Fibrinolysis Inhibitor)
How does TAFI work?
Cleaves C terminal lysine residues from fibrin fragments and decreases recruitment of plasminogen
Patients with elevated TAFI levels are prone to ______
Thrombosis as TAFI cleaves lysine residues from fibrin so that plasminogen cannot get in there
Dabigatran prevents conversion of ____ to ______
Fibrinogen to fibrin as it is a direct thrombin (IIa) inhibitor
In DIC these are the platelet, PT/PTT goals, and fibrinogen goals
Platelet > 50k, FFP for PTT/PT > 1.5x ULN, fibrinogen > 150
Non eponymous name for trousseau syndrome
Chronic DIC (compensated DIC or low-grade DIC)
What cancer is mostly commonly associated with chronic DIC (Trosseau syndrome)
Pancreatic adenocarcinoma
How can VWF and FVIII help to differentiate liver disease from DIC
Will be low in DIC but preserved in liver failure bc made in endothelium
Inheritance of type I VWD? Type III?
Type I = AD; Type 2 = AR
Decreased high molecular weight multimers implies which type of VWD
2A or 2B —2B will have thrombocytopenia and ⬆️ RIPA but need genetic testing really
Which type 2 VWD has preserved activity to antigen ratio?
2N bc there is normal VWF-Plt function but the FVIII binding site is issue so functionally they are like hemophilia A
A VWF activity:antigen ratio < 0.7 with normal multimers suggests ____
Type IIM VWD
PTT mixing study with partial correction and subsequent prolongation with incubation is absolutely characteristic of ______
Factor VIII inhibitor (Acquired Hemophilia)
What pattern will lupus anticoagulants give on a mixing study?
Inhibitor pattern
What acquired factor inhibitor has been associated with fibrin glues and topical thrombin?
Factor V (common pathway)
A pt with ESLD and fibrinogen of 50 needing paracentesis should be managed how?
Transfuse cryo to fibrinogen > 100
Where is the Factor XIIIA subunit synthesized?
Megakaryocytes so in addition to FVIII and VWF, this too is normal in ESLD
FMHx of thrombocytopenia and leukemia is associated with germline mutations in what 5 genes?
DDX41, ETV6, RUNX1, CEBPA, or ANKRD26
What are the two TPO-RAs for periprocedural thrombocytopenia mgmt in ESLD
Avatrombopag and lusutrombopag
FDA indicated use of lusutrombopag
Treatment of thrombocytopenia in pts with ESLD who are going to have a procedure
FDA indication for avatrombopag
Treatment of thrombocytopenia in chronic liver disease patients requiring procedure
3 FDA approved indications for eltrombopag
ITP with insufficient response to steroids, ivig, or splenectomy
SAA
HCV to raise platelet count before starting antivirals
What TPO-RAs are approved for chronic liver disease needing procedure? HCV before antiviral therapy?
Lusutrombopag and Avatrombopag; Eltrombopag
What drug is the MC cause of DITP
Vancomycin followed by TMP-SMX and piperacillin
Potential rescue treatment for a bleeding ITP refractory to IVIG and steroids?
Anti Rh(D) immune globulin if Rh (+) and still have a spleen
What second line ITP treatment will preclude the use of WinRho in the future?
Splenectomy as it leads to hemolysis in spleen
First consideration for thrombocytosis in pt with hereditary hemorrhagic Telangiectasia? 3 genes
Iron deficiency with secondary thrombocytosis… ENG, ACVRL1, SMAD4
2nd MC driver mutation in ET
CALR (JAK2 V617F > CALR > MPL)
Though this agent can be used upfront in TTP what should be added to recurrent episodes in ppl who only got PLEX+steroids the first time
Rituximab 375 mg/m2 weekly x4
Maximum dose romiplostim
10 ug/kg/week
In theory, functional testing for HIT (SRA or HIPA) is not needed when the ELISA OD is >_____
2 as it is so likely at that point that a negative SRA is likely to be a false positive
If HIT is diagnosed but no clinical evidence of clot what should you do, diagnostically?
4 limb US to look for clot
This disease has mutations in GPIIB/IIIA
Glanzmann Thrombasthenia (fibrinogen receptor issue)
What platelet disorder has severely diminished aggregation for all agonists except ristocetin?
Glanzmann Thrombasthenia GPIIB/IIIA defect (platelet fibrinogen receptor)
Glanzmann Thrombasthenia testing will show lack of aggregation to all agonists except _____
Ristocetin
What is the hemostasic defect in Hermansky Pudlak Syndrome?
Platelet Dense Granule Storage Pool deficiency (transfuse platelets and give DDAVP)…. Pulmonary fibrosis, oculocutaneous albinism, Hispanic
Romiplostim and eltrombopag have response rates of approximately what in 2L ITP?
80%
Is rituximab FDA approved for ITP?
No
How do you manage brain bleed in person on aspirin plavix who is not undergoing surgery?
Antifibrinolytics (aminocaproic acid or tranexamic acid) and NOT platelet transfusions which may actually worsen outcomes
What to suspect in a person who cannot achieve therapeutic PTT on heparin gtt? Mgmt?
Antithrombin deficiency; give FFP or antithrombin concentrate
Mgmt of person with antithrombin deficiency who needs heparin gtt
If cannot get therapeutic PTT then either FFP or antithrombin concentrate
Frequency of ppx FXIII concentrate infusion for FXIII def
Monthly Corifact
DDx for a pt with bleeding disorder who has a normal PT, PTT, and PFA-100
Blood vessel abnormality including collagen vascular disease, FXIII def, or abnormal fibrinolysis
Why is there an increased risk of brain abscess in Hereditary Hemorrhagic Telangiectasia? 3 Genes
Hematogenous Seeding from pulmonary AVM; ACVRL1, ENG, SMAD4
Etiology of prolonged thrombin time that corrects with mixing study
Hypofibrinogenemia
What type of hemophilia is autosomal dominant?
Hemophilia C (Factor XI) Ashkenazi Jews
What coagulation factor is in alpha granules?
Factor V
In addition to the endothelium, where else does VWF come from?
Platelet alpha granules
Where does Platelet Factor 4 (PF4) come from?
Alpha Granules of platelets
What is one of the functions of serotonin from dense granules in platelets?
Vasoconstrictor
What are the two mechanisms of platelet adhesion in primary hemostasis?
GpIb-IX binding to VWF and GPVI binding collagen
When are platelet GpIIb/IIIa receptors exposed on platelets?
When they are activated ie after adhesion they undergo shape change (ie after GPIb/IX binds VWF or GPVI binds collagen)
Why does platelet activation play an important role in coagulation?
They provide an anionic aminophospholipid surface the coag cascade
Classic microthrombocytopenia
Wiskott Aldrich syndrome (WAS)
What may be the hemostatic defect in Chediak Higashi syndrome?
Dense granule deficiency (LYST) similar problem as Hermansky Pudlak
The PFA-100 has blood exposed to a membrane containing what?
Collagen + Epinephrine and then if abnormal Collagen + ADP
Explain the steps in the PFA-100
If collagen/epi time prolonged then go to collagen/ADP… if collagen/epi abnormal but collagen/ADP normal likely aspirin; if both prolonged then possible platelet defect or VWD
What are the 5 agonists used in platelet aggregometry
Collagen, arachidonate, epinephrine, ADP, and ristocetin
Explain the X and Y axis on platelet aggregation
Y axis is light transmission from 0 to 100 so the sample is turbid and as the platelets aggregate more light goes through
How does arachidonate work as an agonist in platelet agg?
It gets converted to thromboxane A2 by cyclooxygenase (COX)
Explain this platelet agg
Only aggregate to ristocetin = classic for Glanzmann—note there is more light transmission at the bottom of Y axis
How does ristocetin work as an agonist in platelet aggregometry?
Causes GP1b-VWF dependent platelet agglutination; hence in Glanzmann where there is no GpIIB/IIIA receptor it is the only thing that works
Explain this platelet agg
Bernard Soulier as there is NO response to ristocetin which causes VWF-GPIb aggregation but in BS there is no GPIb/IX
Lack of a second wave to ADP and epinephrine on platelet agg suggests what defect?
Storage pool disorder (ie Hermansky Pudlak)
What is the next step for this platelet agg?
Lack of second wave to ADP and epinephrine = storage pool defect ➡️ do electron microscopy
A deficiency of GPVI on platelet would lead to lack aggregation to what agonist
Collagen
Flow cytometry for platelet disorders would show lack of which marker in Wiskott Aldrich syndrome?
CD43
What genes are mutated in Glanzmann?
ITGA2B and ITGB3
What disease has mutated NBEAL2?
Gray platelet syndrome
What disease has mutated ITGA2B or ITGB3?
Glanzmann (def GPIIB/IIIA)
Reduced CD43 on platelet flow cytometry is seen in _____. Gene?
Wiskott-Aldrich (small platelets) WASP
In addition to macrothrombocytopenia what would you see on a blood smear for MYH9 related diseases?
Dohle bodies in neutrophils
What is THE major receptor for platelet aggregation?
GpIIB/IIIA
What would be seen on a platelet agg for gray platelet syndrome? Gene?
Absent second wave bc storage pool def; NBEAL2
For pregnancy associated ITP what are first line, second line, and late line options?
First line = steroids/IVIG
Second line = splenectomy (second trimester)
Late line = limited data (azathioprine, TPO-RA—none recommended but have been used)
Mgmt of early pregnancy iron deficiency? Late?
Oral iron; IV Iron (iron sucrose)
The heightened thrombotic risk post partum is traditionally defined as _____ weeks but may extend to a lesser extent to _____ weeks
6 weeks but may be some risk up to 13-15 weeks
Mgmt of HIT in pregnancy
Fondaparinux or danaparoid
Only exception to warfarin contraindication in pregnancy
Mechanical valves
What heritable thrombophilia could be misdiagnosed during pregnancy? What heritable bleeding disorder could be missed?
Protein S deficiency as it drops in pregnancy; VWD bc VWF increases in pregnancy
Definition of post partum hemorrhage
> 1000 mL blood loss or bleeding with SS of hypovolemia ; MC cause is uterine atony (70%)
MC cause of post partum hemorrhage
Uterine Atony (70%)
Young patients with monosomy 7 MDS are likely to have germline mutations in what gene?
GATA2
Roman numeral for thrombin
IIa; II is prothrombin
Alpha thalassemias are seen mostly in what geographic regions?
Western Africa and Southeast Asia
What hemoglobin is hemoglobin barts?
Gamma4 seen in alpha thalassemia
What is HBH?
Beta 4 tetramers, B4 will form Heinz bodies
What is the abnormality in SCD?
Sixth amino acid in Beta globin is changed from glutamate (charged) to valine (hydrophobic)
A beta globin with 6th AA glutamate to valine has
HbS
A patient with beta globin that has 6th AA glutamate to lysine has
HbC
What is the genetic abnormality in Hemoglobin C?
Beta globin 6th AA is glutamate to lysine
What are the 3 main genotypes for Sickle Cell Dz?
SS, SC, and Sickle-B thalassemia
MCHC in HbC dz?
Increased due to dehydration
Hemoglobin E and HbA2 migrate together on what type of electrophoresis?
Alkaline AND Citric (Acidic)
Given choices of HbE, HbA2, and HbC what happens on alkaline gel vs citric agar?
HbE and A2 comigrate on alkaline and acidic agar but C migrates differently on citric agar
Is HbE more like a sickle disorder or a thalassemia?
Like B thalassemia as it decreases B globin synthesis
Hemoglobin E is MC where?
India
Though HbE and HbA2 comigrate on both citric and alkaline agar, how to differentiate?
You would never have a HbA2 as high as would be seen on electrophoresis for HbE dz
Hemoglobin Lepore is in what geographic region?
Balkans
