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Hematology RC Editable > Bleeding disorders > Flashcards

Bleeding disorders Flashcards

1
Q

4 treatment options for IST in an acquired inhibitor other than treating the underlying disease. How to treat if bleeding?

A
  1. Corticosteroids
  2. Rituximab
  3. Cyclophosphamide
  4. Cya

IVIG, PLEX are other options aren’t IST.

Bleeding:

  1. rVIIa (preferred)
  2. FIEBA (II, FVII, FIX and FX) avoid in Hemophilia B b/e it contains F9!)
  3. Porcine FVIII
  4. PCC
  5. TXA

Can’t use FIEBA + TXA 2ry to increased thrombosis risk.

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2
Q

Normal fibrinogen, PT, PTT and bleeding diathesis. Other than platelet disorders, name 2 inherited disorders this could be.

A 
VWD
Factor XIII deficiency
Dysfibrinogenemia
Vessel problem/CTD - Marfan’s, Ehlers-Danlos 
Alpha-2 antiplasmin deficiency
PAI-1 or PAI-2 deficiency
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3
Q

What’s the target of FVIII and VIII:RCo for delivery in a pregnant woman with vWD?

A

vWF:RCo target > 100 IU/dL and continue for 3-5 days post partum

FVIII: >100% and continue for 3-5 days post partum or 5-7 days post c-section

> 50 SAFE for epidural (Most type 1 reach that in pregnancy, may be able to reach in Type 2, avoid in type 3)

Adjuncts: IV TXA and 1000mg TID post-partum, uterine massage, uterotonics (oxy/miso), DDAVP (only if history of good response AND closely monitored for hyponatremia.

Monitor for 3-6 weeks as vWF will drop in 1-2 weeks and bleeding may manifest!

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4
Q

Causes of acquired hemophilia A?

A

Idiopathic (50%)
Postpartum – good prognosis in >90%, but high risk of relapse
Autoimmune – especially SLE, RA
Malignancy - adenoCa, lymphoproliferative (CLL)
Drug induced – antibiotics (penicillin), IFN
Skin disease – pemphigus, epidermolysis bullosa
IBD-UC
Chronic GVHD
HBV/HCV

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5
Q

What feature of cold agglutinins makes them typically asymptomatic?

A
  1. Thermoamplitude: hemolysis is not induced until temperatures reach sub-physiologic levels (ie 4 degrees or 28-31 degrees)
  2. Low titre
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6
Q

What is the antigen target of Donath-Landsteiner antibodies?

A

P antigen

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7
Q

2 causes of false negative Donath-Landsteiner test

A

o Complement depleted serum
o Lab error: plasma not stored at 4 degrees or brought up appropriately to 37 degrees
o Using P negative RBCs for the test
o Using plasma instead of serum (serum has more complement)

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8
Q

What is the most sensitive test to detect AVM in HHT? 1) the brain 2) the lungs 3) the liver

A

Brain: MRI/MRA
Lungs: Bubble/contrast Echocardiogram
Liver: MRA

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9
Q

Elevated PTT, N INR, no bleeding Hx. 4 Causes.

A
  1. Heparin contamination
  2. Factor XII deficiency
  3. Pre-kallikrein, HMW kininogen
  4. Lupus anticoagulant

Others:
Preanalytic variable: Underfilled tube, delay between collection and testing

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10
Q

What are some causes of haemorrhagic disease of the newborn?

A

Due to vitamin K deficiency, with resultant dec in factors II, VII, IX, X, protein S and C by the liver (baby liver does not able to utilize vit K effectively to make clotting factors).

Causes:
1. low vit K stores at birth
2. gut flora is immature → low vit K absorption and
low levels of vit K in the breast milk
3. vit K doesnt’ pass through the placenta well
4. Risk is increased by maternal use of warfarin, anticonvulsants, cephalosporins, anti-Tb drugs.

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11
Q

List 3 physiologic causes for elevated vWF

A
  1. Pregnancy
  2. Estrogen replacement/OCP
  3. Menstrual cycle
  4. Exercise
  5. Older age
  6. Trauma
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12
Q

What are 3 causes of avWD?

A
  1. MPNs
  2. LPDs
  3. IgG-MGUS responds to IVIG
  4. Mechanical Circulation (ex. LVAD)
  5. Hypothyroidism
  6. Uremia
  7. Aortic stenosis
  8. Autoimmune conditions
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13
Q

What are SIX risk factors for the development of inhibitors in hemophilia?

A

Genetic Causes:
Type of mutation (Null, nonsense, intron 22 mutations, large deletions of genetic material in factor gene)
FVIII deficiency > FIX deficiency

Disease related:
Undetectable baseline factor level
Frequent, intensive dosing of factor replacement
Early age at first exposure
Use of recombinant factor products compared to plasma derived
Switching products

Other:
African American
Family history of inhibitor

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14
Q

What type of FVIII product would you recommend to reduce the risk of inhibitor in congenital Hemophilia?

A

Porcine>plasma>recombinant

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15
Q

What factor level can be used to distinguish DIC from liver disease?

A

FVIII, high in liver disease

Consumed in DIC

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16
Q

Hemophilia carrier who is pregnant with an affected child. What advice would you give the OB at the time of delivery re factor replacement and delivery precautions

A
  1. Target FVIII/IX level >100 at time of delivery and 3-7 days post-partum.
  2. recombinant factor replacement> DDAVP given risk of hyponatremia.(even if previous good response)
  3. C-section preferred!
  4. Avoid forceps, vacuum, external cephalic inversion
  5. High risk OB, multi D team
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17
Q

What coagulation factors do not increase in pregnancy?

A

Factors II,V, IX, and XI

All other factors increase in pregnancy.

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18
Q

Patient with congenital hypofibrinogenemia in pregnancy. What is the prophylaxis?

A

if < 0.5 g/L, prophylaxis throughout pregnancy with fib concentrate, initially 50 to 100 mg/kg twice weekly adjusted to maintain fibrinogen activity >1 g/L to achieve a level of 1.5 g/L during labor and for 3 days postpartum.

In 30% of pts with afibrinogenemia, they actually clot and don’t bleed and thus thromboprophylaxis should be considered.

19
Q

Pregnant pt on LMWH, when can it be resumes following vaginal and CS delivery?

A

4 to 6 hours–>vaginal delivery
6 to 12 hours–> CS delivery

If an epidural is in place, prophylactic LMWH should be resumed no sooner than 4 hours after epidural removal, and full dose LMWH no sooner than 24 hours.

20
Q

Mechanism of action of ASA?

A

Inhibits the enzyme cyclooxygenase-1 (COX-1), which is needed to form thromboxane A2 in plts.–>
Thromboxane A2 normally is released from platelet granules upon platelet adhesion/aggregation and serve as an agonist to activate + recruit other platelets to the platelet plug.

*B/e plts do not synthesize new COX and aspirin binds irreversibly to COX-1, full recovery of TXA2 production of the platelet pool after stopping aspirin takes approximately 10 days (ie, the platelets’ life span)

21
Q

How does the PFA-100 work? What are it’s limitations?

A

induces high shear stress by flowing whole blood through an aperture with a membrane coated with collagen and either ADP or epi—> Plts adhere to the collagen-coated surface and aggregate, forming a platelet plug occludes the aperture–> cessation of blood flow.

The time to cessation of flow is recorded as closure time (CT)

Limitations: affected by plt and Hg (inaccurate if either are <100), low sensitivity with mild plt disorders.

22
Q

What are 4 agonists used in platelet aggregometry testing?

A
  1. Collagen
  2. ADP
  3. Epinephrine
  4. Ristocetin
  5. Arachadonic acid
  6. thrombin-related activation peptide.
  7. thromboxane A2 mimetic U46619.
23
Q

Potential side effects of DDAVP used in bleeding disorders?

A
  • vasomotor symptoms–> headache, tachycardia, and facial flushing, hypotension
  • hyponatremia
  • seizures
  • tachyphylaxis with repetitive use
24
Q

MOA of TXA

A

lysine analogue which inhibits plasmin-mediated thrombolysis–> clot stabilization and prevention of early dissolution.

25
Q

What is one concern about treating patients with Glanzmann’s or BSS with a platelet transfusion if bleeding?

A

alloimmunization! Because of the formation of Abs against the absent receptor. Once Abs develop, future platelet transfusions are likely to be ineffective.

26
Q

What are the two location that vwf is produced and released?

A
  1. Megakaryocytes (released from alpha granules of plts)

2. Endothelial cells (released from the Weibel-Paladebodies)

27
Q

What are the 3 roles of vWF in hemostatis?

A

(i) promote platelet adhesion to the exposed subendothelium
(ii) promote platelet aggregation
(iii) serve as a chaperone for FVIII in plasma, protecting it from proteolytic degradation by activated protein C

28
Q

Mechanism of type 1 vWD including type 1c vWD? How does type 1c present clinically?

A

Partial quantitative deficiency of VWF due to impaired secretion and increased clearance (the latter is seen in type 1c).

  • Type 1c- vWFpp>vWF (suggesting inc clearance)–> VWFpp/VWF:Ag ratio usually >3
  • see very large multimers!

Brisk response to DDAVP initially but abrupt drop after 2-4 hrs, so high risk for delayed bleeding!

29
Q

What does RIPA study for and how is it used in vWD testing?

A

Low-dose ristocetin-induced platelet aggregation (LD- RIPA) is used to identify abnormally increased binding of VWF to platelets, as occurs in type 2B and platelet-type VWD.

30
Q

What is platelet type or psuedo-vWD?

A

A rare disorder caused by mutations in platelet GPIb that cause it to bind more avidly to normal VWF.

Dx: Pts plts are tested with a normal exogenous VWF substrate in a ristocetin-induced platelet- agglutination-based mixing study. Enhanced binding confirms the diagnosis

Tx: plt tranfusion (it’s a plt issue so vWF concentrate is not helpful!)

31
Q

5 proposed mechanisms of acquired vWD?

A
  1. Decreased production of VWF (eg, hypothyroidism)
  2. Autoabs against VWF and immune complex formation (eg, SLE, Hashimoto thyroiditis)
  3. Adsorption of VWF to tumor cells (eg, Wilms tumor, LPD)
  4. Drug-mediated proteolysis of HMWM (eg, ciprofloxacin)
  5. Increased proteolysis of HMWM under pathological high-shear-stress conditions (eg, congenital heart disease, AS [Heyde syndrome], ECMO, mechanical valves).
32
Q

What is Vonvendi? (hint:Treatment for vWD)

A

New recombinant vWF (humate and wilate are plasma derived

Upside: as recombinant no risk if viral/bacterial transmission).

Downside: Does not contain FVIII so for first infusion, need concomitant recombinant FVIII. Subsequent doses can give as single agent.

33
Q

Can hemophilia A or B be diagnosed on cord blood of a known carrier mother?

A

Hemophilia A-yes
Hemophilia B- yes, BUT FIX levels are low at birth for all infants and thus must be repeated at 6-12 months, to confirm diagnosis.

34
Q

Define the following terms used in the treatment of hemophilia:

  1. Primary prophylaxis
  2. Secondary prophylaxis
  3. Tertiary prophylaxis
  4. Target joint
  5. on-demand therapy
A
  1. Primary- initiation of regular factor replacement therapy started before or shortly after the first hemarthrosis and before the age of 3.
  2. Secondary- initiated after the second hemarthrosis, but before the presence of joint disease on physical exam or imaging.
  3. Tertiary- after the onset of joint disease seen on exam or imaging studies.
  4. Target joint- 3 or more bleeds during a 6-month period in a joint
  5. on-demand-the use of factor replacement therapy only after bleeding occurs
35
Q

What is “anamnesis” with respect to inhibitors in hemophilia?

A

Patients with high-responding inhibitors may exhibit a decrease in, or an undetectable inhibitor titer with complete withdrawal of, the specific clotting factor. Despite this, with subsequent exposure to the deficient factor, these patients mount a memory response and demonstrate an increase in inhibitor titer in 7 to 10 days after exposure.

The term for stimulation and increase of inhibitor titer is anamnesis.

36
Q

What are 4 factors that predict success with ITI in pts with Hemophilia A and inhibitors?

A

1) historical peak inhibitor titer (< 200 BU/mL)
2) titer at start of therapy (< 10 BU/mL)
3) peak titer after the start of ITI(<100BU/mL)
4) age at initiation (< 8 years)
5) time from inhibitor development to ITI start (< 2 years)

*ITI in factor IX pts can lead to nephrotic syndrome and allergic rxn, even anaphylaxis

37
Q

FV deficiency can be co-inherited with which other factor deficiency? What is the treatment

A

Can be co-inherited with FVIII! (LMAN1 and MCFD2 gene mutations)

TX: FFP and plt. Plt alpha granules are a source of FV.

  • There is no recombinant FV replacement.
38
Q

Suspected acquired Hemophilia A, 3 most useful tests for diagnosis? (hint you already have PTT)

A
  1. Mixing study with PROLONGED INCUBATION
  2. Factor levels (FVIII, FIX, FXI)
  3. Bethesda assay (ie. inhibitor titre)
39
Q

Explain the vWF:RCo assay.

A

Ristocetin cofactor assay uses the patient’s platelet poor plasma (with vWF but no platelets) and adds ristocetin and exogenous formalin-fixed platelets which can passively agglutinate (but not actively aggregate, as they are dead).

  • ristocetin causes von Willebrand factor to bind the platelet receptor glycoprotein Ib (GpIb), so when ristocetin is added to normal blood, it causes agglutination of fixed platelets or initiates the initial agglutination phase of aggregation of live platelets.
  • RIPA is similar to the ristocetin cofactor assay but has the added benefit in that it helps in the diagnosis of type 2B/pseudo von Willebrand disease (vWD) and Bernard–Soulier syndrome because it uses patient’s live endogenous platelets, whereas ristocetin cofactor assay tests the function of only the vWF and not the platelets.
40
Q

2 causes of acquired fibrinolysis?

A
  1. Decreased hepatic clearance of tPA due to advanced cirrhosis or during liver transplantation
  2. Increased release of tPA from endothelial cells during cardiopulmonary bypass
  3. Increased release of tPA from endothelial cells in amyloidosis
  4. Snake venom
41
Q

MOA of emicizumab?

A

Bispecific antibody that bridges activated factor IX and factor X together, simulating the function of activated factor VIII.

Emicizumab was associated with a significantly lower rate of bleeding, however there were concerning complications of thrombotic microangiopathy and thrombosis in patients who received emicizumab in combination with aPCC.

42
Q

4 ways that emicizumab interferes with coagulation assays?

A
  1. Decreases (shortens) the aPTT.
  2. Affects aPTT-related assays including factor VIII activity.
  3. Interferes with chromogenic factor VIII activity assays that use human-derived factor IXa and FX (falsely increases results).
  4. Interferes with the standard inhibitor assay (cannot be performed).
43
Q

In a patient with prothrombin (ie. Factor II) def. What acquired condition is important to rule out?

A

– Rule out acquired FII deficiency due to antiprothrombin antibodies (APAs) in a patient with antiphospholipid antibodies.
-They will present with a bleeding phenotype.

44
Q

There are 2 types of FXIII def. It is important to do genetic testing to confirm this. What is the significance clinically with regards to Tx?

A

Majority are Type A and severe. (ICH, umbilical stump, poor wound healing)
If A subunit def= treat with recombinant Factor A subunit
If B subunit def= treatment with plasma derived which has A and B subunit def

All pts with FVIII<10% should receive proph for ICH. Infusion is monthly because long half life

Hematology RC Editable (28 decks)

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