Category Archives: Heme

Clotting Cascade – NOW WITH NOACs

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clotting_cascade_NOAC

The clotting cascade was one of the first doodles posted on Sketchy Medicine, I’ve now updated it to include some of the Novel Oral Anticoagulants (NOACs): Dabigatran, Rivaroxaban and Apixiban.

Dabigatran (Pradaxa)

  • Selective, reversible direct thrombin inhibitor
  • Is actually a prodrug that reaches peak concentration 2-3 h post ingestion
  • Approved (in Canada) for:  Thromboprophylaxis in atrial fib, post-op, and treatment of VTE and VTE recurrence
  • T1/2: 7-17 h
  • CYP independent (not as many drug-drug interactions)
  • Excreted in urine 95% / Feces 5%
  • Reversal: hemodialysis?
  • Big trial = RELY, REMEDY

Rivaroxaban (Xarelto)

  • Selective, reversible direct factor Xa inhibitor
  • Approved (in Canada) for:  Thromboprophylaxis in atrial fib, post-op, and treatment of VTE and VTE recurrence
  • T1/2: 3-9 h (relatively speedy!)
  • CYP3A4
  • Very good oral bioavailability
  • Almost all of it is protein-bound in the serum
  • Urine 70% / Feces 30%
  • Reversal: ???? (not hemodialysis)

Apixaban (Eliquis)

  • Selective, reversible direct factor Xa inhibitor
  • Approved (in Canada) for:  Thromboprophylaxis in atrial fib, post-op, and treatment of VTE and VTE recurrence (only atrial fib in the USA)
  • T1/2: 8-15
  • CYP3A4
  • Almost all (95%) protein-bound in the serum
  • Urine 30% / Feces 70%
  • Reversal: ???? (not hemodialysis)

Reversal agents:

  • Hemodialysis
    • Only good for agents that aren’t highly protein bound (i.e. dabigatran).
    • Warfarin, rivaroxaban and apixaban are all mostly bound to protein in the serum, so dialysis won’t get rid of them
  • PCC
    • Plasma-derived product containing factors II, IX and X (3-factor PCC) or II, VII, IX and X (4-factor PCC) in addition to variable amounts of proteins C and S, and heparin
  • aPCC
    • Plasma-derived product containing activated factors II, VII, IX and X
  • Recombinant factor VIIa
    • Looks good in test tubes, clinical evidence lacking
  • Idarucizumab
    • Humanized monoclonal antibody against dabigatran
  • Andxanet alfa
    • Recombinant factor Xa derivative
    • Could theoretically be used for rivaroxaban and apixaban

Anticoagulation Assays

Effect of oral anticoagulants on coagulation assays (Jackson II & Becker, 2014)

(Adapted from Jackson II & Becker, 2014)

Approach to bleeding

Managing target-specific oral anticoagulant (Siegal, 2015)

(From Siegal, 2015)

References

  • Jackson II LR & Becker RC. (2014). Novel oral anticoagulants: pharmacology, coagulation measures, and considerations for reversal. Journal of Thrombosis and Thrombolysis, 37(3), 380-391.
  • Ufer M. (2010). Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thrombosis and Haemostasis. 103: 572-585.
  • Siegal DM. (2015). Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents. Journal of Thrombosis and Thrombolysis, 1-8.

Iron Metabolism

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When we eat iron, we generally get it in one of two forms: elemental iron or heme (from meat). In the intestine (proximal duodenum to be precise) the iron is either absorbed or actively transferred in. Iron is transported in the blood bound to transferrin and is stored in the liver bound to ferritin. This is why ferritin is measured when assessing iron stores.

Though most of the time you can make the diagnosis of iron deficiency anemia by assessing the patient’s history and CBC (microcytic anemia), you can also do an “iron study” that looks at the following:

  • Ferritin: indicator of iron stores, will be reduced in iron deficiency anemia
  • Serum iron (SI): decreased in iron deficiency anemia
  • Total iron binding capacity (TIBC): measures transferrin, this is elevated when iron is low
  • % saturation = SI/TIBC x 100, reduced in iron deficiency anemia

It’s good to keep the other causes of microcytic anemia in mind. To remember you can use the mnemonic TAILS

  • Thalassemia
  • Anemia of chronic disease
  • Iron deficiency
  • Lead poisoning
  • Sideroblastic anemia

*I realize that using “anemia” as the A is a little bit of a cop out in a mnemonic devoted to anemia, but I wasn’t the one who came up with it and TCILS just isn’t as easy to remember.

Hemostasis & How to Recognize Bleeding Disorders

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Hemostasis – What stops us from bleeding out.

Three main steps:

  1. Vasoconstriction
  2. Primary hemostasis (platelet plug) – the temporary way to stop bleeding
  3. Secondary hemostasis (clotting cascade) – the more permanent way

Bleeding disorders can be broadly divided into whether they affect platelet plug formation or the clotting cascade (if you need a refresher, click here)

 Platelet Disorder Clotting Cascade Disorders
Immediate bleeding
Muscosal and cutaneous
Bruises and petechiae
Nose bleeds (epistaxis)
Menorrhagia (heavy periods)
von Willebrand
Thrombocytopenia
DIC 		 Delayed Bleeding
Deep (muscles and joints)
Palpable bruises, large spreading hematomas
Hemarthrosis
Post-surgical bleeding
Hemophilia A (factor VIII)
Hemophilia B (factor IX)
Warfarin

The 5 classes of white blood cells

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White blood cells are divided into 5 classes.

  1. Neutrophils (70%): These are the big guys in infection. Generally when someone has an “elevated white count” it’s due to the neutrophils (unless there’s a lymphoma grumbling along). They are the major players in fighting off bacterial infection and the main component in pus.
  2. Lymphocytes (20-60%): These are the B cells, T cells, and Natural Killer (NK) cells. When you’re looking at a blood smear, you can’t tell the difference between them.
    • T cells: cell-mediated immunity
    • B cells: humoral (antibody-mediated) immunity
    • Natural Killer cells: protect against viruses and tumours
  3. Monocytes (3-8%): Mature into macrophages and mast cells, they play a major role in mounting an inflammatory reaction. Macrophages are the “professional antigen presenting cells“, displaying foreign peptides in Class II MHC.
  4. Eosinophils (1-6%): fight against parasitic infections (back in the good old days), now they’re the bane of many people’s existence as they’re involved in asthma and allergies.
  5. Basophils (0.1%): contain many base-loving (hence baso-phil) granules containing histamine

Anatomy of a nephron

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The nephron is divided into 6 distinct parts

  1. Proximal (covoluted) tubule
  2. Descending loop of Henle
  3. Ascending loop of Henle
  4. Distal (convoluted) tubule
  5. Cortical collecting duct
  6. Distal collecting duct

Each of these sections has a main function in adjusting the amount and kind of solutes in the urine. Different drugs and diuretics work at distinct areas, which is why some diuretics are potassium sparing while others (like Lasix/furosemide) are potassium wasting.

Erythrocyte growth and regulation

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Red blood cells (fancily known a erythrocytes) are the simple, non-nucleated cells that transport oxygen in the body. This just outlines their development in the bone marrow (hint, they start off with a nucleus) and the major growth factor erythropoietin that stimulates their production.

By looking at the peripheral blood and bone marrow, you can work on sorting out where and what kind of disease process is going on. For example, if there are too many reticulocytes in the peripheral blood.

Direct and indirect antibody tests

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direct antibody Test

Looks for the presence of IgG and/or complement on the RBCs. This causes hemolysis and can be due to an autoimmune disease, transfusion reaction, etc.

Indirect antibody Test

This is used when cross-matching people for a blood transfusion. It tests patients for the presence of unexpected alloantibodies (anti-D, anti-E, anti-C, anti-Kell, anti-Duffy). This is just a screen, if it is positive, you can then test for specific antibodies and then only transfuse blood that is negative for those specific antigens.

* 19/06/2013 Please excuse the doodle for saying “agglutination” though it is testing by agglutinating, the “A” in DAT stands for antibody. Thanks Robina for pointing this out!

Hypersensitivities (type I, II, III, IV, V)

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The types of hypersensitivities can get a little confusing, especially 2, 3, and 5.

Type 1: Plain old allergy (asthma, anaphylaxis, atopy)
Type 2: Antibody-dependent, cytotoxic (think of autoimmune hemolytic anemia)
Type 3: Immune complex disease (like a lot of the autoimmune conditions: rheumatoid, lupus)
Type 4: Delayed/Cell-Mediated (mediated by T cells, T cells are slower to react than antibodies, so this reaction takes a couple days)
Type 5: Receptor-mediated autoimmune disease (Graves, myasthenia gravis)

Liver Enzymes (hepatic vs cholestatic patterns)

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Liver enzymes can be elevated for a number of reasons, but the first step in an approach is to determine if the enzymes are in a hepatic pattern or cholestatic pattern. It is also very important to realize that Alk phos, GGT, ALP, and AST are liver enzymes, but they don’t give an indication of function; for that you need to look at INR and bilirubin.

Clotting Cascade

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It seems as though the clotting cascade is something you can study over and over again and it never sticks.

The important things to know are:

HEPARIN affects factor VIII in the INTRINSIC pathway and this is measured using PTT (partial thromboplastin time)
WARFARIN affects the vitamin K dependent synthesis of some clotting factors (purple in the image), particularly factor VII in the EXTRINSIC pathway and this is measured using PT (prothombin time) or INR (International Normalized Ratio, which is derived from the PT)