HY Lecture notes:
Hemophilia A and B are XR. If you get a difficult vignette where you’re not sure of the Dx, just remember you’ll never see these in girls.
Skewed X-inactivation is called lyonization. But don’t read between the lines: unless the vignette specifically makes the Q about skewed X-inactivation, any XR disorder will always be only in a boy.
vWD is AD. So you’ll often get a vignette with a girl. USMLE will “reward” you sometimes with difficult vignettes. That is, if it’s a girl, you can instantaneously eliminate hemophilia.
vWD is always a mix of a platelet and a clotting factor problem.
Platelet problem = epistaxis, petechiae, bruising; usually cutaneous
Clotting factor problem = excessive bleeding after tooth extraction; menorrhagia (heavy periods)
So vWD vignette you will get, e.g., epistaxis + heavy periods; or petechiae + lots of bleeding after tooth extraction; always a combo of the two
Platelet problem = increased bleeding time (BT); bleeding time has zero relation to clotting factors / clotting
PT / aPTT = reflects clotting factors
In vWD, bleeding time 100% of the time is elevated.
vWF bridges Gp1b on platelets to underlying collagen / vascular endothelium; necessary for platelet adhesion; does not affect aggregation (GpIIb/IIIa). That’s the main function of vWF, which is why BT is always increased (normal is 2-7 MINUTES).
But vWF also has ancillary/secondary function of stabilizing factor VIII in plasma, meaning sometimes aPTT is elevated (normal is 25-40 SECONDS).
Two points:
- Because it’s an ancillary function of vWF, aPTT is only elevated about half the time in questions; it’s not all the time, unlike BT.
- If aPTT is increased, it’s not absurdly increased. Iow, normal aPTT might be 42 seconds. And if it is normal, it might be upper end of normal, like 38 seconds, which can still suggest to you it’s vWD.
PT is always normal in vWD.
Normal BT = 2-7 minutes
Normal PT = 10-15 seconds
Normal aPTT = 25-40 seconds
In hemophilia, because the issue is literally a deficiency of factor VIII in A, or IX in B – and in severe cases, antibodies against these factors – the aPTT WILL be absurdly elevated, like 90 seconds.
Hemarthrosis is a clotting factor issue, however it’s classic for hemophilia vignettes, NOT vWD. Implication being that it takes major clotting factor defect to precipitate full-blown hemarthrosis, whereas perhaps in vWD the effect isn’t salient enough to lead to the bleed in the joint.
Hemophilia will be school boy with hemarthrosis, or if neonate, will be excessive bleeding with circumcision.
Question on the 2CK Free-120 had given a vWD question where they said girl had cut on her finger that took longer to stop than expected (they didn’t tell you bleeding time explicitly, but expected you to easily infer that); then they said in the labs, PT normal, aPTT normal. So remember, aPTT isn’t always elevated. They also say “platelet aggregation studies: normal.” Which makes sense because vWF is necessary for adhesion, not aggregation, as we said above.
Immune thrombocytopenia purpura (ITP) = viral infection in school-age kids causing low platelets, about 80% of the time. 20% of the time the vignette will be a woman 30s-40s, without mention of viral infection, who just has random bruising = ITP. Latter is harder but especially HY on USMLE 2CK.
ITP is caused by autoantibodies against GpIIb/IIIa (type II hypersensitivity); molecular mimicry most likely due to viral infection.
Treatment of ITP = steroids first, then IVIG, then splenectomy.
Steroids = next best step in management. Splenectomy = most effective at decreasing recurrence. Be careful as to what they ask for.
Viral-induced neutropenia is similar to ITP, but instead of autoantibodies against platelets, they’re simply against neutrophils.
Low neutrophils + fever = neutropenic fever / febrile neutropenia = infection without a way to control it via innate immunity = must give immediate broad-spectrum IV antibiotics; generally third- or fourth-gen ceph + vancomycin; or pipericillin-tazobactam.
Thrombotic thrombocytopenic purpura (TPP) is due to antibodies against ADAMTS13 protein, which is normally responsible for cleaving vWF multimers, leading to decreased platelet-clumb breakdown. The clumps will shear RBCs flying past leading to schistocytosis. Combination of thrombocytopenia + schistocytosis = microangiopathic hemolytic anemia (MAHA).
TTP you see a pentad of 1) thrombocytopenia, 2) hemolytic anemia with schistocytosis, 3) renal insufficiency with red urine; 4) fever + 5) neurologic signs
Hemolytic uremic syndrome (HUS) is just the triad of of #1-3 above; fever and neurologic signs not typically seen in HUS.
HUS due to EHEC O157:H7 shiga-like toxin (aka verotoxin), or Shigella’s shiga toxin. Toxin causes endothelial damage that leads to platelet consumption and “jagged edges” in the vessels that shear RBCs. Schistocytes are seen.
Schistocytes = HUS, TTP, DIC, HELPP syndrome, prosthetic values (mechanical hemolysis).
Vitamin K deficiency = increased PT and aPTT; bleeding time is normal
BT is normal because platelets aren’t involved whatsoever. Issue is decreased gamma-carboxylation + activation of clotting factors II, VII, IX, X (and anti-clotting proteins C and S).
Vitamin K deficiency can be seen in neonates with sterile bowels. Although fat-soluble vitamin deficiencies can occur in small bowel malabsorptive disorders, i.e., with conditions like cystic fibrosis, Crohn disease, Celiac, chronic Giardiasis, etc., K deficiency is rare because of functional large bowel with normal flora in non-neonates; A, D, and E would be deficient. E.g., cystic fibrosis kid with rickets (D deficiency).
USMLE wants you to know vitamin K deficiency can occur in patients who are on chronic broad-spectrum antibiotics. They’ll say patient on Abx is requiring a lower dose of warfarin to achieve same INR target range – why? → decrease in colonic normal flora.
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