MYELOFIBROSIS

Megakaryocyte Cancer

Myelofibrosis is a cancer of Megakaryocytes. It affects adults. We all know that Megakaryocytes live in the bone marrow. That should hopefully help you associate Myelofibrosis with Megakaryocytes. Most of the problems with this disease occur due to fuckery within the bone marrow. Early on in the disease, the marrow gets overcrowded (hypercellular), with an especially large amount of Megakaryocytes, but over time the marrow becomes really fibrotic. Fibrotic marrow is barren and useless. The hematopoietic cells that lived there have to emigrate somewhere else (usually the spleen) which can cause very profound splenomegaly. The spleen is willing, but unable, to handle all of the body’s hematopoiesis. So it starts cutting corners: blasts, nucleated RBCs and weird looking white cells leak into the blood. That constellation of weird findings on a blood smear is called leukoerythroblastosis. One particular cell is characteristic of Myelofibrosis: the teardrop cell (Dacrocyte). It’s theorized that these suckers occur when the few stem cells who remained in the marrow try to make red cells. The teardrop shape is formed due to mechanically squeezing out from the fibrotic bone marrow. Furthermore the loss of hematopoietic real estate leads to a drop in red cells (anemia), white cells (infection) and platelets (clotting and bleeding). There is a small chance of transformation into acute leukemia.

Why do Megakaryocytes cause fibrosis? The exact MOA isn’t fully understood, but Megakaryocytes do happen to release some cytokines (Platelet Derived Growth Factor) that activate fibroblasts. So this seems like a plausible explanation.

Why does Myelofibrosis begin in the first place? A JAK2 Kinase mutation. 

POLYCYTHEMIA VERA

Red Blood Cell Cancer

Polycythemia Vera is cancer of red blood cells. It’s caused by a JAK2 Kinase mutation. The mutated cells are constantly getting JAK signals telling them to grow, grow, grow.

“Polycythemia” is a lab value interpretation, where the RBC count is high. Physiologic Polycythemia occurs with tissue hypoxia (COPD, high altitude) which causes a subsequent rise in EPO.  Pathologic Polycythemia occurs with blood cancer (Polycythemia Vera) or ectopic EPO secretion (renal adenocarcinoma). Polycythemia Vera is the only condition with polycythemia and low EPO (which is like the body slamming on the brakes to compensate for the fuck load of red cells).

The H’s of Polycythemia Vera

• High Hemoglobin - duh. 

• Hyperviscosity - this is the big one. The increased number of red cells turns the blood to sludge. This predisposes them to blood clots

• Hepatic Vein Thrombosis (Budd-Chiari) - BC is very rare. PV is one of the few causes of this (oh hey Paroxysmal Nocturnal Hemoglobinuria).

• Hepatosplenomegaly - the excess red cells are stored in the spleen, plus extramedullary erythropoiesis results in an enlarged spleen

• Histaminemia - PV is a myeloproliferative disorder. All myeloid cell lines are increased, including mast cells. Mast cells degranulate when they get hot. So when the patient takes a hot bath, they get itchy all over. There are very few causes of full body itching (without a rash) in medicine (basically just PV or kidney/liver disease). Furthermore, MAST CELLS ARE THE CAUSE OF THE RED SKIN (aka “plethora”). It’s tempting to think that their skin is ruddy and red because of the increased red cells, but that isn’t the case. The mast cells are swarming around and vasodilating everything! Vasodilation of the skin produces redness. Vasodilation in the brain produces headaches and dizziness (remember that was the MOA with migraines). 

• Hyperuricemia - Like all myeloproliferative conditions (except Essential Thrombocytopenia), PV causes hyperuricemia because there is a high turnover of nucleated cells. DNA is turned into uric acid, which causes gout when it accumulates and crystalizes in a joint and renal failure when it overloads the kidney. The treatment btw is Allopurinol.

• Hypervolemia - low yield. Their volume grows accordingly with their red cells.

Treatment is with phlebotomy (draining their blood). Phlebotomy not only lowers their RBC count, but it slows the production of new RBCs (by draining iron and putting them into a mild IDA)! I think you can give Hydroxyurea too, but that’s less important.