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Coagulation Disorders

There are three phases of coagulation, as one injures oneself. The first one obviously is a phase of vascular constriction which cuts down the blood flow to areas that have been injured and makes the blood flow go slower so that the coagulation process can be undertaken. The second is the formation of a primary hemostatic plug that involves the putting of platelets against the injured wall of the endothelium. And only finally, and later, is the production of a definitive fibrin clot. Now this cartoon here sort of goes into that and you can see here on the left a vessel before injury and here on the inside of the blood vessel youíve got the blood contents. Weíve simplified this so that we only have the relevant factors sitting around there. There are no white cells or red cells or anything like that. But what you have here is the circulation of platelets in a discoid configuration, some fibrinogen and von Willebrand gram factor. When there is an injured vessel, the von Willebrand factor.

Well, letís start putting this to work. Vascular disorders leading to bleeding are unusual. Two are listed here, Ehlers-Danlos, which is the disorder of collagen, and scurvy which is vitamin C deficiency. Chances are you wonít see this too often in your pediatric practice. But you will see problems in the formation of the platelet plug. As I mentioned, the carboxyl residues form one side of the sandwich. The von Willebrand factor is the meat, and the platelets are the other piece of bread.

We will turn now to the disorders of platelet function and there are several. The first and most serious is Glanzmannís thrombasthenia. This is a disorder that appears very early in life. It is due to a deficiency of glycoprotein QB3A. These patients have severe bleeding tendencies and they have impaired aggregation of platelets to all agonists, thrombin, ristocetin, ATP, everything doesnít work. These patients have a very very severe bleeding disorder.

There is an entity called the Bernard-Soulier syndrome. These patients have large platelets, a prolonged bleeding time, impaired adhesion in the presence of von Willebrand factor, and they have a deficiency of the glycoprotein to which von Willebrand factor attaches. And that explains the problem of their platelets malfunctioning. Again, these patients with qualitative bleeding disorders have a disorder that causes immediate bleeding when they cut themselves.

There is an entity called the Hermansky-Pudlak syndrome. This is a disorder that is associated with oculocutaneous albinism, bruising because of storage pool deficiency, defective granules in the platelets, and these patients get pulmonary fibrosis.

We turn now to quantitative disorders of platelets; that is thrombocytopenia. And just like everything in hematology, if you are deficient in something it can be due to decreased production or increased destruction. In decreased platelet production there are the same issues that you have with decreased red cell production. You can have a generalized marrow aplasia. Something like severe aplastic pancytopenia. You can have a localized, a pure functioning a-megakaryocytosis. This is relatively infrequent but we see it sometimes in very young children, either as a pure phenomenon or in association with some morphologic abnormalities as seen in the thrombocytopenia and absent radius, or TAR syndrome. And you can have marrow failure on a secondary basis, whether due to myofibrosis, leukemia, metastatic cancer or whatever. Aplastic pancytopenia can be acquired.

Patients with pure a-megakaryocytosis include patients with TAR syndrome, as I mentioned. Patients with Wiskott-Aldrich syndrome, and patients with isolated a-megakaryocytosis. Secondary marrow failure can be malignancy, myelofibrosis. Storage disease, some patients with Gaucherís disease will have thrombocytopenia due to the overwhelming presence of the storage material in the bone marrow macrophages. And patients with megaloblastic anemia, pernicious anemia, or folate deficiency.

Immune thrombocytopenia is most commonly seen in childhood. Itís a benign form of ITP. Most of these patients have a history of prior viral infection. But some of them do not. Most of the patients are three or four or five-years-old. There is an equal distribution of males and females. It may come on very suddenly. They have very severe thrombocytopenia, platelet counts of 1,000-5,000, they have a lot of bleeding manifestations but they almost invariably get better, whether you treat them with steroids or immunoglobulin. But they almost always get better and they very, very, very, very rarely die. Severe intracranial hemorrhage, which is the usual cause of demise in these patients, is extraordinarily rare. I have seen it only once and that was a very atypical patient who presented in infancy with severe thrombocytopenia, and we were never able to provide another cause. But Iím not convinced that that child actually had ITP.

There are more chronic forms of autoimmune diseases and these patients usually present a little differently from patients with ITP. These patients may have some bruising but they present with platelet counts of 40 or 50 or 60,000. Their bleeding manifestations are generally mild and they tend to be chronic. So even if you treat them with steroids, you get their platelets up, they tend to come down when you stop treating and they become what we call "the chronic patients."

Autoimmune phenomena are also associated with immunodeficiency, whether congenital or acquired. These patients are not typically the SKDS patients but they are more the subtle immunodeficiencies, the patients with common, variable immunodeficiencies who get into problems and then only with time as their immunodeficiency becomes more defined and more severe, do they get into problems other than their autoimmune problems.

Drug-induced thrombocytopenia is also common. Itís seen with a variety of drugs and the mechanisms are well identified. Two of the common drugs that are associated with thrombocytopenia are the quinidine group of drugs and heparin. It would not surprise me at all if you saw something about heparin-induced thrombocytopenia on your Boards.

Finally, and you certainly will see something on your Boards about neonatal alloimmune thrombocytopenia. This is the platelet of Rh disease where one of the platelet associated glycoproteins form an antigen that is not carried on the motherís platelets and the mother becomes immunized and then the antibody crosses back across the placenta. Itís important to recognize this because in succeeding pregnancies this thrombocytopenia becomes more severe, it is associated with significant risks both in utero and in the process of delivery. Itís also easily treatable by the administration of platelets that lack the offending antigen.

Platelet trapping is seen in hypersplenism, in DIC and focal intravascular trapping as might be seen in hemangiomas, so-called Kasabach-Merrittís syndrome, and in hemolytic uremic syndrome; which is a form of focal intravascular coagulation.

Iím going to turn now to the coagulation cascade. All the slides I have of the cascade are going to follow this pattern. When I introduce a new factor you will see that showing up in red, and the old factors will be black. So that as I add new things to the cascade theyíll show up in red and I think they are stressed in double stripe in your syllabus.

Protein C. Protein C is another serine protease. Remember this. Itís just like the coagulation cascade. Synthesized by the liver, vitamin K dependent and it requires a co-factor, protein S. What this does is it inactivates factor V-a. It is this interaction between protein C and V-a that goes awry in patients who have an abnormal factor V, so-called factor V leyden which is the most common hyper-coagulant cause of a hyper-coagulable state. What Iíve tried to describe to you in this pathophysiological approach is a balance between the procoagulants and the anticoagulant.

Letís turn now to how you go about dealing with patients who are suspected of having a coagulopathy. Itís the same way you deal with everything else. A good history, physical examination and appropriate laboratory evaluation. You want to know about things like the nature of the bleeding. Whether it happens immediately when they cut themselves or whether it is delayed. Immediate bleeding suggests a platelet disorder, or von Willebrand disease. Delayed bleeding suggests a hemophilioid state. Superficial bleeding, petechiae, prolonged bleeding from a cut, suggests a platelet or von Willebrand factor.

Von Willebrand disease is a problem of the initial phase of coagulation, the formation of a platelet plug. Their bleeding tends to be superficial, whereas hemophilia itís deep and itís delayed. Whereas itís immediate over here. In hemophilia itís almost always males because itís a sex-linked recessive. Von Willebrandís disease is an autosomal dominant so the sex ratio is about equal. The history is abnormal in both. The PTT is always increased in hemophilia, and may be normal or increased in von Willebrandís.

Hemophilia A and hemophilia B are not so easy to distinguish because they are exactly the same except for which factor is involved. They are at the same level in that cascade. The only way that you can distinguish between them is to either measure their factor level - and VIII is low in hemophilia A, and IX is low in hemophilia B - or to do corrections with known deficient plasmas.

Neonatal thrombocytopenia. Again, just like everything else, decreased production or increased destruction. With thrombocytopenia you want to take a careful maternal history. What medications is the mother taking? What illness had she had during her pregnancy? Is there a history of thrombocytopenia - even in herself - because patients with lupus or ITP may still carry the antibody around even though they may not have thrombocytopenia at the time that they deliver. If the antibody crosses that placenta it may cause thrombocytopenia in the newborn. Or were prior children involved? Prior pregnancies?