Pediatrics

Bleeding Disorders

OVERVIEW: What every practitioner needs to know

Are you sure your patient has a bleeding disorder? What are the typical findings for this disease?

The hallmark of bleeding disorders are excessive bleeding i.e. bleeding that cannot be stopped, that which is beyond what is expected for the given degree/amount of trauma, or bleeding in usual locations.

  1. The most common symptoms are easy bruising, nose bleeding (epistaxis) and menorrhagia.

  2. The next most common symptoms are excess bleeding after surgical procedures and oral mucosal bleeding.

  3. In hemophilia, joint and muscle bleeding are common.

Bleeding disorders can be divided into disorders of primary hemostasis which include platelet disorders and von Willebrand disease and disorders of secondary hemostasis (factor deficiencies).

Disorders of primary hemostasis are manifested by mucocutaneous bleeding such as bruising, petechiae, epistaxis and menorrhagia. In additon, these disorders can also be diagnosed secondary to excessive bleeding from oral surgery (tooth extraction, tonsillectomy).

Disorders of secondary hemostasis are comprised of all the factor deficiencies. The hemophilias due to deficiencies of factor VIII and IX are the most well described. Factor XI deficiency is more common but not as important as it is a mild bleeding disorder. Hemophilia is manifested by deep tissue bleeding with joint and muscle hemorrhages being the two most common sites of bleeding.

What other disease/condition shares some of these symptoms?

The major condition that could present like a bleeding disorder is non-accidental trauma. Other conditions that could mimic bleeding disorders are vascular malformations.

What caused this disease to develop at this time?

The vast majority of bleeding disorders are inherited. Disorders of primary hemostasis (platelet function disorders and von Willebrand disease) are most often inherited in an autosomal dominant fashion.

Hemophilia (factor VIII and IX deficiency) are X-linked recessive.

Most other factor deficiencies (factors VII, X, XIII, for example) are inherited in autosomal recessive fashion as are rare variants of platelet function defects and the rarest and most severe form of von Willebrand disease (type 3).

Bleeding disorders can be acquired and the most common cause are medications (aspirin, NSAIDs, others) and rarely autoimmune disorders can lead to factor deficiencies.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The typical screening for bleeding disorders involved obtaining a CBC with a platelet count. In addition, a prothrombin time (PT) and activated partial thromboplastin time (aPTT) are useful to screen for factor deficiencies.

Importantly, the PT and PTT are normal in factor XIII deficiency (rare.)

These screening tests do not rule out platelet function defects or von Willebrand disease thus specific testing for these conditions will need to be performed if they are clinically suspected.

Would imaging studies be helpful? If so, which ones?

Typically, diagnostic imaging is not part of the evaluation of bleeding disorders. An unsuspected hematoma or hemorrhage noted on an imaging study obtained for other reasons may suggest an underlying bleeding disorder.

Confirming the diagnosis

There are no specific algorithms for diagnosing bleeding disorders. The most important aspect of diagnosing bleeding disorders is taking a good history. A personal and family history of bleeding are the most sensitive signs for the presence of a bleeding disorder. Clinical suspicion should lead to laboratory testing as described above which will likely unmask the specific disorder.

If you are able to confirm that the patient has a bleeding disorder, what treatment should be initiated?

Uncontrolled bleeding should lead to admission to the hospital and consultation with a pediatric hematologist to help determine which laboratory tests and treatments to order. It is important to send a diagnostic work up prior to instituting any type of therapy as some therapies will make it harder to diagnose a bleeding disorder if they are administered prior to a complete laboratory evaluation.

Longer term treatment will depend on the the specific underlying diagnosis.

For von Willebrand disease, the main therapies are DDAVP which is available as a nasal spray for home use or intravenously for hospital or pre-operative use and antifibrinolytic agents (aminocaproic acid and tranexamic acid). For more severe bleeding, von Willebrand factor concentrates are used to treat active bleeding or prevent bleeding when it might be expeced such as prior to surgery.

For platelet function disorders, DDAVP and antifibrinolytics are the mainstays of therapy as well. For severe bleeding, platelet transfusions can be given, however in some conditions such as Glanzmann's thrombasthenia, platelet transfusions should be given only under the supervision of a pediatric hematologist.

For hemophilia and other factor deficiencies, factor replacement therapy is the hallmark of therapy.

What are the adverse effects associated with each treatment option?

The main side effects of DDAVP are flushing, hypotension, and rarely, syncope due to vasodilation. In young children, hyponatremia can occur.

Antifibrinolytic agents can rarely lead to thrombosis, but otherwise these agents are safe with only rare side effects such as nausea and abdominal pain.

The main adverse effect of factor replacements is the development of antibodies ot the factor rendering further factor replacement difficult if not impossible which could lead to more severe bleeding complication.

What are the possible outcomes of bleeding disorders?

Bleeding disorders vary from essentially asymptomatic to severe life-threatening bleeding.

For patients with mild von Willebrand disease and platelet function defects, bleeding is usually minimal and more of a nuisance than a serious medical problem whereas for patients with severe factor deficiencies such as hemophilia, bleeding can be severe to life-threatening. Fortunately, even for the most severe cases, there are excellent treatments which can not just treat but even prevent bleeding from occurring.

The treatments for the most severe conditions involve replacing the missing factor and for many of these, there are synthetic (recombinant) factor treatments which have essentially no risks other than developing an antibody. For the milder disorders, use of medications such as aminocaproic acid and DDAVP are quite effective and have minimal to no side effects such that the benefits greatly outweigh the risks.

What causes this disease and how frequent is it?

Bleeding disorders are nearly all genetic. The most common factor deficiencies (factors VIII and IX) are X-linked recessive while the rest of the factor deficiencies are autosomal recessive disorders. Von Willebrand disease and platelet function defects are mostly inherited in an autosomal dominant fashion though the more severe forms of these disorders are also autosomal recessive.

There are some acquired bleeding disorders, and their causes vary greatly from vitamin K deficiency to severe liver disease to renal failure among others. Factor VIII deficiency occurs in 1 per 5000 males while factor IX deficiency occurs in 1 per 20,000 males. The other factor deficiencies are for the most part even less common with incidence rates of 1 per 50,000 to 1 per million. The exception is factor XI deficiency which occurs commonly among Ashkenazi Jews (about 1 per 100 to 500) and 1 per 5000 among other ethnic groups.

Von Willebrand disease is the most common bleeding disorder with perhaps 1 per 100 people having low von Willebrand factor levels though truly symptomatic cases are probably more in the order of 1 per 1000 people.

The genetics are well-described for nearly all of these conditions and are explained above.

Other clinical manifestations that might help with diagnosis and management

Post-circumcision bleeding in a newborn or bleeding from the umbilical stump should immediately raise serious concerns for the presence of an inherited bleeding disorder.

What complications might you expect from the disease or treatment of the disease?

The major complication of hemophilia is the development of arthritis due to repeated bleeding into joints. This can result in crippling arthritis most commonly in the elbows, knees, and ankles. For the prevention of arthropathy in hemophilia, long-term cohort studies and one randomized clinical trial have clearly demonstrated that prophylactic factor therapy is the most effective way to prevent the long-term morbidity of hemophliia which is joint disease.

For the milder bleeding disorders, levels of evidence are not as strong, however the medications that are recommended have been demonstrated to be effective in multiple clinical trials.

Are additional laboratory studies available; even some that are not widely available?

The typical laboratory studies to screen for a bleeding disorder include a CBC to assess the platelet count and check for anemia in the case of bleeding.

In order to diagnose each specific factor deficiency, the factor in question can be assayed for. For von Willebrand disease, there are tests which can determine the amount of von Willebrand factor present (the von Willebrand factor antigen) and its function (Ristocetin cofactor or von Willebrand factor activity). For platelet function abnormalities, platelet aggregation studies need to be performed. Further testing of platelet function can include electron microscopy and flow cytometry to diagnose specific platelet function defects.

How can bleeding disorders be prevented?

There are no methods to prevent these genetic conditions. In order to prevent one of the more common acquired disorders which is vitamin K deficiency, it is highly recommended that all newborns receive parenteral vitamin K immediately after birth.

What is the evidence?

Manco-Johnson, MJ, Abshire, TC, Shapiro, AD. N Engl J Med. vol. 357. 2007. pp. 535-544.

(This study demonstrated that prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in severe hemophilia A. Without factor prophylaxis, joint damage as demonstrated by MRI will occur in patients who are not on prophylactic therapy.)

Ongoing controversies regarding etiology, diagnosis, treatment

The current major controversies in hemophilia include whether recombinant forms of factor lead to a higher incidence of inhibitor (antibody) development. As previously mentioned this is the most serious consequence of factor treatment leading to the inability to treat bleeds effectively. The issue of the source of factor (recombinant DNA or plasma-derived factor) remains an issue that is controversial. A clinical trial currently under way should answer this question eventually.

Other issues of controversy in hemophilia include when to start prophylaxis in young children. Some advocate starting early as this will prevent bleeding from occurring and may prevent inhibitor formation as well though this is not yet clear.

Lastly, another major issue is the cost of care which is extremely high - in the order of several hundred thousand dollars per year for prophylactic therapy.

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