Figure 18.1. This schematic represents the relationship between von Willebrand factor with platelets and the endothelium.

    The vast majority (85%) of patients with vWD have type 1 disease caused by missense mutations that perturb multimer assembly (table 18.1). They have a parallel decrease in vWF antigen, vWF activity measured as Ristocetin cofactor activity, and factor VIII. vWF levels are influenced by a number of physiological/pathologic states or additional genes. For example, acute or chronic inflammation can raise the vWF level, whereas hypothyroidism lowers the vWF level. The unique hormonal milieu present during pregnancy can completely normalize the vWF level, allowing for easy labor and delivery. vWF protein contains ABO blood group molecules that influence the rate of vWF clearance from plasma. Type O vWF is cleared most rapidly, types A and B less so, and type AB the slowest. Thus, type O patients have the lowest plasma levels of vWF and are more likely to have bleeding when they have inherited a mutant vWD allele.

    Most of the remaining patients have type 2 vWD characterized by specific mutations in the vWF A1 domain that make the molecule abnormally sensitive to proteolytic degradation (type 2a disease) or partially activated and continually binding to circulating platelets (type 2b). There are some rare patients with mutations that inactivate the site in the A1 domain that binds to GpIb (type 2M disease). Some patients have a disorder that has been called autosomal hemophilia and have a mutation in the region of vWF that binds to and stabilizes factor VIII (type 2N disease). When a type 2N allele is combined with a type 1 mutant allele, the resulting double heterozygote patient can have very low VIII levels and present with hemarthroses that mimic classic hemophilia. Because the platelet adhesive function of vWF is preserved, there is no mucosal bleeding. An autosomal inheritance pattern can provide the clue to diagnosis and distinguish this condition from classic hemophilia A. There are a small number of patients with type 3 disease, which is due to large deletions in the vWF gene. These patients have inherited two abnormal alleles and have severe lifelong bleeding with no detectable vWF in their plasma.

QUALITATIVE PLATELET DISORDERS

The qualitative platelet disorders are a heterogeneous group of abnormalities that affect many different steps in platelet adhesion, signaling, granule packaging, and secretion and aggregation. Some disorders are quite common, whereas others are exceedingly rare and one may spend an entire career in a primary-care or subspecialty practice without seeing a patient with one of these disorders. Some abnormalities occur in isolation, whereas others are a manifestation of a multiorgan systemic disorder. It is convenient to link the disorders to specific steps in platelet function as shown in Figure 18.2.

    Platelet membrane disorders affecting adhesion or aggregation, two critical steps in platelet function, are the result of cooperative activity between a membrane glycoprotein and a plasma glycoprotein. The interaction of vWF with the GpIb/IX/V complex facilitates platelet adhesion, while the binding of fibrinogen to GpIIb/IIIa regulates platelet aggregation. Rare patients with mutations in GpIb a or b polypeptides or GpIX fail to synthesize the GpIb/IX/V complex, a condition called the Bernard-Soulier syndrome. It is characterized by abnormally large platelets, mild to moderate thrombocytopenia, and an inability to support vWF-dependent adhesion. It is an autosomal recessive trait and causes lifelong bleeding. In a similar vein, patients with mutations in the GpIIb or GpIIIa polypeptides fail to synthesize the platelet GpIIb/IIIa complex and have platelets that cannot bind fibrinogen or aggregate. This disorder, called Glanzmann thrombasthenia, is also an autosomal recessive trait. It differs from Bernard-Soulier in that patients have a normal platelet count and normal-sized platelets. Like Bernard-Soulier patients, they also have severe, recurrent lifelong hemorrhage. In both cases, repeated platelet transfusions can lead to alloimmunization well as antibodies directed against the missing proteins, which can both limit the effectiveness of platelet transfusions.

    Patients have been identified with selective defects in the transport and packaging of materials in platelet granules. Patients with dense body or delta storage pool disease have low levels of granule ATP, ADP, calcium, and serotonin and have defective secondary platelet aggregation. In contrast, patients with alpha granule or alpha storage pool disease have normal or near-normal aggregation. Patients with combined alpha/delta disease have platelets that have the appearance of Swiss cheese with multiple holes representing the limiting membrane of empty granules. They have a hemostatic defect and can also develop marrow fibrosis as proteins like the platelet-derived growth factor leak from megakaryocytes and stimulate the growth of marrow fibroblasts.

    Patients with oculocutaneous albinism and patients with the Chediak-Higashi syndrome, who may also be partial albinos, have a generalized granule packaging defect that extends to the platelet and presents as delta storage pool disease. Patients with the Hermansky-Pudlak syndrome have delta storage pool disease and often develop severe pulmonary fibrosis. Many of these patients end up requiring continuous oxygen therapy and eventual lung transplants.

    Patients have been identified with mutations in the P₂Y₁₂ ADP receptor and in some of the important intraplatelet signaling molecules. A mutation in a myosin isoform, MyH9, causes the May-Hegglin anomaly, which is characterized by very large platelets, moderate thrombocytopenia, Dohle bodies in their leukocytes, but no hemostatic defect.

    In clinical practice the most common platelet abnormalities are those caused by the administration of antithrombotic medications. Aspirin is far and away the most commonly administered drug and induces a mild hemostatic defect. Since it irreversibly inactivates platelet cyclo-oxygenase, a single dose can perturb hemostasis for 5–7 days. Other nonsteroidal antiinflammatory drugs (NSAIDs) such as naproxen or ibuprofen are transient reversible cyclo-oxygenase inhibitors and rarely cause clinical bleeding. Of far more importance is their competition with aspirin for cyclo-oxygenase binding. Simultaneous ingestion of sodium naproxen or ibuprofen and aspirin will block the desired cardiovascular effect of aspirin and is one of the leading causes of “aspirin resistance.” Patients need to be instructed to take aspirin first and to wait at least 30 minutes before taking an NSAID.

    Clopidogrel and prasugrel are both P₂Y₁₂ inhibitors that block ADP-induced aggregation. They are prodrugs whose active metabolites are irreversible inhibitors, so their effect is also prolonged. Two other popular drugs, integrelin and abciximab (Rheo Pro), bind to the GpII/IIIa complex and block platelet fibrinogen binding and platelet aggregation. Integrelin has a short biological half-life and can be rapidly reversed by stopping its infusion. The effect of abciximab can persist for several days.

HEMOPHILIA A

Although patients have been described with deficits in each of the known coagulation proteins, three diseases predominate and account for well over 90% of patients with inherited coagulation disorders—deficiencies in factors VIII, IX, and XI. They are also known as hemophilias A, B, and C. Factors VIII and IX deficiency are X-linked disorders affecting primarily males, whereas factor XI deficiency is an autosomal recessive disorder that can affect both males and females.

    Factor VIII deficiency occurs in 1 in 10,000 male births and causes lifelong recurrent soft tissue, muscle, and, most importantly, joint bleeding or hemarthroses. There is a close relationship between factor VIII level and severity of bleeding. Patients with <1% activity have severe disease with frequent, life-threatening bleeding. Patients with 1–5% activity have moderate disease with bleeding weekly or even monthly. Patients with levels over 5% have milder disease with infrequent bleeding.

    Treatment of hemophiliacs has steadily improved. At present, (1) many children and adolescents receive prophylactic therapy several times a week and have few major bleeds; (2) almost all children and adults self-administer coagulation factor concentrates at home on demand with minimal medical supervision; (3) most patients utilize highly purified recombinant factor concentrates that are free of all known viruses.

    Although the life expectancy of a hemophilia patient is near normal and many patients have few damaged joints, there are unresolved health issues such as the increased incidence of hypertension and the enormous expense of optimal therapy. Perhaps the most dreaded complication of hemophilia at present is the development of an inhibitor to factor VIII. This occurs in 15–20% of patients and both complicates therapy and reduces the patient’s quality of life.

HEMOPHILIA B AND C

Almost everything written above about factor VIII deficiency holds true for factor IX deficiency. It is less common, appearing in 1 in 50,000 births, and the protein has a longer plasma half-life so infusions are less frequent. Otherwise the diseases are nearly identical.

    Factor XI deficiency is, however, quite distinct. First, it is autosomal recessive and usually presents as postoperative bleeding. It is more common in Ashkenazi Jewish populations. Also, the correlation between factor level and bleeding is not very strong for unknown reasons. Finally, the only available treatment is infusion with fresh frozen plasma because there is no approved factor XI concentrate.

ACQUIRED HEMOPHILIA AND VON WILLEBRAND DISEASE

Rarely, patients with perfectly normal hemostasis for their entire lives can develop a severe hemostatic defect due to acquisition of an antibody inhibitor to a particular coagulation factor, the adsorption of a coagulation factor onto a tumor surface, or an abnormal protein. These disorders present particular challenges and can, at times, cause very severe, sometimes lethal bleeding.

    Acquired hemophilia is usually due to an antibody to factor VIII. It is seen as a reaction to drugs in patients with an autoimmune disorder such as systemic lupus, in pregnant women, and in otherwise healthy elderly individuals. The presentation in otherwise healthy older patients is the most common event. Patients require intensive support with factor VIII concentrates and, more recently, recombinant factor VIIa. With immunosuppressive therapy using agents like Rituxan, along with the passage of time, most of these inhibitors will disappear and patients make a complete recovery.

    The first example of coagulation factor adsorption causing an acquired deficiency is the interaction of factor X with amyloid protein in patients with primary light-chain amyloidosis. Subsequently, various groups have noted acquired von Willebrand disease due to adsorption of vWF onto tumor surfaces. This is particularly common in patients with lymphoproliferative disorders. Effective therapy requires reduction of the tumor mass.

    Patients with monoclonal gammopathy of uncertain significance (MGUS) may have antibodies against the vWF protein and significant bleeding. A substantial number of patients with Waldenstrom macroglobulinemia, myeloma, and other lymphoproliferative disorders will develop anti-vWF antibodies and acquired vWD.

    Finally, patients with aortic stenosis, patients with ventricular assist devices, and patients with myeloproliferative disorders may unfold and then proteolyze vWF and develop mild to moderate vWD.

IMMUNE THROMBOCYTOPENIA

Immune thrombocytopenia, formerly called idiopathic thrombocytopenic purpura (ITP), is the most common autoimmune disorder. In young children it is a transient disorder that follows a viral infection. In adults ITP is usually a chronic problem, affecting otherwise healthy women three times as often as men. Patients may, rarely, have other autoimmune phenomena. For example, the simultaneous or sequential appearance of autoimmune hemolytic anemia and thrombocytopenia is referred to as Evan syndrome. Although ITP is rarely fatal, it can cause recurrent and sometimes serious mucocutaneous and occasional intracerebral bleeding.

    The most frequent target antigen is the platelet GpIIb/IIIa complex. A small number of patients have antibodies to the GpIb/IX/V complex or other platelet cell-surface proteins. In most cases the antibodies act as opsonins and increase the clearance of platelets from the circulation without perturbing platelet function. Occasionally the antibody may perturb fibrinogen binding, and patients will have both thrombocytopenia and platelet dysfunction that mimics Glanzmann disease. There have been multiple attempts to develop laboratory tests for platelet autoantibodies in ITP patients. None of the tests has been successful for myriad reasons, including a high level of background IgG on the platelet surface and the presence of Fc receptors, which may bind immunoglobulins or immune complexes in a nonspecific manner.

    The typical patient with ITP presents with a history of easy bruising, mucocutaneous bleeding, and—if the platelet count is sufficiently low—petechiae, which arise from the movement of red cells through leaky capillaries into the skin. Most patients have no pathognomonic physical findings or laboratory tests, and ITP remains a diagnosis of exclusion. In contrast with patients who have autoimmune hemolytic anemia, ITP patients have a normal-sized spleen. Typically, other than thrombocytopenia, the blood count is normal, although some patients may have atypical lymphocytes suggesting a recent viral infection. There is debate about what constitutes an adequate workup for ITP. Most hematologists have stopped performing bone marrow examinations in ITP patients unless a more global hematologic abnormality is suspected. The workup usually includes an antinuclear antibodies (ANA), which is usually normal. Many practitioners routinely order HIV testing in all sexually active patients, whereas others order it only if the patient has engaged in a high-risk behavior. Serologic panels for toxoplasmosis, cytomegalovirus, and other viral disorders are rarely positive and not recommended. Chronic ITP is defined as thrombocytopenia that has been present for at least 3 months. The likelihood of a viral etiology or a spontaneous remission is extremely low after 3 months.

    For many years the standard initial therapy has been administration of large doses of glucocorticoids, usually 50 mg of prednisone or equivalent daily. In most patients the platelet count will return to normal after several doses of prednisone, but it falls to pretreatment values as the steroid dose is reduced. If the count remains low after several months of prednisone therapy, the well-established second-line therapy is splenectomy. In most large centers this is a laparoscopic procedure with minimal morbidity and mortality. Patients are immunized against encapsulated organisms such as pneumococcus, meningococcus, and Haemophilus influenzae that are cleared primarily in the spleen. The only remaining infection that is worsened by splenectomy is babesiosis. In adults the spleen seems to be dispensable, and immune function is largely preserved. Splenectomy raises the platelet count to normal in approximately 70% of ITP patients.

    Patients who fail splenectomy and have dangerously low platelet counts (<50,000/µL) are usually given the immunosuppressive medications Imuran or oral cyclophosphamide. Recently, the favored drug is the anti-CD20 monoclonal antibody rituximab (Rituxan). It will induce a remission in 70% of patients who have failed corticosteroids and splenectomy but may require a second course of treatment within a year in 25% of initial responders. Although the complication rate is low, opportunistic infections are a potential problem; several patients have developed progressive multifocal leukoencephalopathy after Rituxan treatment, so caution is advised.

    There is a great desire among patients and treating physicians to avoid splenectomy. One new approach is the administration of pulses of very high-dose dexamethasone given for 4 days a month. After several months of therapy, a small percentage of patients go into remission. The remission rate may increase when patients are given both dexamethasone pulses and four doses of Rituxan as initial therapy. Although this regimen may induce remissions in 70% of patients, the ability to spare patients from splenectomy needs to be balanced against the known and unknown risks of these potent medications. Although not all my colleagues concur, my own approach is to use prednisone followed by splenectomy and to use Rituxan only in the small number of patients who fail these two standard therapies.

    For patients who cannot be put into remission, there are several drugs that can transiently raise the platelet count. Large doses of intravenous immunoglobulin (IVIG) or the anti-RhD immunoglobulin RhoGam have both been used for many years. They both appear to reduce the clearance of antibody-coated platelets. RhoGam is not effective after splenectomy. Because of their expense, the need to administer them intravenously, and their short duration of action, they are recommended only for emergency use or to prepare patients for surgery. Recently, two thrombopoietin mimetics, romiplostim and eltrombopag, have received FDA approval. Both drugs will stimulate marrow production of megakaryocytes, which is suboptimal in many ITP patients, and thereby raise the platelet count. Romiplostim is a novel peptibody TPO mimetic, given as a weekly subcutaneous injection, that binds to the same site on the TPO receptor as native TPO. Eltrombopag is a small molecule, administered orally, that binds to the transmembrane domain of the TPO receptor.

    These drugs may be useful as substitutes for IVIG and RhoGam or for the small number of ITP patients who cannot be put into remission with splenectomy and immunosuppressive medication. The drugs may cause a reversible increase in marrow reticulin and collagen with prolonged use, and there are reports of thrombotic events in association with their use.

HEPARIN-INDUCED THROMBOCYTOPENIA

Heparin is the most common cause of thrombocytopenia in hospitalized patients, affecting 15–20% of patients receiving unfractionated heparin. Heparin-induced thrombocytopenia (HIT) is caused by an antibody directed against a complex of heparin and the heparin-neutralizing protein, platelet factor 4. The heparin-PF4 antibody complex binds to the platelet Fc receptor, which induces both platelet activation and secretion and thrombocytopenia. The spectrum of HIT ranges from patients with mild nonprogressive thrombocytopenia to patients who develop profound thrombocytopenia and to an occasional patient who develops life-threatening thrombosis despite being fully anticoagulated. There is an increased risk of thrombus formation in all HIT patients, which persists for several months after heparin is discontinued.

    HIT is diagnosed by a combination of clinical observation and judicious laboratory testing. The four key features are (1) the degree of thrombocytopenia, (2) the timing of thrombocytopenia, (3) the presence of concomitant thrombosis, and (4) the absence of other obvious causes of thrombocytopenia. A fall of over 50% of the platelet count since starting heparin with a nadir > 20,000/µL; onset of thrombocytopenia 5–14 days after starting heparin, 48 hours if previously exposed to heparin within 30 days; and new thrombosis, skin necrosis, or anaphylactic reaction to heparin infusion are all considered strong predictors of HIT. If HIT is suspected, a heparin-PF-4 enzyme-linked immunosorbent assay (ELISA) test should be ordered. The test has a reported sensitivity of 95% and thus a high negative predictive value. The limitation of the test is that it does not distinguish between IgM and IgA antibodies or the IgG antibodies that cause platelet activation. The reported specificity of 50% can be improved by looking at the optical density (OD) of the ELISA test. An OD >1.00 is more likely to be due to a pathologic IgG antibody. Newer tests are being introduced using IgG-specific antisera that should increase the specificity of the test. A second set of tests that measure platelet activation, such as the serotonin release assay, can identify those antibodies that are most likely to cause HIT and are said to have >90% sensitivity and specificity. The test is quite specialized, not widely available, and may only be run once or twice a week even in large reference laboratories.

    Once HIT is identified, heparin infusion should be immediately discontinued and patients switched to a direct thrombin inhibitor. The two drugs most often used to treat HIT are argatroban, a small-molecule derivative of l-arginine with a plasma half-life of 45 minutes and lepirudin (recombinant hirudin), which has a half-life of 2 hours. Both drugs are given by intravenous infusion and monitored by measuring the PTT. When the platelet count has returned to >150,000/µL, patients are bridged to warfarin, which is continued for 30 days in patients with no thrombosis and 3–6 months in patients with heparin-induced thrombocytopenia with thrombosis (HITT).

    The incidence of HIT should decrease and eventually disappear as newer forms of heparin are introduced that are less immunogenic. For example, the incidence of HIT is <1% for low-Mr heparins like enoxaparin (Lovenox) or dalteparin (Fragmin). Only a handful of HIT cases have been reported in patients receiving the synthetic pentasaccharide fondaparinux (Arixtra). Given the efficacy and safety of the new heparins, unfractionated heparin should probably be reserved for patients who require minute-to-minute titration of heparin dose and prompt reversibility. Unfractionated heparin should only be needed for cardiac catheterization, cardiopulmonary bypass, in intensive care units, and, perhaps, in patients with impaired renal function. There is great interest in the pharmaceutical industry in the design and manufacture of reversible low-Mr heparins, and some are in clinical trials. Given the morbidity and mortality of HIT, and especially HITT, one hopes that the new designer heparins reach the market soon.

THROMBOTIC THROMBOCYTOPENIC PURPURA

Thrombotic thrombocytopenic purpura (TTP) is a relatively rare disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, varying degrees of renal failure, and fluctuating neurologic symptoms. A majority of patients with sporadic TTP have an acquired deficiency in ADAMTS13, a plasma metalloprotease enzyme that remodels the vWF secreted by endothelial cells. In the absence of this enzyme, superlarge vWF multimers interact with circulating platelets and form the hyaline thrombi characteristic of TTP. Although there are rare patients who have a congenital deficiency in ADAMTS13, most patients with acquired deficiency have an autoantibody inhibitor. Patients who develop TTP after stem cell transplantation or drug ingestion have normal levels of ADAMTS13 and may have endothelial damage or dysfunction that induces the release of large quantities of large multimers.

    Patients with the abrupt onset of thrombocytopenia, anemia, elevated blood urea nitrogen and creatinine, and neurologic abnormalities (usually fluctuating levels of consciousness or fluctuating focal findings) are good candidates for TTP. The blood smear should show the presence of schistocytes, while coagulation parameters including PT, PTT, fibrinogen, and D-dimer levels are normal. Elevated lactate dehydrogenase (LDH) is a cardinal feature. Blood should be sent to a reference laboratory for ADAMTS13 activity and inhibitor levels, although the results may not be available for several days or a week.

    The best therapy for TTP is intensive plasmapheresis accompanied by infusion of fresh frozen plasma. Although the therapy was derived empirically, it is rational. Plasmapheresis may remove antibody or antibody-enzyme complexes, while plasma infusion replaces ADAMTS13. Once initiated, daily plasmapheresis should be continued until neurologic symptoms have abated and the creatinine returns to normal along with the platelet count and LDH. Approximately 20% of patients may relapse immediately after plasmapheresis is stopped and may require retreatment. Within a year of initial treatment, 20% of patients may relapse and require additional plasmapheresis. Before the advent of plasmapheresis and plasma replacement, the mortality of TTP was close to 100%. Now it is down to 10–15%.

    There is a long list of therapies that have not been effective in TTP. They include antiplatelet drugs, splenectomy, and some of the older immunosuppressive medications such as prednisone and azathioprine. There are small case series suggesting that the anti-CD20 monoclonal antibody rituximab (Rituxan) may be beneficial in TTP and certainly should be tried in patients with relapsing forms of the disorder.

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