Thrombocytopenias: immune mediated thrombocytopenias, neonatal thrombocytopenias, inherited platelet function disorders.
Immune mediated coagulopathies: hemolytic uremic syndrome, thrombotic thrombocytopenia purpura.
Congenital bleeding disorders.
Acquired bleeding disorders: bleeding in liver disease, bleeding in renal disease, disseminated intravascular coagulation.
1. Description of the problem
What every clinician needs to know
The initial evaluation of a patient with a hemorrhagic problem involves obtaining a very detailed history of bleeding symptoms. The bleeding history forms the basis of the laboratory tests and therapy. There should be no specific or extensive laboratory testing performed until a history and focused physical examination have been gathered. Questioning must be specific and designed to ascertain whether bleeding has occurred in response to trauma or was spontaneous. The diagnostic value of the hemorrhagic symptom will vary with the different bleeding disorders.
Mucosal bleeding: Mucosal bleeding such as petechiae or purpura are important findings that give insight into potential bleeding disorders. Mucosal bleeding can manifest with oral mucocutaneous bleeding such as epistaxis, gum bleeding, menorrhagia, gastrointestinal bleeding, bruising and petechiae. These symptoms usually will indicate platelet vessel disorders such as thrombocytopenias, von Willebrands disease (vWD), platelet function defects and vascular disorders.
Hemarthroses/deep hematomas: Deep hematomas, which are of palpable skin or soft tissue bleeding, and hemarthroses are most often associated with coagulation factor deficiencies or abnormalities.
Surgical versus systemic bleeding: It is important to understand that localized bleeding confined to a single site is often mechanical/surgical in nature and may not be from a systemic coagulopathy. Surgical or mechanical bleeding is usually brisk and out of proportion to laboratory evidence of abnormality, whereas systemic bleeding caused by an underlying or acquired bleeding disorder usually involves multiple bleeding sites and can be prolonged and delayed and thus laboratory testing is usually abnormal.
Platelet/vessel bleeding vs. factor deficiency: Bleeding symptoms from factor deficiency are usually described as delayed type of bleeding and deeper bleeding such as muscle and joints bleeds, whereas platelet/vessel bleeding is more immediate and involves mucosal surface, skin, genitourinary and gastrointestinal tract.
Key management points
1. Thorough history and physical examination:
– Family history is important in developing a differential diagnosis with respect to inherited forms of bleeding disorders.
– Recent medications and past and recent surgical procedures.
– Assessment of bleeding: Systemic vs. local/surgical site bleeding. Sick/ill patient vs. well appearing. Mucosal type bleeding vs. deep muscle or joint bleeding.
2. Coagulation testing:
– Complete blood count and differential.
– PT, PTT, fibrinogen, thrombin time and D-dimers.
3. Stabilization of the patient:
– The therapeutic goals for patients who are bleeding or worse, in hemorrhagic shock, are to stop bleeding and to restore intravascular volume.
2. Emergency Management
Emergency management steps
The main goals are to stop the source of hemorrhage and to ensure there is normal circulating blood volume. Actively bleeding patients must maintain their intravascular fluid and volume replacement must be performed immediately because tissue oxygenation will not be compromised, even at low hemoglobin concentrations, as long as circulating volume is maintained. Hemoglobin concentration and the hematocrit in an actively bleeding individual may be inaccurate because it takes time for the various intravascular compartments to equilibrate. Management should be guided by the rate of bleeding and changes in hemodynamic parameters, such as blood pressure, heart rate, cardiac output, central venous pressure, pulmonary artery wedge pressure and mixed venous saturation.
1. Need to first stabilize the patient and ensure the ABCs of CPR:
Assess the patient and find the source of bleeding.
Ensure there is appropriate IV access.
Aggressive volume expansion and fluid resuscitation.
Blood product support with red cell transfusion.
2. Evaluation of coagulopathy:
Obtain CBC with differential.
Protime, PTT, fibrinogen, D-dimer, thrombin time.
Specific factor evaulation.
3. Correction of coagulopathy:
Fresh frozen plasma (FFP).
Specific factor replacement product.
See Table III. Blood components.
See Table IV. Differential diagnosis of thrombocytopenia in children.
How do I establish a specific diagnosis?
The initial evaluation and assessment of the acutely bleeding patient initially involves a focused but thorough bleeding history as well as a family history at the same time as a detailed physical examination. If the patient’s bleeding history is significant, specific laboratory testing needs to be performed. Laboratory testing needs to be aggressive in the context of significant bleeding, followed with specific laboratory testing as indicated by the initial coagulation results. (Figure 2)
There needs to be a required overall assessment of the coagulation system that can be investigated by the following specific laboratory tests:
Complete blood count (CBC), including a platelet count.
Prothrombin time (PT).
Activated partial thromboplastin time (aPTT).
Thrombin time (TT).
Laboratory tests to be be performed
Prothrombin time (PT): The PT is an in vitro analysis of the coagulation factors inherent in the extrinsic and common pathways. These factors include: factor II, V, VII, X and fibrinogen.The PT is very sensitive to FVII and least sensitive to fibrinogen and thus a specific fibrinogen assay should be performed to evaluate fibrinogen levels and function. The PT test is performed by adding tissue factor (TF), which usually is a prepared reagent of TF (derived from brain tissue), to patient’s plasma and measuring the amount of time for the specimen to clot. Normal time is 11.5-13.5 seconds (depending on laboratory reference range).
Activated partial thromboplastin time (aPTT): The PTT is an in vitro analysis of the coagulation factors inherent to the intrinsic, contact and common pathway factors. Intrinsic pathway include factors VIII, IX and XI; Contact factors include factor XII, high molecular weight kininogen (HMWK) and prekallikrein; and common pathway factors are II, V, X and fibrinogen. The PTT is sensitive to factors XII, XI, IX and VIII, and less sensitive to common pathway factors and fibrinogen. The PTT is very sensitive to the effects of heparin and samples contaminated with heparin will give a falsely elevated PTT. The testing is performed by adding a phospholipid source and a contact initiator such as celite/silica to a patient’s plasma and measuring the amount of time for the sample to clot. Normal time is 25-39 seconds (depending on laboratory reference range).
Thrombin time (TT): The TT is an in vitro test that assesses deficiency in fibrinogen or the function of fibrinogen (dysfibrogenemia). It is the time required for plasma fibrinogen to form thrombin, measured as the time for clot formation after exogenous thrombin is added to citrated plasma. Prolonged TT is seen with abnormalities of fibrinogen and in the presence of heparin or degradation products of fibrin or fibrinogen. Normal time is less than 22 seconds.
Fibrinogen: The test for fibrinogen is a functional assay that measures clotting activity upon addition of excess thrombin and diluted plasma and is detected by measuring electromagnetic viscosity or by an immunologic assay that measures the protein, usually by ELISA technique. Normal is 200-400 mg/dL.
Platelet count: This is a quantitative analysis of platelets and is standard in a complete blood count (CBC). The gold standard is a manual counting of platelets on peripheral smears but most platelet counts are done through Coulter counters and optical or flow cytometric based methods. Normal is150-450,000 thou/UL.
1:1 Mixing study: A mixing study is used to investigate the cause of a prolonged screening test (PT or aPTT) result. Using patient plasma that has been mixed with an equal volume of normal pooled plasma, the cause of the initial prolonged result may be determined to be either a deficiency of one or more factors or an inhibitor. Correction of the prolonged test result generally indicates a factor deficiency. Non-correction or partial correction generally indicates an inhibitor or a severe (or sometimes multiple) factor deficiency.
Overview of the coagulation system
When a blood vessel is damaged the smooth muscle in the vessel wall causes vasoconstriction, at the same time von Willebrand factor (vWF) binds to circulating platelets which in turn bind to exposed collagen in the broken vessel walls. These platelets become activated, changing from a round to a flat and pointed shape. They degranulate, releasing several substances to attract more platelets, cause vasoconstriction, and activate clotting factors in the blood. Soluble clotting factors circulating in the area are triggered to convert the soluble protein fibrinogen into insoluble fibrin strands, trapping and binding together platelets and RBCs.
This system is tightly regulated by a negative feedback mechanism in which the anticoagulation system as well as the finbrinolytic system is simultaneously activated. The classical coagulation cascade is initiated when cells bearing tissue factor (TF), a transmembrane protein that acts as a receptor and cofactor for FVII, are exposed at a site of injury. Subsequent (and simultaneous) events can be summarized as follows.
The resulting FVIIa/TF complex catalyzes activation of FX and FIX. FXa then interacts with its cofactor Va to generate a small amount of thrombin. Simultaneously, FVIII bound to multimeric vWF and platelets bind to the extracellular matrix at the site of injury forming a platelet plug (primary hemostasis). This provides a phospholipid platform upon which the small amount of “priming” thrombin activates the bound platelets and other factors (FV, FVIII and FXI) that then amplify the process. The platelet can thus be seen to perform two functions: primary hemostasis through formation of the vWF-platelet collagen plug and service as a phospholipid platform that facilitates activity of the TF-FVIIa complex.
Propagation of the clotting cascade is then achieved by a burst of thrombin on the platelet phospholipid membrane surface mediated by assembly of the “tenase” (FIXa/FVIIIa) complex and the “prothrombinase complex” (FXa and FVa), which results in formation of a sufficient amount of fibrin to form a meshwork and to stabilize the initial platelet plug. Thrombin generation is essential if a stable clot is to be formed. Thrombin generation is a key component in the steps of fibrin formation.
Thrombin is important in release of FVIII from vWF and activation of FVIII; activates factor V and XI; activates FXIII causing crosslinking of fibrin; promotes platelet activation; binds to thrombomodulin, activating the protein C complex; and finally, down regulates the fibrinolytic pathway by activating the inhibitor, thrombin activator fibrinolytic inhibitor (TAFI) .
This cell-based model (Figure 1) that integrates both the humoral cascade and cellular factors is now widely accepted as representative of actual hemostasis in vivo from inactive to activated in a dual sequence known as the clotting cascade. Understanding the coagulation process will help in understanding the potential defects that can occur and cause either congenital bleeding disorder or acquired bleeding disorders. Most coagulopathies that are encountered in the ICU setting are more often than not acquired disorders such as disseminated intravascular coagulation (DIC), liver disease and renal disease. Theses topics will be detailed further.
I. Disseminated intravascular coagulation
DIC is a clinical and pathological syndrome that is a secondary coagulation response to a range of illnesses. It is characterized by systemic activation of the coagulation pathways that regulate the body’s hemostasis and thrombosis, which can then result in the generation of fibrin clots that may cause organ failure with concomitant consumption of platelets and coagulation factors that may result in clinical bleeding. DIC never occurs in isolation and recognition that a patient has a clinical disorder which may result in the development of DIC is the key to appropriate investigation and management.
The most common causes of DIC are endotoxin generated such as sepsis; other causes include major trauma, burns, obstetrical complications, vascular malformations, envenomations and malignancy. The result of DIC is end organ damage/failure mainly due to microthrombi. (Table I)
These conditions have the ability to induce systemic activation of coagulation either by activating cytokines as part of a systemic inflammatory response or by causing the release of, or exposure to, procoagulant substances. The pathogenesis of DIC is complex and the main driving force is on the enhanced generation of thrombin in vivo. Other important components include increased tissue factor expression, suboptimal function of natural anticoagulant systems, dysregulation of fibrinolysis and increased anionic phospholipid availability.
During DIC there is generalize activation of the coagulation system leading the thrombin generation, fibrin formation and activation of the anticoagulation and fibrinolytic systems, which results in microthrombi formation and consumption of coagulation factors and platelets. Initially, there is excessive TF release which leads to thrombin production. In normal physiology, TF is inhibited by tissue factor pathway inhibitor (TFPI), which leads to downregulation of thrombin generation. ,In DIC, there is continued thrombin generation, usually by prolonged TF exposure or production from the underlying process, such as sepsis or trauma or by activation of the intrinsic system.
Clinical Manifestations: Patient may present in a variety of ways based upon the underlying disease. The most common manifestations include hemorrhage, multisystem organ damage (renal, CNS, hepatic, respiratory) and shock. Patient will have manifestation of petechiae, purpura and bleeding from lines, ET tubes and IV sticks, indicating systemic coagulopathy. Diagnosis of DIC is made by assessing the whole clinical picture, circumstances, underlying disease and laboratory evaluation.
There is no single laboratory test that can establish or rule out the diagnosis of DIC. The ISTH scoring system can be helpful in establishing the diagnosis of DIC. This scoring system has be proven to be both sensitive and specific for the diagnosis of overt DIC and a worsening score may be helpful in predicting patient morbidity and mortality. (Table II)
Both liver disease and Vitamin K deficiency can have very similar laboratory findings as DIC and with respect to severe liver disease there is likely a component of both DIC and coagulopathy of liver disease. The laboratory diagnosis of DIC is based on evidence of fragmentary hemolysis, fibrinogen and platelet consumption with evidence increased fibrinolytic activity. The PT is prolonged, which reflects coagulation factor consumption; however, the aPTT may be variable, depending on the plasma level of FVIII.
Fibrinogen levels are usually significantly decreased, but initially may be only slightly low because of the acute phase response. The thrombin time is prolonged because of interference from the increase in fibrin degradation products (FDPs) and the hypofibrogenemia. Levels of fibrinopeptide A, F1.2 and thrombin antithrombin are increased and antithrombin is decreased. The peripheral smear may show schistocytes and reduced platelets.
Therapy: Treatment of DIC is aimed at the underlying disease process and secondly at the coagulopathy that follows. It is important not to treat the abnormal numbers but rather to treat the patient who is bleeding or who may have a thrombotic complication. Platelets can be given to maintain a platelet count above 20,000/μL. Fresh frozen plasma (FFP) is administered to replaced generalized factor deficiencies. Cryoprecipitate should be given for hypofibrinogenemia of less that 100mg/dL.
Recent evidence suggests that the depletion of anticoagulant proteins such as antithrombin, protein S and protein C play a role in DIC. Replacement of these factor deficiencies have been shown to improve the coagulopathy in DIC. Protein C concentrate and activated protein C (APC) have been used effectively in treating purpura fuminans in infants with homozygous protein C deficiency.
More recently there have been large clinical trials in adults and pediatrics in which patients with DIC were treated with APC infusion. These trials showed decreased overall mortality at 28 days compared to controls but there was a trend to increased bleeding complications in the treatment arm. Further studies need to be done to support the regular use of APC concentrates.
With respect to antithrombin replacement therapy, there have been some studies that showed that the 28 day mortality rate in patients that received AT showed benefit, while other studies did not show any benefit and the use of AT remains on a case-by-case basis and not standard treatment.
Other options are the use of anticoagulation therapy with heparin. The theory is that heparin can decrease or inhibit thrombin formation and thus interrupt coagulation activation. Heparin in low dose (10U/kg/hr) may be used to block thrombin generation. Heparin also may be considered in DIC caused by leukemias such as acute promyelocytic leukemia (M3) and monocytic, myelomonocytic (M4-M5) leukemia.
II. Liver disease
Moderate to severe liver disease leads to deficiencies of the coagulation factors that are normally produced in the liver. Liver disease can either be acute or chronic and is associated with bleeding manifestations but sometimes also with thrombotic complications. The bleeding complications of liver disease are directly related to decreased hepatic synthesis of coagulation factors, Vitamin K deficiency, thrombocytopenia with acquired platelet dysfunction.
Decreased production of clotting factors: The liver is the organ that primarily produces all the coagulation factors except for FVIII and vWF, and therefore impairment of the liver function will affect the production of these factors. The deficiency of each factor is proportional to the coagulation factor half-life; as such, FVII has the shortest half-life and thus it is the first coagulation factor deficiency to appear during acute liver dysfunction. Along with decreased fibrinogen production, there is usually a component of dysfibrinogenemia.
Thrombocytopenia and platelet dysfunctions: Thrombocytopenia is a common finding in liver disease and is usually multifactorial. There is splenomegaly and hypersplenism which causes sequestration and trapping of the platelets. There may also be associated immune mediated thrombocytopenia, and finally, there is decreased thrombopoietin production by the liver and therefore decreased platelet production by the megakaryocytes.
Platelet dysfunction is also seen in liver disease. Platelet dysfunction arises from increased fibrin degradation production (FDP) production and a high level of high density lipoprotein altering nitric oxide content, all of which impairs platelet adhesion and aggregation.
Systemic fibrinolysis and DIC: There is decreased synthesis of alpha2-antiplasmin and PAI-1 and increase of fibrinolytic enzymes such a tPA which then increases systemic fibrinolysis. There may be concomitant DIC where one can see increased thrombin formation because of decreased natural inhibitors to clotting such as antithrombin, protein C and protein S. There may also be injury to the hepatocytes causing tissue factor release.
Diagnosis: The main clinical differential diagnosis in severe liver disease is DIC, and laboratory testing may help in differentiating between the two. Usually in liver dease, the PT is more prolonged compared to the aPTT, whereas in DIC both are equally prolonged. The platelet count may be only mildly decreased in liver disease. With respect to coagulation factors, both factors V and VII are decreased while FVIII is increased in liver disease.
Management of bleeding complications in liver disease involves replacement of factor deficiencies, correction of acquired vitamin K deficiency and thrombocytopenia. There is likely a componernt of vitamin K deficiency and replacement of vitamin K should be an initial step. Vitamin K should be administered daily for 3 days. For factor replacement, FFP should be administered at 10-15 ml/kg IV and for hypofibrinogememia, cryoprecipitate may be given.
Platelet transfusion may be given if the platelet count is less than 50,000 or if patient is actively bleeding or in preparation for high risk procedures or surgeries. If bleeding continues despite these conventional tactics, then prothrombin complex concentrates and more recently recombinant factor VIIa (Novoseven) have been used. One must weigh the possible increased risk of thrombotic complication when using these products to control hemostasis.
III. Vitamin K deficiency
Vitamin K is important in the carboxylation of factors II, VII, IX and X as well as Protein C and Protein S. Vitamin K is derived from yellow and green plants as vitamin K1 (phylloquinone), is absorbed through an intact GI mucosa and is a lipid soluble vitamin. Any condition which could impair absorption, such as malabsorption syndromes and liver dysfunction, will impact production of the vitamin dependent clotting factors. Clinical presentation can be varied. Infants with hemolytic disease of the newborn may present with intracranial hemorrhage or gastrointestinal bleeding. In children and adults, presentation is usually bruising, epistaxis and mouth bleeding.
Hemolytic disease of the newborn is caused by lack of vitamin K administration during the neonatal period in infants who are exclusively breast-fed and the infant develops a diarrheal illness. Other important causes are maternal medication taken during pegnancy with anticonvulsants and anti-TB medication. In the childhood and adult age group, prolonged fasting, profuse and excessive emesis and medications such as antibiotics can predispose patient into developing relative vitamin K deficiency.
Malabsorption syndrome from many causes, such as celiac disease, cystic fibrosis, cholestatic liver disease, biliary astresia and alpha-1 antitrypsin all may cause vitamin K deficiency. Laboratory findings show an elevated PT with lesser or no prolongation of the PTT, normal fibrinogen and normal platelet count.
Therapy is based on severity of the bleeding/clinical manifestation and laboratory findings. If there is no bleeding symptoms and only elevated PT/PTT then administration of vitamin K either IM, SQ or IV may be given at 1-5 mg for infants and 5-10 mg for children and 10 mg for adults. However, if there is severe bleeding, then plasma products such as FFP should be given at 10-15ml/kg along with administration of IV vitamin K. If there is an issue with volume restriction then prothrombin complex concentrates may be used.
IV. Renal disease
Renal disease has been associated with coagulopathy and is correlated with the degree or severity of the renal dysfunction. The most common hemostatic derangement is platelet dysfunction and abnormal platelet-vessel interaction. There are substances in a uremic patient that contributes to platelet dysfunction. Guanidinosuccinic acid is known to be a byproduct and accumulate in uremic patients. This product is an L-arginine derivative and can increase nitric oxide and cyclic GMP, which in turn cause vascular relaxation and platelet dysfunction. There may be a component of thrombocytopenia associated with chromic renal disease.
Also, anemia of chronic disease and decreased erythropoietin production cause decreased red cell production and red cell mass. This disturbs the rheologic normal process that occurs between the blood and vessels. Clinical manifestations of bleeding are usually mucosal type bleeding such as mouth and gum bleeding, epistaxis, excessive bruising and sometime gastrointestinal bleeding. Initial screening laboratory testing is normal unless there is loss of factor IX and XII in the urine, in which case the PTT may be prolonged.
The bleeding time and the platelet function analyzer (PFA) are usually prolonged, which is an indication of platelet dysfunction. The main therapy for bleeding is correction of renal dysfunction either by dialysis or the underlying renal pathology improves over time. Supportive measures include correction of anemia with either red cell transfusion in the acute bleeding period and the correction of platelet dysfunction with the use of desmopressin (DDAVP).
DDAVP exerts its action by releasing vWF and other agonists from platelets and endothelial cells and improves platelet dysfunction. Platelet transfusion can also be used in the acute setting and is a short term fix, as the transfused platelets in a uremic patient will eventually become dysfunctional and ineffective.
There are many causes of thrombocytopenia, and these are usually categorized into three general mechanisms: increased platelet destruction, decreased platelet production or platelet sequestration, usually by hypersplenism. The differential diagnosis of thrombocytopenia is outlined in Table IV. It is important to discern the etiology of the thrombocytopenia because it may affect the type of therapy needed to treat the bleeding symptoms. The normal platelet count range is 150,000-450,000 μ/L. of thrombocytopenia is outline
Most agree that a platelet count of greater than 20,000 μ/L rarely causes spontaneous bleeding and a general threshold for intervention is a platelet count less than 20,000μ/L. One must always assess the clinical findings and disease process in the decision to intervene. Therapy is dependent on the etiology of the thrombocytopenia.
In the ICU setting, sepsis induced thrombocytopenia is a common etiology of thrombocytopenia and bleeding. Sepsis-induced thrombocytopenia is multifactorial and caused by a combination of platelet destruction/consumption such as DIC and marrow suppression. Therapy is treatment of the underlying infection and supportive care with platelet and blood product support.
Immune thrombocytopenia purpura
Immune thrombocytopenia purpura is a bleeding disorder that is secondary to an immune-mediated platelet destruction by macrophages in the reticuloendothelial system. The disease can either be acute or chronic. In the acute setting, it is mostly seen in children and is a common diagnosis for thrombocytopenia in children. In children, the peak age is 2-4 year with equal frequency in males and females. There may be an antecedent viral syndrome noted in the history. Most will resolve spontaneously over a period of weeks to months and without any specific therapy. Most patients will present with mucosal-type bleeding with increased bruising, petechial rash, mouth bleeding, epistaxis and sometimes gastrointestinal bleeding.
However, despite the severely low platelet count of even less than 10,000μ/L, most patient will have little to none overt bleeding. The most devastating bleeding complication seen in ITP is intracranial hemorrhage (ICH). The estimated incidence is less than 0.1%. Thrombocytopenia that persists in children greater that 12 months is likely due to the chronic form of ITP, but is less common.
Therapy is based on clinical bleeding symptoms but there is debate if there is an absolute number that patients should be treated. There is some evidence that severe life-threatening bleeding is rare in children with acute ITP even if the platelet count is less then 20,000 and that therapy may actually not prevent these severe bleeding complications. Thus most patients with typical ITP with no or mild bleeding such as dry purpura (bruising and petechiae) only may be managed conservatively with close observation alone and no medical therapy.
Patients with mucosal bleeding or are unable to get close followup or patients prone to trauma such as toddlers therapy may be indicated to raise the platelet count over 20,000.Therapy: The most common and reliable therapeutic option (see Table VI) is intravenous immunoglobulin (IVig) and corticosteroids. Both are equally good at raising the platelet count and have equal efficacy. IVIg will have a more rapid response compared to corticosteroids ( 24 hours vs. 48-72 hours).
There is no therapeutic use of platelet transfusions because the transfused platelets will also be coated with the IgG autoantibodies and cleared by the reticuloendothelial system. However, in a patient with severe life-threatening bleeding such as an intracranial hemorrhage then platelet transfusion is a viable option in that it may give a transient response and help in hemostasis. For these life-threatening scenarios, one would use all of the therapeutic options (Corticosteroid at high dose 30mg/kg/day IV; IVIg 1gm/kg/day X 2 days, Platelet transfusion either continuous or q6 hours for 24 hours).
Thrombotic microangiopathy: hemolytic uremic syndrome and thrombotic thrombocytopenia purpura
Hemolytic uremic syndrome (HUS) is characterized by severe thrombocytopenia, renal failure and microangiopathic hemolytic anemia. HUS is associated with a range of disorders but commonly associated with bloody diarrhea caused by shiga-like toxin producing bacteria in more than 90% of cases of infected-related HUS in children. Non-diarrheal associated HUS is commonly termed atypical HUS and can result from a variety of disorders. The pathophysiology is marked by endothelial damage resulting in platelet-associated thrombosis and microvascular occlusion. The primary organ affected are the kidneys.
Histologically, one sees accumulation of the platelet thombi containing vWF with very little fibrin. The red blood cells are mechanically sheared as they try to pass through these narrowed vessels, leading to schistocyte formations. HUS has been caused by a shiga-like toxin producing strains of Escherichia coli O157:H7 (STEC). Infection with other E. coli serotypes, Shigella dysentariae and other microbes can also cause HUS. Atypical HUS or non-diarrheal HUS also can be caused by Streptococcus pneumoniae infections.
A minority of HUS cases can be caused by mutations in the complement system which are inherited in either an autosomal dominant or recessive inheritance pattern. These patients have low levels of the third component of the complement system (C3), which is associated with genetic mutation of Factor H gene (CHF). Laboratory findings typically are moderate to severe thrombocytopenia, indications of hemolysis with elevated reticulocyte count, elevated LDH and negative DAT.
The peripheral smear will show fragmented red cell schistocytes. Coagulation testing with the PT and PTT are normal, with elevated fibrinogen, FVIII, vWF and D-dimers. Treatment is support care, including dialysis. Platelet transfusions should be avoided as they could cause worsening of the microangiopathy and should be reserved for patients with severe life-threatening hemorrhage.
Thrombotic thrombocytopenia purpura (TTP) also consists of thrombocytopenia, microangiopathy hemolytic anemia and renal insufficiency with associated neurologolical signs. The pathophysiology is different in that TTP is from a deficiency of von Willeband factor cleaving metalloprotease – ADAMTS13. This deficiency results in accumulation of ultra large vWF multimers which in turn binds to platelets leading to microthrombi formation in the microvasculature of all organs. The microthrombi then lead to red cell destruction and formation of schistocytes.
ADAMTS13 deficiency can either be primary (congenital) or acquired, mostly due to antibody formation. TTP is be considered in patients with microangiopathy hemolytic anemia and thrombocytopenia and there is evidence of hemolytic anemia with elevated reticulocytosis, elevated LDH with associated thrombocytopenia and red cell fragmentation seen in the peripheral smear. The renal dysfunction may be mild to normal. The PT, PTT and DAT are typically normal and testing for the ADAMTS13 activity level will usually confirm the diagnosis, but therapy should be instituted well before the results of this is obtained.
Management is immediate initiation of therapeutic plasma exchange (TPE). Plasma exchange uses FFP as the exchange blood product. The patient’s plasma is removed and replaced by FFP, which removes the ultra-high multimers, repletes back the ADAMTS13 and removes the autoantibody. TPE should be preformed daily until the platelet count normalizes to greater than 150,000 on two consecutive days and LDH normalizes; at that point the TPE can be weaned off.
Adjunctive therapy includes the use of corticosteroid, espicially in cases that initially do not respond well to TPE or in refractory cases. Rituximab (antiCD20 antibody) therapy has recently been used, espicially in patients who have demonstrated to have an inhibitor. Platelet transfusion should be avoided and should only be used in patients with severe life-threatening hemorrhage.
VI. Inherited bleeding disorders
Deficiencies of factors VIII (hemophilia A), IX (hemophilia B) and vWF in vWD comprise the spectrum of common hemophilias and bleeding disorders seen. The X-linked disorders of hemophilia A and B are similar in clinical manifestations and treatment, while vWD is slightly different. The clinical manifestation of factor VIII and IX deficiencies correlates with the baseline factor levels of the patient. Severe hemophiliacs have a factor level of less than 1% and are at risk for spontaneous bleeding such as hemarthrosis, hematomas, GI bleeding and intracranial hemorrhage.
Hemophilia patients at 1-5% factor levels are termed moderates and have less severe bleeding complications, while factor levels above 5% are a mild form of the disease which rarely cause spontaneous bleeds and bleeds that do occur are usually precipitated by trauma. vWD results from either a quantitative or qualitative deficiency in vWF, which usually manifests with mucosal-type bleeding; however, some forms can have bleeding severity similar to hemophilia patients.
Hemophilia A and Hemophilia B: Factor VIII deficiency is a congenital X-linked recessive inheritance that results in absent or decreased circulating factor VIII activity, leading to bleeding. Incidence is 1:5000 male births. Because it is X-linked recessive, there is usually a family history, but 30% of newly diagnosed patients will have a negative family history so spontaneous mutation is the likely cause. Factor IX also results from a congenital deficiency or absence of factor IX. It is also a an X-linked recessive disorder; its incidence is 1:25,000 male births and accounts for about 20% of hemophilia patients.
Factor VIII and factor IX are important cofactors in the coagulation cascade in that both act as cofactors on the phospholipid surface of the platelets causing further activation of FX and FV, ultimately producing thrombin. Patients with deficiency in factor VIII or IX are unable to produce enough thrombin to sustain stable clot formation. The hallmarks of hemophilia patients are delayed bleeding along with deep tissue bleeding such as hemarthrosis and muscle hematomas. Management relies on factor replacement for bleeding complications.
von Willebrand Disease
vWD is a disorder characterized by either a quantitative or qualitative deficiency in vWF and is the most common inherited bleeding disorder, affecting about 1% of the population. Inheritance is usually autosomal dominant but some forms are autosomal recessive. it affects both male and females equally and there are not racial of ethnic differences. vWF is a large multimeric protein which is important in the bridging of the platelet to the vessel endothelium and platelet to platelet binding, and therefore is critical in platelet adhesion and aggregation.
It also acts as a carrier protein for factor VIII and prevents its degradation maintaining its normal half-life. vWD is classified into three types; type 1, a partial quantitative deficiency of vWF; type 2, functional defect in vWF; and type 3, complete absence of vWF. Type 1 is the most common and accounts for about 75-80% of all vWD while Type 3 account for about 1% of all vWD patients and type II accounts for the remainder. Diagnosis relies on careful history and laboratory testing, which includes vWF antigen level, a function assay such as ristocetin cofactor activity, multimers studies and FVIII activity level.
Because vWF is an acute phase reactant and is also affected by various clinical conditons such as stress, blood type, thyroid levels and age, testing can be difficult and may need to be repeated. Bleeding manifestation is mainly mucosal-type bleeding with easy bruising, epistaxis, menorrhagia and GI bleeding. Some type 2 and type 3 vWD will manifest very similar to hemophilia patients. Therapy is multimodal therapy with with the use of antifibrinolytic agents and DDAVP, as well as factor replacement therapy with plasma derived products such as Humate-P. (Table V)
What's the evidence?
Drews, RE. “Critical issues in hematology: anemia, thrombocytopenia, coagulopathy, and blood product transfusion in critically ill patients”. Clin Chest Med.. vol. 24. 2003. pp. 606-22. (Good review article of management of bleeding in an ICU setting.)
Goodnight, SH, Hathaway, WE. Disorders of Thrombosis and Hemostasis: A Clinical Guide. 2001. pp. 3-19. (Excellent overview of hemostasis and discussion of clinical conditions seen in children and adults.)
Dahlbach, B. “Blood Coagulation”. Lancet. vol. 355. 2000. pp. 1627-32. (A concise review of the coagulation pathways and its interactions.)
Kor, DJ, Gajic, O. “Blood product transfusion in the critical care setting”. Current Opinions in Critical Care.. vol. 16. 2010. pp. 309-16. (Good review of transfusion management in the ICU setting.)
“Guidelines for the diagnosis and management of disseminated intravascular coagulation”. British Journal of Haematology.. vol. 145. 2009. pp. 24-33. (Excellent review of DIC, pathophysiology and management.)
Toh, CH, Hoots, WK. “The scoring system of the Scientific and Standardisation Committee on Disseminated Intravascular Coagulation of the International Society of Thrombosis and Haemostasis: A 5 year overview”. J Thrombosis and Haemostasis.. vol. 5. 2007. pp. 604-6.
Bernard, GR, Ely, EW. “Safety and dose relationship of recombinant human activated factor protein C for coagulopathy in severe sepsis”. Critical Care Medicine. vol. 29. 2001. pp. 2051-9. (Discusses the evidence and role of Protein C in sepsis.)
Kujovich, JL. “Hemostatic defects in end stage liver disease”. Critical Care Clin.. vol. 21. 2005. pp. 563-87. (Excellent review of coagulopathy seen in liver disease.)
Trotter, JF. “Coagulation abnormalities in patients who have liver disease”. Clinical Liver Disease.. vol. 10. 2006. pp. 665-78. (Excellent review of coagulopathy seen in liver disease.)
Flood, VH, Galderisi, FC, Lowas, SR. “Hemorrhagic disease of the newborn despite vitamin K prophylaxis at birth”. Pediatric Blood and Cancer. vol. 50. 2008. pp. 1075-1077. (Discusses issues with hemorrhagic disease of the newborn and vitamin K deficiency.)
Blonski, W, Siropaides, T. “Coagulopathy in liver disease”. Current Treatment Options Gastoenterology. vol. 10. 2007. pp. 464-73. (Good review of current therapeutic options in liver disease.)
Holden, RM, Harman, GJ. “Major bleeding in hemodialysis patients”. Clinical Journal of American Society Nephrology. vol. 3. 2008. pp. 105-10.
Noris, M. “Uremic bleeding: closing the circle after 30 years of controversies?”. Blood. vol. 94. 1999. pp. 2569-74.
Buchanan, GR. “Thrombocytopenia during childhood: what the pediatrician need to know”. Peadiatrics Review.. vol. 26. 2005. pp. 401-9. (Excellent review on the differential diagnosis of thrombocytopenia in children.)
Neunert, C, Lim, W. “The American Society of Hematology 2011 evidence-based practice guidelines for immune thrombocytopenia”. Blood. vol. 117. 2011. pp. 4190-207. (This reviews all published evidence related to ITP in both adults and children and recommendations on therapeutic options.)
Blanchette, V, Bolton-Maggs. “Childhood immune thrombocytopenia pupura: diagnosis and management”. Pediatric Clinics of North America. vol. 55. 2008. pp. 393-420. (Good review of childhood ITP and therapeutic recommendations.)
Caprioli, J, Pengb, L. “The hemolytic uremic syndromes”. Current Opinions in Critical Care. vol. 11. 2005. pp. 487-92. (Good review of hemolytic uremic syndrome.)
Caprioli, J, Noris, M. “International registry of recurrent and familial HUS/TTP. Genetic of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment and outcomes”. Blood. vol. 108. 2006. pp. 1267-79. (Excellent review on pathogenesis, etiology and prognosis of atypical HUS.)
Zheng, XL, Sadler, JE. “Pathogenesis of thrombotic microangiopathies”. Annual Review of Pathology.. vol. 3. 2008. pp. 249-77.
George, JN. “How I treat patients with thrombotic thrombocytopenia purpura: 2010”. Blood.. vol. 116. 2010. pp. 4060-9. (Excellent review on therapeutic options and management of patients with TTP.)
Sohal, AS, Gangji, AS. “Uremic bleeding: patholophysiology and clinical risk factors”. Thrombosis Research. vol. 118. 2006. pp. 417-22. (Reviews the clinical causes and importance of bleeding in patients with renal insufficiency.)
Dunn, AL, Abshire, TC. “Recent advances in the management of the child who has hemophilia”. Hematology Oncology Clinics of North America.. vol. 18. 2004. pp. 1249-76. (A very good review of children with hemophilia, genetic, clinical presentation and treatment options.)
Manco-Johnson, MJ, Abshire, TC, Shapiro, AD. “Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia”. New England Journal of Medicine. vol. 357. 2007. pp. 535-44. (Review of clinical trial of treatment option of joint disease in hemophilia patients.)
Mannucci, PM. “Treatment of von Willebrand Disease”. New England Journal of Medicine.. vol. 351. 2004. pp. 683-94. (Discusses the management of patient with vWD.)
Federici, AB, Mannucci, PM. “Management of inherited von Willebrand disease in 2007”. Annals of Medicine.. vol. 39. 2007. pp. 346-58. (Reviews treament options in patients with vWD.)
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- 1. Description of the problem
- 2. Emergency Management
- 3. Diagnosis
- What's the evidence?