How I diagnose and treat thrombocytopenia in geriatric patients.

ABSTRACT: Thrombocytopenia in older individuals is a common but diagnostically challenging condition that has variable clinical impact to those who are affected. Diagnostic approach requires evaluation of the preexisting clinical conditions, detailed review of medications, and assessment for disorders that warrant urgent treatment. In this article, we describe a systematic approach to diagnosis of thrombocytopenia and present a schematic review for management strategies. Three clinical scenarios are presented that are relevant for their prevalence and management challenges in an older adult population. The first scenario addresses primary immune thrombocytopenia (ITP) and reviews different treatment options. The second one addresses complications of thrombocytopenia in management of the myelodysplastic syndrome. The last one reviews diagnostic challenges of drug-induced ITP.

Impact of treatment and outcomes for patients with posttransplant drug-associated thrombotic microangiopathy.

BACKGROUND: Drug-induced transplant-associated thrombotic microangiopathy (DTA-TMA) is a rare but serious complication that can occur after hematopoietic cell transplantation (HCT) or solid organ transplantation (SOT) without guidelines for optimal management of this condition. STUDY DESIGN AND METHODS: Given the ambiguity surrounding the treatment for DTA-TMA, we conducted a retrospective review to evaluate the impact of different treatment strategies in DTA-TMA patients. Our primary endpoint was to determine the overall response rate (ORR) for DTA-TMA based on the type of treatment modality chosen while secondary endpoints included the time to response, relapse rates, and overall survival for DTA-TMA cases. RESULTS: There were a total of 14 DTA-TMA patients of whom nine were post-HCT and five were post-SOT. Most of the DTA-TMA cases were due to tacrolimus (n = 11) with a minority related to sirolimus (n = 3). A total of nine of 14 patients demonstrated response and five had no response to therapy. The ORR among the DTA-TMA patients after HCT and SOT who received plasma exchange (PLEX) were 25 and 100%, respectively. The ORRs among the patients (includes HCT and SOT) who received rituximab (n = 3) and eculizumab (n = 5) were 67 and 60%, respectively. There were two relapses noted in our study and both were in the HCT group. CONCLUSION: While discontinuation of the offending agent may be sufficient for treatment of DTA-TMA after HCT, PLEX may be a reasonable option for DTA-TMA after SOT. Although the results are encouraging with rituximab and eculizumab in the treatment of DTA-TMA, larger prospective studies are needed to validate our findings.

Acquired von Willebrand syndrome in a child following Berlin Heart EXCOR Pediatric Ventricular Assist Device implantation: case report and concise literature review.

The development of acquired von Willebrand syndrome (AVWS) after placement of a pulsatile-flow left ventricular assist device (LVAD) is rare and only recently recognized. We report the case of a young infant who was diagnosed with ventricular assist device (VAD)-related AVWS following implantation of a Berlin Heart EXCOR Pediatric Ventricular Assist Device (Berlin Heart Inc., The Woodlands, Texas, USA) for treatment of severe heart failure. Despite significant bleeding, the patient was successfully managed with von Willebrand factor-containing concentrate until VAD explantation led to definitive resolution of the AVWS. This case demonstrates that the possibility of this diagnosis should be considered in pediatric patients when extensive, nonsurgical bleeding is encountered after pulsatile-flow VAD implantation.

Life-threatening bleeding in a patient with mild hemophilia A and heterozygosity for von Willebrand disease Type 2N.

Hemophilia A and von Willebrand disease (VWD) are distinct bleeding disorders with a spectrum of clinical phenotypes. They are characterized by mutations in either factor VIII (F8) or von Willebrand factor (VWF) genes, respectively. The pattern of inheritance and appropriate laboratory evaluation differentiates these diseases, and treatment strategies for both are different. Here, we report a male patient with hemophilia A and VWD Type 2 Normandy (N) mutations who presented with life-threatening bleeding. We document his medical history, clinical course, management, and diagnostic work up.

Use of purified fibrinogen concentrate for dysfibrinogenemia and importance of laboratory fibrinogen activity measurement.

We report a patient with dysfibrinogenemia treated with purified fibrinogen concentrate who had discrepant post-treatment laboratory values. The patient had mild bleeding symptoms and was diagnosed with dysfibrinogenemia based on fibrinogen activity of 51 mg/dl and antigen of 240 mg/dl. He was treated for an adenoidectomy with purified fibrinogen concentrate (RiaSTAP®) at a dose of 70 mg/kg. A discrepancy in post-treatment fibrinogen activity was observed between the hospital and reference laboratories. Investigation revealed differences in laboratory assay and calibration methods. Fibrinogen concentrate may be a treatment option for patients with dysfibrinogenemia, but accurate laboratory technique is critical for fibrinogen measurement.

Intersection of mechanisms of type 2A VWD through defects in VWF multimerization, secretion, ADAMTS-13 susceptibility, and regulated storage.

Type 2A VWD is characterized by the absence of large VWF multimers and decreased platelet-binding function. Historically, type 2A variants are subdivided into group 1, which have impaired assembly and secretion of VWF multimers, or group 2, which have normal secretion of VWF multimers and increased ADAMTS13 proteolysis. Type 2A VWD patients recruited through the T. S. Zimmerman Program for the Molecular and Clinical Biology of VWD study were characterized phenotypically and potential mutations identified in the VWF D2, D3, A1, and A2 domains. We examined type 2A variants and their interaction with WT-VWF through expression studies. We assessed secretion/intracellular retention, multimerization, regulated storage, and ADAMTS13 proteolysis. Whereas some variants fit into the traditional group 1 or 2 categories, others did not fall clearly into either category. We determined that loss of Weibel-Palade body formation is associated with markedly reduced secretion. Mutations involving cysteines were likely to cause abnormalities in multimer structure but not necessarily secretion. When coexpressed with wild-type VWF, type 2A variants negatively affected one or more mechanisms important for normal VWF processing. Type 2A VWD appears to result from a complex intersection of mechanisms that include: (1) intracellular retention or degradation of VWF, (2) defective multimerization, (3) loss of regulated storage, and (4) increased proteolysis by ADAMTS13.

Factor VIII/von Willebrand factor concentrate therapy for ventricular assist device-associated acquired von Willebrand disease.

BACKGROUND: Acquired von Willebrand disease (aVWD) can lead to a propensity to bleed, and many different modalities have been used to treat this condition. The efficacy of these agents in patients with aVWD secondary to cardiac assist devices is not fully understood. STUDY DESIGN AND METHODS: A case is reported of a patient with two risk factors for aVWD, multiple myeloma and ventricular assist device (VAD), who was successfully treated with von Willebrand factor (VWF)/Factor VIII concentrate (Humate-P, CSL Behring) during the bridge to VAD replacement. RESULTS: Although continued absence of high-molecular-weight VWF persisted after VWF replacement with Humate-P, the patient's VWF antigen and activity increased and clinical hemostasis was achieved. The VAD clotted on a few occasions, despite a continuous heparin infusion; however, these events were resolved with temporarily holding the Humate-P. A VAD exchange was performed and the patient was successfully bridged to heart transplant. CONCLUSION: The treatment of VAD-associated aVWD may be augmented with Humate-P, and successful treatment can allow a bridge to heart transplantation. However, careful monitoring for thrombosis in the VAD circuit must be undertaken.

Therapeutic consequences for misdiagnosis of type 2N von Willebrand disease.

Patients presenting with a low FVIII:C and with normal VWF levels are usually presumed to have hemophilia (males) or be carriers for hemophilia (females). Some of these patients may instead have VWD:2N. Such patients if misdiagnosed are likely to suffer from insufficiently treated bleeds. We report 2 males and 1 female who presented with a low FVIII:C (1-21%) and minimally reduced/normal VWF and were assumed to have, or be a carrier for, hemophilia A. Eventually all were found to have VWD:2N. Prior to the correct diagnosis the males had been treated with rFVIII with poor responses and ultimately adverse clinical consequences.

Type 2B von Willebrand disease associated with the release of platelet agglutinates from megakaryocytes in the bone marrow.

We report a child with thrombocytopenia since birth, circulating platelet agglutinates, and a tendency to bleed. A bone marrow aspirate revealed large platelet clumps within the bone marrow and megakaryocyte nuclei surrounded by halos of clumped platelets. Laboratory evaluation revealed type 2B von Willebrand disease. Gene sequencing revealed a G to C mutation at base 3923 of the VWF gene. This mutation was previously described in a family with circulating platelet clumps and abnormal megakaryopoiesis with release of clumped platelets in culture. This same mutation was previously described in a family with circulating platelet aggregates and abnormalities of platelet release from megakaryocytes in vitro. Presence of megakaryocytes with halos of clumped platelets in our patient suggests that platelet agglutinate occurs in the bone marrow in some type 2B von Willebrand disease patients.

Anti-GPVI-associated ITP: an acquired platelet disorder caused by autoantibody-mediated clearance of the GPVI/FcRgamma-chain complex from the human platelet surface.

Platelet glycoprotein (GP) VI is a 62-kDa membrane glycoprotein that exists on both human and murine platelets in a noncovalent complex with the Fc receptor (FcR) gamma chain. The GPVI/FcRgamma-chain complex serves as the major activating receptor for collagen, as evidenced by observations that platelets genetically deficient in GPVI or the FcRgamma chain are highly refractory to collagen-induced platelet activation. Recently, several different rat anti-murine GPVI monoclonal antibodies, termed JAQs 1, 2, and 3, were produced that had the unique property of "immunodepleting" GPVI from the murine platelet surface and rendering it unresponsive to collagen or GPVI-specific agonists like convulxin or collagen-related peptide (CRP). Herein, we describe a patient with a mild bleeding disorder and a moderately reduced platelet count whose platelets fail to become activated in response to collagen or CRP and inefficiently adhere to and form thrombi on immobilized collagen under conditions of arterial shear. Although the amount of GPVI platelet mRNA and the nucleotide sequence of the GPVI gene were found to be normal, both GPVI and the FcRgamma chain were nearly absent from the platelet surface and were markedly reduced in wholeplatelet detergent lysates. Patient plasma contained an autoantibody that bound specifically to GPVI-positive, normal platelets, and cleared soluble GPVI from the plasma, suggesting that the patient suffers from a rare form of idiopathic thrombocytopenic purpura caused by a GPVI-specific autoantibody that mediates clearance of the GPVI/FcRgamma-chain complex from the platelet surface. Since antibody-induced GPVI shedding now has been demonstrated in both humans and mice, these studies may provide a rationale for developing therapeutic reagents that induce temporary depletion of GPVI for the treatment of clinical thrombosis.